bluuebunny/crossref_metadata_2025 huggingface dataset:
Shc and Fak Differentially Regulate Cell Motility and Directionality Modulated by Pten
Authors: Gu Jianguo , Tamura Masahito , Pankov Roumen , Danen Erik H.J. , Takino Takahisa , Matsumoto Kazue , Yamada Kenneth M.
Published: July 2002

Cell migration is modulated by regulatory molecules such as growth factors, oncogenes, and the tumor suppressor PTEN. We previously described inhibition of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK) and p130 Crk-associated substrate (p130Cas). We now report a novel pathway regulating random cell motility involving Shc and mitogen-activated protein (MAP) kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating directional migration. Overexpression of Shc or constitutively activated MEK1 in PTEN- reconstituted U87-MG cells stimulated integrin- mediated MAP kinase activation and cell migration. Conversely, overexpression of dominant negative Shc inhibited cell migration; Akt appeared uninvolved. PTEN directly dephosphorylated Shc. The migration induced by FAK or p130Cas was directionally persistent and involved extensive organization of actin microfilaments and focal adhesions. In contrast, Shc or MEK1 induced a random type of motility associated with less actin cytoskeletal and focal adhesion organization. These results identify two distinct, additive pathways regulating cell migration that are downregulated by tumor suppressor PTEN: one involves Shc, a MAP kinase pathway, and random migration, whereas the other involves FAK, p130Cas, more extensive actin cytoskeletal organization, focal contacts, and directionally persistent cell motility. Integration of these pathways provides an intracellular mechanism for regulating the speed and the directionality of cell migration.
Physiological Role of Gap-Junctional Hemichannels
Authors: Quist Arjan Pieter , Rhee Seung Keun , Lin Hai , Lal Ratneshwar
Published: July 2002

Hemichannels in the overlapping regions of apposing cells plasma membranes join to form gap junctions and provide an intercellular communication pathway. Hemichannels are also present in the nonjunctional regions of individual cells and their activity is gated by several agents, including calcium. However, their physiological roles are unknown. Using techniques of atomic force microscopy (AFM), fluorescent dye uptake assay, and laser confocal immunofluorescence imaging, we have examined the extracellular calcium-dependent modulation of cell volume. In response to a change in the extracellular physiological calcium concentration (1.8 to ≤1.6 mM) in an otherwise isosmotic condition, real-time AFM imaging revealed a significant and reversible increase in the volume of cells expressing gap-junctional proteins (connexins). Volume change did not occur in cells that were not expressing connexins. However, after the transient or stable transfection of connexin43, volume change did occur. The volume increase was accompanied by cytochalasin D-sensitive higher cell stiffness, which helped maintain cell integrity. These cellular physical changes were prevented by gap-junctional blockers, oleamide and β-glycyrrhetinic acid, or were reversed by returning extracellular calcium to the normal level. We conclude that nongap-junctional hemichannels regulate cell volume in response to the change in extracellular physiological calcium in an otherwise isosmotic situation.
Assembly of Myelin by Association of Proteolipid Protein with Cholesterol- and Galactosylceramide-Rich Membrane Domains
Authors: Simons Mikael , Krämer Eva-Maria , Thiele Christoph , Stoffel Wilhelm , Trotter Jacqueline
Published: July 2002

Myelin is a specialized membrane enriched in glycosphingolipids and cholesterol that contains a limited spectrum of proteins. We investigated the assembly of myelin components by oligodendrocytes and analyzed the role of lipid–protein interactions in this process. Proteolipid protein (PLP), the major myelin protein, was recovered from cultured oligodendrocytes from a low-density CHAPS-insoluble membrane fraction (CIMF) enriched in myelin lipids. PLP associated with the CIMF after leaving the endoplasmic reticulum but before exiting the Golgi apparatus, suggesting that myelin lipid and protein components assemble in the Golgi complex. The specific association of PLP with myelin lipids in CIMF was supported by the finding that it was efficiently cross-linked to photoactivable cholesterol, but not to phosphatidylcholine, which is underrepresented in both myelin and CIMF. Furthermore, depletion of cholesterol or inhibition of sphingolipid synthesis in oligodendrocytes abolished the association of PLP with CIMF. Thus, PLP may be recruited to myelin rafts, represented by CIMF, via lipid–protein interactions. In contrast to oligodendrocytes, after transfection in BHK cells, PLP is absent from isolated CIMF, suggesting that PLP requires specific lipids for raft association. In mice deficient in the enzyme ceramide galactosyl transferase, which cannot synthesize the main myelin glycosphingolipids, a large fraction of PLP no longer associates with rafts. Formation of a cholesterol- and galactosylceramide-rich membrane domain (myelin rafts) may be critical for the sorting of PLP and assembly of myelin in oligodendrocytes.
Phosphatidylinositol 4,5-bisphosphate and Arf6-regulated membrane traffic
Authors: Brown Fraser D. , Rozelle Andrew L. , Yin Helen L. , Balla Tamás , Donaldson Julie G.
Published: July 2002

