bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice
Authors: Kennedy Mary K. , Glaccum Moira , Brown Sandra N. , Butz Eric A. , Viney Joanne L. , Embers Monica , Matsuki Naoto , Charrier Keith , Sedger Lisa , Willis Cynthia R. , Brasel Kenneth , Morrissey Philip J. , Stocking Kim , Schuh JoAnn C. L. , Joyce Sebastian , Peschon Jacques J.
Published: July 2002

C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.
Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production
Authors: Breitfeld Dagmar , Ohl Lars , Kremmer Elisabeth , Ellwart Joachim , Sallusto Federica , Lipp Martin , Förster Reinhold
Published: July 2002

Chemokines and their receptors have been identified as major regulators controlling the functional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD4+CXCR5+ cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4+CD45RO+CXCR5− cells, CD4+CD45RO+CXCR5+ tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4+CD45RO+CXCR5− population, suggesting that CXCR5+CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells “follicular B helper T cells” (TFH).
Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function
Authors: Schaerli Patrick , Willimann Katharina , Lang Alois B. , Lipp Martin , Loetscher Pius , Moser Bernhard
Published: July 2002

Leukocyte traffic through secondary lymphoid tissues is finely tuned by chemokines. We have studied the functional properties of a human T cell subset marked by the expression of CXC chemokine receptor 5 (CXCR5). Memory but not naive T cells from tonsils are CXCR5+ and migrate in response to the B cell–attracting chemokine 1 (BCA-1), which is selectively expressed by reticular cells and blood vessels within B cell follicles. Tonsillar CXCR5+ T cells do not respond to other chemokines present in secondary lymphoid tissues, including secondary lymphoid tissue chemokine (SLC), EBV-induced molecule 1 ligand chemokine (ELC), and stromal cell–derived factor 1 (SDF-1). The involvement of tonsillar CXCR5+ T cells in humoral immune responses is suggested by their localization in the mantle and light zone germinal centers of B cell follicles and by the concomitant expression of activation and costimulatory markers, including CD69, HLA-DR, and inducible costimulator (ICOS). Peripheral blood CXCR5+ T cells also belong to the CD4+ memory T cell subset but, in contrast to tonsillar cells, are in a resting state and migrate weakly to chemokines. CXCR5+ T cells are very inefficient in the production of cytokines but potently induce antibody production during coculture with B cells. These properties portray CXCR5+ T cells as a distinct memory T cell subset with B cell helper function, designated here as follicular B helper T cells (TFH).
Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4
Authors: Takahashi Takeshi , Tagami Tomoyuki , Yamazaki Sayuri , Uede Toshimitsu , Shimizu Jun , Sakaguchi Noriko , Mak Tak W. , Sakaguchi Shimon
Published: July 2002

This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25+CD4+ T cells, which constitute 5–10% of peripheral CD4+ T cells. When the CD25+CD4+ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25+CD4+ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25+CD4+ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.
Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers
Authors: Matsuda Jennifer L. , Naidenko Olga V. , Gapin Laurent , Nakayama Toshinori , Taniguchi Masaru , Wang Chyung-Ru , Koezuka Yasuhiko , Kronenberg Mitchell
Published: July 2002

A major group of natural killer (NK) T cells express an invariant Vα14+ T cell receptor (TCR) specific for the lipoglycan α-galactosylceramide (α-GalCer), which is presented by CD1d. These cells may have an important immune regulatory function, but an understanding of their biology has been hampered by the lack of suitable reagents for tracking them in vivo. Here we show that tetramers of mouse CD1d loaded with α-GalCer are a sensitive and highly specific reagent for identifying Vα14+ NK T cells. Using these tetramers, we find that α-GalCer–specific T lymphocytes are more widely distributed than was previously appreciated, with populations of largely NK1.1− but tetramer-binding T cells present in the lymph nodes and the intestine. Injection of α-GalCer leads to the production of both interferon γ and interleukin 4 by nearly all NK T cells in the liver and the majority of the spleen within 2 h. These cells mostly disappear by 5 h, and they do not reappear after 1 wk. Curiously, tetramer-positive thymocytes do not rapidly synthesize cytokines, nor do they undergo decreases in cell number after lipid antigen stimulation, although they express equivalent TCR levels. In summary, the data presented here demonstrate that α-GalCer–specific NK T cells undergo a unique and highly compartmentalized response to antigenic stimulation.
Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells
Authors: Yang De , Chen Qian , Schmidt Albert P. , Anderson G. Mark , Wang Ji Ming , Wooters Joseph , Oppenheim Joost J. , Chertov Oleg
Published: July 2002

