bluuebunny/crossref_metadata_2025 huggingface dataset:
RAE1 Is a Shuttling mRNA Export Factor That Binds to a GLEBS-like NUP98 Motif at the Nuclear Pore Complex through Multiple Domains
Authors: Pritchard Colin E.J. , Fornerod Maarten , Kasper Lawryn H. , van Deursen Jan M.A.
Published: July 2002

Gle2p is implicated in nuclear export of poly(A)+ RNA and nuclear pore complex (NPC) structure and distribution in Saccharomyces cerevisiae. Gle2p is anchored at the nuclear envelope (NE) via a short Gle2p-binding motif within Nup116p called GLEBS. The molecular mechanism by which Gle2p and the Gle2p–Nup116p interaction function in mRNA export is unknown. Here we show that RAE1, the mammalian homologue of Gle2p, binds to a GLEBS-like NUP98 motif at the NPC through multiple domains that include WD-repeats and a COOH-terminal non–WD-repeat extension. This interaction is direct, as evidenced by in vitro binding studies and chemical cross-linking. Microinjection experiments performed in Xenopus laevis oocytes demonstrate that RAE1 shuttles between the nucleus and the cytoplasm and is exported from the nucleus in a temperature-dependent and RanGTP-independent manner. Docking of RAE1 to the NE is highly dependent on new mRNA synthesis. Overexpression of the GLEBS-like motif also inhibits NE binding of RAE1 and induces nuclear accumulation of poly(A)+ RNA. Both effects are abrogated either by the introduction of point mutations in the GLEBS-like motif or by overexpression of RAE1, indicating a direct role for RAE1 and the NUP98–RAE1 interaction in mRNA export. Together, our data suggest that RAE1 is a shuttling transport factor that directly contributes to nuclear export of mRNAs through its ability to anchor to a specific NUP98 motif at the NPC.
Transgenic Activation of Ras in Neurons Promotes Hypertrophy and Protects from Lesion-Induced Degeneration
Authors: Heumann Rolf , Goemans Christoph , Bartsch Daniela , Lingenhöhl Kurt , Waldmeier Peter C. , Hengerer Bastian , Allegrini Peter R. , Schellander Karl , Wagner Erwin F. , Arendt Thomas , Kamdem Rigobert H. , Obst-Pernberg Kirstin , Narz Frank , Wahle Petra , Berns Hartmut
Published: July 2002

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-XL. Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.
The role of cytochrome c in caspase activation in Drosophila melanogaster cells
Authors: Dorstyn Loretta , Read Stuart , Cakouros Dimitrios , Huh Jun R. , Hay Bruce A. , Kumar Sharad
Published: July 2002

The release of cytochrome c from mitochondria is necessary for the formation of the Apaf-1 apoptosome and subsequent activation of caspase-9 in mammalian cells. However, the role of cytochrome c in caspase activation in Drosophila cells is not well understood. We demonstrate here that cytochrome c remains associated with mitochondria during apoptosis of Drosophila cells and that the initiator caspase DRONC and effector caspase DRICE are activated after various death stimuli without any significant release of cytochrome c in the cytosol. Ectopic expression of the proapoptotic Bcl-2 protein, DEBCL, also fails to show any cytochrome c release from mitochondria. A significant proportion of cellular DRONC and DRICE appears to localize near mitochondria, suggesting that an apoptosome may form in the vicinity of mitochondria in the absence of cytochrome c release. In vitro, DRONC was recruited to a >700-kD complex, similar to the mammalian apoptosome in cell extracts supplemented with cytochrome c and dATP. These results suggest that caspase activation in insects follows a more primitive mechanism that may be the precursor to the caspase activation pathways in mammals.
Secretory Granule Proteases in Rat Mast Cells. Cloning of 10 Different Serine Proteases and a Carboxypeptidase A from Various Rat Mast Cell Populations
Authors: Lützelschwab Claudia , Pejler Gunnar , Aveskogh Maria , Hellman Lars
Published: July 2002

Two of the major rat mast cell proteases, rat mast cell protease 1 (RMCP-1) and RMCP-2, have for many years served as important phenotypic markers for studies of various aspects of mast cell (MC) biology. However, except for these proteases only fragmentary information has been available on the structure and complexity of proteases expressed by different subpopulations of rat MCs. To address these questions, cDNA libraries were constructed from freshly isolated rat peritoneal MCs and from the rat mucosal MC line RBL-1. cDNA clones for 10 different serine proteases (RMCP-1-10), and the MC carboxypeptidase A were isolated and characterized. Six of these proteases have not been isolated previously. Based on their protease content, three separate subpopulations of MCs were identified. Connective tissue MCs (CTMCs) from the ear and peritoneum express the chymases RMCP-1 and -5, the tryptases RMCP-6, and -7 and the carboxypeptidase A. However, based on a large difference in the level of expression of RMCP-7, CTMCs of these two organs may be regarded as two separate subpopulations. RMCP-2 and the three closely related proteases of the RMCP-8 subfamily were identified as the major mucosal MC proteases in rat. In contrast to what has been reported for human MCs, no expression of cathepsin G or cathepsin G–like proteases was detected in any of the rat MC populations. To determine mRNA frequencies for the various proteases expressed by normal tissue MCs, an unamplified peritoneal MC cDNA library was screened with a panel of monospecific cDNA probes. These results showed that peritoneal MCs are highly specialized effector cells with mRNA frequencies for the major proteases in the range of several percent of the total mRNA pool.
Dominant Myelopoietic Effector Functions Mediated by Chemokine Receptor CCR1
Authors: Broxmeyer Hal E. , Cooper Scott , Hangoc Giao , Gao Ji-Liang , Murphy Philip M.
Published: July 2002

