bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunization with a Peptide Surrogate for Double-stranded DNA (dsDNA) Induces Autoantibody Production and Renal Immunoglobulin Deposition
Authors: Putterman Chaim , Diamond Betty
Published: July 2002

Anti–double-stranded DNA (dsDNA) antibodies are the serologic abnormality characteristically associated with systemic lupus erythematosus (SLE) and may play an important role in disease pathogenesis. Although the anti-dsDNA antibodies present in SLE are indicative of an antigen-driven response, the antigen has not been conclusively identified.

By screening a phage peptide display library, we demonstrated previously that the decapeptide DWEYSVWLSN is specifically bound by the pathogenic murine IgG2b anti-dsDNA antibody R4A. To investigate the possibility that a protein antigen might trigger lupus-like autoimmunity, we immunized BALB/c mice with DWEYSVWLSN in adjuvant. Mice developed significant titers of IgG anti-dsDNA antibodies 2–3 wk after the initial immunization. Immunized mice also developed antibodies against some other lupus autoantigens, and immunoglobulin deposition was present in renal glomeruli at 49 d. Although an immune response to peptide and dsDNA was evident in BALB/c mice, there was little response in other inbred strains.

This study demonstrates that lupus-like anti-dsDNA reactivity can be generated in nonautoimmune mice by immunization with a peptide antigen. Peptide-induced autoimmunity may prove useful in understanding the spreading of antigenic specificities targeted in SLE. However, most importantly, the demonstration that a peptide antigen can initiate a SLE-like immune response opens a new chapter on the potential antigenic stimuli that might trigger SLE.
The Molecular Mechanism of B Cell Activation by toll-like Receptor Protein RP-105
Authors: Chan Vivien W.F. , Mecklenbräuker Ingrid , Su I-hsin , Texido Gemma , Leitges Michael , Carsetti Rita , Lowell Clifford A. , Rajewsky Klaus , Miyake Kensuke , Tarakhovsky Alexander
Published: July 2002

The B cell–specific transmembrane protein RP-105 belongs to the family of Drosophila toll-like proteins which are likely to trigger innate immune responses in mice and man. Here we demonstrate that the Src-family protein tyrosine kinase Lyn, protein kinase C β I/II (PKCβI/II), and Erk2-specific mitogen-activated protein (MAP) kinase kinase (MEK) are essential and probably functionally connected elements of the RP-105–mediated signaling cascade in B cells. We also find that negative regulation of RP-105–mediated activation of MAP kinases by membrane immunoglobulin may account for the phenomenon of antigen receptor–mediated arrest of RP-105–mediated B cell proliferation.
Engagement of Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Induces Transforming Growth Factor β (TGF-β) Production by Murine CD4+ T Cells
Authors: Chen Wanjun , Jin Wenwen , Wahl Sharon M.
Published: July 2002

Evidence indicates that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) may negatively regulate T cell activation, but the basis for the inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor β (TGF-β) production by murine CD4+ T cells. CD4+ T helper type 1 (Th1), Th2, and Th0 clones all secrete TGF-β after antibody cross-linking of CTLA-4, indicating that induction of TGF-β by CTLA-4 signaling represents a ubiquitous feature of murine CD4+ T cells. Stimulation of the CD3–T cell antigen receptor complex does not independently induce TGF-β, but is required for optimal CTLA-4–mediated TGF-β production. The consequences of cross-linking of CTLA-4, together with CD3 and CD28, include inhibition of T cell proliferation and interleukin (IL)-2 secretion, as well as suppression of both interferon γ (Th1) and IL-4 (Th2). Moreover, addition of anti–TGF-β partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-β1 gene–deleted (TGF-β1−/−) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our data demonstrate that engagement of CTLA-4 leads to CD4+ T cell production of TGF-β, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-β, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4+ T cell activation.
Complement-dependent Proinflammatory Properties of the Alzheimer's Disease β-Peptide
Authors: Bradt Bonnie M. , Kolb William P. , Cooper Neil R.
Published: July 2002

Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the β-amyloid peptide (Aβ), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Aβ deposits in NP. We report that Aβ peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Aβ with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.
Early Function of Pax5 (BSAP) before the Pre-B Cell Receptor Stage of B Lymphopoiesis
Authors: Thévenin Claire , Nutt Stephen L. , Busslinger Meinrad
Published: July 2002

