bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspirin-triggered 15-Epi-Lipoxin A4 (LXA4) and LXA4 Stable Analogues Are Potent Inhibitors of Acute Inflammation: Evidence for Anti-inflammatory Receptors
Authors: Takano Tomoko , Fiore Stefano , Maddox Jane F. , Brady Hugh R. , Petasis Nicos A. , Serhan Charles N.
Published: July 2002

Lipoxins are bioactive eicosanoids that are immunomodulators. In human myeloid cells, lipoxin (LX) A4 actions are mediated by interaction with a G protein–coupled receptor. To explore functions of LXA4 and aspirin-triggered 5(S),6(R),15(R)-trihydroxy-7,9,13-trans-11-cis–eicosatetraenoic acid (15-epi-LXA4) in vivo, we cloned and characterized a mouse LXA4 receptor (LXA4R). When expressed in Chinese hamster ovary cells, the mouse LXA4R showed specific binding to [3H]LXA4 (Kd ≈ 1.5 nM), and with LXA4 activated GTP hydrolysis. Mouse LXA4R mRNA was most abundant in neutrophils. In addition to LXA4 and 15-epi-LXA4, bioactive LX stable analogues competed with both [3H]LXA4 and [3H]leukotriene D4 (LTD4)– specific binding in vitro to neutrophils and endothelial cells, respectively. Topical application of LXA4 analogues and novel aspirin-triggered 15-epi-LXA4 stable analogues to mouse ears markedly inhibited neutrophil infiltration in vivo as assessed by both light microscopy and reduced myeloperoxidase activity in skin biopsies. The 15(R)-16-phenoxy-17,18, 19,20-tetranorLXA4 methyl ester (15-epi-16-phenoxy-LXA4), an analogue of aspirin triggered 15-epi-LXA4, and 15(S)-16-phenoxy-17,18,19,20-tetranor-LXA4 methyl ester (16-phenoxy-LXA4) were each as potent as equimolar applications of the anti-inflammatory, dexamethasone. Thus, we identified murine LXA4R, which is highly expressed on murine neutrophils, and showed that both LXA4 and 15-epi-LXA4 stable analogues inhibit neutrophil infiltration in the mouse ear model of inflammation. These findings provide direct in vivo evidence for an anti-inflammatory action for both aspirin-triggered LXA4 and LXA4 stable analogues and their site of action in vivo.
The Human Toll Signaling Pathway: Divergence of Nuclear Factor κB and JNK/SAPK Activation Upstream of Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6)
Authors: Muzio Marta , Natoli Gioacchino , Saccani Simona , Levrero Massimo , Mantovani Alberto
Published: July 2002

The human homologue of Drosophila Toll (hToll) is a recently cloned receptor of the interleukin 1 receptor (IL-1R) superfamily, and has been implicated in the activation of adaptive immunity. Signaling by hToll is shown to occur through sequential recruitment of the adapter molecule MyD88 and the IL-1R–associated kinase. Tumor necrosis factor receptor–activated factor 6 (TRAF6) and the nuclear factor κB (NF-κB)–inducing kinase (NIK) are both involved in subsequent steps of NF-κB activation. Conversely, a dominant negative version of TRAF6 failed to block hToll-induced activation of stress-activated protein kinase/c-Jun NH2-terminal kinases, thus suggesting an early divergence of the two pathways.
Establishment of a Functional Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcription Complex Involves the Cytoskeleton
Authors: Bukrinskaya Alissa , Brichacek Beda , Mann Angela , Stevenson Mario
Published: July 2002

After interaction of human immunodeficiency virus type 1 (HIV-1) virions with cell surface receptors, a series of poorly characterized events results in establishment of a viral reverse transcription complex in the host cell cytoplasm. This process is coordinated in such a way that reverse transcription is initiated shortly after formation of the viral reverse transcription complex. However, the mechanism through which virus entry and initiation of reverse transcription are coordinated and how these events are compartmentalized in the infected cell are not known. In this study, we demonstrate that viral reverse transcription complexes associate rapidly with the host cell cytoskeleton during HIV-1 infection and that reverse transcription occurs almost entirely in the cytoskeletal compartment. Interruption of actin polymerization before virus infection reduced association of viral reverse transcription complexes with the cytoskeleton. In addition, efficient reverse transcription was dependent on intact actin microfilaments. The localization of reverse transcription to actin microfilaments was mediated by the interaction of a reverse transcription complex component (gag MA) with actin but not vimentin (intermediate filaments) or tubulin (microtubules). In addition, fusion, but not endocytosis-mediated HIV-1 infectivity, was impaired when actin depolymerizing agents were added to target cells before infection but not when added after infection. These results point to a previously unsuspected role for the host cell cytoskeleton in HIV-1 entry and suggest that components of the cytoskeleton promote establishment of the reverse transcription complex in the host cell and also the process of reverse transcription within this complex.
gp100/pmel 17 Is a Murine Tumor Rejection Antigen: Induction of “Self”-reactive, Tumoricidal T Cells Using High-affinity, Altered Peptide Ligand
Authors: Overwijk Willem W. , Tsung Allan , Irvine Kari R. , Parkhurst Maria R. , Goletz Theresa J. , Tsung Kangla , Carroll Miles W. , Liu Chunlei , Moss Bernard , Rosenberg Steven A. , Restifo Nicholas P.
Published: July 2002