We have previously shown that antimicrobial peptides like defensins have the capacity to mobilize leukocytes in host defense. LL-37 is the cleaved antimicrobial 37-residue, COOH-terminal peptide of hCAP18 (human cationic antimicrobial protein with a molecular size of 18 kD), the only identified member in humans of a family of proteins called cathelicidins. LL-37/hCAP18 is produced by neutrophils and various epithelial cells. Here we report that LL-37 is chemotactic for, and can induce Ca2+ mobilization in, human monocytes and formyl peptide receptor–like 1 (FPRL1)-transfected human embryonic kidney 293 cells. LL-37–induced Ca2+ mobilization in monocytes can also be cross-desensitized by an FPRL1-specific agonist. Furthermore, LL-37 is also chemotactic for human neutrophils and T lymphocytes that are known to express FPRL1. Our results suggest that, in addition to its microbicidal activity, LL-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and T cells to sites of microbial invasion by interacting with FPRL1.
Murine Cytomegalovirus Is Regulated by a Discrete Subset of Natural Killer Cells Reactive with Monoclonal Antibody to Ly49h
Authors: Daniels Keith A. , Devora Gene , Lai Wayne C. , O'Donnell Carey L. , Bennett Michael , Welsh Raymond M.
Published: July 2002

Antiviral roles of natural killer (NK) cell subsets were examined in C57BL/6 mice infected with murine cytomegalovirus (MCMV) and other viruses, including lymphocytic choriomeningitis virus (LCMV), vaccinia virus (VV), and mouse hepatitis virus (MHV). Each virus vigorously induced an NK cell infiltrate into the peritoneal cavity and liver, causing some redistributions of NK cell subsets defined by monoclonal antibody (mAb) directed against Ly49A, C/I, D, and G2. Striking results were seen with a mAb (1F8) reactive with the positively signaling molecule Ly49H, present in MCMV-resistant C57BL/6 mice. mAb 1F8 also stains Ly49 C and I, but exclusion of those reactivities with mAb 5E6, which recognizes Ly49 C and I, indicated that Ly49H+ cells infiltrated the peritoneal cavity and liver and were particularly effective at synthesizing interferon γ. Depletion of 1F8+ but not 5E6+ cells in vivo by mAb injections enhanced MCMV titers by 20-1,000-fold in the spleen and approximately fivefold in the liver. Titers of LCMV or VV were not enhanced. These anti-MCMV effects were attributed to prototypical NK1.1+CD3− NK cells and not to NK1.1+CD3+ “NK/T” cells. This is the first evidence that control of a virus infection in vivo is mediated by a distinct NK cell subset.
Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells
Authors: Klein Ulf , Tu Yuhai , Stolovitzky Gustavo A. , Mattioli Michela , Cattoretti Giorgio , Husson Hervé , Freedman Arnold , Inghirami Giorgio , Cro Lilla , Baldini Luca , Neri Antonino , Califano Andrea , Dalla-Favera Riccardo
Published: July 2002

B cell–derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that >50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more favorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of IgV hypermutation. To further investigate the phenotype of CLLs, their cellular derivation and their relationship to normal B cells, we have analyzed their gene expression profiles using oligonucleotide-based DNA chip microarrays representative of ∼12,000 genes. The results show that CLLs display a common and characteristic gene expression profile that is largely independent of their IgV genotype. Nevertheless, a restricted number of genes (<30) have been identified whose differential expression can distinguish IgV mutated versus unmutated cases and identify them in independent panels of cases. Comparison of CLL profiles with those of purified normal B cell subpopulations indicates that the common CLL profile is more related to memory B cells than to those derived from naive B cells, CD5+ B cells, and GC centroblasts and centrocytes. Finally, this analysis has identified a subset of genes specifically expressed by CLL cells of potential pathogenetic and clinical relevance.
Inactivation of Lrg-47 and Irg-47 Reveals a Family of Interferon γ–Inducible Genes with Essential, Pathogen-Specific Roles in Resistance to Infection
Authors: Collazo Carmen M. , Yap George S. , Sempowski Gregory D. , Lusby Kimberly C. , Tessarollo Lino , Woude George F. Vande , Sher Alan , Taylor Gregory A.
Published: July 2002