ADP-ribosylation factor (Arf) 6 regulates the movement of membrane between the plasma membrane (PM) and a nonclathrin-derived endosomal compartment and activates phosphatidylinositol 4-phosphate 5-kinase (PIP 5-kinase), an enzyme that generates phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we show that PIP2 visualized by expressing a fusion protein of the pleckstrin homology domain from PLCδ and green fluorescent protein (PH-GFP), colocalized with Arf6 at the PM and on tubular endosomal structures. Activation of Arf6 by expression of its exchange factor EFA6 stimulated protrusion formation, the uptake of PM into macropinosomes enriched in PIP2, and recycling of this membrane back to the PM. By contrast, expression of Arf6 Q67L, a GTP hydrolysis-resistant mutant, induced the formation of PIP2-positive actin-coated vacuoles that were unable to recycle membrane back to the PM. PM proteins, such as β1-integrin, plakoglobin, and major histocompatibility complex class I, that normally traffic through the Arf6 endosomal compartment became trapped in this vacuolar compartment. Overexpression of human PIP 5-kinase α mimicked the effects seen with Arf6 Q67L. These results demonstrate that PIP 5-kinase activity and PIP2 turnover controlled by activation and inactivation of Arf6 is critical for trafficking through the Arf6 PM-endosomal recycling pathway.
Vaccinia virus utilizes microtubules for movement to the cell surface
Authors: Hollinshead Michael , Rodger Gaener , Van Eijl Henriette , Law Mansun , Hollinshead Ruth , Vaux David J.T. , Smith Geoffrey L.
Published: July 2002

Vaccinia virus (VV) egress has been studied using confocal, video, and electron microscopy. Previously, intracellular-enveloped virus (IEV) particles were proposed to induce the polymerization of actin tails, which propel IEV particles to the cell surface. However, data presented support an alternative model in which microtubules transport virions to the cell surface and actin tails form beneath cell-associated enveloped virus (CEV) particles at the cell surface. Thus, VV is unique in using both microtubules and actin filaments for egress. The following data support this proposal. (a) Microscopy detected actin tails at the surface but not the center of cells. (b) VV mutants lacking the A33R, A34R, or A36R proteins are unable to induce actin tail formation but produce CEV and extracellular-enveloped virus. (c) CEV formation is inhibited by nocodazole but not cytochalasin D or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine (PP1). (d) IEV particles tagged with the enhanced green fluorescent protein fused to the VV B5R protein moved inside cells at 60 μm/min. This movement was stop-start, was along defined pathways, and was inhibited reversibly by nocodazole. This velocity was 20-fold greater than VV movement on actin tails and consonant with the rate of movement of organelles along microtubules.
Bacterial Lipopolysaccharide Rapidly Inhibits Expression of C–C Chemokine Receptors in Human Monocytes
Authors: Sica Antonio , Saccani Alessandra , Borsatti Alessandro , Power Christine A. , Wells Timothy N.C. , Luini Walter , Polentarutti Nadia , Sozzani Silvano , Mantovani Alberto
Published: July 2002

The present study was designed to investigate the effect of bacterial lipopolysaccharide (LPS) on C–C chemokine receptors (CCR) expressed in human mononuclear phagocytes. LPS caused a rapid and drastic reduction of CCR2 mRNA levels, which binds MCP-1 and -3. CCR1 and CCR5 mRNAs were also reduced, though to a lesser extent, whereas CXCR2 was unaffected. The rate of nuclear transcription of CCR2 was not affected by LPS, whereas the mRNA half life was reduced from 1.5 h to 45 min. As expected, LPS-induced inhibition of CCR2 mRNA expression was associated with a reduction of both MCP-1 binding and chemotactic responsiveness. The capacity to inhibit CCR2 expression in monocytes was shared by other microbial agents and cytokines (inactivated Streptococci, Propionibacterium acnes, and to a lesser extent, IL-1 and TNF-α). In contrast, IL-2 augmented CCR2 expression and MCP-1 itself had no effect. These results suggest that, regulation of receptor expression in addition to agonist production is likely a crucial point in the regulation of the chemokine system.
Anti-CD43 Inhibition of  T Cell Homing
Authors: McEvoy Leslie M. , Sun Hailing , Frelinger John G. , Butcher Eugene C.
Published: July 2002

The homing of lymphocytes from the blood is controlled by specialized processes of lymphocyte–endothelial cell interaction. Interference with these processes offers the potential to manipulate lymphocyte traffic, and thus to modulate normal and pathologic immune and inflammatory responses. We selected antilymphocyte monoclonal antibodies (mAbs) for inhibition of lymphocyte binding in vitro to lymph node high endothelial venules (HEV), specialized vessels that support lymphocyte recruitment into lymph nodes. mAb L11 blocks T cell binding to lymph node and Peyer's patch HEV and inhibits T cell extravasation from the blood into organized secondary lymphoid tissues. In contrast, L11 has no effect on lymphocyte binding to purified vascular ligands for L-selectin, α4β7, or LFA-1, suggesting that it inhibits by a novel mechanism. The L11 antigen is CD43, a sialomucin implicated in vitro in regulation of lymphocyte activation, whose expression is often dysregulated in the Wiskott-Aldrich syndrome. CD43 represents a novel target for experimental and therapeutic manipulation of lymphocyte traffic and may help regulate T cell distribution in vivo.
Suppressive Role of B Cells in Chronic Colitis of  T Cell Receptor α Mutant Mice
Authors: Mizoguchi Atsushi , Mizoguchi Emiko , Smith R. Neal , Preffer Frederic I. , Bhan Atul K.
Published: July 2002