The formation of the pre-B cell receptor (BCR) corresponds to an important checkpoint in B cell development that selects pro-B (pre-BI) cells expressing a functionally rearranged immunoglobulin μ (Igμ) heavy chain protein to undergo the transition to the pre-B (pre-BII) cell stage. The pre-BCR contains, in addition to Igμ, the surrogate light chains λ5 and VpreB and the signal transducing proteins Igα and Igβ. The absence of one of these pre-BCR components is known to arrest B cell development at the pre-BI cell stage. Disruption of the Pax5 gene, which codes for the B cell–specific activator protein (BSAP), also blocks adult B lymphopoiesis at the pre-BI cell stage. Moreover, expression of the mb-1 (Igα) gene and VH-to-DHJH recombination at the IgH locus are reduced in Pax5-deficient B lymphocytes ∼10- and ∼50-fold, respectively. Here we demonstrate that complementation of these deficiencies in pre-BCR components by expression of functionally rearranged Igμ and chimeric Igμ-Igβ transgenes fails to advance B cell development to the pre-BII cell stage in Pax5 (−/−) mice in contrast to RAG2 (−/−) mice. Furthermore, the pre-BCR is stably expressed on cultured pre-BI cells from Igμ transgenic, Pax5-deficient bone marrow, but is unable to elicit its normal signaling responses. In addition, the early developmental block is unlikely to be caused by the absence of a survival signal, as it could not be rescued by expression of a bcl2 transgene in Pax5-deficient pre-BI cells. Together, these data demonstrate that the absence of Pax5 arrests adult B lymphopoiesis at an early developmental stage that is unresponsive to pre-BCR signaling.
Hierarchical and Redundant Lymphocyte Subset Control Precludes Cytomegalovirus Replication during Latent Infection
Authors: Polić Bojan , Hengel Hartmut , Krmpotić Astrid , Trgovcich Joanne , Pavić Ivica , Lučin Pero , Jonjić Stipan , Koszinowski Ulrich H.
Published: July 2002

Reactivation from latent cytomegalovirus (CMV) infection is often associated with conditions of immunosuppression and can result in fatal disease. Whether the maintenance of systemic CMV latency is mainly governed by factors of the infected cell or by immune control functions is unknown. Likewise, the putative immune control mechanisms which could prevent the induction and spread of recurrent CMV infection are not clearly identified. We took advantage of latently infected B cell–deficient mice and a sensitive method for virus detection to study CMV reactivation after ablation of lymphocyte subsets. A crucial role of both T lymphocytes and natural killer (NK) cells was demonstrated. Within 5 d after depletion of lymphocytes, productive infection occurred in 50% of mice, and 14 d later 100% of mice exhibited recurrent infection. A hierarchy of immune control functions of CD8+, NK, and CD4+ cells was established. Reactivation was rare if only one of the lymphocyte subsets was depleted, but was evident after removal of a further subset, indicating a functional redundancy of control mechanisms. The salivary glands were identified as the site of most rapid virus shedding, followed by the detection of recurrent virus in the lungs, and eventually in the spleen. Our findings document a previously unknown propensity of latent CMV genomes to enter productive infection immediately and with a high frequency after immune cell depletion. The data indicate that only the sustained cellular immune control prevents CMV replication and restricts the viral genome to a systemic state of latency.
The Inositol Polyphosphate 5-Phosphatase Ship Is a Crucial Negative Regulator of B Cell Antigen Receptor Signaling
Authors: Liu Qiurong , Oliveira-Dos-Santos Antonio J. , Mariathasan Sanjeev , Bouchard Denis , Jones Jamie , Sarao Renu , Kozieradzki Ivona , Ohashi Pamela S. , Penninger Josef M. , Dumont Daniel J.
Published: July 2002

Ship is an Src homology 2 domain containing inositol polyphosphate 5-phosphatase which has been implicated as an important signaling molecule in hematopoietic cells. In B cells, Ship becomes associated with Fcγ receptor IIB (FcγRIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)–FcγRIIB coligation. The function of Ship in lymphocytes was investigated in Ship−/− recombination-activating gene (Rag)−/− chimeric mice generated from gene-targeted Ship−/− embryonic stem cells. Ship−/−Rag−/− chimeras showed reduced numbers of B cells and an overall increase in basal serum Ig. Ship−/− splenic B cells displayed prolonged Ca2+ influx, increased proliferation in vitro, and enhanced mitogen-activated protein kinase (MAPK) activation in response to BCR–FcγRIIB coligation. These results demonstrate that Ship plays an essential role in FcγRIIB-mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca2+ flux and MAPK activation.
Evolution of Antigen-specific T Cell Receptors In Vivo: Preimmune and Antigen-driven Selection of Preferred Complementarity-determining Region 3 (CDR3) Motifs
Authors: McHeyzer-Williams Louise J. , Panus Joanne Fanelli , Mikszta John A. , McHeyzer-Williams Michael G.
Published: July 2002

Antigen (Ag)-driven selection of helper T cells (Th) in normal animals has been difficult to study and remains poorly understood. Using the major histocompatibility complex class II– restricted murine response to pigeon cytochrome c (PCC), we provide evidence for both preimmune and Ag-driven selection in the evolution of Ag-specific immunity in vivo. Before antigenic challenge, most Vα11+Vβ3+ Th (70%) express a critical complementarity-determining region 3 (CDR3) residue (glutamic acid at TCR-α93) associated with PCC peptide contact. Over the first 5 d of the primary response, PCC-responsive Vα11+Vβ3+ Th expressing eight preferred CDR3 features are rapidly selected in vivo. Clonal dominance is further propagated through selective expansion of the PCC-specific cells with T cell receptor (TCR) of the “best fit.” Ag-driven selection is complete before significant emergence of the germinal center reaction. These data argue that thymic selection shapes TCR-α V region bias in the preimmune repertoire; however, Ag itself and the nongerminal center microenvironment drive the selective expansion of clones with preferred TCR that dominate the response to Ag in vivo.
Dual Role for Fas Ligand in the Initiation of and Recovery from Experimental Allergic Encephalomyelitis
Authors: Sabelko-Downes Kimberly A. , Cross Anne H. , Russell John H.
Published: July 2002

