bluuebunny/crossref_metadata_2025 huggingface dataset:
Ges, a Human Gtpase of the Rad/Gem/Kir Family, Promotes Endothelial Cell Sprouting and Cytoskeleton Reorganization
Authors: Pan Julie Y. , Fieles William E. , White Anne M. , Egerton Mark M. , Silberstein David S.
Published: July 2002

Rad, Gem/Kir, and mRem (RGK) represent a unique GTPase family with largely unknown functions (Reynet, C., and C.R. Kahn. 1993. Science. 262:1441–1444; Cohen, L., R. Mohr, Y. Chen, M. Huang, R. Kato, D. Dorin, F. Tamanoi, A. Goga, D. Afar, N. Rosenberg, and O. Witte. Proc. Natl. Acad. Sci. USA. 1994. 91:12448–12452; Maguire, J., T. Santoro, P. Jensen, U. Siebenlist, J. Yewdell, and K. Kelly. 1994. Science. 265:241–244; Finlin, B.S., and D.A. Andres. 1997. J. Biol. Chem. 272:21982–21988). We report that Ges (GTPase regulating endothelial cell sprouting), a human RGK protein expressed in the endothelium, functions as a potent morphogenic switch in endothelial cells (ECs). Ges function is sufficient to substitute for angiogenic growth factor/extracellular matrix (ECM) signals in promoting EC sprouting, since overexpression of Ges in ECs cultured on glass leads to the development of long cytoplasmic extensions and reorganization of the actin cytoskeleton. Ges function is also necessary for Matrigel-induced EC sprouting, since this event is blocked by its dominant negative mutant, GesT94N, predicted to prevent the activation of endogenous Ges through sequestration of its guanine nucleotide exchange factor. Thus, Ges appears to be a key transducer linking extracellular signals to cytoskeleton/morphology changes in ECs.
Drosophila Integrin-Linked Kinase Is Required at Sites of Integrin Adhesion to Link the Cytoskeleton to the Plasma Membrane
Authors: Zervas Christos G. , Gregory Stephen L. , Brown Nicholas H.
Published: July 2002

Integrin-linked kinase (ILK) was identified by its interaction with the cytoplasmic tail of human β1 integrin and previous data suggest that ILK is a component of diverse signaling pathways, including integrin, Wnt, and protein kinase B. Here we show that the absence of ILK function in Drosophila causes defects similar to loss of integrin adhesion, but not similar to loss of these signaling pathways. ILK mutations cause embryonic lethality and defects in muscle attachment, and clones of cells lacking ILK in the adult wing fail to adhere, forming wing blisters. Consistent with this, an ILK–green fluorescent protein fusion protein colocalizes with the position-specific integrins at sites of integrin function: muscle attachment sites and the basal junctions of the wing epithelium. Surprisingly, mutations in the kinase domain shown to inactivate the kinase activity of human ILK do not show any phenotype in Drosophila, suggesting a kinase-independent function for ILK. The muscle detachment in ILK mutants is associated with detachment of the actin filaments from the muscle ends, unlike integrin mutants, in which the primary defect is detachment of the plasma membrane from the extracellular matrix. Our data suggest that ILK is a component of the structure linking the cytoskeleton and the plasma membrane at sites of integrin-mediated adhesion.
Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions
Authors: Xu X. , Li W.E.I. , Huang G.Y. , Meyer R. , Chen T. , Luo Y. , Thomas M.P. , Radice G.L. , Lo C.W.
Published: July 2002

Connexin 43 (Cx43α1) gap junction has been shown to have an essential role in mediating functional coupling of neural crest cells and in modulating neural crest cell migration. Here, we showed that N-cadherin and wnt1 are required for efficient dye coupling but not for the expression of Cx43α1 gap junctions in neural crest cells. Cell motility was found to be altered in the N-cadherin–deficient neural crest cells, but the alterations were different from that elicited by Cx43α1 deficiency. In contrast, wnt1-deficient neural crest cells showed no discernible change in cell motility. These observations suggest that dye coupling may not be a good measure of gap junction communication relevant to motility. Alternatively, Cx43α1 may serve a novel function in motility. We observed that p120 catenin (p120ctn), an Armadillo protein known to modulate cell motility, is colocalized not only with N-cadherin but also with Cx43α1. Moreover, the subcellular distribution of p120ctn was altered with N-cadherin or Cx43α1 deficiency. Based on these findings, we propose a model in which Cx43α1 and N-cadherin may modulate neural crest cell motility by engaging in a dynamic cross-talk with the cell's locomotory apparatus through p120ctn signaling.
Vav1/Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells
Authors: Villalba Martin , Bi Kun , Rodriguez Fernando , Tanaka Yoshihiko , Schoenberger Stephen , Altman Amnon
Published: July 2002