The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-α−/− mice was explored by creating double mutant mice (TCR-α−/− × immunoglobulin (Ig)μ−/−), which lack B cells. TCR-α−/− × Igμ−/− mice spontaneously developed colitis at an earlier age, and the colitis was more severe than in TCR-α−/− mice. Colitis was induced in recombination-activating gene-1 (RAG-1−/−) mice by the transfer of mesenteric lymph node (MLN) cells from TCR-α−/− × Igμ−/− mice. When purified B cells from TCR-α−/− mice were mixed with MLN cells before cell transfer, colitis did not develop in RAG-1−/− mice. Administration of the purified Ig from TCR-α−/− mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-α−/− × Igμ−/− mice. Apoptotic cells were increased in the colon, MLN, and spleen of TCR-α−/− × Igμ−/− mice as compared to Igμ−/− mice and TCR-α−/− mice. Administration of the purified Ig from TCR-α−/− mice into TCR-α−/− × Igμ−/− mice led to decrease in the number of apoptotic cells. These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.
Interferon–inducible T Cell Alpha Chemoattractant (I-TAC): A Novel Non-ELR CXC Chemokine with Potent Activity on Activated T Cells through Selective High Affinity Binding to CXCR3
Authors: Cole Katherine E. , Strick Christine A. , Paradis Timothy J. , Ogborne Kevin T. , Loetscher Marcel , Gladue Ronald P. , Lin Wen , Boyd James G. , Moser Bernhard , Wood Douglas E. , Sahagan Barbara G. , Neote Kuldeep
Published: July 2002

Chemokines are essential mediators of normal leukocyte trafficking as well as of leukocyte recruitment during inflammation. We describe here a novel non-ELR CXC chemokine identified through sequence analysis of cDNAs derived from cytokine-activated primary human astrocytes. This novel chemokine, referred to as I-TAC (interferon-inducible T cell alpha chemoattractant), is regulated by interferon (IFN) and has potent chemoattractant activity for interleukin (IL)-2–activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocytes. I-TAC interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-γ–inducible 10-kD protein (IP-10) and IFN-γ– induced human monokine (HuMig), but with a significantly higher affinity. In addition, higher potency and efficacy of I-TAC over IP-10 and HuMig is demonstrated by transient mobilization of intracellular calcium as well as chemotactic migration in both activated T cells and transfected cell lines expressing CXCR3. Stimulation of astrocytes with IFN-γ and IL-1 together results in an ∼400,000-fold increase in I-TAC mRNA expression, whereas stimulating monocytes with either of the cytokines alone or in combination results in only a 100-fold increase in the level of I-TAC transcript. Moderate expression is also observed in pancreas, lung, thymus, and spleen. The high level of expression in IFN- and IL-1–stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T cells involved in the pathophysiology of neuroinflammatory disorders, although I-TAC may also play a role in the migration of activated T cells during IFN-dominated immune responses.
T Cell Receptor β Chain Lacking the Large Solvent-exposed Cβ FG Loop Supports Normal α/β T Cell Development and Function in Transgenic Mice
Authors: Degermann Sylvie , Sollami Giuseppina , Karjalainen Klaus
Published: July 2002

The striking and unique structural feature of the T cell receptor (TCR) β chain is the bulky solvent-exposed FG loop on the Cβ domain, the size of almost half an immunoglobulin domain. The location and size of this loop suggested immediately that it could be a crucial structural link between the invariant CD3 subunits and antigen-recognizing α/β chains during TCR signaling. However, functional analysis does not support the above notion, since transgene coding for TCR β chain lacking the complete FG loop supports normal α/β T cell development and function.
Susceptibility of Mice Deficient in CD1D or TAP1 to Infection with Mycobacterium tuberculosis
Authors: Behar Samuel M. , Dascher Chris C. , Grusby Michael J. , Wang Chyung-Ru , Brenner Michael B.
Published: July 2002

Cellular immunity against Mycobacterium tuberculosis controls infection in the majority of infected humans. Studies in mice have delineated an important role for CD4+ T cells and cytokines including interferon γ and tumor necrosis factor α in the response to infection with mycobacteria. Recently, the identification of CD8+ CD1-restricted T cells that kill M. tuberculosis organisms via granulysin and the rapid death after infection of β2 microglobulin deficient mice in humans has drawn attention to a critical role for CD8+ T cells. The nature of mycobacterial-specific CD8+ T cells has been an enigma because few have been identified in any species. Here, we delineate the contribution of class I MHC–restricted T cells in the defense against tuberculosis as transporter associated with antigen processing (TAP)1-deficient mice died rapidly, bore a greater bacterial burden, and had more severe tissue pathology than control mice. In contrast, CD1D−/− mice were not significantly different in their susceptibility to infection than control mice. This data demonstrates a critical role for TAP-dependent peptide antigen presentation and provides further evidence that class I MHC–restricted CD8+ T cells, the major T cell subset activated by this antigen processing pathway, play an essential role in immunity to tuberculosis.
Cd5 Maintains Tolerance in Anergic B Cells
Authors: Hippen Keli L. , Tze Lina E. , Behrens Timothy W.
Published: July 2002

Clonal anergy of autoreactive B cells is a key mechanism regulating tolerance. Here, we show that anergic B cells express significant surface levels of CD5, a molecule normally found on T cells and a subset of B-1 cells. Breeding of the hen egg lysozyme (HEL) transgenic model for B cell anergy onto the CD5 null background resulted in a spontaneous loss of B cell tolerance in vivo. Evidence for this included elevated levels of anti-HEL immunoglobulin M (IgM) antibodies in the serum of CD5−/− mice transgenic for both an HEL-specific B cell receptor (BCR) and soluble lysozyme. “Anergic” B cells lacking CD5 also showed enhanced proliferative responses in vitro and elevated intracellular Ca2+ levels at rest and after IgM cross-linking. These data support the hypothesis that CD5 negatively regulates Ig receptor signaling in anergic B cells and functions to inhibit autoimmune B cell responses.
Activation of the Cooh-Terminal Src Kinase (Csk) by Camp-Dependent Protein Kinase Inhibits Signaling through the T Cell Receptor
Authors: Vang Torkel , Torgersen Knut Martin , Sundvold Vibeke , Saxena Manju , Levy Finn Olav , Skålhegg Bjørn S. , Hansson Vidar , Mustelin Tomas , Taskén Kjetil
Published: July 2002