We have previously demonstrated a role for Fas and Fas ligand (FasL) in the pathogenesis of experimental allergic encephalomyelitis (EAE). However, using an active induction paradigm we could not distinguish between FasL expressed on activated CD4+ T cells from that expressed on other inflammatory or resident central nervous system (CNS) cells. To address this issue, we have conducted reciprocal adoptive transfer experiments of nontransgenic or myelin basic protein–specific T cell receptor transgenic wild-type, lpr, or gld lymphocytes into congenic wild-type, lpr, and gld hosts. We found that FasL expressed on donor cells is important for the development of EAE, as FasL-deficient lymphocytes transfer attenuated disease. Furthermore, Fas expressed in the recipient animals is important for the progression of EAE, as clinical signs of disease in lpr recipients were dramatically attenuated after transfer of either wild-type or lpr T cells. Surprisingly, these experiments also identified CNS cells as a source of functional FasL. Host-derived FasL appears to be especially important in the recovery from EAE, as many gld recipients of wild-type lymphocytes develop prolonged clinical signs of disease. Thus it appears that FasL plays distinct roles in EAE during the initiation of and recovery from disease.
Defects in Hemopoietic Stem Cell Activity in Ikaros Mutant Mice
Authors: Nichogiannopoulou Aliki , Trevisan Maryanne , Neben Steve , Friedrich Christoph , Georgopoulos Katia
Published: July 2002

Here we provide evidence that the Ikaros family of DNA binding factors is critical for the activity of hemopoietic stem cells (HSCs) in the mouse. Mice homozygous for an Ikaros null mutation display a >30-fold reduction in long-term repopulation units, whereas mice homozygous for an Ikaros dominant negative mutation have no measurable activity. The defect in HSC activity is also illustrated by the ability of wild-type marrow to repopulate unconditioned Ikaros mutants. A progressive reduction in multipotent CFU-S14 (colony-forming unit-spleen) progenitors and the earliest erythroid-restricted precursors (BFU-E [burst-forming unit-erythroid]) is also detected in the Ikaros mutant strains consistent with the reduction in HSCs. Nonetheless, the more mature clonogenic erythroid and myeloid precursors are less affected, indicating either the action of a compensatory mechanism to provide more progeny or a negative role of Ikaros at later stages of erythromyeloid differentiation. In Ikaros mutant mice, a decrease in expression of the tyrosine kinase receptors flk-2 and c-kit is observed in the lineage-depleted c-kit+Sca-1+ population that is normally enriched for HSCs and may in part contribute to the early hemopoietic phenotypes manifested in the absence of Ikaros.
Lymph-Borne Chemokines and Other Low Molecular Weight Molecules Reach High Endothelial Venules via Specialized Conduits While a Functional Barrier Limits Access to the Lymphocyte Microenvironments in Lymph Node Cortex
Authors: Gretz J. Elizabeth , Norbury Christopher C. , Anderson Arthur O. , Proudfoot Amanda E.I. , Shaw Stephen
Published: July 2002

Lymph-borne, soluble factors (e.g., chemokines and others) influence lymphocyte recirculation and endothelial phenotype at high endothelial venules (HEVs) in lymph node cortex. Yet the route lymph-borne soluble molecules travel from the subcapsular sinus to the HEVs is unclear. Therefore, we injected subcutaneously into mice and rats a wide variety of fluorophore-labeled, soluble molecules and examined their distribution in the draining lymph nodes. Rather than percolating throughout the draining lymph node, all molecules, including microbial lipopolysaccharide, were very visible in the subcapsular and medullary sinuses but were largely excluded from the cortical lymphocyte microenvironments. Exclusion prevailed even during the acute lymph node enlargement accompanying viral infection. However, low molecular mass (MW) molecules, including chemokines, did gain entry into the cortex, but in a very defined manner. Low MW, fluorophore-labeled molecules highlighted the subcapsular sinus, the reticular fibers, and the abluminal and luminal surfaces of the associated HEVs. These low MW molecules were in the fibers of the reticular network, a meshwork of collagen fibers ensheathed by fibroblastic reticular cells that connects the subcapsular sinus floor and the HEVs by intertwining with their basement membranes. Thus, low MW, lymph-borne molecules, including chemokines, traveled rapidly from the subcapsular sinus to the HEVs using the reticular network as a conduit.
Interferon γ Signaling Alters the Function of T Helper Type 1 Cells
Authors: Tau Gregory Z. , von der Weid Thierry , Lu Binfeng , Cowan Simone , Kvatyuk Marina , Pernis Alessandra , Cattoretti Giorgio , Braunstein Ned S. , Coffman Robert L. , Rothman Paul B.
Published: July 2002