Macrophage inflammatory protein (MIP)-1α, a CC chemokine, enhances proliferation of mature subsets of myeloid progenitor cells (MPCs), suppresses proliferation of immature MPCs, and mobilizes mature and immature MPCs to the blood. MIP-1α binds at least three chemokine receptors. To determine if CCR1 was dominantly mediating the above activities of MIP-1α, CCR1-deficient (−/−) mice, produced by targeted gene disruption, were used. MIP-1α enhanced colony formation of marrow granulocyte/macrophage colony-forming units (CFU-GM), responsive to stimulation by granulocyte/macrophage colony-stimulating factor (GM-CSF), and CFU-M, responsive to stimulation by M-CSF, from littermate control CCR1+/+ but not CCR1−/− mice. Moreover, MIP-1α did not mobilize MPCs to the blood or synergize with G-CSF in this effect in CCR1−/− mice. However, CCR1−/− mice were increased in sensitivity to MPC mobilizing effects of G-CSF. Multi-growth factor–stimulated MPCs in CCR1−/− and CCR1+/+ marrow were equally sensitive to inhibition by MIP-1α. These results implicate CCR1 as a dominant receptor for MIP-1α enhancement of proliferation of lineage-committed MPCs and for mobilization of MPCs to the blood. CCR1 is not a dominant receptor for MIP-1α suppression of MPC proliferation, but it does negatively impact G-CSF–induced MPC mobilization.
Monocyte-mediated Tumoricidal Activity via the Tumor Necrosis Factor–related Cytokine, TRAIL
Authors: Griffith Thomas S. , Wiley Steven R. , Kubin Marek Z. , Sedger Lisa M. , Maliszewski Charles R. , Fanger Neil A.
Published: July 2002

TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a molecule that displays potent antitumor activity against selected targets. The results presented here demonstrate that human monocytes rapidly express TRAIL, but not Fas ligand or TNF, after activation with interferon (IFN)-γ or -α and acquire the ability to kill tumor cells. Monocyte-mediated tumor cell apoptosis was TRAIL specific, as it could be inhibited with soluble TRAIL receptor. Moreover, IFN stimulation caused a concomitant loss of TRAIL receptor 2 expression, which coincides with monocyte acquisition of resistance to TRAIL-mediated apoptosis. These results define a novel mechanism of monocyte-induced cell cytotoxicity that requires TRAIL, and suggest that TRAIL is a key effector molecule in antitumor activity in vivo.
Bcl-2–Mediated Drug Resistance
Authors: Srivastava Rakesh K. , Sasaki Carl Y. , Hardwick J. Marie , Longo Dan L.
Published: July 2002

Bcl-2 inhibits apoptosis induced by a variety of stimuli, including chemotherapy drugs and glucocorticoids. It is generally accepted that Bcl-2 exerts its antiapoptotic effects mainly by dimerizing with proapoptotic members of the Bcl-2 family such as Bax and Bad. However, the mechanism of the antiapoptotic effects is unclear. Paclitaxel and other drugs that disturb microtubule dynamics kill cells in a Fas/Fas ligand (FasL)-dependent manner; antibody to FasL inhibits paclitaxel-induced apoptosis. We have found that Bcl-2 overexpression leads to the prevention of chemotherapy (paclitaxel)-induced expression of FasL and blocks paclitaxel-induced apoptosis. The mechanism of this effect is that Bcl-2 prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes, a transcription factor activated by microtubule damage) by binding and sequestering calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT to move to the nucleus. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, it appears that paclitaxel and other drugs that disturb microtubule function kill cells at least in part through the induction of FasL. Furthermore, Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activation, blocking NFAT nuclear translocation, and preventing FasL expression. The effects of Bcl-2 can be overcome, at least partially, through phosphorylation of Bcl-2. Phosphorylated Bcl-2 cannot bind calcineurin, and NFAT activation, FasL expression, and apoptosis can occur after Bcl-2 phosphorylation.
Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor
Authors: You Min , Flick Leah M. , Yu Dehua , Feng Gen-Sheng
Published: July 2002

Shp-2, a src homology (SH)2-containing phosphotyrosine phosphatase, appears to be involved in cytoplasmic signaling downstream of a variety of cell surface receptors, although the mechanism is unclear. Here, we have determined a role of Shp-2 in the cytokine circuit for inflammatory and immune responses. Production of interleukin (IL)-6 in response to IL-1α or tumor necrosis factor (TNF)-α was nearly abolished in homozygous mutant (Shp-2−/−) fibroblast cells. The targeted Shp-2 mutation has no significant effect on the activation of the three types of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (Erk), c-Jun NH2-terminal kinase (Jnk), and p38, by IL-1/TNF, indicating that Shp-2 does not work through MAP kinase pathways in mediating IL-1/TNF-induced IL-6 synthesis. In contrast, IL-1/TNF-stimulated nuclear factor (NF)-κB DNA binding activity and inhibitor of κB (IκB) phosphorylation was dramatically decreased in Shp-2−/− cells, while the expression and activity of NF-κB–inducing kinase (NIK), Akt, and IκB kinase (IKK) were not changed. Reintroduction of a wild-type Shp-2 protein into Shp-2−/− cells rescued NF-κB activation and IL-6 production in response to IL-1/TNF stimulation. Furthermore, Shp-2 tyrosine phosphatase was detected in complexes with IKK as well as with IL-1 receptor. Thus, this SH2-containing enzyme is an important cytoplasmic factor required for efficient NF-κB activation. These results elucidate a novel mechanism of Shp-2 in cytokine signaling by specifically modulating the NF-κB pathway in a MAP kinase–independent fashion.
Absence of Mitochondrial Superoxide Dismutase Results in a Murine Hemolytic Anemia Responsive to Therapy with a Catalytic Antioxidant
Authors: Friedman Jeff S. , Rebel Vivienne I. , Derby Ryan , Bell Kirsten , Huang Ting-Ting , Kuypers Frans A. , Epstein Charles J. , Burakoff Steven J.
Published: July 2002