The cytokine interferon (IFN)-γ regulates immune clearance of parasitic, bacterial, and viral infections; however, the underlying mechanisms are poorly understood. Recently, a family of IFN-γ–induced genes has been identified that encode 48-kD GTP-binding proteins that localize to the endoplasmic reticulum of cells. The prototype of this family, IGTP, has been shown to be required for host defense against acute infections with the protozoan parasite Toxoplasma gondii, but not for normal clearance of the bacterium Listeria monocytogenes and murine cytomegalovirus (MCMV). To determine whether other members of the gene family also play important roles in immune defense, we generated mice that lacked expression of the genes LRG-47 and IRG-47, and examined their responses to representative pathogens. After infection with T. gondii, LRG-47–deficient mice succumbed uniformly and rapidly during the acute phase of the infection; in contrast, IRG-47–deficient mice displayed only partially decreased resistance that was not manifested until the chronic phase. After infection with L. monocytogenes, LRG-47–deficient mice exhibited a profound loss of resistance, whereas IRG-47–deficient mice exhibited completely normal resistance. In addition, both strains displayed normal clearance of MCMV. Thus, LRG-47 and IRG-47 have vital, but distinct roles in immune defense against protozoan and bacterial infections.
A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis
Authors: Huseby Eric S. , Liggitt Denny , Brabb Thea , Schnabel Bryan , Öhlén Claes , Goverman Joan
Published: July 2002

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4+ and CD8+ T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4+ myelin-specific T cells. The role of CD8+ myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8+ T cell–mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4+ T cell–mediated EAE. These data suggest that myelin-specific CD8+ T cells could function as effector cells in the pathogenesis of MS.
Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4
Authors: Termeer Christian , Benedix Frauke , Sleeman Jonathon , Fieber Christina , Voith Ursula , Ahrens Thomas , Miyake Kensuke , Freudenberg Marina , Galanos Christopher , Simon Jan Christoph
Published: July 2002

Low molecular weight fragmentation products of the polysaccharide of Hyaluronic acid (sHA) produced during inflammation have been shown to be potent activators of immunocompetent cells such as dendritic cells (DCs) and macrophages. Here we report that sHA induces maturation of DCs via the Toll-like receptor (TLR)-4, a receptor complex associated with innate immunity and host defense against bacterial infection. Bone marrow–derived DCs from C3H/HeJ and C57BL/10ScCr mice carrying mutant TLR-4 alleles were nonresponsive to sHA-induced phenotypic and functional maturation. Conversely, DCs from TLR-2–deficient mice were still susceptible to sHA. In accordance, addition of an anti–TLR-4 mAb to human monocyte–derived DCs blocked sHA-induced tumor necrosis factor α production. Western blot analysis revealed that sHA treatment resulted in distinct phosphorylation of p38/p42/44 MAP-kinases and nuclear translocation of nuclear factor (NF)-κB, all components of the TLR-4 signaling pathway. Blockade of this pathway by specific inhibitors completely abrogated the sHA-induced DC maturation. Finally, intravenous injection of sHA-induced DC emigration from the skin and their phenotypic and functional maturation in the spleen, again depending on the expression of TLR-4. In conclusion, this is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.
Identification of Amino Acid Residues in the α, β, and γ Subunits of the Epithelial Sodium Channel (ENaC) Involved in Amiloride Block and Ion Permeation
Authors: Schild Laurent , Schneeberger Estelle , Gautschi Ivan , Firsov Dmitri
Published: July 2002

The amiloride-sensitive epithelial Nachannel (ENaC) is a heteromultimeric channel made of three αβγ subunits. The structures involved in the ion permeation pathway have only been partially identified, and the respective contributions of each subunit in the formation of the conduction pore has not yet been established. Using a site-directed mutagenesis approach, we have identified in a short segment preceding the second membrane-spanning domain (the pre-M2 segment) amino acid residues involved in ion permeation and critical for channel block by amiloride. Cys substitutions of Gly residues in β and γ subunits at position βG525 and γG537 increased the apparent inhibitory constant (Ki) for amiloride by >1,000-fold and decreased channel unitary current without affecting ion selectivity. The corresponding mutation S583 to C in the α subunit increased amiloride Ki by 20-fold, without changing channel conducting properties. Coexpression of these mutated αβγ subunits resulted in a nonconducting channel expressed at the cell surface. Finally, these Cys substitutions increased channel affinity for block by externalZn2+ ions, in particular the αS583C mutant showing a Ki for Zn2+of 29 μM. Mutations of residues αW582L or βG522D also increased amiloride Ki, the later mutation generating a Ca2+blocking site located 15% within the membrane electric field. These experiments provide strong evidence that αβγ ENaCs are pore-forming subunits involved in ion permeation through the channel. The pre-M2 segment of αβγ subunits may form a pore loop structure at the extracellular face of the channel, where amiloride binds within the channel lumen. We propose that amiloride interacts with Na+ions at an external Na+binding site preventing ion permeation through the channel pore.
Kcsa
Authors: LeMasurier Meredith , Heginbotham Lise , Miller Christopher
Published: July 2002