Many tumor-associated antigens are nonmutated, poorly immunogenic tissue differentiation antigens. Their weak immunogenicity may be due to “self”-tolerance. To induce autoreactive T cells, we studied immune responses to gp100/pmel 17, an antigen naturally expressed by both normal melanocytes and melanoma cells. Although a recombinant vaccinia virus (rVV) encoding the mouse homologue of gp100 was nonimmunogenic, immunization of normal C57BL/6 mice with the rVV encoding the human gp100 elicited a specific CD8+ T cell response. These lymphocytes were cross-reactive with mgp100 in vitro and treated established B16 melanoma upon adoptive transfer. To understand the mechanism of the greater immunogenicity of the human version of gp100, we characterized a 9-amino acid (AA) epitope, restricted by H-2Db, that was recognized by the T cells. The ability to induce specific T cells with human but not mouse gp100 resulted from differences within the major histocompatibility complex (MHC) class I–restricted epitope and not from differences elsewhere in the molecule, as was evidenced by experiments in which mice were immunized with rVV containing minigenes encoding these epitopes. Although the human (hgp10025–33) and mouse (mgp10025–33) epitopes were homologous, differences in the three NH2-terminal AAs resulted in a 2-log increase in the ability of the human peptide to stabilize “empty” Db on RMA-S cells and a 3-log increase in its ability to trigger interferon γ release by T cells. Thus, the fortuitous existence of a peptide homologue with significantly greater avidity for MHC class I resulted in the generation of self-reactive T cells. High-affinity, altered peptide ligands might be useful in the rational design of recombinant and synthetic vaccines that target tissue differentiation antigens expressed by tumors.
Human Immunoglobulin (Ig)M+IgD+ Peripheral Blood B Cells Expressing the CD27 Cell Surface Antigen Carry Somatically Mutated Variable Region Genes: CD27 as a General Marker for Somatically Mutated (Memory) B Cells
Authors: Klein Ulf , Rajewsky Klaus , Küppers Ralf
Published: July 2002

Immunoglobulin (Ig)M+IgD+ B cells are generally assumed to represent antigen-inexperienced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM+IgD+ peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM+IgD+ B cells. IgM+IgD+CD27+ B cells resemble class-switched and IgM-only memory cells in terms of cell phenotype, and comprise ∼15% of PB B lymphocytes in healthy adults. Moreover, a very small population (<1% of PB B cells) of highly mutated IgD-only B cells was detected, which likely represent the PB counterpart of IgD-only tonsillar germinal center and plasma cells. Overall, the B cell pool in the PB of adults consists of ∼40% mutated memory B cells and 60% unmutated, naive IgD+CD27− B cells (including CD5+ B cells). In the somatically mutated B cells, VH region genes carry a two- to threefold higher load of somatic mutation than rearranged Vκ genes. This might be due to an intrinsically lower mutation rate in κ light chain genes compared with heavy chain genes and/or result from κ light chain gene rearrangements in GC B cells. A common feature of the somatically mutated B cell subsets is the expression of the CD27 cell surface antigen which therefore may represent a general marker for memory B cells in humans.
An Inflammatory Polypeptide Complex from Staphylococcus epidermidis: Isolation and Characterization
Authors: Mehlin Christopher , Headley Catherine M. , Klebanoff Seymour J.
Published: July 2002

Staphylococcus epidermidis releases factors that activate the HIV-1 long terminal repeat, induce cytokine release, and activate nuclear factor κB in cells of macrophage lineage. The active material had a mass of 34,500 daltons, was inactivated by proteases and partitioned into the phenol layer on hot aqueous phenol extraction, and thus was termed phenol-soluble modulin (PSM). High performance liquid chromatography (HPLC) of crude PSM yielded two peaks of activity designated PSM peak 1 and peak 2. MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) mass spectroscopy indicated the presence of two components in peak 1, which were designated PSMα and PSMβ. Peak 2 contained a single component, designated PSMγ. Separation of PSMα and PSMβ in peak 1 could be achieved by a second HPLC procedure. The structure of each component was determined by amino acid sequence analysis and identification and sequencing of their genes. PSMα, PSMβ, and PSMγ were 22-, 44-, and 25-amino acid, respectively, strongly hydrophobic polypeptides. PSMγ was identified as Staphylococcus epidermidis delta toxin, whereas PSMα and PSMβ exhibited more distant homology to previously described staphylococcal toxins. They appeared to exist as a complex or aggregate with activity greater than the component parts. The properties of the S. epidermidis PSMs suggest that they may contribute to the systemic manifestations of Gram-positive sepsis.
TRANCE, a Tumor Necrosis Factor Family Member Critical for CD40 Ligand–independent T Helper Cell Activation
Authors: Bachmann Martin F. , Wong Brian R. , Josien Régis , Steinman Ralph M. , Oxenius Annette , Choi Yongwon
Published: July 2002

CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in antigen-specific T cell responses in vivo. CD40L expressed on activated CD4+ T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4+ T cell priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount protective CD4+ T cell responses that produce normal levels of interferon γ, suggesting a CD40L/CD40-independent mechanism of CD4+ T cell priming that to date has not been elucidated. Here we show that CD4+ T cell responses to viral infection were greatly diminished in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member, TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required for efficient CD4+ T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is sufficient to elicit efficient CD4+ T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that TRANCE/TRANCE-R may be a novel and important target for immune intervention.
An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation
Authors: Asseman Chrystelle , Mauze Smita , Leach Michael W. , Coffman Robert L. , Powrie Fiona
Published: July 2002

A T helper cell type 1–mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RBhigh CD4+ T cells and can be prevented by cotransfer of the CD45RBlow subset. The immune-suppressive activities of the CD45RBlow T cell population can be reversed in vivo by administration of an anti-transforming growth factor β antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RBlow population. This population isolated from IL-10–deficient (IL-10−/−) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti–murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RBlow CD4+ cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RBhigh CD4+ cells, as CD45RBlow CD4+ cells from WT mice were able to inhibit colitis induced by IL-10−/− CD45RBhigh CD4+ cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.
Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5–Positive Cd4 Cells and Germinal Centers
Authors: Walker Lucy S.K. , Gulbranson-Judge Adam , Flynn Sarah , Brocker Thomas , Raykundalia Chandra , Goodall Margaret , Förster Reinhold , Lipp Martin , Lane Peter
Published: July 2002

Mice rendered deficient in CD28 signaling by the soluble competitor, cytotoxic T lymphocyte–associated molecule 4–immunoglobulin G1 fusion protein (CTLA4-Ig), fail to upregulate OX40 expression in vivo or form germinal centers after immunization. This is associated with impaired interleukin 4 production and a lack of CXC chemokine receptor (CXCR)5 on CD4 T cells, a chemokine receptor linked with migration into B follicles. Germinal center formation is restored in CTLA4-Ig transgenic mice by coinjection of an agonistic monoclonal antibody to CD28, but this is substantially inhibited if OX40 interactions are interrupted by simultaneous injection of an OX40-Ig fusion protein. These data suggest that CD28-dependent OX40 ligation of CD4 T cells at the time of priming is linked with upregulation of CXCR5 expression, and migration of T cells into B cell areas to support germinal center formation.
In Situ Tolerance within the Central Nervous System as a Mechanism for Preventing Autoimmunity
Authors: Brabb Thea , von Dassow Peter , Ordonez Nadia , Schnabel Bryan , Duke Blythe , Goverman Joan
Published: July 2002

Multiple sclerosis (MS) is believed to be an autoimmune disease in which autoreactive T cells infiltrate the central nervous system (CNS). Animal models of MS have shown that CNS-specific T cells are present in the peripheral T cell repertoire of healthy mice and cause autoimmune disease only when they are activated by immunization. T cell entry into the CNS is thought to require some form of peripheral activation because the blood–brain barrier prohibits trafficking of this tissue by naive cells. We report here that naive T cells can traffic to the CNS without prior activation. Comparable numbers of T cells are found in the CNS of both healthy recombinase activating gene (Rag)−/− T cell receptor (TCR) transgenic mice and nontransgenic mice even when the transgenic TCR is specific for a CNS antigen. Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phenotypically naive and proliferate robustly to antigenic stimulation in vitro. Strikingly, transgenic T cells isolated from the CNS that are specific for myelin basic protein (MBP) are also primarily phenotypically naive but are unresponsive to antigenic stimulation in vitro. Mononuclear cells from the CNS of MBP TCR transgenic but not nontransgenic mice can suppress the response of peripheral MBP-specific T cells in vitro. These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.
Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia
Authors: Rosenwald Andreas , Alizadeh Ash A. , Widhopf George , Simon Richard , Davis R. Eric , Yu Xin , Yang Liming , Pickeral Oxana K. , Rassenti Laura Z. , Powell John , Botstein David , Byrd John C. , Grever Michael R. , Cheson Bruce D. , Chiorazzi Nicholas , Wilson Wyndham H. , Kipps Thomas J. , Brown Patrick O. , Staudt Louis M.
Published: July 2002

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.
Intestinal Mast Cell Progenitors Require CD49dβ7 (α4β7 Integrin) for Tissue-specific Homing
Authors: Gurish Michael F. , Tao Hong , Abonia J. Pablo , Arya Anu , Friend Daniel S. , Parker Christina M. , Austen K. Frank
Published: July 2002