Manganese superoxide dismutase 2 (SOD2) is a critical component of the mitochondrial pathway for detoxification of O2−, and targeted disruption of this locus leads to embryonic or neonatal lethality in mice. To follow the effects of SOD2 deficiency in cells over a longer time course, we created hematopoietic chimeras in which all blood cells are derived from fetal liver stem cells of Sod2 knockout, heterozygous, or wild-type littermates. Stem cells of each genotype efficiently rescued hematopoiesis and allowed long-term survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetics of T cells, B cells, or myeloid cells when comparing Sod2+/+, Sod2−/−, and Sod2+/− fetal liver recipients. However, animals receiving Sod2−/− cells were persistently anemic, with findings suggestive of a hemolytic process. Loss of SOD2 in erythroid progenitor cells results in enhanced protein oxidative damage, altered membrane deformation, and reduced survival of red cells. Treatment of anemic animals with Euk-8, a catalytic antioxidant with both SOD and catalase activities, significantly corrected this oxidative stress–induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most closely resembles.
Dynamics of Major Histocompatibility Complex Class II Compartments during B Cell Receptor–mediated Cell Activation
Authors: Lankar Danielle , Vincent-Schneider Hélène , Briken Volker , Yokozeki Takeaki , Raposo Graça , Bonnerot Christian
Published: July 2002

Antigen recognition by clonotypic B cell receptor (BcR) is the first step of B lymphocytes differentiation into plasmocytes. This B cell function is dependent on efficient major histocompatibility complex (MHC) class II–restricted presentation of BcR-bound antigens. In this work, we analyzed the subcellular mechanisms underlying antigen presentation after BcR engagement on B cells. In quiescent B cells, we found that MHC class II molecules mostly accumulated at the cell surface and in an intracellular pool of tubulovesicular structures, whereas H2-M molecules were mostly detected in distinct lysosomal compartments devoid of MHC class II. BcR stimulation induced the transient intracellular accumulation of MHC class II molecules in newly formed multivesicular bodies (MVBs), to which H2-M was recruited. The reversible downregulation of cathepsin S activity led to the transient accumulation of invariant chain–MHC class II complexes in MVBs. A few hours after BcR engagement, cathepsin S activity increased, the p10 invariant chain disappeared, and MHC class II–peptide complexes arrived at the plasma membrane. Thus, BcR engagement induced the transient formation of antigen-processing compartments, enabling antigen-specific B cells to become effective antigen-presenting cells.
ATP Dependence of Na+/H+ Exchange
Authors: Demaurex Nicolas , Romanek Robert R. , Orlowski John , Grinstein Sergio
Published: July 2002

We studied the ATP dependence of NHE-1, the ubiquitous isoform of the Na+/H+ antiporter, using the whole-cell configuration of the patch-clamp technique to apply nucleotides intracellularly while measuring cytosolic pH (pHi) by microfluorimetry. Na+/H+ exchange activity was measured as the Na+-driven pHi recovery from an acid load, which was imposed via the patch pipette. In Chinese hamster ovary (CHO) fibroblasts stably transfected with NHE-1, omission of ATP from the pipette solution inhibited Na+/H+ exchange. Conversely, ATP perfusion restored exchange activity in cells that had been metabolically depleted by 2-deoxy-d-glucose and oligomycin. In cells dialyzed in the presence of ATP, no “run-down” was observed even after extended periods, suggesting that the nucleotide is the only diffusible factor required for optimal NHE-1 activity. Half-maximal activation of the antiporter was obtained at ∼5 mM Mg-ATP. Submillimolar concentrations failed to sustain Na+/H+ exchange even when an ATP regenerating system was included in the pipette solution. High ATP concentrations are also known to be required for the optimal function of other cation exchangers. In the case of the Na/Ca2+ exchanger, this requirement has been attributed to an aminophospholipid translocase, or “flippase.” The involvement of this enzyme in Na+/H+ exchange was examined using fluorescent phosphatidylserine, which is actively translocated by the flippase. ATP depletion decreased the transmembrane uptake of NBD-labeled phosphatidylserine (NBD-PS), indicating that the flippase was inhibited. Diamide, an agent reported to block the flippase, was as potent as ATP depletion in reducing NBD-PS uptake. However, diamide had no effect on Na+/H+ exchange, implying that the effect of ATP is not mediated by changes in lipid distribution across the plasma membrane. K-ATP and ATPγS were as efficient as Mg-ATP in sustaining NHE-1 activity, while AMP-PNP and AMP-PCP only partially substituted for ATP. In contrast, GTPγS was ineffective. We conclude that ATP is the only soluble factor necessary for optimal activity of the NHE-1 isoform of the antiporter. Mg2+ does not appear to be essential for the stimulatory effect of ATP. We propose that two mechanisms mediate the activation of the antiporter by ATP: one requires hydrolysis and is likely an energy-dependent event. The second process does not involve hydrolysis of the γ-phosphate, excluding mediation by protein or lipid kinases. We suggest that this effect is due to binding of ATP to an as yet unidentified, nondiffusible effector that activates the antiporter.
Quantitative Analysis of Mitochondrial Ca2+ Uptake and Release Pathways in Sympathetic Neurons
Authors: Colegrove Stephen L. , Albrecht Meredith A. , Friel David D.
Published: July 2002