Ion conduction and selectivity properties of KcsA, a bacterial ion channel of known structure, were studied in a planar lipid bilayer system at the single-channel level. Selectivity sequences for permeant ions were determined by symmetrical solution conductance (K+ > Rb+, NH4+, Tl+ ≫ Cs+, Na+, Li+) and by reversal potentials under bi-ionic or mixed-ion conditions (Tl+ > K+ > Rb+ > NH4+ ≫ Na+, Li+). Determination of reversal potentials with submillivolt accuracy shows that K+ is over 150-fold more permeant than Na+. Variation of conductance with concentration under symmetrical salt conditions is complex, with at least two ion-binding processes revealing themselves: a high affinity process below 20 mM and a low affinity process over the range 100–1,000 mM. These properties are analogous to those seen in many eukaryotic K+ channels, and they establish KcsA as a faithful structural model for ion permeation in eukaryotic K+ channels.
A Reference Price Model of Brand Choice for Frequently Purchased Products
Authors: Winer Russell S.
Published: July 2002

A brand choice model that incorporates both reference and observed prices is proposed for frequently purchased products. The model is composed of a probability-of-purchase component and a reference-price-formation component. Empirical testing of the model using coffee UPC scanner panel data demonstrates that for two of the three brands, the model predicts probability of purchase better than do standard demand models that utilize only current observed brand prices.
Paradoxes of Technology: Consumer Cognizance, Emotions, and Coping Strategies
Authors: Mick David Glen , Fournier Susan
Published: July 2002

Although technological products are unavoidable in contemporary life, studies focusing on them in the consumer behavior field have been few and narrow. In this article, we investigate consumers' perspectives, meanings, and experiences in relation to a range of technological products, emphasizing lengthy and repeated interviews with 29 households, including a set of first-time owners. We draw on literatures spanning from technology, paradox, and postmodernism to clinical and social psychology, and combine them with data collection and analysis in the spirit of grounded theory. The outcome is a new conceptual framework on the paradoxes of technological products and their influences on emotional reactions and behavioral coping strategies. We discuss the findings in terms of implications for theories of technology, innovation diffusion, and human coping, and an expanded role for the paradox construct in consumer research.
Scientific publishing, 17th‐century style: precepts of Francis Bacon
Authors: Bell Hazel
Published: July 2002

Some principles of scientific investigation, writing and publishing developed by Francis Bacon are quoted and discussed. Many are found to be just as applicable in today's world as they were in the 17th century when his major works were written.
Reviews, Letters and Listings
Authors: Bell Hazel , Toledano Kathryn
Published: July 2002

The Internet: A Writer's Guide by Jane Dorner. London: A. & C. Black, 2000. Pp. x + 196, Hardback, £9.99. ISBN 0‐7136‐5192‐X
Digitisation: issues and solutions
Authors: Barrow Edward
Published: July 2002

Rightsholders' groups have given CLA approval to develop sector‐by‐sector licences for the digitisation of existing print material. The first two licences, for pharmaceutical regulatory submissions and for higher education, are approaching completion. Rightsholders will be asked to opt‐in to each of them and to determine applicable fees for each of their publications.
Home on the electronic range: bringing the Journal of Animal Science online
Authors: Lewis Gregory S. , Edwards John W.
Published: July 2002

This article describes why the American Society of Animal Science decided to make the Journal of Animal Science available online, some of the issues that were considered before and during the project, and the responses of those who use the electronic journal. The article also contains discussions of new additions to our electronic offerings and the challenge of granting library access to electronic publications. Based on feedback received from American Society of Animal Science members, our online endeavors have been well received, and members perceive these offerings as an important enhancement of membership services.
Learned societies and electronic publishing
Authors: Donovan Bernard
Published: July 2002

Electronic publishing techniques are introducing inevitable changes in scholarly publishing as a whole and in the academic journal publishing business in particular. What will be the effect of the changes on the function and role of learned societies?
The Image Directory: an electronic publishing project cataloguing art images
Authors: Bentley J. Scott
Published: July 2002

The Image Directory is an online catalogue of information about art images unifying data from many sources into an easily searchable format. It breaks new ground in its aim to provide record‐level access to the vast body of scholarly, but non‐standardised, data on images that resides in the libraries, galleries and museums of the world.
Agents — the future of exclusivity
Authors: Davenport Anne
Published: July 2002