In T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the T cell receptor–CD3 complex (TCR/CD3) and inhibits T cell function via a previously unknown proximal target. Here we examine the mechanism for this PKA-mediated immunomodulation. cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 ζ chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on ζ chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion. Both PKA type I and Csk are targeted to lipid rafts where proximal T cell activation occurs, and phosphorylation of raft-associated Lck by Csk is increased in cells treated with forskolin. We propose a mechanism whereby PKA through activation of Csk intersects signaling by Src kinases and inhibits T cell activation.
The Intestinal Chemokine Thymus-expressed Chemokine (CCL25) Attracts IgA Antibody-secreting Cells
Authors: Bowman Edward P. , Kuklin Nelly A. , Youngman Kenneth R. , Lazarus Nicole H. , Kunkel Eric J. , Pan Junliang , Greenberg Harry B. , Butcher Eugene C.
Published: July 2002

Immunoglobulin A (IgA) provides protection against pathogens at mucosal surfaces. Chemotactic responses have been hypothesized to target IgA plasma cells involved in mucosal immune responses. We show here that thymus-expressed chemokine (TECK, CCL25) is a potent and selective chemoattractant for IgA antibody-secreting cells (ASC), efficiently recruiting IgA-producing cells from spleen, Peyer's patches, and mesenteric lymph node. Cells secreting IgA antibody in response to rotavirus, an intestinal pathogen, also respond well. In contrast, IgG– and IgM–ASC respond poorly. Epithelial cells in the small intestines, a principal site of IgA–ASC localization and IgA production in the body, highly and selectively express TECK. The migration of IgA–ASC to the intestinal epithelial cell chemokine TECK may help target IgA-producing cells to the gut wall, thus helping define and segregate the intestinal immune response.
Electrogenic Sulfate/Chloride Exchange in Xenopus Oocytes Mediated by Murine AE1 E699Q
Authors: Chernova M.N. , Jiang L. , Crest M. , Hand M. , Vandorpe D.H. , Strange K. , Alper S.L.
Published: July 2002

Functional evaluation of chemically modified human erythrocytes has led to the proposal that amino acid residue E681 of the band 3 anion exchanger AE1 lies on the anion translocation pathway and is a proton carrier required for H+/SO42− cotransport. We have tested in Xenopus oocytes the functional consequences of mutations in the corresponding residue E699 of mouse AE1. Most mutations tested abolished AE1-mediated Cl− influx and efflux. Only the E699Q mutation increased stilbene disulfonate-sensitive efflux and influx of SO42−. E699Q-mediated Cl− influx was activated by elevation of intracellular SO42−, but E699Q-mediated Cl− efflux was undetectable. The DNDS (4,4′-dinitrostilbene-2,2′-disulfonic acid) sensitivity of E699Q-mediated SO42− efflux was indistinguishable from that of wt AE1-mediated Cl− efflux. The extracellular anion selectivity of E699Q-mediated SO42− efflux was similar to that of wt AE1-mediated Cl− efflux. The stoichiometry of E699Q-mediated exchange of extracellular Cl− with intracellular SO42− was 1:1. Whereas SO42− injection into oocytes expressing wt AE1 produced little change in membrane potential or resistance, injection of SO42−, but not of Cl− or gluconate, into oocytes expressing E699Q depolarized the membrane by 17 mV and decreased membrane resistance by 66%. Replacement of bath Cl− with isethionate caused a 28-mV hyperpolarization in SO42−-loaded oocytes expressing E699Q, but had no effect on oocytes expressing wt AE1. Extracellular Cl−-dependent depolarization of SO42−-preloaded oocytes was blocked by DNDS. AE1 E699Q-mediated inward current measured in the presence of extracellular Cl− was of magnitude sufficient to account for measured 35SO42− efflux. Thus, AE1 E699Q-mediated SO42−/ Cl− exchange operated largely, if not exclusively, as an electrogenic, asymmetric, 1:1 anion exchange. The data confirm the proposal that E699 resides on or contributes to the integrity of the anion translocation pathway of AE1. A single amino acid change in the sequence of AE1 converted electroneutral to electrogenic anion exchange without alteration of SO42−/Cl− exchange stoichiometry.
Protein Kinase C Activity and Light Sensitivity of Single Amphibian Rods
Authors: Xiong W.-H. , Nakatani K. , Ye B. , Yau K.-W.
Published: July 2002