Formation of the immunological synapse (IS) in T cells involves large scale molecular movements that are mediated, at least in part, by reorganization of the actin cytoskeleton. Various signaling proteins accumulate at the IS and are localized in specialized membrane microdomains, known as lipid rafts. We have shown previously that lipid rafts cluster and localize at the IS in antigen-stimulated T cells. Here, we provide evidence that lipid raft polarization to the IS depends on an intracellular pathway that involves Vav1, Rac, and actin cytoskeleton reorganization. Thus, lipid rafts did not translocate to the IS in Vav1-deficient (Vav1−/−) T cells upon antigen stimulation. Similarly, T cell receptor transgenic Jurkat T cells also failed to translocate lipid rafts to the IS when transfected with dominant negative Vav1 mutants. Raft polarization induced by membrane-bound cholera toxin cross-linking was also abolished in Jurkat T cells expressing dominant negative Vav1 or Rac mutants and in cells treated with inhibitors of actin polymerization. However, Vav overexpression that induced F-actin polymerization failed to induce lipid rafts clustering. Therefore, Vav is necessary, but not sufficient, to regulate lipid rafts clustering and polarization at the IS, suggesting that additional signals are required.
Glycan-regulated Antigen Processing of a Protein in the Endoplasmic Reticulum Can Uncover Cryptic Cytotoxic T Cell Epitopes
Authors: Wood Philip , Elliott Tim
Published: July 2002

We and others have shown that influenza A nucleoprotein (NP) targeted to the secretory pathway cannot be processed to yield several cytotoxic T lymphocyte (CTL) epitopes in cell lines that lack the transporter associated with antigen processing (TAP). However, a large COOH-terminal fragment of NP is processed and presented in these cells. Full-length NP is cotranslationally glycosylated in the lumen of the endoplasmic reticulum at two sites distal to the major H2-Kk and H2-Db restricted CTL epitopes, and we show here that pharmacological or genetic inhibition of N-linked glycosylation, leads to the processing and presentation of both these epitopes in a TAP-independent way.
Neutrophil-derived 5′-Adenosine Monophosphate Promotes Endothelial Barrier Function via CD73-mediated Conversion to Adenosine and Endothelial A2B Receptor Activation
Authors: Lennon Paul F. , Taylor Cormac T. , Stahl Gregory L. , Colgan Sean P.
Published: July 2002

During episodes of inflammation, polymorphonuclear leukocyte (PMN) transendothelial migration has the potential to disturb vascular barrier function and give rise to intravascular fluid extravasation and edema. However, little is known regarding innate mechanisms that dampen fluid loss during PMN-endothelial interactions. Using an in vitro endothelial paracellular permeability model, we observed a PMN-mediated decrease in endothelial paracellular permeability. A similar decrease was elicited by cell-free supernatants from activated PMN (FMLP 10−6 M), suggesting the presence of a PMN-derived soluble mediator(s). Biophysical and biochemical analysis of PMN supernatants revealed a role for PMN-derived 5′-adenosine monophosphate (AMP) and its metabolite, adenosine, in modulation of endothelial paracellular permeability. Supernatants from activated PMN contained micromolar concentrations of bioactive 5′-AMP and adenosine. Furthermore, exposure of endothelial monolayers to authentic 5′-AMP and adenosine increased endothelial barrier function more than twofold in both human umbilical vein endothelial cells and human microvascular endothelial cells. 5′-AMP bioactivity required endothelial CD73-mediated conversion of 5′-AMP to adenosine via its 5′-ectonucleotidase activity. Decreased endothelial paracellular permeability occurred through adenosine A2B receptor activation and was accompanied by a parallel increase in intracellular cAMP. We conclude that activated PMN release soluble mediators, such as 5′-AMP and adenosine, that promote endothelial barrier function. During inflammation, this pathway may limit potentially deleterious increases in endothelial paracellular permeability and could serve as a basic mechanism of endothelial resealing during PMN transendothelial migration.
Alteration of Interleukin 4 Production Results in the Inhibition of T Helper Type 2 Cell–Dominated Inflammatory Bowel Disease in T Cell Receptor α Chain–Deficient Mice
Authors: Iijima Hideki , Takahashi Ichiro , Kishi Daisuke , Kim Jin-Kyung , Kawano Sunao , Hori Masatsugu , Kiyono Hiroshi
Published: July 2002

T cell receptor α chain–deficient (TCR-α−/−) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4+TCR-ββ (CD4+ββ) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4+ββ T cells, we treated TCR-α−/− mice with anti–IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-α−/− mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti–IL-4 mAb–treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab–treated mice. Although TCR-α−/− mice treated with either specific or mock Ab developed CD4+ββ T cells, only those treated with anti–IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon γ–specific expression. These findings suggest that IL-4–producing Th2-type CD4+ββ T cells play a major immunopathological role in the induction of IBD in TCR-α−/− mice, a role that anti–IL-4 mAb inhibits by causing Th2-type CD4+ββ T cells to shift to the Th1 type.
T Helper Cell Type 2 Cytokines Coordinately Regulate Immunoglobulin E–Dependent Cysteinyl Leukotriene Production by Human Cord Blood–Derived Mast Cells
Authors: Hsieh Fred H. , Lam Bing K. , Penrose John F. , Austen K. Frank , Boyce Joshua A.
Published: July 2002