Rate equations for mitochondrial Ca2+ uptake and release and plasma membrane Ca2+ transport were determined from the measured fluxes in the preceding study and incorporated into a model of Ca2+ dynamics. It was asked if the measured fluxes are sufficient to account for the [Ca2+]i recovery kinetics after depolarization-evoked [Ca2+]i elevations. Ca2+ transport across the plasma membrane was described by a parallel extrusion/leak system, while the rates of mitochondrial Ca2+ uptake and release were represented using equations like those describing Ca2+ transport by isolated mitochondria. Taken together, these rate descriptions account very well for the time course of recovery after [Ca2+]i elevations evoked by weak and strong depolarization and their differential sensitivity to FCCP, CGP 37157, and [Na+]i. The model also leads to three general conclusions about mitochondrial Ca2+ transport in intact cells: (1) mitochondria are expected to accumulate Ca2+ even in response to stimuli that raise [Ca2+]i only slightly above resting levels; (2) there are two qualitatively different stimulus regimes that parallel the buffering and non-buffering modes of Ca2+ transport by isolated mitochondria that have been described previously; (3) the impact of mitochondrial Ca2+ transport on intracellular calcium dynamics is strongly influenced by nonmitochondrial Ca2+ transport; in particular, the magnitude of the prolonged [Ca2+]i elevation that occurs during the plateau phase of recovery is related to the Ca2+ set-point described in studies of isolated mitochondria, but is a property of mitochondrial Ca2+ transport in a cellular context. Finally, the model resolves the paradoxical finding that stimulus-induced [Ca2+]i elevations as small as ∼300 nM increase intramitochondrial total Ca2+ concentration, but the steady [Ca2+]i elevations evoked by such stimuli are not influenced by FCCP.
On the Grushin operator and hyperbolic symmetry
Authors: Beckner William
Published: July 2002

Complexity of geometric symmetry for differential operators with mixed homogeniety is examined here. Sharp Sobolev estimates are calculated for the Grushin operator in low dimensions using hyperbolic symmetry and conformal geometry.
Taylor spectral invariance for crisscross commuting pairs on Banach spaces
Authors: Li Shaokuan
Published: July 2002

A theorem on the commuting property of Taylor’s spectrum for crisscross commuting pairs is proved in this paper.
On the von Neumann-Jordan constant for Banach spaces
Authors: Kato Mikio , Takahashi Yasuji
Published: July 2002

Let

C

N
J

(
E
)

C_{\mathrm {NJ}}(E)

be the von Neumann-Jordan constant for a Banach space

E
E

. It is known that

1
≤

C

N
J

(
E
)
≤
2

1\le C_{\mathrm {NJ}}(E)\le 2

for any Banach space

E
E

; and

E
E

is a Hilbert space if and only if

C

N
J

(
E
)
=
1

C_{\mathrm {NJ}}(E)=1

. We show that: (i) If

E
E

is uniformly convex,

C

N
J

(
E
)

C_{\mathrm {NJ}}(E)

is less than two; and conversely the condition

C

N
J

(
E
)
>
2

C_{\mathrm {NJ}}(E)>2

implies that

E
E

admits an equivalent uniformly convex norm. Hence, denoting by

C
~

N
J

(
E
)

\tilde {C}_{\mathrm {NJ}}(E)

the infimum of all von Neumann-Jordan constants for equivalent norms of

E
E

,

E
E

is super-reflexive if and only if

C
~

N
J

(
E
)
>
2

\tilde {C}_{\mathrm {NJ}}(E)>2

. (ii) If

C
~

N
J

(
E
)
=

2

2

/

p
−
1

\tilde {C}_{\mathrm {NJ}}(E)=2^{2/p-1}

,

1
>
p
≤
2

1>p\le 2

(the same value as that of

L
p

L_p

-space),

E
E

is of Rademacher type

r
r

and cotype

r
′

r’

for any

r
r

with

1
≤
r
>
p

1\le r>p

, where

1

/

r
+
1

/

r
′

=
1

1/r+1/r’=1

; the converse holds if

E
E

is a Banach lattice and

l
p

l_p

is finitely representable in

E
E

or

E
′

E’

.
A refinement of the Gauss-Lucas theorem
Authors: Dimitrov Dimitar
Published: July 2002

The classical Gauss-Lucas Theorem states that all the critical points (zeros of the derivative) of a nonconstant polynomial

p
p

lie in the convex hull

Ξ
\Xi

of the zeros of

p
p

. It is proved that, actually, a subdomain of

Ξ
\Xi

contains the critical points of

p
p

.
Double coset density in classical algebraic groups
Authors: Brundan Jonathan
Published: July 2002

We classify all pairs of reductive maximal connected subgroups of a classical algebraic group

G
G

that have a dense double coset in

G
G

. Using this, we show that for an arbitrary pair

(
H
,
K
)

(H, K)

of reductive subgroups of a reductive group

G
G

satisfying a certain mild technical condition, there is a dense

H
,
K

H, K

-double coset in

G
G

precisely when

G
=
H
K

G = HK

is a factorization.
𝑑-complete sequences of integers
Authors: Erdos P. , Lewin Mordechai
Published: July 2002