One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon γ receptor (IFN-γR), whereas Th1 cells do not express the second chain of the IFN-γR (IFN-γR2) and are therefore unresponsive to IFN-γ. To determine whether the regulation of IFN-γR2 expression, and therefore IFN-γ responsiveness, is important for the differentiation of naive CD4+ T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-γR2 is controlled by the CD2 promoter and enhancer. CD4+ T cells from IFN-γR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-γ production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-γR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-γ–unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.
Burkitt Lymphoma in the Mouse
Authors: Kovalchuk Alexander L. , Qi Chen-Feng , Torrey Ted A. , Taddesse-Heath Lekidelu , Feigenbaum Lionel , Park Sung Sup , Gerbitz Armin , Klobeck Gustav , Hoertnagel Konstanze , Polack Axel , Bornkamm Georg W. , Janz Siegfried , Morse Herbert C.
Published: July 2002

Chromosomal translocations juxtaposing the MYC protooncogene with regulatory sequences of immunoglobulin (Ig) H chain or kappa (Igκ) or lambda (Igλ) L chain genes and effecting deregulated expression of MYC are the hallmarks of human Burkitt lymphoma (BL). Here we report that lymphomas with striking similarities to BL develop in mice bearing a mutated human MYC gene controlled by a reconstructed Igλ locus encompassing all the elements required for establishment of locus control in vitro. Diffusely infiltrating lymphomas with a typical starry sky appearance occurred in multiple founders and an established line, indicating independence from positional effects. Monoclonal IgM+CD5−CD23− tumors developed from an initially polyclonal population of B cells. These results demonstrate that the phenotype of B lineage lymphomas induced by MYC dysregulation is highly dependent on cooperativity among the regulatory elements that govern expression of the protooncogene and provide a new system for studying the pathogenesis of BL.
Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense
Authors: Ye Peng , Rodriguez Fred H. , Kanaly Suzanne , Stocking Kim L. , Schurr Jill , Schwarzenberger Paul , Oliver Peter , Huang Weitao , Zhang Ping , Zhang Jason , Shellito Judd E. , Bagby Greg J. , Nelson Steve , Charrier Keith , Peschon Jacques J. , Kolls Jay K.
Published: July 2002

Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4+ lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4+ T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R–deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.
Voltage Sensitivity and Gating Charge in Shaker and Shab Family Potassium Channels
Authors: Islas Leon D. , Sigworth Fred J.
Published: July 2002

The members of the voltage-dependent potassium channel family subserve a variety of functions and are expected to have voltage sensors with different sensitivities. The Shaker channel of Drosophila, which underlies a transient potassium current, has a high voltage sensitivity that is conferred by a large gating charge movement, ∼13 elementary charges. A Shaker subunit's primary voltage-sensing (S4) region has seven positively charged residues. The Shab channel and its homologue Kv2.1 both carry a delayed-rectifier current, and their subunits have only five positively charged residues in S4; they would be expected to have smaller gating-charge movements and voltage sensitivities. We have characterized the gating currents and single-channel behavior of Shab channels and have estimated the charge movement in Shaker, Shab, and their rat homologues Kv1.1 and Kv2.1 by measuring the voltage dependence of open probability at very negative voltages and comparing this with the charge–voltage relationships. We find that Shab has a relatively small gating charge, ∼7.5 eo. Surprisingly, the corresponding mammalian delayed rectifier Kv2.1, which has the same complement of charged residues in the S2, S3, and S4 segments, has a gating charge of 12.5 eo, essentially equal to that of Shaker and Kv1.1. Evidence for very strong coupling between charge movement and channel opening is seen in two channel types, with the probability of voltage-independent channel openings measured to be below 10−9 in Shaker and below 4 × 10−8 in Kv2.1.
The Role of Na,k-Atpase α Subunit Serine 775 and Glutamate 779 in Determining the Extracellular K+And Membrane Potential–Dependent Properties of the Na,k -Pump
Authors: Peluffo R. Daniel , Argüello José M. , Berlin Joshua R.
Published: July 2002

The roles of Ser775 and Glu779, two amino acids in the putative fifth transmembrane segment of the Na,K -ATPase α subunit, in determining the voltage and extracellular K + (K +o) dependence of enzyme-mediated ion transport, were examined in this study. HeLa cells expressing the α1 subunit of sheep Na,K -ATPase were voltage clamped via patch electrodes containing solutions with 115 mM Na+ (37°C). Na,K -pump current produced by the ouabain-resistant control enzyme (RD), containing amino acid substitutions Gln111Arg and Asn122Asp, displayed a membrane potential and K +o dependence similar to wild-type Na,K -ATPase during superfusion with 0 and 148 mM Na+-containing salt solutions. Additional substitution of alanine at Ser775 or Glu779 produced 155- and 15-fold increases, respectively, in the K +o concentration that half-maximally activated Na,K -pump current at 0 mV in extracellular Na+-free solutions. However, the voltage dependence of Na,K -pump current was unchanged in RD and alanine-substituted enzymes. Thus, large changes in apparent K +o affinity could be produced by mutations in the fifth transmembrane segment of the Na,K -ATPase with little effect on voltage-dependent properties of K + transport. One interpretation of these results is that protein structures responsible for the kinetics of K +o binding and/or occlusion may be distinct, at least in part, from those that are responsible for the voltage dependence of K +o binding to the Na,K -ATPase.
Invariants of piecewise-linear 3-manifolds
Authors: Barrett John , Westbury Bruce
Published: July 2002