Human mast cells (hMCs) derived in vitro from cord blood mononuclear cells exhibit stem cell factor (SCF)-dependent comitogenic responses to T helper cell type 2 (Th2) cytokines. As cysteinyl leukotriene (cys-LT) biosynthesis is a characteristic of immunoglobulin (Ig)E-activated mucosal hMCs, we speculated that Th2 cytokines might regulate eicosanoid generation by hMCs. After passive sensitization for 5 d with IgE in the presence of SCF, anti-IgE–stimulated hMCs elaborated minimal cys-LT (0.1 ± 0.1 ng/106 hMCs) and abundant prostaglandin (PG)D2 (16.2 ± 10.3 ng/106 hMCs). Priming of hMCs by interleukin (IL)-4 with SCF during passive sensitization enhanced their anti-IgE–dependent histamine exocytosis and increased their generation of both cys-LT (by 27-fold) and PGD2 (by 2.5-fold). Although priming with IL-3 or IL-5 alone for 5 d with SCF minimally enhanced anti-IgE–mediated cys-LT generation, these cytokines induced further six- and fourfold increases, respectively, in IgE-dependent cys-LT generation when provided with IL-4 and SCF; this occurred without changes in PGD2 generation or histamine exocytosis relative to hMCs primed with IL-4 alone. None of these cytokines, either alone or in combination, substantially altered the levels of cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), or 5-LO activating protein (FLAP) protein expression by hMCs. In contrast, IL-4 priming dramatically induced the steady-state expression of leukotriene C4 synthase (LTC4S) mRNA within 6 h, and increased the expression of LTC4S protein and functional activity in a dose- and time-dependent manner, with plateaus at 10 ng/ml and 5 d, respectively. Priming by either IL-3 or IL-5, with or without IL-4, supported the localization of 5-LO to the nucleus of hMCs. Thus, different Th2-derived cytokines target distinct steps in the 5-LO/LTC4S biosynthetic pathway (induction of LTC4S expression and nuclear import of 5-LO, respectively), each of which is necessary for a full integrated functional response to IgE-dependent activation, thus modulating the effector phenotype of mature hMCs.
Blocking Chemokine Responsive to γ–2/Interferon (IFN)-γ Inducible Protein and Monokine Induced by IFN-γ Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus–specific Cytotoxic T Lymphocytes
Authors: Kakimi Kazuhiro , Lane Thomas E. , Wieland Stefan , Asensio Valerie C. , Campbell Iain L. , Chisari Francis V. , Guidotti Luca G.
Published: July 2002

Using transgenic mice that replicate hepatitis B virus (HBV) at high levels in the liver as recipients of HBV-specific cytotoxic T lymphocytes (CTLs), we showed that the chemokines responsive to γ–2/IFN-γ inducible protein ([Crg2]IP-10) and monokine induced by interferon-γ (Mig) are rapidly and strongly induced in the liver after CTL transfer. The transferred CTLs produce neither chemokine; rather, they activate (via the secretion of IFN-γ) hepatocytes and nonparenchymal cells of the liver to produce (Crg2)IP-10 and Mig. Importantly, blocking these chemokines in vivo reduces the recruitment of host-derived lymphomononuclear cells into the liver and the severity of the liver disease without affecting the IFN-γ–dependent antiviral potential of the CTLs. The finding that neutralization of these chemokines is associated with maintenance of antiviral effects but diminished tissue damage may be significant for the development of immunotherapeutic approaches for the treatment of chronic HBV infection.
Requirement for Tyrosine Residues 315 and 319 within ζ Chain–Associated Protein 70 for T Cell Development
Authors: Gong Qian , Jin Xiaohua , Akk Antonina M. , Foger Niko , White Mike , Gong Guoqing , Wardenburg Julie Bubeck , Chan Andrew C.
Published: July 2002

Engagement of the T cell antigen receptor (TCR) induces the transphosphorylation of the ζ chain–associated protein of 70,000 Mr (ZAP-70) protein tyrosine kinase (PTK) by the CD4/8 coreceptor associated Lck PTK. Phosphorylation of Tyr 493 within ZAP-70's activation loop results in the enzymatic activation of ZAP-70. Additional tyrosines (Tyrs) within ZAP-70 are phosphorylated that play both positive and negative regulatory roles in TCR function. Phosphorylation of Tyr residues (Tyrs 315 and 319) within the Interdomain B region of the ZAP-70 PTK plays important roles in the generation of second messengers after TCR engagement. Here, we demonstrate that phosphorylation of these two Tyr residues also play important roles in mediating the positive and negative selection of T cells in the thymus.
Survival and Clonal Expansion of Mutating “Forbidden” (Immunoglobulin Receptor–Deficient) Epstein-Barr Virus–Infected B Cells in Angioimmunoblastic T Cell Lymphoma
Authors: Bräuninger Andreas , Spieker Tilmann , Willenbrock Klaus , Gaulard Philippe , Wacker Hans-Heinrich , Rajewsky Klaus , Hansmann Martin-Leo , Küppers Ralf
Published: July 2002

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV− B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.
Divalent Cation Selectivity Is a Function of Gating in Native and Recombinant Cyclic Nucleotide–gated Ion Channels from Retinal Photoreceptors
Authors: Hackos David H. , Korenbrot Juan I.
Published: July 2002

