bluuebunny/crossref_metadata_2025 huggingface dataset:
CEACAM1-4S, a cell–cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture
Authors: Kirshner Julia , Chen Charng-Jui , Liu Pingfang , Huang Jie , Shively John E.
Published: January 2003

In a 3D model of breast morphogenesis, CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) plays an essential role in lumen formation in a subline of the nonmalignant human breast cell line (MCF10A). We show that mammary carcinoma cells (MCF7), which do not express CEACAM1 or form lumena when grown in Matrigel, are restored to a normal morphogenic program when transfected with CEACAM1-4S, the short cytoplasmic isoform of CEACAM1 that predominates in breast epithelia. During the time course of lumen formation, CEACAM1-4S was found initially between the cells, and in mature acini, it was found exclusively in an apical location, identical to its expression pattern in normal breast. Lumena were formed by apoptosis as opposed to necrosis of the central cells within the alveolar structures, and apoptotic cells within the lumena expressed CEACAM1-4S. Dying cells exhibited classical hallmarks of apoptosis, including nuclear condensation, membrane blebbing, caspase activation, and DNA laddering. Apoptosis was mediated by Bax translocation to the mitochondria and release of cytochrome
c
into the cytoplasm, and was partially inhibited by culturing cells with caspase inhibitors. The dynamic changes in CEACAM1 expression during morphogenesis, together with studies implicating extracellular matrix and integrin signaling, suggest that a morphogenic program integrates cell–cell and cell–extracellular matrix signaling to produce the lumena in mammary glands. This report reveals a function of CEACAM1-4S relevant to cellular physiology that distinguishes it from its related long cytoplasmic domain isoform.
Identification of a gene causing human cytochrome
c
oxidase deficiency by integrative genomics
Authors: Mootha Vamsi K. , Lepage Pierre , Miller Kathleen , Bunkenborg Jakob , Reich Michael , Hjerrild Majbrit , Delmonte Terrye , Villeneuve Amelie , Sladek Robert , Xu Fenghao , Mitchell Grant A. , Morin Charles , Mann Matthias , Hudson Thomas J. , Robinson Brian , Rioux John D. , Lander Eric S.
Published: January 2003

Identifying the genes responsible for human diseases requires combining information about gene position with clues about biological function. The recent availability of whole-genome data sets of RNA and protein expression provides powerful new sources of functional insight. Here we illustrate how such data sets can expedite disease-gene discovery, by using them to identify the gene causing Leigh syndrome, French-Canadian type (LSFC, Online Mendelian Inheritance in Man no. 220111), a human cytochrome
c
oxidase deficiency that maps to chromosome 2p16-21. Using four public RNA expression data sets, we assigned to all human genes a “score” reflecting their similarity in RNA-expression profiles to known mitochondrial genes. Using a large survey of organellar proteomics, we similarly classified human genes according to the likelihood of their protein product being associated with the mitochondrion. By intersecting this information with the relevant genomic region, we identified a single clear candidate gene,
LRPPRC
. Resequencing identified two mutations on two independent haplotypes, providing definitive genetic proof that
LRPPRC
indeed causes LSFC.
LRPPRC
encodes an mRNA-binding protein likely involved with mtDNA transcript processing, suggesting an additional mechanism of mitochondrial pathophysiology. Similar strategies to integrate diverse genomic information can be applied likewise to other disease pathways and will become increasingly powerful with the growing wealth of diverse, functional genomics data.
Mission Impossible? Communicating and Sharing Knowledge via Information Technology
Authors: Hislop Donald
Published: January 2003

This paper critiques the perspective that information technology can play a central role in knowledge-sharing processes. Fundamentally, it suggests that the nature of knowledge itself makes it extremely difficult and that quite specific conditions are required for information technology-based knowledge sharing to occur successfully. The paper proceeds by criticizing the objectivist philosophy of knowledge, which typically underpins the literature advocating information technology-based knowledge management. The centre point of this critique involves questioning one of the foundational assumptions of the objectivist perspective, namely the dichotomy made between tacit and explicit knowledge. Instead, a ‘practice‘-based philosophy of knowledge is proposed that suggests that all knowledge has both tacit and explicit components, is to some extent embodied in human brains and bodies and is embedded in organizational routines, practices and contexts. These characteristics therefore suggest that the role of information technology systems in the sharing of knowledge is likely to be somewhat limited.
Managing Risk in a New Telecommunications Service Development Process through a Scenario Planning Approach
Authors: Ahn Jae-Hyeon , Skudlark Ann
Published: January 2003