Mast cells (MCs) are centrally important in allergic inflammation of the airways, as well as in the intestinal immune response to helminth infection. A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues. Because the mechanisms of MC progenitor (MCp) homing to peripheral tissues have not been evaluated, we used limiting dilution analysis to measure the concentration of MCp in various tissues of mice deficient for candidate homing molecules. MCp were almost completely absent in the small intestine but were present in the lung, spleen, BM, and large intestine of β7 integrin-deficient mice (on the C57BL/6 background), indicating that a β7 integrin is critical for homing of these cells to the small intestine. MCp concentrations were not altered in the tissues of mice deficient in the αE integrin (CD103), the β2 integrin (CD18), or the recombination activating gene (RAG)-2 gene either alone or in combination with the interleukin (IL)-receptor common γ chain. Therefore, it is the α4β7 integrin and not the αEβ7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions. When MCp in BALB/c mice were eliminated with sublethal doses of γ-radiation and then reconstituted with syngeneic BM, the administration of anti-α4β7 integrin, anti-α4 integrin, anti-β7 integrin, or anti–MAdCAM-1 monoclonal antibodies (mAbs) blocked the recovery of MCp in the small intestine. The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine. Inasmuch as MCp are preserved in the lungs of β7 integrin-deficient and anti-α4β7 integrin-treated mice but not in the small intestine, α4β7 integrin is critical for tissue specific extravasation for localization of MCp in the small intestine, but not the lungs.
Extremal points of a functional on the set of convex functions
Authors: Lachand-Robert T. , Peletier M.
Published: July 2002

We investigate the extremal points of a functional

∫
f
(
∇
u
)

\int f(\nabla u)

, for a convex or concave function

f
f

. The admissible functions

u
:
Ω
⊂

R

N

→

R

u:\Omega \subset \mathbf {R}^N\to \mathbf {R}

are convex themselves and satisfy a condition

u
2

≤
u
≤

u
1

u_2\leq u \leq u_1

. We show that the extremal points are exactly

u
1

u_1

and

u
2

u_2

if these functions are convex and coincide on the boundary

∂
Ω

\partial \Omega

. No explicit regularity condition is imposed on

f
f

,

u
1

u_1

, or

u
2

u_2

. Subsequently we discuss a number of extensions, such as the case when

u
1

u_1

or

u
2

u_2

are non-convex or do not coincide on the boundary, when the function

f
f

also depends on

u
u

, etc.
The best constant in the Davis inequality for the expectation of the martingale square function
Authors: Burkholder Donald
Published: July 2002

A method is introduced for the simultaneous study of the square function and the maximal function of a martingale that can yield sharp norm inequalities between the two. One application is that the expectation of the square function of a martingale is not greater than

3

\sqrt 3

times the expectation of the maximal function. This gives the best constant for one side of the Davis two-sided inequality. The martingale may take its values in any real or complex Hilbert space. The elementary discrete-time case leads quickly to the analogous results for local martingales

M
M

indexed by

[
0
,
∞
)

[0,\infty )

. Some earlier inequalities are also improved and, closely related, the Lévy martingale is embedded in a large family of submartingales.
The Trotter-Kato theorem and approximation of PDEs
Authors: Ito Kazufumi , Kappel Franz
Published: July 2002

We present formulations of the Trotter-Kato theorem for approximation of linear C

0

{}_0

-semigroups which provide very useful framework when convergence of numerical approximations to solutions of PDEs are studied. Applicability of our results is demonstrated using a first order hyperbolic equation, a wave equation and Stokes’ equation as illustrative examples.
Compactifying the space of stable maps
Authors: Abramovich Dan , Vistoli Angelo
Published: July 2002

In this paper we study a notion of twisted stable map, from a curve to a tame Deligne-Mumford stack, which generalizes the well-known notion of stable map to a projective variety.
Hidden Markov models for detecting remote protein homologies.
Authors: Karplus K , Barrett C , Hughey R
Published: July 2002

MOTIVATION: A new hidden Markov model method (SAM-T98) for finding remote homologs of protein sequences is described and evaluated. The method begins with a single target sequence and iteratively builds a hidden Markov model (HMM) from the sequence and homologs found using the HMM for database search. SAM-T98 is also used to construct model libraries automatically from sequences in structural databases. METHODS: We evaluate the SAM-T98 method with four datasets. Three of the test sets are fold-recognition tests, where the correct answers are determined by structural similarity. The fourth uses a curated database. The method is compared against WU-BLASTP and against DOUBLE-BLAST, a two-step method similar to ISS, but using BLAST instead of FASTA. RESULTS: SAM-T98 had the fewest errors in all tests-dramatically so for the fold-recognition tests. At the minimum-error point on the SCOP (Structural Classification of Proteins)-domains test, SAM-T98 got 880 true positives and 68 false positives, DOUBLE-BLAST got 533 true positives with 71 false positives, and WU-BLASTP got 353 true positives with 24 false positives. The method is optimized to recognize superfamilies, and would require parameter adjustment to be used to find family or fold relationships. One key to the performance of the HMM method is a new score-normalization technique that compares the score to the score with a reversed model rather than to a uniform null model. AVAILABILITY: A World Wide Web server, as well as information on obtaining the Sequence Alignment and Modeling (SAM) software suite, can be found at http://www.cse.ucsc.edu/research/compbi o/ CONTACT: karplus@cse.ucsc.edu; http://www.cse.ucsc.edu/karplus
Exploiting the past and the future in protein secondary
structure prediction
Authors: Baldi Pierre , Brunak Søren , Frasconi Paolo , Soda Giovanni , Pollastri Gianluca
Published: July 2002

Motivation: Predicting the secondary structure of a protein (alpha-helix, beta-sheet, coil) is an important step towards elucidating its three-dimensional structure, as well as its function. Presently, the best predictors are based on machine learning approaches, in particular neural network architectures with a fixed, and relatively short, input window of amino acids, centered at the prediction site. Although a fixed small window avoids overfitting problems, it does not permit capturing variable long-rang information.