The selectivity of Ca2+ over Na+ is ∼3.3-fold larger in cGMP-gated channels of cone photoreceptors than in those of rods when measured under saturating cGMP concentrations, where the probability of channel opening is 85–90%. Under physiological conditions, however, the probability of opening of the cGMP-gated channels ranges from its largest value in darkness of 1–5% to essentially zero under continuous, bright illumination. We investigated the ion selectivity of cGMP-gated channels as a function of cyclic nucleotide concentration in membrane patches detached from the outer segments of rod and cone photoreceptors and have found that ion selectivity is linked to gating. We determined ion selectivity relative to Na+ (PX/PNa) from the value of reversal potentials measured under ion concentration gradients. The selectivity for Ca2+ over Na+ increases continuously as the probability of channel opening rises. The dependence of PCa/PNa on cGMP concentration, in both rods and cones, is well described by the same Hill function that describes the cGMP dependence of current amplitude. At the cytoplasmic cGMP concentrations expected in dark-adapted intact photoreceptors, PCa/PNa in cone channels is ∼7.4-fold greater than that in rods. The linkage between selectivity and gating is specific for divalent cations. The selectivity of Ca2+ and Sr2+ changes with cGMP concentration, but the selectivity of inorganic monovalent cations, Cs+ and NH4+, and organic cations, methylammonium+ and dimethylammonium+, is invariant with cGMP. Cyclic nucleotide–gated channels in rod photoreceptors are heteromeric assemblies of α and β subunits. The maximal PCa/PNa of channels formed from α subunits of bovine rod channels is less than that of heteromeric channels formed from α and β subunits. In addition, Ca2+ is a more effective blocker of channels formed by α subunits than of channels formed by α and β subunits. The cGMP-dependent shift in divalent cation selectivity is a property of αβ channels and not of channels formed from α subunits alone.
On the number of abelian left symmetric algebras
Authors: Dekimpe Karel , Ongenae Veerle
Published: July 2002

In this paper we prove that there are infinitely many abelian left symmetric algebras in dimensions

≥
6

\geq 6

. Equivalently this means that there are, up to affine conjugation, infinitely many simply transitive affine actions of

R

k

\mathbb R^k

, for

k
≥
6

k\geq 6

. This is a result which is usually credited to A.T. Vasquez, but for which there is no proof in the literature.
Fell bundles over groupoids
Authors: Kumjian Alex
Published: July 2002

We study the C*-algebras associated to Fell bundles over groupoids and give a notion of equivalence for Fell bundles which guarantees that the associated C*-algebras are strongly Morita equivalent. As a corollary we show that any saturated Fell bundle is equivalent to a semi-direct product arising from the action of the groupoid on a C*-bundle.
The 𝑞-Schur² algebra
Authors: Du Jie , Scott Leonard
Published: July 2002

We study a class of endomomorphism algebras of certain

q
q

-permutation modules over the Hecke algebra of type

B
B

, whose summands involve both parabolic and quasi-parabolic subgroups, and prove that these algebras are integrally free and quasi-hereditary, and are stable under base change. Some consequences for decomposition numbers are discussed.
On the group of homotopy equivalences of a manifold
Authors: Baues Hans
Published: July 2002

We consider the group of homotopy equivalences

E

(
M
)

\mathcal E(M)

of a simply connected manifold

M
M

which is part of the fundamental extension of groups due to Barcus-Barratt. We show that the kernel of this extension is always a finite group and we compute this kernel for various examples. This leads to computations of the group

E

(
M
)

\mathcal E(M)

for special manifolds

M
M

, for example if

M
M

is a connected sum of products

S
n

×

S
m

S^n\times S^m

of spheres. In particular the group

E

(

S
n

×

S
n

)

\mathcal E(S^n\times S^n)

is determined completely. Also the connection of

E

(
M
)

\mathcal E(M)

with the group of isotopy classes of diffeomorphisms of

M
M

is studied.
Quasi-interpolatory splines based on Schoenberg points
Authors: Demichelis V.
Published: July 2002

By using the Schoenberg points as quasi-interpolatory points, we achieve both generality and economy in contrast to previous sets, which achieve either generality or economy, but not both. The price we pay is a more complicated theory and weaker error bounds, although the order of convergence is unchanged. Applications to numerical integration are given and numerical examples show that the accuracy achieved, using the Schoenberg points, is comparable to that using other sets.
Local geometric properties of real submanifolds in complex space
Authors: Baouendi M. , Ebenfelt P. , Rothschild Linda
Published: July 2002

We survey some recent results on local geometric properties of real submanifolds of complex space. Our main focus is on the structure and properties of mappings between such submanifolds. We relate these results to the classification of real submanifolds under biholomorphic, algebraic, or formal transformations. Examples and open problems in this context are also mentioned.
Eigenvalues, invariant factors, highest weights, and Schubert calculus
Authors: Fulton William
Published: July 2002

We describe recent work of Klyachko, Totaro, Knutson, and Tao that characterizes eigenvalues of sums of Hermitian matrices and decomposition of tensor products of representations ofGLn(C)GL_{n}(\mathbb {C}). We explain related applications to invariant factors of products of matrices, intersections in Grassmann varieties, and singular values of sums and products of arbitrary matrices.
The Erdos-Szekeres problem on points in convex position – a survey
Authors: Morris W. , Soltan V.
Published: July 2002

In 1935 Erdős and Szekeres proved that for any integer

n
≥
3

n \ge 3

there exists a smallest positive integer

N
(
n
)

N(n)

such that any set of at least

N
(
n
)

N(n)

points in general position in the plane contains

n
n

points that are the vertices of a convex

n
n

-gon. They also posed the problem to determine the value of

N
(
n
)

N(n)

and conjectured that

N
(
n
)
=

2

n
−
2

+
1

N(n) = 2^{n-2} +1

for all

n
≥
3.

n \ge 3.