The Japanese market is changing and the sole agency route to marketing must develop and evolve alongside these changes if it is to have a future. Sole agency agreements need to redirect their focus away from merely closed market distribution agreements towards innovative sales and marketing contracts. Contracts between partners with shared objectives. The trend towards sales and marketing agreements was evident at the ALPSP Seminar on Marketing to Japan, held on 8 October 1997, from which this paper developed.
Book reviews
Authors: Hirschmann P N , Fox Mary
Published: July 2002

Journal Publishing By Gillian Page, Robert Campbell and Jack Meadows, Cambridge: Cambridge University Press, 1997, 420 pp £35.00, ISBN: 0 521 44137 4

Small Publishers A–Z: The guide to good publishing By Daphne Macara, West Molesey: Pandor House Publications, 1997, 44pp £6.50, ISBN: 1 871248 03 5
Fair use in US scholarly publishing
Authors: Orlans Harold
Published: July 2002

US law sanctions the fair use of copyright matter for scholarly purposes but defines it vaguely. The definitions employed by publishers are reviewed. In practice, restraints on fair use seem to be growing. A strong defence is warranted by its importance both to scholarship and to society.
New Journal of Physics: a web‐based and author‐funded journal
Authors: Haynes John
Published: July 2002

The journal publishing landscape is undergoing rapid change with economic pressures, spiralling journal prices, technological developments, and information overload a familiar picture to the players involved. Traditional academic journals, especially those based on the subscription model, are under increasing pressure and various alternative models have been suggested. Recently the Institute of Physics has combined with the German Physical Society (Deutsche Physikalische Gesellschaft) to launch New Journal of Physics (www.njp.org), an innovative, on‐line journal. This paper will describe why IOP and DPG were attracted to start a new, all‐electronic, general physics journal available free to all via the internet and funded by an article charge on authors. The main features of NJP will be outlined together with the early experiences. Key challenges for the future will be examined.
Preserving digital scholarship: the future is now
Authors: Russell Kelly , Weinberger Ellis , Stone Andy
Published: July 2002

The Cedars project in the UK has been set up to explore some of the issues associated with archiving of digital materials and to make recommendations to libraries about preserving digital materials. Cedars, which is led by the Consortium of University Research Libraries (CURL), is funded as part of the Electronic Libraries Programme (eLib) by the Joint Information Systems Committee of the Higher Education Funding Councils.
Journals metadata: information about content
Authors: Morgan Cliff
Published: July 2002

Metadata is data about data, or information about content. It is important to have standard ways of describing content for efficient resource discovery on the world‐wide web, and to tie this in with information about people and rights to build the foundations for e‐commerce. The most significant emerging standard is the Dublin Core, which has recently stabilized its simple (minimum) set as DC 1.0. Various organizations (including Wiley) have already been exploring the use of Dublin Core tags in a number of implementations. Other initiatives are taking place to bring all metadata schemes within an overarching data model. As the industry responsible for managing content from commissioning through to authenticated release, publishing should play a major role in metadata creation and promulgation.
The valence of harmonic polynomials
Authors: Wilmshurst A.
Published: July 2002

The paper gives an upper bound for the valence of harmonic polynomials. An example is given to show that this bound is sharp.
Integration on a convex polytope
Authors: Lasserre Jean
Published: July 2002

We present an exact formula for integrating a (positively) homogeneous function

f
f

on a convex polytope

Ω
⊂

R
n

\Omega \subset R^n

. We show that it suffices to integrate the function on the

(
n
−
1
)

(n-1)

-dimensional faces of

Ω
\Omega

, thus reducing the computational burden. Further properties are derived when

f
f

has continuous higher order derivatives. This result can be used to integrate a continuous function after approximation via a polynomial.
𝛽𝐧𝐛𝐜-bases for cohomology of local systems on hyperplane complements
Authors: Falk Michael , Terao Hiroaki
Published: July 2002

We study cohomology with coefficients in a rank one local system on the complement of an arrangement of hyperplanes

A

\mathcal {A}

. The cohomology plays an important role for the theory of generalized hypergeometric functions. We combine several known results to construct explicit bases of logarithmic forms for the only non-vanishing cohomology group, under some nonresonance conditions on the local system, for any arrangement

A

\mathcal {A}

. The bases are determined by a linear ordering of the hyperplanes, and are indexed by certain “no-broken-circuits" bases of

A

\mathcal {A}

. The basic forms depend on the local system, but any two bases constructed in this way are related by a matrix of integer constants which depend only on the linear orders and not on the local system. In certain special cases we show the existence of bases of monomial logarithmic forms.
Nonsmooth data error estimates for approximations of an evolution equation with a positive-type memory term
Authors: Lubich Ch. , Sloan I. , Thomée V.
Published: July 2002