Results: We introduce a family of novel architectures which can learn to make predictions based on variable ranges of dependencies. These architectures extend recurrent neural networks, introducing non-causal bidirectional dynamics to capture both upstream and downstream information. The prediction algorithm is completed by the use of mixtures of estimators that leverage evolutionary information, expressed in terms of multiple alignments, both at the input and output levels. While our system currently achieves an overall performance close to 76% correct prediction – at least comparable to the best existing systems – the main emphasis here is on the development of new algorithmic ideas.

Availability: The executable program for predicting protein secondary structure is available from the authors free of charge.

Contact: pfbaldi@ics.uci.edu, gpollast@ics.uci.edu, brunak@cbs.dtu.dk, paolo@dsi.unifi.it
Ontology for immunogenetics: the IMGT-ONTOLOGY
Authors: Giudicelli Véronique , Lefranc Marie-Paule
Published: July 2002

Motivation: IMGT, the international ImMunoGene- Tics database (http://imgt.cines.fr:8104), created by M.-P. Lefranc, is an integrated database specializing in antigen receptors (immunoglobulins and T-cell receptors) and major histocompatibility complex (MHC) of all vertebrate species. IMGT accurate immunogenetics data are based on the standardization of the biological knowledge provided by the ‘ImMunoGeneTics’ IMGT-ONTOLOGY.

The IMGT-ONTOLOGY describes the classification and specification of terms needed for immunogenetics and bioinformatics. IMGT-ONTOLOGY covers four main concepts: ‘IDENTIFICATION’, ‘DESCRIPTION’, ‘CLASSIFICATION’ and ‘OBTENTION’. These concepts allow an extensive and standardized description and characterization of immunoglobulin and T-cell receptor data. The controlled vocabulary and the annotation rules are indispensable to ensure accuracy, consistency and coherence in IMGT. IMGT-ONTOLOGY allows scientists and clinicians to use, for the first time, identical terms with the same meaning in immunogenetics. It provides a semantic repository that will improve interoperability between specialist and generalist databases.

Availability: Controlled vocabulary and annotation rules are described in the IMGT Scientific chart from the IMGT Marie-Paule page at http://imgt.cines.fr:8104

Contact: lefranc@ligm.igh.cnrs.fr
Identifying DNA and protein patterns with statistically significant alignments of multiple sequences.
Authors: Hertz G Z , Stormo G D
Published: July 2002

MOTIVATION: Molecular biologists frequently can obtain interesting insight by aligning a set of related DNA, RNA or protein sequences. Such alignments can be used to determine either evolutionary or functional relationships. Our interest is in identifying functional relationships. Unless the sequences are very similar, it is necessary to have a specific strategy for measuring-or scoring-the relatedness of the aligned sequences. If the alignment is not known, one can be determined by finding an alignment that optimizes the scoring scheme. RESULTS: We describe four components to our approach for determining alignments of multiple sequences. First, we review a log-likelihood scoring scheme we call information content. Second, we describe two methods for estimating the P value of an individual information content score: (i) a method that combines a technique from large-deviation statistics with numerical calculations; (ii) a method that is exclusively numerical. Third, we describe how we count the number of possible alignments given the overall amount of sequence data. This count is multiplied by the P value to determine the expected frequency of an information content score and, thus, the statistical significance of the corresponding alignment. Statistical significance can be used to compare alignments having differing widths and containing differing numbers of sequences. Fourth, we describe a greedy algorithm for determining alignments of functionally related sequences. Finally, we test the accuracy of our P value calculations, and give an example of using our algorithm to identify binding sites for the Escherichia coli CRP protein. AVAILABILITY: Programs were developed under the UNIX operating system and are available by anonymous ftp from ftp://beagle.colorado.edu/pub/consensus.
MEGA2: molecular evolutionary genetics analysis software
Authors: Kumar Sudhir , Tamura Koichiro , Jakobsen Ingrid B. , Nei Masatoshi
Published: July 2002

Summary: We have developed a new software package, Molecular Evolutionary Genetics Analysis version 2 (MEGA2), for exploring and analyzing aligned DNA or protein sequences from an evolutionary perspective. MEGA2 vastly extends the capabilities of MEGA version 1 by: (1) facilitating analyses of large datasets; (2) enabling creation and analyses of groups of sequences; (3) enabling specification of domains and genes; (4) expanding the repertoire of statistical methods for molecular evolutionary studies; and (5) adding new modules for visual representation of input data and output results on the Microsoft Windows platform.

Availability: http://www.megasoftware.net.