Despite the efforts of many mathematicians, the Erdős-Szekeres problem is still far from being solved. This paper surveys the known results and questions related to the Erdős-Szekeres problem in the plane and higher dimensions, as well as its generalizations for the cases of families of convex bodies and the abstract convexity setting.
Convergence and finite determination of formal CR mappings
Authors: Baouendi M. , Ebenfelt P. , Rothschild Linda
Published: July 2002

It is shown that a formal mapping between two real-analytic hypersurfaces in complex space is convergent provided that neither hypersurface contains a nontrivial holomorphic variety. For higher codimensional generic submanifolds, convergence is proved e.g. under the assumption that the source is of finite type, the target does not contain a nontrivial holomorphic variety, and the mapping is finite. Finite determination (by jets of a predetermined order) of formal mappings between smooth generic submanifolds is also established.
Definable sets, motives and 𝑝-adic integrals
Authors: Denef Jan , Loeser François
Published: July 2002

We associate a canonical virtual motive to definable sets over a field of characteristic zero. We use this construction to show that very general

p
p

-adic integrals are canonically interpolated by motivic ones.
Total positivity in partial flag manifolds
Authors: Lusztig G.
Published: July 2002

The projective space of

R

n

\mathbf {R}^{n}

has a natural open subset: the set of lines spanned by vectors with all coordinates

>
0

>0

. Such a subset can be defined more generally for any partial flag manifold of a split semisimple real algebraic group. The main result of the paper is that this subset can be defined by algebraic equalities and inequalities.
Establishing a method of vector contamination identification in database sequences.
Authors: Seluja G A , Farmer A , McLeod M , Harger C , Schad P A
Published: July 2002

MOTIVATION: The nucleotide sequence databases are invaluable tools both for the private and the academic research communities, from the retrieval of sequences to homology searching. Several issues related to data quality, such as the existence of sequencing artifacts and errors, are facing the databases. We investigated a major source of these errors, i.e. the presence of vector-contaminated sequences. RESULTS: Using a panel of 180 vector polylinker sequences, we found 0.36% or 3029 vector-matching sequences in GenBank Release 95-96, with an average vector-matching length of 72 nucleotides. The number of vector-contaminated sequences has been growing with the database; however, the percent contamination has remained approximately constant at an average of 0.28% from 1982 to 1996. AVAILABILITY: Access to the database of vector polylinker sequences via sequence similarity searching is available at http://seqsim.ncgr.org/vector/ CONTACT: gas@molinfo.com
PIR-ALN: a database of protein sequence alignments.
Authors: Srinivasarao G Y , Yeh L S , Marzec C R , Orcutt B C , Barker W C
Published: July 2002

MOTIVATION: The Protein Information Resource (PIR) maintains a database of annotated and curated alignments in order to visually represent interrelationships among sequences in the PIR-International Protein Sequence Database, to spread and standardize protein names, features and keywords among members of a family or superfamily, and to aid us in classifying sequences, in identifying conserved regions, and in defining new homology domains. RESULTS: Release 22.0, (December 1998), of the PIR-ALN database contains a total of 3806 alignments, including 1303 superfamily, 2131 family and 372 homology domain alignments. This is an appropriate dataset to develop and extract patterns, test profiles, train neural networks or build Hidden Markov Models (HMMs). These alignments can be used to standardize and spread annotation to newer members by homology, as well as to understand the modular architecture of multidomain proteins. PIR-ALN includes 529 alignments that can be used to develop patterns not represented in PROSITE, Blocks, PRINTS and Pfam databases. The ATLAS information retrieval system can be used to browse and query the PIR-ALN alignments. AVAILABILITY: PIR-ALN is currently being distributed as a single ASCII text file along with the title, member, species, superfamily and keyword indexes. The quarterly and weekly updates can be accessed via the WWW at pir.georgetown.edu. The quarterly updates can also be obtained by anonymous FTP from the PIR FTP site at NBRF.Georgetown.edu, directory [ANONYMOUS.PIR.ALIGNMENT].
Darwin v. 2.0: an interpreted computer language for the
biosciences
Authors: Gonnet G. H. , Hallett M. T. , Korostensky C. , Bernardin L.
Published: July 2002

Motivation: We announce the availability of the second release of Darwin v. 2.0, an interpreted computer language especially tailored to researchers in the biosciences. The system is a general tool applicable to a wide range of problems.

Results: This second release improves Darwin version 1.6 in several ways: it now contains (1) a larger set of libraries touching most of the classical problems from computational biology (pairwise alignment, all versus all alignments, tree construction, multiple sequence alignment), (2) an expanded set of general purpose algorithms (search algorithms for discrete problems, matrix decomposition routines, complex/long integer arithmetic operations), (3) an improved language with a cleaner syntax, (4) better on-line help, and (5) a number of fixes to user-reported bugs.