We study the numerical approximation of an integro-differential equation which is intermediate between the heat and wave equations. The proposed discretization uses convolution quadrature based on the first- and second-order backward difference methods in time, and piecewise linear finite elements in space. Optimal-order error bounds in terms of the initial data and the inhomogeneity are shown for positive times, without assumptions of spatial regularity of the data.
Simple groups, permutation groups, and probability
Authors: Liebeck Martin , Shalev Aner
Published: July 2002

We derive a new bound for the minimal degree of an almost simple primitive permutation group, and settle a conjecture of Cameron and Kantor concerning the base size of such a group. Additional results concern random generation of simple groups, and the so-called genus conjecture of Guralnick and Thompson. Our proofs are based on probabilistic arguments, together with a new result concerning the size of the intersection of a maximal subgroup of a classical group with a conjugacy class of elements.
TeXshade: shading and labeling of multiple sequence alignments
using LaTeX2e
Authors: Beitz Eric
Published: July 2002

Motivation: Typesetting, shading and labeling of nucleotide and peptide alignments using standard word processing or graphics software is time consuming. Available automatic sequence shading programs usually do not allow manual application of additional shadings or labels. Hence, a flexible alignment shading package was designed for both calculated and manual shading, using the macro language of the scientific typesetting software LaTeX2e.

Results: TeXshade is the first TeX-based alignment shading software featuring, in addition to standard identity and similarity shading, special modes for the display of functional aspects such as charge, hydropathy or solvent accessibility. A plenitude of commands for manual shading, graphical labels, re-arrangements of the sequence order, numbering, legends etc. is implemented. Further, TeXshade allows the inclusion and display of secondary structure predictions in the DSSP-, STRIDE- and PHD-format.

Availability: From http://homepages.uni-tuebingen.de/beitz/tse.html(macro package and on-line documentation)

Contact: eric.beitz@uni-tuebingen.de
Adaptive encoding neural networks for the recognition of human
signal peptide cleavage sites
Authors: Jagla B. , Schuchhardt J.
Published: July 2002

*To whom correspondence should be addressed.

Motivation: Data representation and encoding are essential for classification of protein sequences with artificial neural networks (ANN). Biophysical properties are appropriate for low dimensional encoding of protein sequence data. However, in general there is no a priori knowledge of the relevant properties for extraction of representative features.

Results: An adaptive encoding artificial neural network (ACN) for recognition of sequence patterns is described. In this approach parameters for sequence encoding are optimized within the same process as the weight vectors by an evolutionary algorithm. The method is applied to the prediction of signal peptide cleavage sites in human secretory proteins and compared with an established predictor for signal peptides.

Conclusion: Knowledge of physico-chemical properties is not necessary for training an ACN. The advantage is a low dimensional data representation leading to computational efficiency, easy evaluation of the detected features, and high prediction accuracy.

Availability: A cleavage site prediction server is located at the Humboldt University http://itb.biologie.hu-berlin.de/~jo/sig-cleave/ACNpredictor.cgi

Contact: jo@itb.hu-berlin.de; berndj@zedat.fu-berlin.de
Independent Service Organizations and Economic Efficiency
Authors: Elzinga Kenneth G. , Mills David E.
Published: July 2002

Following the Supreme Court's Kodak decision, numerous antitrust cases have revolved around practices of manufacturers which deter independent service organizations (ISOs) from servicing the manufacturer's equipment. Such practices include tying equipment sales to service, tying service sales to other “aftermarket” products, and refusing to sell replacement parts to ISOs. We show that interbrand systems competition without ISOs curbs service and equipment price distortions and, under plausible conditions, confers greater benefits to users of durable equipment than intrabrand service competition with ISOs. Hence, the effect of manufacturers' practices that foreclose ISOs from service aftermarkets can be efficiency promoting rather than anticompetitive.
A novel approach to antiviral therapy for influenza
Authors: Colman Peter M.
Published: July 2002

The influenza glycoprotein, neuraminidase, destroys sialic acid–containing receptors on the surface of infected cells and on progeny virions. This activity facilitates the elution of newly budded virus from the infected cell surface and thus contributes to the viral burden in the host. On the basis of the three–dimensional structure of neuraminidase and the structure of the enzyme—product complex, novel analogues of the product (sialic acid, Neu5Ac) were designed and were shown to be potent inhibitors of neuraminidase in vitro and in vivo. Zanamivir (4–guanidino–Neu5Ac2en) is one of the most potent of the sialic acid analogues described to date. It is broadly inhibitory of all type A and B neuraminidases, probably because one of its design features was the requirement that it should interact only with strain–invariant amino acids inside the active site of the enzyme. Inhibition of neuraminidase translates into antiviral activity in tissue culture, in animal models of influenza and in both experimental and naturally acquired influenza in humans. Zanamivir is a minimal modification of the natural ligand (Neu5Ac) of the enzyme. This feature is expected to minimize the viability of drug–resistant virus that might arise through mutations in the enzyme active site. Studies to date of drug–resistant variants selected in tissue culture confirm this expectation. To deliver zanamivir directly to the lungs of patients the agent has been formulated for inhalation using a modified Diskhaler, which ensures high local concentrations and maximizes inhibition of viral neuraminidase.
Factors affecting levels of genetic diversity in natural populations
Authors: Amos William , Harwood John
Published: July 2002