Contact: s.kumar@asu.edu

* To whom correspondence should be addressed.
GRIMM: genome rearrangements web server
Authors: Tesler Glenn
Published: July 2002

Summary: Genome Rearrangements In Man and Mouse (GRIMM) is a tool for analyzing rearrangements of gene orders in pairs of unichromosomal and multichromosomal genomes, with either signed or unsigned gene data. Although there are several programs for analyzing rearrangements in unichromosomal genomes, this is the first to analyze rearrangements in multichromosomal genomes. GRIMM also provides a new algorithm for analyzing comparative maps for which gene directions are unknown.

Availability: A web server, with instructions and sample data, is available at http://www-cse.ucsd.edu/groups/bioinformatics/GRIMM.

Contact: gptesler@ucsd.edu
Regulation of mitochondrial D‐loops by transcription factor A and single‐stranded DNA‐binding protein
Authors: Takamatsu Chihiro , Umeda Shuyo , Ohsato Takashi , Ohno Tetsuji , Abe Yoshito , Fukuoh Atsushi , Shinagawa Hideo , Hamasaki Naotaka , Kang Dongchon
Published: July 2002

During replication, mitochondrial DNA (mtDNA) takes on a triple‐stranded structure called a D‐loop. Although their physiological roles are not understood, D‐loops are implicated in replication and transcription of mtDNA. Little is known about the turnover of D‐loops. We investigated the effects of mitochondrial transcription factor A (TFAM) and single‐stranded DNA‐binding protein (mtSSB) on D‐loops. In human HeLa cells, TFAM and mtSSB are, respectively, 1700‐ and 3000‐fold more abundant than mtDNA. This level of TFAM is two orders of magnitude higher than reported previously and is sufficient to wrap human mtDNA entirely. TFAM resolves D‐loops in vitro if added in similar stoichiometries. mtSSB inhibits the resolution of mtDNA by TFAM but enhances resolution by RecG, a junction‐specific helicase from Escherichia coli. Hence, mtSSB functions in both stabilization and resolution. We propose that TFAM and mtSSB are cooperatively involved in stabilizing D‐loops and in the maintenance of mtDNA.
Magma Origin and Evolution of White Island (Whakaari) Volcano, Bay of Plenty, New Zealand
Authors: COLE J. W. , THORDARSON T. , BURT R. M.
Published: July 2002

White Island is an active composite stratovolcano in the Bay of Plenty, New Zealand, that comprises many small volume (<0·1 km3) andesite–dacite lava flows and pyroclastic deposits with phenocryst contents of ∼15–44%. Minor high-Mg basaltic andesite explosive eruptions, such as those of 1976–1992, may have occurred at intervals throughout the history of White Island, but are rarely preserved. These alternate with major episodes of andesite–dacite lava extrusion. The high-Mg magmas form by hydrous melting of mantle, metasomatized by fluids from the dehydrating slab at the slab–mantle wedge interface, that rise rapidly to shallow magma chambers (2–7 km?) where limited mixing and contamination occurs before eruption. Some of this magma remains in the magma chamber where it interacts with the crystal mush, from which it inherits phenocrysts, to form so-called ‘dirty’ lavas. Total phenocryst content of these lavas is correspondingly higher. As more magma is intruded into the chamber, the heat flux will increase and melt fraction will eventually rise to the surface to form high-silica andesite–dacite magma (‘clean’ lavas) with fewer inherited phenocrysts. Similar multi-magma chamber plumbing systems, with complex evolution involving fractionation and contamination, probably occur in most andesite–dacite arc volcanoes.
Palaeogene Continental to Oceanic Magmatism on the SE Greenland Continental Margin at 63°N: a Review of the Results of Ocean Drilling Program Legs 152 and 163
Authors: FITTON J. G. , LARSEN L. M. , SAUNDERS A. D. , HARDARSON B. S. , KEMPTON P. D.
Published: July 2002

Drilling along a 63°N transect off SE Greenland during Ocean Drilling Program (ODP) Legs 152 and 163 recovered a succession of volcanic rocks representing all stages in the break-up of the volcanic rifted margin. The rocks range from pre-break-up continental tholeiitic flood basalt, through syn-break-up picrite, to truly oceanic basalt forming the main part of the seaward-dipping reflector sequence (SDRS). All the lava flows recovered from the transect were erupted in a subaerial environment. 40Ar–39Ar dating shows that the earliest magmas were erupted at ∼61 Ma and has confirmed that the main part of the SDRS was erupted during C24r (56–53 Ma) following continental break-up. Magma represented by the pre-break-up lava flows was stored in crustal reservoirs where it evolved by fractional crystallization and assimilation of continental crust. Trace element and radiogenic isotope data show that the contaminant changed, through time, from lower-crustal granulite to a mixture of granulite and amphibolite, suggesting storage of magma at progressively shallower levels in the crust. The degree of contamination declined rapidly as break-up proceeded, and the youngest rocks sampled in the transect are uncontaminated by continental basement. Variation of, for example, Sc/Zr and Sm/Lu through the succession suggests a shallowing of the top of the mantle melting zone, accompanied by an increase in the average degree of melting with time from ∼4% to ∼12%. These modest degrees of melting imply mantle temperatures only ∼100°C hotter than normal upper mantle. Upwelling mantle must therefore have been fed dynamically to the melt zone to generate the igneous crust of 18 km thickness deduced from seismic and gravity studies. N-MORB-like magmas dominated the earliest part of the succession although a few flows of ‘Icelandic’ basalt were erupted in the pre-break-up phase. In contrast, the post-break-up magmas had an Icelandic mantle source. This suggests that the developing head of the ancestral Iceland plume was compositionally zoned, with a core of Icelandic mantle surrounded by a thick outer zone of hot, depleted upper mantle.
Long-Term Effectiveness of a Peer-Based Intervention to Promote Condom and Contraceptive Use among HIV-Positive and at-Risk Women
Authors: Fogarty Linda A. , Heilig Charles M. , Armstrong Kay , Cabral Rebecca , Galavotti Christine , Gielen Andrea C. , Green Brian M.
Published: July 2002

Objective.