Availability: Darwin is made available for most operating systems free of charge from the Computational Biochemistry Research Group (CBRG), reachable at http://cbrg.inf.ethz.ch.

Contact: darwin@inf.ethz.ch
The SWIB and the MDM2 domains are homologous and share a common
fold
Authors: Bennett-Lovsey Riccardo , Hart Sarah E. , Shirai Hiroki , Mizuguchi Kenji
Published: July 2002

Using a novel algorithm for protein sequence/structure analysis, we propose a probable homology between the SWIB domain (the conserved domain of the 60 kda subunit of the SWIB complex involved in chromatin remodelling) and the p53-binding domain of the MDM2 oncoprotein. The homology suggests that the SWIB domain would adopt a structure similar to that of the MDM2 domain and that these two families of proteins may share a similar functional mechanism.

Contact: kenji@cryst.bioc.cam.ac.uk

* To whom correspondance should be addressed.
DETERMINING THE BASE COST OF EDUCATION: AN ANALYSIS OF OHIO SCHOOL DISTRICTS
Authors: Ruggiero John
Published: July 2002

The Ohio Supreme Court recently ruled that Ohio's elementary and secondary public school financing system violates the state's constitution. It was estimated that an additional $1 billion is necessary to overhaul the current system. These costs are based on a report that defined the base cost of an adequate education using an overly simplified and flawed approach. This article recognizes that variations in spending arise from differences in outcomes provided, in the cost of providing a given level of outcomes, and in the efficiency of outcome provision. The study also critiques the approach used to determine the base cost of providing an adequate education.
Dynamic association of human insulin receptor with lipid rafts in cells lacking caveolae
Authors: Vainio Saara , Heino Sanna , Månsson Jan‐Eric , Fredman Pam , Kuismanen Esa , Vaarala Outi , Ikonen Elina
Published: July 2002

Cholesterol‐sphingolipid rich plasma membrane domains, known as rafts, have emerged as important regulators of signal transduction. The adipocyte insulin receptor (IR) is localized to and signals via caveolae that are formed by polymerization of caveolins. Caveolin binds to IR and stimulates signalling. We report that, in liver‐derived cells lacking caveolae, autophosphorylation of the endogenous IR is dependent on raft lipids, being compromised by acute cyclodextrin‐mediated cholesterol depletion or by antibody clustering of glycosphingolipids. Moreover, we provide evidence that IR becomes recruited to detergent‐resistant domains upon ligand binding and that clustering of GM2 ganglioside inhibits IR signalling apparently by excluding the ligand‐bound IR from these domains. Our results indicate that, in cells derived from liver, an important insulin target tissue, caveolae are not required for insulin signalling. Rather, the dynamic recruitment of the ligand‐bound IR into rafts may serve to regulate interactions in the initiation of the IR signalling cascade.
Dielectric function for a material containing hyperspherical inclusions to
O
(
c
2
): II. Method of images
Authors: Choy T. C. , Alexopoulos Aris , Thorpe M. F.
Published: July 2002

We have developed the method of images for the solution of two
hyperspheres
in
d
dimensions in a uniform field in order to study the
O
(
c
2
) coefficient κ in the dielectric constant of the medium. The method employs extensions of image theory for classical charges and dipoles for dielectric spheres, which produce novel line charge and line dipole densities. Numerical results for κ with arbitrary integer
d
are consistent with our previous paper I (this issue), and demonstrate that the image method shows superior convergence properties. Although computationally less convenient, the procedure is, in principle, calculable term–by–term and leads to useful analytic results in the weak scattering limit. This work also produces a simple algebraic approximation that is useful everywhere.
Can anything be done to maintain the effectiveness of pyrethroid–impregnated bednets against malaria vectors?
Authors: Curtis C. F. , Miller J. E. , Hodjati M. H. , Kolaczinski J. H. , Kasumba I.
Published: July 2002

Pyrethroid–treated bednets are the most promising available method of controlling malaria in the tropical world. Every effort should be made to find methods of responding to, or preventing, the emergence of pyrethroid resistance in the
Anopheles
vectors. Some cases of such resistance are known, notably in
An. gambiae
in West Africa where the
kdr
type of resistance has been selected, probably because of the use of pyrethroids on cotton. Because pyrethroids are irritant to mosquitoes, laboratory studies on the impact of, and selection for, resistance need to be conducted with free–flying mosquitoes in conditions that are as realistic as possible. Such studies are beginning to suggest that, although there is cross–resistance to all pyrethroids, some treatments are less likely to select for resistance than others are. Organophosphate, carbamate and phenyl pyrazole insecticides have been tested as alternative treatments for nets or curtains. Attempts have been made to mix an insect growth regulator and a pyrethroid on netting to sterilize pyrethroid–resistant mosquitoes that are not killed after contact with the netting. There seems to be no easy solution to the problem of pyrethroid resistance management, but further research is urgently needed.
On variability in the density of corticocortical and thalamocortical connections
Authors: Scannell Jack W. , Grant Simon , Payne Bertram R. , Baddeley Roland
Published: July 2002

Variability is an important but neglected aspect of connectional neuroanatomy. The quantitative density of the ‘same’ corticocortical or thalamocortical connection may vary by over two orders of magnitude between different injections of the same tracer. At present, however, the frequency distribution of connection densities is unknown. Therefore, it is unclear what kind of sampling strategies or statistical methods are appropriate for quantitative studies of connectivity. Nor is it clear if the measured variability represents differences between subjects, or if it is simply a consequence of intra–individual differences resulting from experimental technique and the exact placement of tracers relative to local spatial and laminar variation in connectivity.