Biochemical experiments by others have indicated that protein kinase C activity is present in the rod outer segment, with potential or demonstrated targets including rhodopsin, transducin, cGMP-phosphodiesterase (PDE), guanylate cyclase, and arrestin, all of which are components of the phototransduction cascade. In particular, PKC phosphorylations of rhodopsin and the inhibitory subunit of PDE (PDE γ) have been studied in some detail, and suggested to have roles in downregulating the sensitivity of rod photoreceptors to light during illumination. We have examined this question under physiological conditions by recording from a single, dissociated salamander rod with a suction pipette while exposing its outer segment to the PKC activators phorbol-12-myristate,13-acetate (PMA) or phorbol-12,13-dibutyrate (PDBu), or to the PKC-inhibitor GF109203X. No significant effect of any of these agents on rod sensitivity was detected, whether in the absence or presence of a background light, or after a low bleach. These results suggest that PKC probably does not produce any acute downregulation of rod sensitivity as a mechanism of light adaptation, at least for isolated amphibian rods.
Multiplicity results for periodic solutions of second order ODEs with asymmetric nonlinearities
Authors: Rebelo C. , Zanolin F.
Published: July 2002

We prove various results on the existence and multiplicity of harmonic and subharmonic solutions to the second order nonautonomous equation

x
+
g
(
x
)
=
s
+
w
(
t
,
x
)

x + g(x) = s + w(t,x)

, as

s
→
+
∞

s\to +\infty

or

s
→
−
∞
,

s\to - \infty ,

where

g
g

is a smooth function defined on a open interval

]
a
,
b
[
⊂

R

.

]a,b[\subset {\mathbb {R}}.

The hypotheses we assume on the nonlinearity

g
(
x
)

g(x)

allow us to cover the case

b
=
+
∞

b=+\infty

(or

a
=
−
∞

a = -\infty

) and

g
g

having superlinear growth at infinity, as well as the case

b
>
+
∞

b > +\infty

(or

a
>
−
∞

a > -\infty

) and

g
g

having a singularity in

b
b

(respectively in

a
a

). Applications are given also to situations like

g
′

(
−
∞
)
≠

g
′

(
+
∞
)

g’(-\infty ) \not = g’(+\infty )

(including the so-called “jumping nonlinearities”). Our results are connected to the periodic Ambrosetti - Prodi problem and related problems arising from the Lazer - McKenna suspension bridges model.
The parameterized 𝑆𝑅 algorithm for symplectic (butterfly) matrices
Authors: Faßbender H.
Published: July 2002

TheSRSRalgorithm is a structure-preserving algorithm for computing the spectrum of symplectic matrices. Any symplectic matrix can be reduced to symplectic butterfly form. A symplectic matrixBBin butterfly form is uniquely determined by4n−14n-1parameters. Using these4n−14n-1parameters, we show how one step of the symplecticSRSRalgorithm forBBcan be carried out inO(n)\mathcal {O}(n)arithmetic operations compared toO(n3)\mathcal {O}(n^3)arithmetic operations when working on the actual symplectic matrix. Moreover, the symplectic structure, which will be destroyed in the numerical process due to roundoff errors when working with a symplectic (butterfly) matrix, will be forced by working just with the parameters.
Three- and four-dimensional 𝐾-optimal lattice rules of moderate trigonometric degree
Authors: Cools Ronald , Lyness James
Published: July 2002

A systematic search for optimal lattice rules of specified trigonometric degreeddover the hypercube[0,1)s[0,1)^shas been undertaken. The search is restricted to a populationK(s,δ)K(s,\delta )of lattice rulesQ(Λ)Q(\Lambda ). This includes those where the dual latticeΛ⊥\Lambda ^\perpmay be generated bysspointsh\bf hfor each of which|h|=δ=d+1|\textbf {h} | = \delta =d+1. The underlying theory, which suggests that such a restriction might be helpful, is presented. The general character of the search is described, and, fors=3s=3,d≤29d \leq 29ands=4s=4,d≤23d \leq 23, a list ofKK-optimal rules is given. It is not known whether these are also optimal rules in the general sense; this matter is discussed.
A conjecture of Erdös on 3-powerful numbers
Authors: Cohn J.
Published: July 2002

Erdös conjectured that the Diophantine equation

x
+
y
=
z

x+y=z

has infinitely many solutions in pairwise coprime 3-powerful integers, i.e., positive integers

n
n

for which

p
∣
n

p\mid n

implies

p
3

∣
n

p^3\mid n

. This was recently proved by Nitaj who, however, was unable to verify the further conjecture that this could be done infinitely often with integers

x
x

,

y
y

and

z
z

none of which is a perfect cube. This is now demonstrated.
Combinatorial Laplacians of matroid complexes
Authors: Kook W. , Reiner V. , Stanton D.
Published: July 2002

We combinatorially interpret the spectra of discrete Laplace operators from the boundary maps in the simplicial complex of independent sets of a matroid. The interpretation follows from a surprising orthogonal decomposition of the simplicial chain groups. This decomposition is in general finer than the spectral decomposition. As a consequence, the spectra are integral. One corollary to our combinatorial interpretation may be paraphrased as stating that one can “hear" the characteristic polynomial of a matroid.
Left-distributive embedding algebras
Authors: Dougherty Randall , Jech Thomas
Published: July 2002

We consider algebras with one binary operation ⋅\cdotand one generator, satisfying the left distributive lawa⋅(b⋅c)=(a⋅b)⋅(a⋅c)a\cdot (b\cdot c)=(a\cdot b)\cdot (a\cdot c); such algebras have been shown to have surprising connections with set-theoretic large cardinals and with braid groups. One can construct a sequence of finite left-distributive algebras AnA_{n}, and then take a limit to get an infinite left-distributive algebra A∞A_{\infty }on one generator. Results of Laver and Steel assuming a strong large cardinal axiom imply thatA∞A_{\infty } is free; it is open whether the freeness of A∞A_{\infty }can be proved without the large cardinal assumption, or even in Peano arithmetic. The main result of this paper is the equivalence of this problem with the existence of a certain left-distributive algebra of increasing functions on natural numbers, called anembedding algebra, which emulates some properties of functions on the large cardinal. Using this and results of the first author, we conclude that the freeness of A∞A_{\infty }is unprovable in primitive recursive arithmetic.
Occupational and Environmental Risk Factors for Idiopathic Pulmonary Fibrosis: A Multicenter Case-Control Study
Authors: Baumgartner Kathy B. , Samet Jonathan M. , Coultas David B. , Stidley Christine A. , Hunt William C. , Colby Thomas V. , Waldron James A. , Collaborating Centers
Published: July 2002