The authors used data from a larger study to evaluate the long-term effects of a peer advocate intervention on condom and contraceptive use among HIV-infected women and women at high risk for HIV infection.

Methods.

HIV-infected women in one study and women at high risk for HIV infection in a second study were selected from the Women and Infants Demonstration Project and assigned to a standard or an enhanced HIV prevention treatment group. The enhanced intervention included support groups and one-on-one contacts with peer advocates tailored to clients' needs. The authors interviewed women at baseline and at 6-, 12- and 18-months, and measured changes in consistency of condom and contraceptive use and in self-efficacy and perceived advantages and disadvantages of condom and contraceptive use.

Results.

Of HIV-infected women, the enhanced group had improved consistency in condom use, increased perceived advantages of condom use, and increased level of self-efficacy compared with the standard group. Of women at risk, the enhanced intervention group at six months maintained consistent condom use with a main partner and perceived more benefit of condom use compared with the standard group. These differences diminished at 12 months.

Conclusions.

The enhanced intervention was generally effective in the HIV+ study. In the at-risk study, however, intervention effects were minimal and short-lived. Factors related to the theory, intervention design, and sample characteristics help explain these differences.
A Venue-Based Method for Sampling Hard-to-Reach Populations
Authors: Muhib Farzana B. , Lin Lillian S. , Stueve Ann , Miller Robin L. , Ford Wesley L. , Johnson Wayne D. , Smith Philip J. ,   Community Intervention Trial for Youth Study Team
Published: July 2002

Constructing scientifically sound samples of hard-to-reach populations, also known as hidden populations, is a challenge for many research projects. Traditional sample survey methods, such as random sampling from telephone or mailing lists, can yield low numbers of eligible respondents while non-probability sampling introduces unknown biases.

The authors describe a venue-based application of time-space sampling (TSS) that addresses the challenges of accessing hard-to-reach populations. The method entails identifying days and times when the target population gathers at specific venues, constructing a sampling frame of venue, day-time units (VDTs), randomly selecting and visiting VDTs (the primary sampling units), and systematically intercepting and collecting information from consenting members of the target population. This allows researchers to construct a sample with known properties, make statistical inference to the larger population of venue visitors, and theorize about the introduction of biases that may limit generalization of results to the target population.

The authors describe their use of TSS in the ongoing Community Intervention Trial for Youth (CITY) project to generate a systematic sample of young men who have sex with men. The project is an ongoing community level HIV prevention intervention trial funded by the Centers for Disease Control and Prevention.

The TSS method is reproducible and can be adapted to hard-to-reach populations in other situations, environments, and cultures.
The carbon cycle and carbon dioxide over Phanerozoic time: the role of land plants
Authors: Berner Robert A.
Published: July 2002

A model (GEOCARB) of the long–term, or multimillion year, carbon cycle has been constructed which includes quantitative treatment of (1) uptake of atmospheric CO
2
by the weathering of silicate and carbonate rocks on the continents, and the deposition of carbonate minerals and organic matter in oceanic sediments; and (2) the release of CO
2
to the atmosphere via the weathering of kerogen in sedimentary rocks and degassing resulting from the volcanic–metamorphic–diagenetic breakdown of carbonates and organic matter at depth.

Sensitivity analysis indicates that an important factor affecting CO
2
was the rise of vascular plants in the Palaeozoic. A large Devonian drop in CO
2
was brought about primarily by the acceleration of weathering of silicate rock by the development of deeply rooted plants in well–drained upland soils. The quantitative effect of this accelerated weathering has been crudely estimated by present–day field studies where all factors affecting weathering, other than the presence or absence of vascular plants, have been held relatively constant. An important additional factor, bringing about a further CO
2
drop into the Carboniferous and Permian, was enhanced burial of organic matter in sediments, due probably to the production of microbially resistant plant remains (e.g. lignin).