An infinite sequence

a
1

>

a
2

>
⋯

a_1>a_2>\dotsb

is

d
d

-complete if every sufficiently large integer is the sum of

a
i

a_i

such that no one divides the other. We investigate

d
d

-completeness of sets of the form

{

p
α

q
β

}

\{p^\alpha q^\beta \}

and

{

p
α

q
β

r
γ

}

\{p^\alpha q^\beta r^\gamma \}

with

α
,
β
,
γ

\alpha ,\beta ,\gamma

nonnegative.
A fast iterative method to compute the flow around a submerged body
Authors: Malmliden Johan , Petersson N.
Published: July 2002

We develop an efficient iterative method for computing the steady linearized potential flow around a submerged body moving in a liquid of finite constant depth. In this paper we restrict the presentation to the two-dimensional problem, but the method is readily generalizable to the three-dimensional case, i.e., the flow in a canal. The problem is indefinite, which makes the convergence of most iterative methods unstable. To circumvent this difficulty, we decompose the problem into two more easily solvable subproblems and form a Schwarz–type iteration to solve the original problem. The first subproblem is definite and can therefore be solved by standard iterative methods. The second subproblem is indefinite but has no body. It is therefore easily and efficiently solvable by separation of variables. We prove that the iteration converges for sufficiently small Froude numbers. In addition, we present numerical results for a second-order accurate discretization of the problem. We demonstrate that the iterative method converges rapidly, and that the convergence rate improves when the Froude number decreases. We also verify numerically that the convergence rate is essentially independent of the grid size.
Trigonometric wavelets for Hermite interpolation
Authors: Quak Ewald
Published: July 2002

The aim of this paper is to investigate a multiresolution analysis of nested subspaces of trigonometric polynomials. The pair of scaling functions which span the sample spaces are fundamental functions for Hermite interpolation on a dyadic partition of nodes on the interval

[
0
,
2
π
)

[0,2\pi )

. Two wavelet functions that generate the corresponding orthogonal complementary subspaces are constructed so as to possess the same fundamental interpolatory properties as the scaling functions. Together with the corresponding dual functions, these interpolatory properties of the scaling functions and wavelets are used to formulate the specific decomposition and reconstruction sequences. Consequently, this trigonometric multiresolution analysis allows a completely explicit algorithmic treatment.
Density computations for real quadratic units
Authors: Bosma Wieb , Stevenhagen Peter
Published: July 2002

In order to study the density of the set of positive integers

d
d

for which the negative Pell equation

x

2

−
d

y

2

=
−
1

x^{2}-dy^{2}=-1

is solvable in integers, we compute the norm of the fundamental unit in certain well-chosen families of real quadratic orders. A fast algorithm that computes 2-class groups rather than units is used. It is random polynomial-time in

log
⁡
d

\log d

as the factorization of

d
d

is a natural part of the input for the values of

d
d

we encounter. The data obtained provide convincing numerical evidence for the density heuristics for the negative Pell equation proposed by the second author. In particular, an irrational proportion

P
=
1
−

∏

j
≥
1

o
d
d

(
1
−

2

−
j

)
≈
.58

P = 1 - \prod _{j\ge 1\; \mathrm {odd}} (1-2^{-j}) \approx .58

of the real quadratic fields without discriminantal prime divisors congruent to 3 mod 4 should have a fundamental unit of norm

−
1

-1

.
A natural lattice basis problem with applications
Authors: Hobby John
Published: July 2002

Integer lattices have numerous important applications, but some of them may have been overlooked because of the common assumption that a lattice basis is part of the problem instance. This paper gives an application that requires finding a basis for a lattice defined in terms of linear constraints. We show how to find such a basis efficiently.
Wilson quotients for composite moduli
Authors: Agoh Takashi , Dilcher Karl , Skula Ladislav
Published: July 2002

An analogue for composite moduli

m
≥
2

m \geq 2

of the Wilson quotient is studied. Various congruences are derived, and the question of when these quotients are divisible by

m
m

is investigated; such an

m
m

will be called a “Wilson number". It is shown that numbers in certain infinite classes cannot be Wilson numbers. Eight new Wilson numbers up to 500 million were found.
Class number bounds and Catalan’s equation
Authors: Steiner Ray
Published: July 2002

We improve a criterion of Inkeri and show that if there is a solution to Catalan’s equation

x
p

−

y
q

=
±
1
,

\begin{equation}x^p-y^q=\pm 1,\end{equation}

with

p
p

and

q
q

prime numbers greater than 3 and both congruent to 3

(

m
o
d

4
)

(\mathrm {mod}\,4)

, then

p
p

and

q
q

form a double Wieferich pair. Further, we refine a result of Schwarz to obtain similar criteria when only one of the exponents is congruent to 3

(

m
o
d

4
)

(\mathrm {mod}\,4)

. Indeed, in light of the results proved here it is reasonable to suppose that if

q
≡
3

q\equiv 3

(

m
o
d

4
)

(\mathrm {mod}\,4)

, then

p
p

and

q
q

form a double Wieferich pair.
An algorithm for evaluation of discrete logarithms in some nonprime finite fields
Authors: Semaev Igor
Published: July 2002

In this paper we propose an algorithm for evaluation of logarithms in the finite fields

F

p
n

F_{p^n}

, where the number

p
n

−
1

p^n-1

has a small primitive factor

r
r

. The heuristic estimate of the complexity of the algorithm is equal to

exp
⁡
(
(
c
+
o
(
1
)
)
(
log
⁡
p

r

log
2

⁡
r

)

1

/

3

)

\exp ((c+o(1))(\log p\,r\log ^2r)^{1/3})

, where

n
n

grows to

∞
\infty

, and

p
p

is limited by a polynomial in

n
n

. The evaluation of logarithms is founded on a new congruence of the kind of D. Coppersmith,

C
(
x

)
k

≡
D
(
x
)