Occupational exposures were investigated in a multicenter case-control study of clinically and histologically diagnosed idiopathic pulmonary fibrosis (IPF), a chronic diffuse interstitial lung disease of unknown etiology. Results are based on 248 cases, aged 20–75 years, diagnosed at 16 referral centers between January 1989 and July 1993. There were 491 controls ascertained by random digit dialing and matched to cases on sex, age, and geographic region. Data were collected using a standard telephone questionnaire. Occupational factors were based on a detailed history of jobs lasting 6 months or more and job activity, hobby, and specific substance checklists. Several occupational factors, adjusted for age and smoking in conditional multivariate logistic regression analyses, were significantly associated with IPF: farming (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5); livestock (OR = 2.7, 95% CI: 1.3, 5.5); hairdressing (OR = 4.4, 95% CI: 1.2, 16.3); metal dust (OR = 2.0, 95% CI: 1.0, 4.0); raising birds (OR = 4.7, 95% CI: 1.6, 14.1); stone cutting/polishing (OR = 3.9, 95% CI: 1.2, 12.7); and vegetable dust/animal dust (OR = 4.7, 95% CI: 2.1, 10.4). Interaction was detected between smoking and exposure to livestock (p = 0.06) and farming (p = 0.08). Results confirm previous studies showing increased risk associated with dusty environments. Am J Epidemiol 2000;152:307–15.
SOAP, cleaning multiple alignments from unstable blocks
Authors: Löytynoja A. , Milinkovitch M. C.
Published: July 2002

Summary: SOAP is a stand-alone, multi-platform program to test the stability of a multiple alignment of molecular sequences.

Availability: The software is available free of charge at http://dbm.ulb.ac.be/ueg/SOAP/.

Contact: apl@dbm.ulb.ac.be; mcmilink@ulb.ac.be

* To whom correspondence should be addressed.
Easier threading through web-based comparisons and
cross-validations
Authors: Douguet Dominique , Labesse Gilles
Published: July 2002

Summary: We have developed a WWW server for the integration and comparison of protein structure predictions performed by five different servers. Users submit an amino acid sequence to a selected set of these prediction methods. Results are gathered on a web-based page in order to facilitate comparison and analysis. All the alignments are further evaluated through a common threading tool making their comparisons easier.

Availability: The meta-server is available free at http://www.infobiosud.cnrs.fr/bioserver

Contact: douguet@cbs.univ-montp1.fr; labesse@cbs.univ-montp1.fr

Supplementary information: http://www.infobiosud.cnrs.fr/bioserver/hah1.html

* To whom correspondence should be addressed.
Functional magnetic resonance imaging: imaging techniques and contrast mechanisms
Authors: Howseman Alistair M. , Bowtel Richard W.
Published: July 2002

Functional magnetic resonance imaging (fMRI) is a widely used technique for generating images or maps of human brain activity. The applications of the technique are widespread in cognitive neuroscience and it is hoped they will eventually extend into clinical practice. The activation signal measured with fMRI is predicated on indirectly measuring changes in the concentration of deoxyhaemoglobin which arise from an increase in blood oxygenation in the vicinity of neuronal firing. The exact mechanisms of this blood oxygenation level dependent (BOLD) contrast are highly complex. The signal measured is dependent on both the underlying physiological events and the imaging physics. BOLD contrast, although sensitive, is not a quantifiable measure of neuronal activity. A number of different imaging techniques and parameters can be used for fMRI, the choice of which depends on the particular requirements of each functional imaging experiment. The high–speed MRI technique, echo–planar imaging provides the basis for most fMRI experiments. The problems inherent to this method and the ways in which these may be overcome are particularly important in the move towards performing functional studies on higher field MRI systems. Future developments in techniques and hardware are also likely to enhance the measurement of brain activity using MRI.
Identification of overlapping but distinct cAMP and cGMP interaction sites with cyclic nucleotide phosphodiesterase 3A by site‐directed mutagenesis and molecular modeling based on crystalline PDE4B
Authors: Zhang Wei , Ke Hengming , Tretiakova Anna P. , Jameson Bradford , Colman Robert W.
Published: July 2002