Managing risk in a new product and service development process is one of the major challenges for many business managers. A scenario planning approach was incorporated into a new telecommunications service development process in order to understand the uncertainties shaping the future economic, business and technological environments. Understanding the major drivers for uncertainties helped in gaining insight and thereby generated new strategies for reducing risks and taking advantage of opportunities from uncertainty. In order to demonstrate the process and value of the approach, it was applied to a new telecommunications service concept, the Phoneweb service, which allows Internet access through telephones rather than a computer interface.
Examining the Effects of Information Technology on Control and Coordination Relationships: An Exploratory Study in Subsidiaries of Pan-National Corporations
Authors: Finnegan Pat , Longaigh Sinead Ni
Published: January 2003

The pan-national corporation, with its inherently complex structure, is the organizational form most severely affected by globalization. It is therefore important for the management of such corporations to improve the control and coordination of the corporations’ spatially dispersed subsidiaries. Information technology (IT) has been hailed as an important tool in changing traditional control and coordination processes in complex environments. This paper presents the results of a study that examined the role of IT in the control and coordination of pan-national corporation subsidiaries in Ireland. The findings indicate that IT is being used for changing the nature of the relationship between headquarters and subsidiaries in a manner that makes the pan-national corporation more global in orientation. This is occurring as operations and decision-making processes in subsidiaries are redesigned in order to improve global management and local responsiveness.
Tenascin-C signaling through induction of 14-3-3 tau
Authors: Martin Doris , Brown-Luedi Marianne , Chiquet-Ehrismann Ruth
Published: January 2003

We searched by a cDNA subtraction screen for differentially expressed transcripts in MCF-7 mammary carcinoma cells grown on tenascin-C versus fibronectin. On tenascin-C, cells had irregular shapes with many processes, whereas on fibronectin they were flat with a cobble stone–like appearance. We found elevated levels of 14-3-3 tau transcripts and protein in cells grown on tenascin-C. To investigate the consequences of an increased level of this phospho-serine/threonine–binding adaptor protein, we transfected MCF-7 cells with a construct encoding full-length 14-3-3 tau protein and selected clones with the highest expression levels. The morphology of these cells on tenascin-C was flat, resembling that of cells on fibronectin. This was reflected by a similar pattern of F-actin staining on either substratum. Furthermore, the growth rate on tenascin-C was increased compared with the parental cells. After transient transfection of HT1080 fibrosarcoma and T98G glioblastoma cells with 14-3-3 tau, only the 14-3-3 tau–expressing cells were able to adhere and survive on tenascin-C, whereas all cells adhered well on fibronectin. Therefore, we postulate that tenascin-C promotes the growth of tumor cells by causing an increase in the expression of 14-3-3 tau, which in turn has a positive effect on tumor cell adhesion and growth.
Spatio-temporal activation of caspase revealed by indicator that is insensitive to environmental effects
Authors: Takemoto Kiwamu , Nagai Takeharu , Miyawaki Atsushi , Miura Masayuki
Published: January 2003

Indicator molecules for caspase-3 activation have been reported that use fluorescence resonance energy transfer (FRET) between an enhanced cyan fluorescent protein (the donor) and enhanced yellow fluorescent protein (EYFP; the acceptor). Because EYFP is highly sensitive to proton (H+) and chloride ion (Cl−) levels, which can change during apoptosis, this indicator's ability to trace the precise dynamics of caspase activation is limited, especially in vivo. Here, we generated an H+- and Cl−-insensitive indicator for caspase activation, SCAT, in which EYFP was replaced with Venus, and monitored the spatio-temporal activation of caspases in living cells. Caspase-3 activation was initiated first in the cytosol and then in the nucleus, and rapidly reached maximum activation in 10 min or less. Furthermore, the nuclear activation of caspase-3 preceded the nuclear apoptotic morphological changes. In contrast, the completion of caspase-9 activation took much longer and its activation was attenuated in the nucleus. However, the time between the initiation of caspase-9 activation and the morphological changes was quite similar to that seen for caspase-3, indicating the activation of both caspases occurred essentially simultaneously during the initiation of apoptosis.
EpsinR
Authors: Mills Ian G. , Praefcke Gerrit J.K. , Vallis Yvonne , Peter Brian J. , Olesen Lene E. , Gallop Jennifer L. , Butler P. Jonathan G. , Evans Philip R. , McMahon Harvey T.
Published: January 2003