W e used quantitative measurements of the density of a large number of corticocortical and thalamocortical connections from our own laboratories and from the literature. V ariability in the density of given corticocortical and thalamocortical connections is high, with the standard deviation of density proportional to the mean. The frequency distribution is close to exponential. Therefore, analysis methods relying on the normal distribution are not appropriate. W e provide an appendix that gives simple statistical guidance for samples drawn from exponentially distributed data.

For a given corticocortical or thalamocortical connection density, between–individual standard deviation is 0.85 to 1.25 times the within–individual standard deviation. Therefore, much of the variability reported in conventional neuroanatomical studies (with one tracer deposited per animal) is due to within–individual factors. W e also find that strong, but not weak, corticocortical connections are substantially more variable than thalamocortical connections. We propose that the near exponential distribution of connection densities is a simple consequence of ‘patchy’ connectivity. W e anticipate that connection data will be well described by the negative binomial, a class of distribution that applies to events occurring in clumped or patchy substrates. Local patchiness may be a feature of all corticocortical connections and could explain why strong corticocortical connections are more variable than strong thalamocortical connections. This idea is supported by the columnar patterns of many corticocortical but few thalamocortical connections in the literature.
Role of B cells in maintaining helper T–cell memory
Authors: van Essen Dominic , Dullforce Per , Gray David
Published: July 2002

The cellular interactions involved in maintaining CD4
+
T–cell memory have hitherto not been identified. In this report, we have investigated the role played by B cells in this process. We show that that longlasting helper T–cell memory depends on the presence of B cells, but that direct antigen presentation by B cells is not required. These findings provide new insights into the mechanisms which underlie helper T–cell memory. They also suggest that the efficacy of future vaccines will depend critically on the inclusion of B– as well as T–cell epitopes.
The Croonian Lecture 2000. Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission,Lecture delivered 5 October 2000 at University College London
Authors: Unwin Nigel
Published: July 2002

Communication in the nervous system takes place at chemical and electrical synapses, where neurotransmitter–gated ion channels, such as the nicotinic acetylcholine (ACh) receptor, and gap junction channels control propagation of electrical signals from one cell to the next. Newly developed electron crystallographic methods have revealed the structures of these channels trapped in open as well as closed states, suggesting how they work. The ACh receptor has large vestibules extending from the membrane which shape the ACh–binding pockets and facilitate selective transport of cations across a narrow membranespanning pore. When ACh enters the pockets it triggers a concerted conformational change that opens the pore by destabilizing a gate in the middle of the membrane made by a ring of pore–lining α–helical segments. The alternative ‘open’ configuration of pore–lining segments reshapes the lumen and creates new surfaces, allowing the ions to pass through. The gap junction channel uses a similar structural mechanism, involving coordinated rearrangements of α–helical segments in the plane of the membrane, to open its pore.
The resurgence of tuberculosis in Russia
Authors: Shilova Margarita V. , Dye Christopher
Published: July 2002

This paper documents and attempts to explain the epidemic spread of tuberculosis (TB) in Russia during the 1990s. After several decades of decline, the notification rate of all new TB cases among permanent residents increased by 7.5% per year from 1991–1999 and the death rate by 11% per year. Growth was quickest from 1993–1995 but increased again after the economic crisis of August 1998. Approximately 120 000 new cases and 30 000 deaths were reported in 1999. Case detection and cure rates have fallen in Russia since the mid–1980s; the fall has been accompanied by a higher frequency of severe disease among cases, and higher death and case fatality rates. With a mathematical model describing the deterioration in case finding and cure rates we could replicate the average rate of increase in incidence 1991–1999 but not the precise timing of the observed changes. Other factors that probably helped to shape the observed rise in caseload include enhanced transmission due to the mixing of prison and civilian populations, an increase in susceptibility to disease, and changes in the proportion of cases detected by surveillance. Although our explanation for the resurgence of TB is incomplete, we have identified a set of measures that can be implemented now to cut transmission, incidence and deaths.
A model of the interaction between ‘good genes’ and direct benefits in courtship-feeding animals: when do males of high genetic quality invest less?
Authors: Bussière L. F.
Published: July 2002

Conflict between mates over the amount of parental investment by each partner is probably the rule except in rare cases of genetic monogamy. In systems with parental care, males may frequently benefit by providing smaller investments than are optimal for individual female partners. Females are therefore expected to choose males that will provide the largest amounts of parental investment. In some species, however, the preferred males provide less care than their rivals. Focusing on species in which males invest by feeding their mates, I use a simple model to demonstrate the conditions under which males preferred by females may have optimal donations that are smaller than those of less–preferred rivals. Pre–mating female choice may sufficiently bias the perception of mate availability of preferred males relative to their rivals such that preferred males gain by conserving resources for future matings. Similarly, ‘cryptic’ biases in favour of high–quality ejaculates by females can compensate for smaller than average donations received from preferred males. However, post–fertilization cryptic choice should not change the optimal donations of preferred males relative to their rivals. I discuss the implications of this work for understanding sexual selection in courtship–feeding animals, and the relevance of these systems to understanding patterns of investment for animals in general.
A theoretical analysis of the energetic costs and consequences of parental care decisions
Authors: Webb J. N. , Székely T. , Houston A. I. , McNamara J. M.
Published: July 2002