Cyclic nucleotide phosphodiesterase 3A (PDE3A) hydrolyzes cAMP to AMP, but is competitively inhibited by cGMP due to a low kcat despite a tight Km. Cyclic AMP elevation is known to inhibit all pathways of platelet activation, and thus regulation of PDE3 activity is significant. Although cGMP elevation will inhibit platelet function, the major action of cGMP in platelets is to elevate cAMP by inhibiting PDE3A. To investigate the molecular details of how cGMP, a similar but not identical molecule to cAMP, behaves as an inhibitor of PDE3A, we constructed a molecular model of the catalytic domain of PDE3A based on homology to the recently determined X‐ray crystal structure of PDE4B. Based on the excellent fit of this model structure, we mutated nine amino acids in the putative catalytic cleft of PDE3A to alanine using site‐directed mutagenesis. Six of the nine mutants (Y751A, H840A, D950A, F972A, Q975A, and F1004A) significantly decreased catalytic efficiency, and had kcat/Km less than 10% of the wild‐type PDE3A using cAMP as substrate. Mutants N845A, F972A, and F1004A showed a 3‐ to 12‐fold increase of Km for cAMP. Four mutants (Y751A, H840A, D950A, and F1004A) had a 9‐ to 200‐fold increase of Ki for cGMP in comparison to the wild‐type PDE3A. Studies of these mutants and our previous study identified two groups of amino acids: E866 and F1004 contribute commonly to both cAMP and cGMP interactions while N845, E971, and F972 residues are unique for cAMP and the residues Y751, H836, H840, and D950 interact with cGMP. Therefore, our results provide biochemical evidence that cGMP interacts with the active site residues differently from cAMP.
Computerized analysis of radiographic bone patterns: Effect of imaging conditions on performance
Authors: Chinander Michael R. , Giger Maryellen L. , Martell John M. , Favus Murray J.
Published: July 2002

We are developing computerized methods for characterizing the bone texture pattern from digitized skeletal radiographs. For this method to be useful clinically, it must be able to distinguish between weak and strong bone under the range of exposure conditions potentially encountered in the clinical setting. In this study, we examined the effect of exposure conditions on Fourier‐based texture features. Thirty‐four femoral specimens from total hip arthroplasties were radiographed multiple times under different exposure conditions. The specimens underwent mechanical strength testing from which load to failure values were obtained. The performance of the texture features were investigated in the task of distinguishing between strong and weak bone as characterized by the load to failure values. The texture features showed no dependence upon focal spot size of the x‐ray tube or magnification. The texture features did show a dependence with relative exposure, peak kilovoltage, and amount of scattering material.
Variational alternatives to Kirchhoff’s loop theorem in dc circuits
Authors: Van Baak D. A.
Published: July 2002

Problems involving the flow of direct current in circuits are typically solved through the use of Kirchhoff’s rules—the junction theorem and the loop theorem. Since students typically find the meaning and use of the junction theorem straightforward, but are prone to conceptual and computational difficulties with the loop theorem, we present here a little-known alternative method for solving dc circuit problems. In this method, the junction theorem is retained, but the use of the loop theorem is replaced by the minimization of a single global variational quantity for the circuit. In this paper, the variational method is described and its use is illustrated, and its equivalence to standard methods is proved by vector calculus from the steady-state limit of Maxwell’s equations.
Channel weights for speech recognition in cochlear implant users
Authors: Mehr Maureen A. , Turner Christopher W. , Parkinson Aaron
Published: July 2002

The purpose of this study was to develop and validate a method of estimating the relative “weight” that a multichannel cochlear implant user places on individual channels, indicating its contribution to overall speech recognition. The correlational method as applied to speech recognition was used both with normal-hearing listeners and with cochlear implant users fitted with six-channel speech processors. Speech was divided into frequency bands corresponding to the bands of the processor and a randomly chosen level of corresponding filtered noise was added to each channel on each trial. Channels in which the signal-to-noise ratio was more highly correlated with performance have higher weights, and conversely, channels in which the correlations were smaller have lower weights. Normal-hearing listeners showed approximately equal weights across frequency bands. In contrast, cochlear implant users showed unequal weighting across bands, and varied from individual to individual with some channels apparently not contributing significantly to speech recognition. To validate these channel weights, individual channels were removed and speech recognition in quiet was tested. A strong correlation was found between the relative weight of the channel removed and the decrease in speech recognition, thus providing support for use of the correlational method for cochlear implant users.
A model of echolocation of multiple targets in 3D space from a single emission
Authors: Matsuo Ikuo , Tani Junji , Yano Masafumi
Published: July 2002

Bats, using frequency-modulated echolocation sounds, can capture a moving target in real 3D space. The process by which they are able to accomplish this, however, is not completely understood. This work offers and analyzes a model for description of one mechanism that may play a role in the echolocation process of real bats. This mechanism allows for the localization of targets in 3D space from the echoes produced by a single emission. It is impossible to locate multiple targets in 3D space by using only the delay time between an emission and the resulting echoes received at two points (i.e., two ears). To locate multiple targets in 3D space requires directional information for each target. The frequency of the spectral notch, which is the frequency corresponding to the minimum of the external ear’s transfer function, provides a crucial cue for directional localization. The spectrum of the echoes from nearly equidistant targets includes spectral components of both the interference between the echoes and the interference resulting from the physical process of reception at the external ear. Thus, in order to extract the spectral component associated with the external ear, this component must first be distinguished from the spectral components associated with the interference of echoes from nearly equidistant targets. In the model presented, a computation that consists of the deconvolution of the spectrum is used to extract the external-ear-dependent component in the time domain. This model describes one mechanism that can be used to locate multiple targets in 3D space.
Zones of quiet in a broadband diffuse sound field
Authors: Rafaely Boaz
Published: July 2002