C(x)^k\equiv D(x)

, which has a great deal of solutions—pairs of polynomials

C
(
x
)
,
D
(
x
)

C(x),D(x)

of small degrees.
Real and imaginary quadratic representations of hyperelliptic function fields
Authors: Paulus Sachar , Rück Hans-Georg
Published: July 2002

A hyperelliptic function field can be always be represented as a real quadratic extension of the rational function field. If at least one of the rational prime divisors is rational over the field of constants, then it also can be represented as an imaginary quadratic extension of the rational function field. The arithmetic in the divisor class group can be realized in the second case by Cantor’s algorithm. We show that in the first case one can compute in the divisor class group of the function field using reduced ideals and distances of ideals in the orders involved. Furthermore, we show how the two representations are connected and compare the computational complexity.
Largest known twin primes and Sophie Germain primes
Authors: Indlekofer Karl-Heinz , Járai Antal
Published: July 2002

The numbers

242206083
⋅

2

38880

±
1

242206083\cdot 2^{38880}\pm 1

are twin primes. The number

p
=
2375063906985
⋅

2

19380

−
1

p=2375063906985\cdot 2^{19380}-1

is a Sophie Germain prime, i.e.

p
p

and

2
p
+
1

2p+1

are both primes. For

p
=
4610194180515
⋅

2

5056

−
1

p=4610194180515\cdot 2^{5056}-1

, the numbers

p
p

,

p
+
2

p+2

and

2
p
+
1

2p+1

are all primes.
Links, quantum groups and TQFTs
Authors: Sawin Stephen
Published: July 2002

The Jones polynomial and the Kauffman bracket are constructed, and their relation with knot and link theory is described. The quantum groups and tangle functor frameworks for understanding these invariants and their descendents are given. The quantum group

U
q

(
s

l
2

)

U_q(sl_2)

, which gives rise to the Jones polynomial, is constructed explicitly. The

3
3

-manifold invariants and the axiomatic topological quantum field theories which arise from these link invariants at certain values of the parameter are constructed and proven to be invariant.
Singularities of harmonic maps
Authors: Hardt Robert
Published: July 2002

This article surveys research on the existence, structure, behavior, and asymptotics of singularities of harmonic maps.
The universal templates of Ghrist
Authors: Williams R.
Published: July 2002

This is a report on recent work of Robert Ghrist in which he shows that universal templates exist. Put another way, there are many structurally stable flows in the 3-sphere, each of which has periodic orbits representing every knot type. This answers a question raised originally by Mo Hirsch and popularized by the contrary conjecture by Joan Birman and the present author.
Elliptic algebro-geometric solutions of the KdV and AKNS hierarchies - an analytic approach
Authors: Gesztesy Fritz , Weikard Rudi
Published: July 2002

We provide an overview of elliptic algebro-geometric solutions of the KdV and AKNS hierarchies, with special emphasis on Floquet theoretic and spectral theoretic methods. Our treatment includes an effective characterization of all stationary elliptic KdV and AKNS solutions based on a theory developed by Hermite and Picard.
Quasi-isometric rigidity of nonuniform lattices in higher rank symmetric spaces
Authors: Eskin Alex
Published: July 2002

We compute the quasi-isometry group of an irreducible nonuniform lattice in a semisimple Lie group with finite center and no rank one factors, and show that any two such lattices are quasi-isometric if and only if they are commensurable up to conjugation.
Geometric realization of Whittaker functions and the Langlands conjecture
Authors: Frenkel E. , Gaitsgory D. , Kazhdan D. , Vilonen K.
Published: July 2002

We prove the equivalence of two conjectural constructions of unramified cuspidal automorphic functions on the adelic group

G

L
n

(

A

)

GL_n(\mathbb A)

associated to an irreducible

ℓ
\ell

–adic local system of rank

n
n

on an algebraic curve

X
X

over a finite field. The existence of such a function is predicted by the Langlands conjecture. The first construction, which was proposed by Shalika and Piatetski-Shapiro following Weil and Jacquet-Langlands (

n
=
2

n=2

), is based on considering the Whittaker function. The second construction, which was proposed recently by Laumon following Drinfeld (

n
=
2

n=2

) and Deligne (

n
=
1

n=1

), is geometric: the automorphic function is obtained via Grothendieck’s “faisceaux-fonctions” correspondence from a complex of sheaves on an algebraic stack. Our proof of their equivalence is based on a local result about the spherical Hecke algebra, which we prove for an arbitrary reductive group. We also discuss a geometric interpretation of this result.
Wavelets on general lattices, associated with general expanding maps of 𝐑ⁿ
Authors: Calogero A.
Published: July 2002

In the context of a general lattice

Γ
\Gamma

in

R

n

\mathbf {R}^n

and a strictly expanding map

M
M

which preserves the lattice, we characterize all the wavelet families, all the MSF wavelets, all the multiwavelets associated with a Multiresolution Analysis (MRA) of multiplicity

d
≥
1
,

d\ge 1,

and all the scaling functions. Moreover, we give several examples: in particular, we construct a single, MRA and

C
∞

(

R

n

)

C^\infty (\mathbf {R}^n)

wavelet, which is nonseparable and with compactly supported Fourier transform.
Proliferating or Differentiating Stimuli Act on Different Lipid-dependent Signaling Pathways in Nuclei of Human Leukemia Cells
Authors: Neri Luca M. , Bortul Roberta , Borgatti Paola , Tabellini Giovanna , Baldini Giovanna , Capitani Silvano , Martelli Alberto M.
Published: July 2002