This paper presents an algebraic framework for constructing invariants of closed oriented 3-manifolds by taking a state sum model on a triangulation. This algebraic framework consists of a tensor category with a condition on the duals which we have called a spherical category. A significant feature is that the tensor category is not required to be braided. The main examples are constructed from the categories of representations of involutive Hopf algebras and of quantised enveloping algebras at a root of unity.
Merits and demerits of the orbit method
Authors: Kirillov A.
Published: July 2002

This survey is the expanded version of my talk at the AMS meeting in April 1997. I explain to non-experts how to use the orbit method, discuss its strong and weak points and advertise some open problems.
Topology of symplectomorphism groups of rational ruled surfaces
Authors: Abreu Miguel , McDuff Dusa
Published: July 2002

LetMMbe eitherS2×S2S^2\times S^2or the one point blow-upCP2#CP¯2{\mathbb {C}}P^2\#\overline {{\mathbb {C}}P}^2ofCP2{\mathbb {C}}P^2. In both casesMMcarries a family of symplectic formsωλ\omega _{\lambda }, whereλ>−1\lambda > -1determines the cohomology class[ωλ][\omega _\lambda ]. This paper calculates the rational (co)homology of the groupGλG_\lambdaof symplectomorphisms of(M,ωλ)(M,\omega _\lambda )as well as the rational homotopy type of its classifying spaceBGλBG_\lambda. It turns out that each groupGλG_\lambdacontains a finite collectionKk,k=0,…,ℓ=ℓ(λ)K_k, k = 0,\dots ,\ell = \ell (\lambda ), of finite dimensional Lie subgroups that generate its homotopy. We show that these subgroups “asymptotically commute", i.e. all the higher Whitehead products that they generate vanish asλ→∞\lambda \to \infty. However, for each fixedλ\lambdathere is essentially one nonvanishing product that gives rise to a “jumping generator"wλw_\lambdainH∗(Gλ)H^*(G_\lambda )and to a single relation in the rational cohomology ringH∗(BGλ)H^*(BG_\lambda ). An analog of this generatorwλw_\lambdawas also seen by Kronheimer in his study of families of symplectic forms on44-manifolds using Seiberg–Witten theory. Our methods involve a close study of the space ofωλ\omega _\lambda-compatible almost complex structures onMM.
A bilinear approach to the restriction and Kakeya conjectures
Authors: Tao Terence , Vargas Ana , Vega Luis
Published: July 2002

Bilinear restriction estimates have appeared in work of Bourgain, Klainerman, and Machedon. In this paper we develop the theory of these estimates (together with the analogues for Kakeya estimates). As a consequence we improve the

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Phosphoinositides Regulate Membrane-dependent Actin Assembly by Latex Bead Phagosomes
Authors: Defacque Hélène , Bos Evelyne , Garvalov Boyan , Barret Cécile , Roy Christian , Mangeat Paul , Shin Hye-Won , Rybin Vladimir , Griffiths Gareth
Published: July 2002

Actin assembly on membrane surfaces is an elusive process in which several phosphoinositides (PIPs) have been implicated. We have reconstituted actin assembly using a defined membrane surface, the latex bead phagosome (LBP), and shown that the PI(4,5)P2-binding proteins ezrin and/or moesin were essential for this process ( Defacque et al., 2000b ). Here, we provide several lines of evidence that both preexisting and newly synthesized PI(4,5)P2, and probably PI(4)P, are essential for phagosomal actin assembly; only these PIPs were routinely synthesized from ATP during in vitro actin assembly. Treatment of LBP with phospholipase C or with adenosine, an inhibitor of type II PI 4-kinase, as well as preincubation with anti-PI(4)P or anti-PI(4,5)P2antibodies all inhibited this process. Incorporation of extra PI(4)P or PI(4,5)P2into the LBP membrane led to a fivefold increase in the number of phagosomes that assemble actin. An ezrin mutant mutated in the PI(4,5)P2-binding sites was less efficient in binding to LBPs and in reconstituting actin assembly than wild-type ezrin. Our data show that PI 4- and PI 5-kinase, and under some conditions also PI 3-kinase, activities are present on LBPs and can be activated by ATP, even in the absence of GTP or cytosolic components. However, PI 3-kinase activity is not required for actin assembly, because the process was not affected by PI 3-kinase inhibitors. We suggest that the ezrin-dependent actin assembly on the LBP membrane may require active turnover of D4 and D5 PIPs on the organelle membrane.
Snoring as a Risk Factor for Type II Diabetes Mellitus: A Prospective Study
Authors: Al-Delaimy Wael K. , Manson JoAnn E. , Willett Walter C. , Stampfer Meir J. , Hu Frank B.
Published: July 2002