The zones of quiet in pure-tone diffuse sound fields have been studied extensively in the past, both theoretically and experimentally, with the well-known result of the 10-dB attenuation extending to about a tenth of a wavelength. Recent results on the spatial-temporal correlation of broadband diffuse sound fields are used in this study to develop a theoretical framework for predicting the extension of the zones of quiet in broadband diffuse sound fields. This can be used to study the acoustic limitations imposed on local active sound control systems such as an active headrest when controlling broadband noise. Spatial-temporal correlation is first revised, after which derivations of the diffuse field zones of quiet in the near-field and the far-field of the secondary source are presented. The theoretical analysis is supported by simulation examples comparing the zones of quiet for diffuse fields excited by tonal and broadband signals. It is shown that as a first approximation the zone of quiet of a low-pass filtered noise is comparable to that of a pure-tone with a frequency equal to the center frequency of the broadband noise bandwidth.
Effect of delayed auditory feedback on normal speakers at two speech rates
Authors: Stuart Andrew , Kalinowski Joseph , Rastatter Michael P. , Lynch Kerry
Published: July 2002

This study investigated the effect of short and long auditory feedback delays at two speech rates with normal speakers. Seventeen participants spoke under delayed auditory feedback (DAF) at 0, 25, 50, and 200 ms at normal and fast rates of speech. Significantly two to three times more dysfluencies were displayed at 200 ms (p<0.05) relative to no delay or the shorter delays. There were significantly more dysfluencies observed at the fast rate of speech (p=0.028). These findings implicate the peripheral feedback system(s) of fluent speakers for the disruptive effects of DAF on normal speech production at long auditory feedback delays. Considering the contrast in fluency/dysfluency exhibited between normal speakers and those who stutter at short and long delays, it appears that speech disruption of normal speakers under DAF is a poor analog of stuttering.
Singular points of intensity streamlines in two-dimensional sound fields
Authors: Chien C. F. , Waterhouse R. V.
Published: July 2002

Continuing earlier work on this subject, a more rigorous discussion is given of the singular points of streamlines and the critical points of the stream function. The results for vortex and saddle points obtained earlier in piecemeal fashion and by way of examples are obtained systematically and by generally utilizing the applicable theory of differential equations and calculus. New results are also obtained. For example, a saddle point can occur when the phase of pressure and velocity differ by π/2, and in certain parts of the sound field, specifically inside a closed streamline, the number of vortex points and saddle points are related. Finally, the streamlines and singular point are considered for a discrete source: the line source.
Click-evoked otoacoustic emissions and the influence of high-frequency hearing losses in humans
Authors: Avan Paul , Elbez Michel , Bonfils Pierre
Published: July 2002

Click-evoked otoacoustic emissions (cEOAEs) are thought to reflect the presence of highly tuned mechanisms involved in sound processing inside the cochlea. When the sensitivity and tuning of the inner ear are impaired in some frequency range, the spectral components of cEOAEs in the same frequency range are expected to be altered if the previous premise is correct. Although clinical experience does not contradict such an interpretation, fundamental aspects of cEOAE generation and propagation in the cochlea are not clear enough to preclude possible additional influences of remote cochlear places on cEOAE. In order to analyze this possibility, ultra-high-frequency hearing thresholds between 8 and 16 kHz were assessed in 43 human subjects that had clinically normal hearing thresholds in the frequency range of cEOAEs. The magnitude of their cEOAEs was found to be correlated to their average ultra-high-frequency hearing threshold, especially when ears presenting spontaneous otoacoustic emissions were not taken into account (p=0.002, r2=0.29). Age and ultra-high-frequency hearing thresholds were correlated (p<0.01, r2=0.40); thus it is not possible to exclude that aging was the primary cause of the observed trend. The contribution of ultra-high-frequency hearing status to cEOAE magnitude, perhaps in relation to age, seems to explain a significant part of the variance of “normative” emission data and may be of interest for early detection of high-frequency hearing impairments.
A theoretical study of the hysteresis phenomenon at vocal fold oscillation onset–offset
Authors: Lucero Jorge C.
Published: July 2002

This paper presents a theoretical study on the differences in the biomechanical parameters of the vocal folds between oscillation onset and offset. The dynamics of the oscillation is analyzed from the perspective of the theory of nonlinear dynamical systems, using a mucosal wave model of the vocal folds with the subglottal pressure and the vocal fold half-width as control parameters. It is shown that the oscillation onset occurs through a Hopf bifurcation of the subcritical type, at which an unstable limit cycle is generated. Also, the oscillation offset occurs at a cyclic fold bifurcation, at which the unstable limit cycle and a stable limit cycle (the actual vocal fold oscillation) coalesce and cancel each other. Both bifurcations combine to form an “oscillation hysteresis” phenomenon, common in cases of flow-induced oscillations. An analytical expression for the onset/offset ratio of parameters is derived. The onset/offset ratio is in the range of 0.5–1, in agreement with the experimental evidence. This value depends on the phase delay in motion of the upper edge of the vocal folds versus the lower edge, and on the particular model adopted for airflow separation within the glottis.
Wave motion in an isotropic elastic layer generated by a time-harmonic point load of arbitrary direction
Authors: Achenbach J. D. , Xu Y.
Published: July 2002

Wave motion in an infinite elastic layer due to the application of a time-harmonic point load of arbitrary direction, applied either internally or on one of the faces of the layer, is expressed as a sum of four expansions in Lamb-wave modes and horizontally polarized wave modes. The point load is decomposed into components normal and parallel to the plate faces. Each of these cases is decomposed into a symmetric and an antisymmetric loading case, relative to the mid-plane of the layer. The displacement solutions for the symmetric and antisymmetric cases are expressed as expansions of symmetric and antisymmetric modes, respectively. Appropriate orthogonality relations are derived from reciprocity considerations. Elastodynamic reciprocity is also used in conjunction with dummy wave modes to obtain the coefficients in the wave-mode expansion.