Should a parent care for its young or abandon them before they reach independence? We consider parental care behaviour as an adaptive decision, involving trade–offs between current and future reproduction. The condition of the parent is expected to influence these trade–offs. Using a dynamic programming model we explore how changes in the levels of energetic reserves, and time in the season, determine changes in parental care decisions. The novel feature of our model is that we have included the possibility of remating within the current breeding season in a consistent manner by explicitly modelling the behaviour of unmated animals. We show that there may be several fluctuations in the average duration of care during the breeding season. We also show that, because of the dependence of parental care behaviour on both the condition of the parent and time during the breeding season, changing some of the costs of care may increase the duration of care during one part of the season and decrease it at another. The model also shows that the conditions prevailing for animals with dependent offspring can affect the way in which an unmated animal behaves. For example, the behaviour of unmated animals may change to compensate (partly) for increases in the costs of raising offspring, which are produced at a later date (for example, by increasing the duration of foraging between breeding attempts). Overall, the model provides a good framework for understanding how various ecological and life–history variables should influence parental care behaviour during a breeding season.
The predicted antigenicity of the haemagglutinin of the 1918 Spanish influenza pandemic suggests an avian origin
Authors: Brownlee G. G. , Fodor E.
Published: July 2002

In 1982 we characterized the antigenic sites of the haemagglutinin of influenza A/PR/8/34, which is an influenza strain of the H1 subtype that was isolated from humans in 1934, by studying mutants which escaped neutralization by antibody. Four antigenic sites, namely Cb, Sa, Sb and Ca, were found to be located near the tip of the trimeric haemagglutinin spike. Based on the sequence of the haemagglutinin of the 1918 Spanish influenza, we can now specify the extent of divergence of antigenic sites of the haemagglutinin during the antigenic drift of the virus between 1918 and 1934. This divergence was much more extensive (40%) than the divergence (20%) in predicted antigenic sites between the 1918 Spanish influenza and an avian H1 subtype consensus sequence. These results support the hypothesis that the human 1918 pandemic originated from an avian virus of the H1 subtype that crossed the species barrier from birds to humans and adapted to humans, presumably by mutation and/or reassortment, shortly before 1918.
Brachyury proteins regulate target genes through modular binding sites in a cooperative fashion
Authors: Kusch Thomas , Storck Tobias , Walldorf Uwe , Reuter Rolf
Published: July 2002

Brachyury proteins, a conserved subgroup of the T domain transcription factors, specify gut and posterior mesoderm derivatives throughout the animal kingdom. The T domain confers DNA-binding properties to Brachyury proteins, but little is known how these proteins regulate their target genes. We characterized a direct target gene of the Drosophila Brachyury-homolog Brachyenteron. Brachyenteron activates the homeobox gene orthopedia in a dose-dependent manner via multiple binding sites with the consensus (A/G)(A/T)(A/T)NTN(A/G)CAC(C/T)T. The sites and their A/T-rich flanking regions are conserved between D. melanogaster andDrosophila virilis. Reporter assays and site-directed mutagenesis demonstrate that Brachyenteron binding sites confer in part additive, in part synergistic effects on otp transcription levels. This suggests an interaction of Brachyenteron proteins on the DNA, which we could map to a conserved motif within the T domain. Mouse Brachyury also interacts with Brachyenteron through this motif. We further show that the Xenopus and mouse Brachyury homologs activate orthopedia expression when expressed inDrosophila embryonic cells. We propose that the mechanisms to achieve target gene expression through variable binding sites and through defined protein-protein interactions might be conserved for Brachyury relatives.
Partial Deletion of the Bovine ED1 Gene Causes Anhidrotic Ectodermal Dysplasia in Cattle
Authors: Drögemüller Cord , Distl Ottmar , Leeb Tosso
Published: July 2002

Anhidrotic ectodermal dysplasia (ED1) is characterized by hypotrichosis, reduced number of sweat glands, and incisior anodontia in human, mouse, and cattle. In affected humans and mice, mutations in the ED1 gene coding for ectodysplasin 1 are found. Ectodysplasin 1 is a novel trimeric transmembrane protein with an extracellular TNF-like signaling domain that is believed to be involved in the formation of hair follicles and tooth buds during fetal development. We report the construction of a 480-kb BAC contig harboring the complete bovine ED1 gene on BTA Xq22–Xq24. Physical mapping and sequence analysis of the coding parts of theED1 gene revealed that a large genomic region including exon 3 of the ED1 gene is deleted in cattle with anhidrotic ectodermal dysplasia in a family of German Holstein cattle with three affected maternal half sibs.

[The sequence data described in this paper have been submitted to the EMBL nucleotide database under accession nos. AJ300468, AJ300469, and AJ278907.]