To examine the association between snoring and risk of developing type II diabetes mellitus, the authors analyzed data from the Nurses' Health Study cohort. This analysis included 69,852 US female nurses aged 40–65 years without diagnosed diabetes, cardiovascular disease, or cancer at baseline in 1986. Snoring patterns were ascertained by questionnaire. During 10 years of follow-up, 1,957 women were diagnosed with type II diabetes. In analyses adjusted for age and body mass index, snoring was associated with risk of diabetes (for occasional snoring vs. nonsnoring, relative risk (RR) = 1.48 (95% confidence interval (CI): 1.29, 1.70); for regular snoring vs. nonsnoring, RR = 2.25 (95% CI: 1.91, 2.66); p for trend < 0.0001). Further adjustment for other diabetes risk factors and sleeping-related covariates only slightly attenuated the risk (for occasional snoring, RR = 1.41 (95% CI: 1.22, 1.63); for regular snoring, RR = 2.03 (95% CI: 1.71, 2.40); p for trend < 0.0001). Analyses stratified by body mass index, smoking history, or parental history of diabetes showed a consistent association between snoring and diabetes within the categories of these variables. These results suggest that snoring is independently associated with elevated risk of type II diabetes.
Promoter2.0: for the recognition of PolII promoter sequences.
Authors: Knudsen S
Published: July 2002

MOTIVATION: A new approach to the prediction of eukaryotic PolII promoters from DNA sequence takes advantage of a combination of elements similar to neural networks and genetic algorithms to recognize a set of discrete subpatterns with variable separation as one pattern: a promoter. The neural networks use as input a small window of DNA sequence, as well as the output of other neural networks. Through the use of genetic algorithms, the weights in the neural networks are optimized to discriminate maximally between promoters and non-promoters. RESULTS: After several thousand generations of optimization, the algorithm was able to discriminate between vertebrate promoter and non-promoter sequences in a test set with a correlation coefficient of 0.63. In addition, all five known transcription start sites on the plus strand of the complete adenovirus genome were within 161 bp of 35 predicted transcription start sites. On standardized test sets consisting of human genomic DNA, the performance of Promoter2.0 compares well with other software developed for the same purpose. AVAILABILITY: Promoter2.0 is available as a Web server at http://www.cbs.dtu. dk/services/promoter/
GeneBuilder: interactive in silico prediction of gene structure.
Authors: Milanesi L , D'Angelo D , Rogozin I B
Published: July 2002

MOTIVATION: Prediction of gene structure in newly sequenced DNA becomes very important in large genome sequencing projects. This problem is complicated due to the exon-intron structure of eukaryotic genes and because gene expression is regulated by many different short nucleotide domains. In order to be able to analyse the full gene structure in different organisms, it is necessary to combine information about potential functional signals (promoter region, splice sites, start and stop codons, 3' untranslated region) together with the statistical properties of coding sequences (coding potential), information about homologous proteins, ESTs and repeated elements. RESULTS: We have developed the GeneBuilder system which is based on prediction of functional signals and coding regions by different approaches in combination with similarity searches in proteins and EST databases. The potential gene structure models are obtained by using a dynamic programming method. The program permits the use of several parameters for gene structure prediction and refinement. During gene model construction, selecting different exon homology levels with a protein sequence selected from a list of homologous proteins can improve the accuracy of the gene structure prediction. In the case of low homology, GeneBuilder is still able to predict the gene structure. The GeneBuilder system has been tested by using the standard set (Burset and Guigo, Genomics, 34, 353-367, 1996) and the performances are: 0.89 sensitivity and 0.91 specificity at the nucleotide level. The total correlation coefficient is 0.88. AVAILABILITY: The GeneBuilder system is implemented as a part of the WebGene a the URL: http://www.itba.mi. cnr.it/webgene and TRADAT (TRAncription Database and Analysis Tools) launcher URL: http://www.itba.mi.cnr.it/tradat.
DRAGON: Database Referencing of Array Genes Online
Authors: Bouton Christopher M.L.S. , Pevsner Jonathan
Published: July 2002

Summary: ‘Database Referencing of Array Genes ONline’ or ‘DRAGON’ is a web-accessible database that aids in the analysis of differential gene expression data as a biological annotation tool. Users of DRAGON can submit data sets containing large lists of genes and then choose particular characteristics that DRAGON supplies for all genes on the list rapidly and simultaneously.

Availability: The DRAGON database is available for queries on the DRAGON web site www.kennedykrieger.org/pevsnerlab/dragon.htm.

Contact: pevsner@kennedykrieger.org or cbouton@jhmi.edu

To whom correspondence should be addressed.
Six-fold speed-up of Smith–Waterman sequence database
searches using parallel processing on common microprocessors
Authors: Rognes Torbjørn , Seeberg Erling
Published: July 2002

Motivation: Sequence database searching is among the most important and challenging tasks in bioinformatics. The ultimate choice of sequence-search algorithm is that of Smith–Waterman. However, because of the computationally demanding nature of this method, heuristic programs or special-purpose hardware alternatives have been developed. Increased speed has been obtained at the cost of reduced sensitivity or very expensive hardware.