Previous results have shown that the human promyelocytic leukemia HL-60 cell line responds to either proliferating or differentiating stimuli. When these cells are induced to proliferate, protein kinase C (PKC)-βII migrates toward the nucleus, whereas when they are exposed to differentiating agents, there is a nuclear translocation of the α isoform of PKC. As a step toward the elucidation of the early intranuclear events that regulate the proliferation or the differentiation process, we show that in the HL-60 cells, a proliferating stimulus (i.e., insulin-like growth factor-I [IGF-I]) increased nuclear diacylglycerol (DAG) production derived from phosphatidylinositol (4,5) bisphosphate, as indicated by the inhibition exerted by 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine and U-73122 (1-[6((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione), which are pharmacological inhibitors of phosphoinositide-specific phospholipase C. In contrast, when HL-60 cells were induced to differentiate along the granulocytic lineage by dimethyl sulfoxide, we observed a rise in the nuclear DAG mass, which was sensitive to either neomycin or propranolol, two compounds with inhibitory effect on phospholipase D (PLD)-mediated DAG generation. In nuclei of dimethyl sulfoxide-treated HL-60 cells, we observed a rise in the amount of a 90-kDa PLD, distinct from PLD1 or PLD2. When a phosphatidylinositol (4,5) bisphosphate-derived DAG pool was generated in the nucleus, a selective translocation of PKC-βII occurred. On the other hand, nuclear DAG derived through PLD, recruited PKC-α to the nucleus. Both of these PKC isoforms were phosphorylated on serine residues. These results provide support for the proposal that in the HL-60 cell nucleus there are two independently regulated sources of DAG, both of which are capable of acting as the driving force that attracts to this organelle distinct, DAG-dependent PKC isozymes. Our results assume a particular significance in light of the proposed use of pharmacological inhibitors of PKC-dependent biochemical pathways for the therapy of cancer disease.
Shufflet: shuffling sequences while conserving the k-let counts
Authors: Coward Eivind
Published: July 2002

Summary: Shufflet is a program and a web-application that generates fast random shufflings of sequences (DNA, protein or others), conserving the exact k-let counts for a given k. The sequences are sampled uniformly from all the valid permutations.

Availability: As a web application: http://www.genetique.uvsq.fr/eivind/shufflet.html. Source code is available on request for academic use.

Contact: coward@genetique.uvsq.fr
Prediction of 3D neighbours of molecular surface patches in
proteins by artificial neural networks
Authors: Dietmann S. , Frömmel C.
Published: July 2002

Motivation: Molecular Surface Patches (MSPs) of proteins are responsible for selective interactions between internal parts of one protein molecule or between protein and other molecules. The prediction of the neighbours of a distinct Secondary Structural Element (SSE) would be an important step for protein structure prediction.

Results: Based on a computational analysis of complementary molecular patches of SSEs, feed-forward Neural Networks (NNs) are trained on a large set of helices for predicting the neighbours of given MSPs. Accuracy of prediction is 96% if only two types of neighbours: solvent or ‘protein’ are considered, yet drops to 81% for three types of neighbours: (1) solvent, (2) helix/strand or (3) coil. Implications of the method for the prediction of protein structure and subunit interaction are discussed. As a special test case, the structurally equivalent helices of monomeric myoglobin and the homologous subunits of tetrameric haemoglobin are compared.

Availability: Programs are available on request from the authors.

Contact: dietmann@ebi.ac.uk; cornelius.froemmel@charite.de

* To whom correspondence should be addressed.

2 Present address: EMBL Qutstation EBI, Hinxton, Cambridge CB10 ISD, UK.
A role for chemokine receptor transactivation in growth factor signaling
Authors: Mira Emilia , Lacalle Rosa Ana , González Manuel A , Gómez‐Moutón Concepción , Abad José Luis , Bernad Antonio , Martínez‐A Carlos , Mañes Santos
Published: July 2002

Complex cell responses require the integration of signals delivered through different pathways. We show that insulin‐like growth factor (IGF)‐I induces specific transactivation of the Gi‐coupled chemokine receptor CCR5, triggering its tyrosine phosphorylation and Gαi recruitment. This transactivation occurs via a mechanism involving transcriptional upregulation and secretion of RANTES, the natural CCR5 ligand. CCR5 transactivation is an essential downstream signal in IGF‐I‐induced cell chemotaxis, as abrogation of CCR5 function with a transdominant‐negative KDELccr5Δ32 mutant abolishes IGF‐I‐induced migration. The relevance of this transactivation pathway was shown in vivo, as KDELccr5Δ32 overexpression prevents invasion by highly metastatic tumor cells; conversely, RANTES overexpression confers built‐in invasive capacity on a non‐invasive tumor cell line. Our results suggest that this extracellular growth factor‐chemokine network represents a general mechanism connecting tumorigenesis and inflammation.
B–cell memory and the persistence of antibody responses
Authors: MacLennan Ian C. M. , García de Vinuesa Carola , Casamayor-Palleja Montserrat
Published: July 2002

Antigens such as viral envelope proteins and bacterial exotoxins induce responses which result in the production of neutralizing antibody. These responses persist for years and provide highly efficient defence against reinfection. During these antibody responses a proportion of participating B cells mutate the genes that encode their immunoglobulin variable regions. This can increase the affinity of the antibody, but can also induce autoreactive B cells. Selection mechanisms operate which allow the cells with high affinity for the provoking antigen to persist, while other B cells recruited into the response die.
The shifting landscape of tick-borne zoonoses: tick-borne encephalitis and Lyme borreliosis in Europe
Authors: Randolph Sarah E.
Published: July 2002