Phanerozoic palaeolevels of atmospheric CO
2
calculated from the GEOCARB model generally agree with independent estimates based on measurements of the carbon isotopic composition of palaeosols and the stomatal index for fossil plants. Correlation of CO
2
levels with estimates of palaeoclimate suggests that the atmospheric greenhouse effect has been a major factor in controlling global climate over the past 600 million years.
Terrestrial-marine teleconnections in the Devonian: links between the evolution of land plants, weathering processes, and marine anoxic events
Authors: Algeo Thomas J. , Scheckler Stephen E.
Published: July 2002

The Devonian Period was characterized by major changes in both the terrestrial biosphere, e.g. the evolution of trees and seed plants and the appearance of multi–storied forests, and in the marine biosphere, e.g. an extended biotic crisis that decimated tropical marine benthos, especially the stromatoporoid–tabulate coral reef community. Teleconnections between these terrestrial and marine events are poorly understood, but a key may lie in the role of soils as a geochemical interface between the lithosphere and atmosphere/hydrosphere, and the role of land plants in mediating weathering processes at this interface. The effectiveness of terrestrial floras in weathering was significantly enhanced as a consequence of increases in the size and geographic extent of vascular land plants during the Devonian. In this regard, the most important palaeobotanical innovations were (1) arborescence (tree stature), which increased maximum depths of root penetration and rhizoturbation, and (2) the seed habit, which freed land plants from reproductive dependence on moist lowland habitats and allowed colonization of drier upland and primary successional areas. These developments resulted in a transient intensification of pedogenesis (soil formation) and to large increases in the thickness and areal extent of soils. Enhanced chemical weathering may have led to increased riverine nutrient fluxes that promoted development of eutrophic conditions in epicontinental seaways, resulting in algal blooms, widespread bottomwater anoxia, and high sedimentary organic carbon fluxes. Long–term effects included drawdown of atmospheric pCO2and global cooling, leading to a brief Late Devonian glaciation, which set the stage for icehouse conditions during the Permo–Carboniferous. This model provides a framework for understanding links between early land plant evolution and coeval marine anoxic and biotic events, but further testing of Devonian terrestrial–marine teleconnections is needed.
Epidermal stem cells: markers, patterning and the control of stem cell fate
Authors: Watt Fiona M.
Published: July 2002

Within the epidermis, proliferation takes place in the basal layer of keratinocytes that are attached to an underlying basement membrane. Cells that leave the basal layer undergo terminal differentiation as they move towards the tissue surface. The basal layer contains two types of proliferative keratinocyte: stem cells, which have unlimited self–renewal capacity, and transit amplifying cells, those daughters of stem cells that are destined to withdraw from the cell cycle and terminally differentiate after a few rounds of division. Stem cells express higher levels of the β1–integrin family of extracellular matrix receptors than transit amplifying cells and this can be used to isolate each subpopulation of keratinocyte and to determine its location within the epidermis. Variation in the levels of E–cadherin, β–catenin and plakoglobin within the basal layer suggests that stem cells may also differ from transit amplifying cells in intercellular adhesiveness. Stem cells have a patterned distribution within the epidermal basal layer and patterning is subject to autoregulation. Constitutive expression of the transcription factor c–Myc promotes terminal differentiation by driving keratinocytes from the stem cell compartment into the transit amplifying compartment.
Why is mutual mate choice not the norm? Operational sex ratios, sex roles and the evolution of sexually dimorphic and monomorphic signalling
Authors: Kokko H. , Johnstone R. A.
Published: July 2002

Biases in the operational sex ratio (OSR) are seen as the fundamental reason behind differential competition for mates in the two sexes, and as a strong determinant behind differences in choosiness. This view has been challenged by Kokko and Monaghan, who argue that sex–specific parental investment, mortalities, mate–encounter rates and quality variation determine the mating system in a way that is not reducible to the OSR. We develop a game–theoretic model of choosiness, signalling and parental care, to examine (i) whether the results of Kokko and Monaghan remain robust when its simplifying assumptions are relaxed, (ii) how parental care coevolves with mating strategies and the OSR and (iii) why mutual mate choice is observed relatively rarely even when both sexes vary in quality. We find qualitative agreement with the simpler approach: parental investment is the primary determinant of sex roles instead of the OSR, and factors promoting choosiness are high species–specific mate–encounter rate, high sex–specific mate–encounter rate, high cost of breeding (parental investment), low cost of mate searching and highly variable quality of the opposite sex. The coevolution of parental care and mating strategies hinders mutual mate choice if one parent can compensate for reduced care by the other, but promotes it if offspring survival depends greatly on biparental care. We argue that the relative rarity of mutual mate choice is not due to biases in the OSR. Instead, we describe processes by which sexual strategies tend to diverge. This divergence is prevented, and mutual mate choice maintained, if synergistic benefits of biparental care render parental investment both high and not too different in the two sexes.
An overlapping-feature-based phonological model incorporating linguistic constraints: Applications to speech recognition
Authors: Sun Jiping , Deng Li
Published: July 2002

Modeling phonological units of speech is a critical issue in speech recognition. In this paper, our recent development of an overlapping-feature-based phonological model that represents long-span contextual dependency in speech acoustics is reported. In this model, high-level linguistic constraints are incorporated in automatic construction of the patterns of feature-overlapping and of the hidden Markov model (HMM) states induced by such patterns. The main linguistic information explored includes word and phrase boundaries, morpheme, syllable, syllable constituent categories, and word stress. A consistent computational framework developed for the construction of the feature-based model and the major components of the model are described. Experimental results on the use of the overlapping-feature model in an HMM-based system for speech recognition show improvements over the conventional triphone-based phonological model.