Results: A fast implementation of the Smith–Waterman sequence-alignment algorithm using Single-Instruction, Multiple-Data (SIMD) technology is presented. This implementation is based on the MultiMedia eXtensions (MMX) and Streaming SIMD Extensions (SSE) technology that is embedded in Intel’s latest microprocessors. Similar technology exists also in other modern microprocessors. Six-fold speed-up relative to the fastest previously known Smith–Waterman implementation on the same hardware was achieved by an optimized 8-way parallel processing approach. A speed of more than 150 million cell updates per second was obtained on a single Intel Pentium III 500 MHz microprocessor. This is probably the fastest implementation of this algorithm on a single general-purpose microprocessor described to date.

Availability: Online searches with the software are available at http://dna.uio.no/search/

Contact: torbjorn.rognes@labmed.uio.no

To whom correspondence should be addressed.
Multi-class protein fold recognition using support vector

machines and neural networks
Authors: Ding Chris H.Q. , Dubchak Inna
Published: July 2002

Motivation: Protein fold recognition is an important approach to structure discovery without relying on sequence similarity. We study this approach with new multi-class classification methods and examined many issues important for a practical recognition system.

Results: Most current discriminative methods for protein fold prediction use the one-against-others method, which has the well-known ‘False Positives’ problem. We investigated two new methods: the unique one-against-others and the all-against-all methods. Both improve prediction accuracy by 14–110% on a dataset containing 27 SCOP folds. We used the Support Vector Machine (SVM) and the Neural Network (NN) learning methods as base classifiers. SVMs converges fast and leads to high accuracy. When scores of multiple parameter datasets are combined, majority voting reduces noise and increases recognition accuracy. We examined many issues involved with large number of classes, including dependencies of prediction accuracy on the number of folds and on the number of representatives in a fold. Overall, recognition systems achieve 56% fold prediction accuracy on a protein test dataset, where most of the proteins have below 25% sequence identity with the proteins used in training.

Supplementary information: The protein parameter datasets used in this paper are available online (http://www.nersc.gov/~cding/protein).

Contact: chqding@lbl.gov; ildubchak@lbl.gov

* To whom correspondence should be addressed.
ATV: display and manipulation of annotated phylogenetic trees
Authors: Zmasek Christian M. , Eddy Sean R.
Published: July 2002

Summary: A Tree Viewer (ATV) is a Java tool for the display and manipulation of annotated phylogenetic trees. It can be utilized both as a standalone application and as an applet in a web browser.

Availability: ATV is available via WWW at http://www.genetics.wustl.edu/eddy/atv/ and via FTP at ftp://ftp.genetics.wustl.edu/pub/eddy/software/forester.tar.Z

Contact: eddy@genetics.wustl.edu
A Comparison of the Postal Telegraph Movement in Great Britain and the United States, 1866–1900
Authors: Hochfelder David
Published: July 2002

This article places the British and American postal telegraph movements in the broader context of a transatlantic reform tradition. More specifically, British nationalization in 1870 gave American reformers both a rallying point and a rationale for postalizing the telegraphs. The legacies of both movements were mixed. In Britain, the postal telegraph provided inexpensive and accessible service, but it soon ran a large deficit and retarded the development of the telephone industry. In the United States, reformers failed to nationalize the telegraph or to secure a place in historical memory, but they succeeded in pressuring Western Union to provide better service, and they provided the impetus for the municipal ownership movement of the Progressive Era.
Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3‐kinase‐, Rho‐, and Rac‐dependent signaling pathways
Authors: Attoub Samir , Noe Veerle , Pirola Luciano , Bruyneel Erik , Chastre Eric , Mareel Marc , Wymann Matthias P. , Gespach Christian
Published: July 2002

Leptin plays a key role regulating food intake, body weight and fat mass. These critical parameters are associated with an increased risk for digestive and mammary gland cancer in the Western population. Here we determined whether leptin contributes to the invasive phenotype of colonic and kidney epithelial cells at various stages of the neoplastic progression. First, leptin potently (EC50 = 10–30 ng/ml) induces invasion of collagen gels by premalignant familial adenomatous colonic cells PC/AA/C1 and nontumorigenic MDCK kidney epithelial cells, their src‐transformed counterparts, and the human adenocarcinoma colonic cells LoVo and HCT‐8/S11. Leptin and its Ob‐Rb receptors were consistently identified by RT‐PCR and immunoblotting in these cell lines, as well as in human colonic epithelial crypts, polyps, colonic tumor resections, and adjacent mucosa. Leptin‐induced invasion was effectively blocked by pharmacological inhibitors of several downstream signaling pathways involved in cell transformation, namely, JAK2 tyrosine kinase (AG490), phosphoinositide PI3′‐kinase (wortmannin and LY294002), mTOR kinase (rapamycin), and protein kinases C (GF109203X, Gö6976). Accordingly, leptin induces transient elevation of the PI3′‐kinase lipid products in JAK2 immunoprecipitates prepared from parental MDCK cells. The leptin effect on invasion was potentiated by the activated form of the small GTPase RhoA and was abrogated by dominant negative mutants of RhoA, Rac1, and the p110α of PI3′‐K. Our data indicate that leptin may exert a local and beneficial effect on migration of normal colonic epithelial cells and reparation of the inflamed or wounded digestive mucosa. We also emphasize a new role for leptin, linking the nutritional and body fat status to digestive cancer susceptibility by stimulating the invasive capacity of colonic epithelial cells at early stages of neoplasia. This finding has potential clinical implications for colon cancer progression and management of obesity.— Attoub, S., Noe, V., Pirola, L., Bruyneel, E., Chastre, E., Mareel, M., Wymann, M. P., Gespach, C. Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3‐kinase‐, Rho‐, and Rac‐dependent signaling pathways. FASEB J. 14, 2329‐2338 (2000)
Transmission dynamics and epidemiology of dengue: insights from age–stratified sero–prevalence surveys
Authors: Ferguson Neil M. , Donnelly Christl A. , Anderson Roy M.
Published: July 2002