Genetic variability is the clay of evolution, providing the base material on which adaptation and speciation depend. It is often assumed that most interspecific differences in variability are due primarily to population size effects, with bottlenecked populations carrying less variability than those of stable size. However, we show that population bottlenecks are unlikely to be the only factor, even in classic case studies such as the northern elephant seal and the cheetah, where genetic polymorphism is virtually absent. Instead, we suggest that the low levels of variability observed in endangered populations are more likely to result from a combination of publication biases, which tend to inflate the level of variability which is considered ‘normal’, and inbreeding effects, which may hasten loss of variability due to drift. To account for species with large population sizes but low variability we advance three hypotheses. First, it is known that certain metapopulation structures can result in effective population sizes far below the census size. Second, there is increasing evidence that heterozygous sites mutate more frequently than equivalent homozygous sites, plausibly because mismatch repair between homologous chromosomes during meiosis provides extra opportunities to mutate. Such a mechanism would undermine the simple relationship between heterozygosity and effective population size. Third, the fact that related species that differ greatly in variability implies that large amounts of variability can be gained or lost rapidly. We argue that such cases are best explained by rapid loss through a genome–wide selective sweep, and suggest a mechanism by which this could come about, based on forced changes to a control gene inducing coevolution in the genes it controls. Our model, based on meiotic drive in mammals, but easily extended to other systems, would tend to facilitate population isolation by generating molecular incompatabilities. Circumstances can even be envisioned in which the process could provide intrinsic impetus to speciation.
Algal morphogenesis: modelling interspecific variation inMicrasteriaswith reaction–diffusion patterned catalysis of cell surface growth
Authors: Holloway David M. , Harrison Lionel G.
Published: July 2002

Semi–cell morphogenesis in unicellular desmid algae of the genusMicrasteriasgenerates a stellar shape by repeated dichotomous branching of growing tips of the cell surface. The numerous species of the genus display variations of the branching pattern that differ markedly in number of branchings, lobe width and lobe length. We have modelled this morphogenesis, following previous work by D. M. Harrison and M. Kolár (1988), on the assumptions that patterning occurs by chemical reaction–diffusion activity within the plasma membrane, leading to morphological expression by patterned catalysis of the extension of the cell surface. The latter has been simulated in simplified form by two–dimensional computations. Our results indicate that for generation of repeated branchings and for the control of diverse species–specific shapes, the loss of patterning activity and of rapid growth in regions separating the active growing tips is an essential feature. We believe this conclusion to be much more general than the specific details of our model. We discuss the limitations of the model especially in terms of what extra features might be addressed in three–dimensional computation.
Endocranial preservation of a Carboniferous actinopterygian from Lancashire, UK, and the interrelationships of primitive actinopterygians
Authors: Coates Michael I.
Published: July 2002

The gross brain structure of an Upper Carboniferous (ca. 310 Myr ago) ray–finned fish (Actinopterygii) is described from exceptionally well–preserved fossil material from the Burnley region of Lancashire, UK. Previously identified as ‘Rhadinichthys’planti, the species is reassigned to the genusMesopoma. Morphological characters derived from these data are combined with reviews of cranial skeletal anatomy, enamel composition, oculomoter muscle insertion and paired fin morphology to test and reanalyse hypotheses of primitive actinopterygian interrelationships. Results indicate that ancestral chondrostean (sturgeon and paddlefish) and neopterygian (teleost, amiid and gar) lineages diverged earlier than current theories suggest. Palaeonisciformes, a taxonomic group widely used to include most Palaeozoic actinopterygians, include a significant number of primitive neopterygians, several of which may form a distinct monophyletic clade. Within this revised phylogenetic context, changes in gross brain morphology from primitive conditions, as revealed by fossil data, highlight likely specializations in extant non–teleostean actinopterygians.
Conducting tissues and phyletic relationships of bryophytes
Authors: Ligrone R. , Duckett J. G. , Renzaglia K. S.
Published: July 2002