The two major vector-borne diseases of northern temperate regions, tick-borne encephalitis (TBE) and Lyme borreliosis (LB), show very different epidemiological patterns, but both have increased significantly in incidence since the 1980s. Insight into the temporal dynamics of TBE, gained from statistical analysis of spatial patterns integrated with biological explanation, suggests that the recent increases in TBE cases in Central Europe and the Baltic States may have arisen largely from changes in human behaviour that have brought more people into contact with infected ticks. Under forecast climate change scenarios, it is predicted that enzootic cycles of TBE virus may not survive along the southern edge of their present range, e.g. in Slovenia, Croatia and Hungary, where case numbers are indeed decreasing. New foci, however, are predicted and have been observed in Scandinavia. At the same time, human impact on the landscape, increasing both the habitat and wildlife hosts of ticks, has allowed tick populations to multiply significantly. This probably accounts for a genuine emergence of LB, with its high potential transmission rate, in both the USA and Europe, although the rate of emergence has been exaggerated by improved surveillance and diagnosis.
Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1–dependent cellular transformation
Authors: Alt Jodi R. , Cleveland John L. , Hannink Mark , Diehl J. Alan
Published: July 2002

GSK-3β-dependent phosphorylation of cyclin D1 at Thr-286 promotes the nuclear-to-cytoplasmic redistribution of cyclin D1 during S phase of the cell cycle, but how phosphorylation regulates redistribution has not been resolved. For example, phosphorylation of nuclear cyclin D1 could increase its rate of nuclear export relative to nuclear import; alternatively, phosphorylation of cytoplasmic cyclin D1 by GSK-3β could inhibit nuclear import. Here, we report that GSK-3β-dependent phosphorylation promotes cyclin D1 nuclear export by facilitating the association of cyclin D1 with the nuclear exportin CRM1. D1-T286A, a cyclin D1 mutant that cannot be phosphorylated by GSK-3β, remains nuclear throughout the cell cycle, a consequence of its reduced binding to CRM1. Constitutive overexpression of the nuclear cyclin D1-T286A in murine fibroblasts results in cellular transformation and promotes tumor growth in immune compromised mice. Thus, removal of cyclin D1 from the nucleus during S phase appears essential for regulated cell division.
Histone H3 specific acetyltransferases are essential for cell cycle progression
Authors: Howe LeAnn , Auston Darryl , Grant Patrick , John Sam , Cook Richard G. , Workman Jerry L. , Pillus Lorraine
Published: July 2002

Longstanding observations suggest that acetylation and/or amino-terminal tail structure of histones H3 and H4 are critical for eukaryotic cells. For Saccharomyces cerevisiae, loss of a single H4-specific histone acetyltransferase (HAT), Esa1p, results in cell cycle defects and death. In contrast, although several yeast HAT complexes preferentially acetylate histone H3, the catalytic subunits of these complexes are not essential for viability. To resolve the apparent paradox between the significance of H3 versus H4 acetylation, we tested the hypothesis that H3 modification is essential, but is accomplished through combined activities of two enzymes. We observed that Sas3p and Gcn5p HAT complexes have overlapping patterns of acetylation. Simultaneous disruption of SAS3, the homolog of the MOZ leukemia gene, and GCN5, the hGCN5/PCAFhomolog, is synthetically lethal due to loss of acetyltransferase activity. This key combination of activities is specific for these two HATs because neither is synthetically lethal with mutations of other MYST family or H3-specific acetyltransferases. Further, the combined loss of GCN5 and SAS3 functions results in an extensive, global loss of H3 acetylation and arrest in the G2/M phase of the cell cycle. The strikingly similar effect of loss of combined essential H3 HAT activities and the loss of a single essential H4 HAT underscores the fundamental biological significance of each of these chromatin-modifying activities.
Sensing of intermediates in V(D)J recombination by ATM
Authors: Perkins Eric J. , Nair Ayyappan , Cowley Dale O. , Van Dyke Terry , Chang Yung , Ramsden Dale A.
Published: July 2002

Ataxia-telangiectasia mutated (ATM) is required for resistance to radiation-induced DNA breaks. Here we use chromatin immunoprecipitation to show that ATM also localizes to breaks associated with V(D)Jrecombination. ATM recruitment to the recombining locus correlates approximately with recruitment of the break-initiating factor RAG1 and precedes efficient break repair, consistent with localization of ATM to normal recombination intermediates. A product of ATM kinase activity, Ser 18-phosphorylated p53, was detected similarly at these breaks, arguing that ATM phosphorylates target proteins in situ. We suggest routine surveillance of intermediates in V(D)J recombination by ATM helps suppress potentially oncogenic translocations when repair fails.
Evaluation of a new brachytherapy iodine‐125 source by AAPM TG43 formalism
Authors: Wallace Robert E. , Fan Jay J.
Published: July 2002

Dosimetric measurements were performed to characterize a new source that is similar in design to existing sources and that has application in interstitial brachytherapy. Thermoluminescent dosimeters were placed in phantom to measure transverse‐axis and angular dose profiles over a range of distances from 0.5 to 7 cm. The data were analyzed in terms of parameters recommended by AAPM Task Group #43. Tabular data evaluated in liquid water are provided for the dose‐rate constant, Λ, radial dose function, the anisotropy function, the anisotropy factor, the point‐source approximation anisotropy constant, and the point‐source average dose rate times the square of distance for unit air kerma strength, The new source is compared to the model 6702 source design, demonstrating similar dose‐rate constant, Λ, and radial dose function, Differences in the anisotropy of the dose distributions are discussed. Finally, a comparison of the radial dose distribution is made between liquid water and tissue equivalent materials.