The relationship between infection with the four major serotypes of dengue virus and the occurrence of different forms of disease is complex and not fully understood. Interpreting longitudinal records of the incidence of serious disease to gain insight into the transmission dynamics and epidemiology of the virus is therefore complicated. Since age reflects duration of exposure, age–stratified, strain–specific serological surveys carried out at one point in time, or over a short time interval, can potentially provide a rich source of information on longitudinal patterns. This paper describes the development and application (to data collected in Thailand) of statistically rigorous methods designed to estimate time–varying, strain–specific forces of infection, and thus basic reproduction numbers, from cross–sectional serological data. The analyses provide support for the hypothesis that antibody– dependent enhancement of transmission influences observed epidemiological pattern. Age–stratified serological data also reveal evidence of a propensity for the annual incidence of infection to oscillate over time with a frequency of several years. The latter observation is consistent with the predictions of simple mathematical models of the transmission dynamics of the virus. The estimates of the basic reproduction numbers obtained are similar in magnitude for each dengue serotype, being in the range of four to six. Such values are higher than those obtained from earlier analyses, and the implications of this for dengue control are discussed.
Dynamics of climate and ecosystem coupling: abrupt changes and multiple equilibria
Authors: Higgins Paul A.T. , Mastrandrea Michael D. , Schneider Stephen H.
Published: July 2002

Interactions between subunits of the global climate–biosphere system (e.g. atmosphere, ocean, biosphere and cryosphere) often lead to behaviour that is not evident when each subunit is viewed in isolation. This newly evident behaviour is an emergent property of the coupled subsystems. Interactions between thermohaline circulation and climate illustrate one emergent property of coupling ocean and atmospheric circulation. The multiple thermohaline circulation equilibria that result caused abrupt climate changes in the past and may cause abrupt climate changes in the future. Similarly, coupling between the climate system and ecosystem structure and function produces complex behaviour in certain regions. For example, atmosphere–biosphere interactions in the Sahel region of West Africa lead to multiple stable equilibria. Either wet or dry climate equilibria can occur under otherwise identical forcing conditions. The equilibrium reached is dependent on past history (i.e. initial conditions), and relatively small perturbations to either climate or vegetation can cause switching between the two equilibria. Both thermohaline circulation and the climate–vegetation system in the Sahel are prone to abrupt changes that may be irreversible. This complicates the relatively linear view of global changes held in many scientific and policy communities. Emergent properties of coupled socio–natural systems add yet another layer of complexity to the policy debate. As a result, the social and economic consequences of possible global changes are likely to be underestimated in most conventional analyses because these nonlinear, abrupt and irreversible responses are insufficiently considered.
Stability of a PKCI-1-related mRNA is controlled by the splicing factor ASF/SF2: a novel function for SR proteins
Authors: Lemaire Raphael , Prasad Jayendra , Kashima Tsuyoshi , Gustafson Jennifer , Manley James L. , Lafyatis Robert
Published: July 2002

Pre-mRNA splicing is a widely used regulatory mechanism for controlling gene expression, and a family of conserved proteins, SR proteins, participate in both constitutive and alternative splicing. Here we describe a novel function for the SR protein ASF/SF2. We used an embryonic chicken cDNA library to screen for differential mRNA expression in the chicken B-cell line DT40-ASF, expressing or not expressing ASF/SF2. Remarkably, out of 3 × 106 clones screened, only one, isolated several times independently, showed ASF/SF2-related differential expression. The isolated cDNA, referred to here as PKCI-r (for PKCI-related), is closely related to the protein kinase C interacting protein (PKCI-1) gene. Transcript levels were increased ∼sixfold in ASF/SF2-depleted cells compared with cells expressing ASF/SF2, indicating a negative role for the SR protein. Strikingly, inhibition of ASF/SF2 expression had no significant effect on PKCI-r splicing, or transcription, but markedly increased the half-life of PKCI-r mRNA (6.6-fold). Similarly, increased mRNA stability was also observed upon expression of exogenous PKCI-r mRNA in cells depleted of ASF/SF2. ASF/SF2 bound to a discrete region containing a purine-rich sequence in the 3′ UTR of the PKCI-r transcript, and deletion of this region eliminated ASF/SF2-mediated regulation of transcript stability. Together these data indicate a novel, direct effect of ASF/SF2 onPKCI-r mRNA stability. Therefore, ASF/SF2, and perhaps other SR proteins, affects gene expression in vertebrate cells through regulation of mRNA stability as well as splicing.