Internal specialized conducting tissues, if present, are restricted to the gametophytic generation in liverworts while they may occur in both generations in mosses. Conducting tissues are unknown in the anthocerotes. Water–conducting cells (WCCs) with walls perforated by plasmodesma–derived pores occur in the Calobryales and Pallaviciniaceae (Metzgeriales) among liverworts and in
Takakia
among mosses. Imperforate WCCs (hydroids) are present in bryoid mosses. A polarized cytoplasmic organization and a distinctive axial system of microtubules is present in the highly specialized food–conducting cells of polytrichaceous mosses (leptoids) and in less specialized parenchyma cells of the leafy stem and seta in other mosses including
Sphagnum
. A similar organization, suggested to reflect specialization in long–distance symplasmic transport of nutrients, also occurs in other parts of the plant in mosses, including rhizoids and caulonemata, and may be observed in thallus parenchyma cells of liverworts. Perforate WCCs in the Calobryales, Metzgeriales and
Takakia
, and hydroids in bryoid mosses, probably evolved independently. Because of fundamental differences in developmental design, homology of any of these cells with tracheids is highly unlikely. Likewise, putative food–conducting of bryophytes present highly distinctive characteristics and cannot be considered homologous with the sieve cells of tracheophytes.
The laterophysic connection in chaetodontid butterflyfish: morphological variation and speculations on sensory function
Authors: Webb Jacqueline F. , Smith W. Leo
Published: July 2002

The laterophysic connection is a novel specialization in chaetodontid butterflyfish, in which paired diverticula of the swim–bladder (‘horns’) extend anteriorly and approach or directly contact a medial fossa in the lateral line canal contained within the supracleithrum. This study examined the morphology of the laterophysic connection in eight ecologically diverse species belonging to five subgenera within
Chaetodon
. Two types of laterophysic connections, indirect and direct, were found among
Chaetodon
species. Intraspecific variation (including sexual dimorphism) in the morphology of the laterophysic connection was not found. The type of laterophysic connection is not correlated with ecological characteristics among
Chaetodon
species, but appears to be correlated with subgeneric affinities of
Chaetodon
species. The presence of swim–bladder horns probably increases pressure sensitivity to the inner ear. It is suggested that the presence of a direct laterophysic connection, and possibly an indirect laterophysic connection, imparts pressure sensitivity to the lateral line canal system as well.
Inositol phosphates in the environment
Authors: Turner Benjamin L. , Papházy Michael J. , Haygarth Philip M. , Mckelvie Ian D.
Published: July 2002

The inositol phosphates are a group of organic phosphorus compounds found widely in the natural environment, but that represent the greatest gap in our understanding of the global phosphorus cycle. They exist as inositols in various states of phosphorylation (bound to between one and six phosphate groups) and isomeric forms (e.g.
myo
, D–
chiro
,
scyllo
,
neo
), although
myo
–inositol hexakisphosphate is by far the most prevalent form in nature. In terrestrial environments, inositol phosphates are principally derived from plants and accumulate in soils to become the dominant class of organic phosphorus compounds. Inositol phosphates are also present in large amounts in aquatic environments, where they may contribute to eutrophication. Despite the prevalence of inositol phosphates in the environment, their cycling, mobility and bioavailability are poorly understood. This is largely related to analytical difficulties associated with the extraction, separation and detection of inositol phosphates in environmental samples. This review summarizes the current knowledge of inositol phosphates in the environment and the analytical techniques currently available for their detection in environmental samples. Recent advances in technology, such as the development of suitable chromatographic and capillary electrophoresis separation techniques, should help to elucidate some of the more pertinent questions regarding inositol phosphates in the natural environment.
Xenotransplantation and tolerance
Authors: Samstein Benjamin , Piatt Jeffrey L.
Published: July 2002

The application of xenotransplantation faces daunting immunological hurdles, some of which might be overcome with the induction of tolerance. Porcine organs transplanted into primates are subject to several types of rejection responses. Hyperacute rejection mediated by naturally occurring xenoreactive antibodies and complement can be overcome without tolerance. Acute vascular rejection and cellular rejection, however, may present important opportunities for immunological tolerance, and humoral rejection might be approached by various mechanisms including (i) clonal deletion, (ii) anergy, (iii) immune deviation, (iv) induction of immunoregulatory or suppressor cells, or (v) veto cells. B-cell tolerance, useful for preventing humoral rejection, might be approached through clonal anergy. It remains to be determined, however, whether tolerance induction is required for xenotransplantation and by which means the various mechanisms of tolerance can be applied in the setting of xenotransplantation. Regardless, the study of tolerance will surely expand understanding of the physiology and pathophysiology of the immune system.