EpsinR is a clathrin-coated vesicle (CCV) enriched 70-kD protein that binds to phosphatidylinositol-4-phosphate, clathrin, and the gamma appendage domain of the adaptor protein complex 1 (AP1). In cells, its distribution overlaps with the perinuclear pool of clathrin and AP1 adaptors. Overexpression disrupts the CCV-dependent trafficking of cathepsin D from the trans-Golgi network to lysosomes and the incorporation of mannose-6-phosphate receptors into CCVs. These biochemical and cell biological data point to a role for epsinR in AP1/clathrin budding events in the cell, just as epsin1 is involved in the budding of AP2 CCVs. Furthermore, we show that two gamma appendage domains can simultaneously bind to epsinR with affinities of 0.7 and 45 μM, respectively. Thus, potentially, two AP1 complexes can bind to one epsinR. This high affinity binding allowed us to identify a consensus binding motif of the form DFxDF, which we also find in γ-synergin and use to predict that an uncharacterized EF-hand–containing protein will be a new gamma binding partner.
Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles
Authors: Bagnato Paola , Barone Virigina , Giacomello Emiliana , Rossi Daniela , Sorrentino Vincenzo
Published: January 2003

Assembly of specialized membrane domains, both of the plasma membrane and of the ER, is necessary for the physiological activity of striated muscle cells. The mechanisms that mediate the structural organization of the sarcoplasmic reticulum with respect to the myofibrils are, however, not known. We report here that ank1.5, a small splice variant of the ank1 gene localized on the sarcoplasmic reticulum membrane, is capable of interacting with a sequence of 25 aa located at the COOH terminus of obscurin. Obscurin is a giant sarcomeric protein of ∼800 kD that binds to titin and has been proposed to mediate interactions between myofibrils and other cellular structures. The binding sites and the critical aa required in the interaction between ank1.5 and obscurin were characterized using the yeast two-hybrid system, in in vitro pull-down assays and in experiments in heterologous cells. In differentiated skeletal muscle cells, a transfected myc-tagged ank1.5 was found to be selectively restricted near the M line region where it colocalized with endogenous obscurin. The M line localization of ank1.5 required a functional obscurin-binding site, because mutations of this domain resulted in a diffused distribution of the mutant ank1.5 protein in skeletal muscle cells. The interaction between ank1.5 and obscurin represents the first direct evidence of two proteins that may provide a direct link between the sarcoplasmic reticulum and myofibrils.

In keeping with the proposed role of obscurin in mediating an interaction with ankyrins and sarcoplasmic reticulum, we have also found that a sequence with homology to the obscurin-binding site of ank1.5 is present in the ank2.2 isoform, which in striated muscles has been also shown to associate with the sarcoplasmic reticulum. Accordingly, a peptide containing the COOH terminus of ank2.2 fused with GST was found to bind to obscurin. Based on reported evidence showing that the COOH terminus of ank2.2 is necessary for the localization of ryanodine receptors and InsP3 receptors in the sarcoplasmic reticulum, we propose that obscurin, through multiple interactions with ank1.5 and ank2.2 isoforms, may assemble a large protein complex that, in addition to a structural function, may play a role in the organization of specific subdomains in the sarcoplasmic reticulum.
HA95 and LAP2β mediate a novel chromatin–nuclear envelope interaction implicated in initiation of DNA replication
Authors: Martins Sandra , Eikvar Sissel , Furukawa Kazuhiro , Collas Philippe
Published: January 2003

HA95 is a chromatin-associated protein that interfaces the nuclear envelope (NE) and chromatin. We report an interaction between HA95 and the inner nuclear membrane protein lamina-associated polypeptide (LAP) 2β, and a role of this association in initiation of DNA replication. Precipitation of GST–LAP2β fusion proteins and overlays of immobilized HA95 indicate that a first HA95-binding region lies within amino acids 137–242 of LAP2β. A second domain sufficient to bind HA95 colocalizes with the lamin B–binding domain of LAP2β at residues 299–373. HA95–LAP2β interaction is not required for NE formation. However, disruption of the association of HA95 with the NH2-terminal HA95-binding domain of LAP2β abolishes the initiation, but not elongation, of DNA replication in purified G1 phase nuclei incubated in S-phase extract. Inhibition of replication initiation correlates with proteasome-mediated proteolysis of Cdc6, a component of the prereplication complex. Rescue of Cdc6 degradation with proteasome inhibitors restores replication. We propose that an interaction of LAP2β, or LAP2 proteins, with HA95 is involved in the control of initiation of DNA replication.
A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death
Authors: Trapani Joseph A. , Sutton Vivien R. , Thia Kevin Y.T. , Li Yu Qin , Froelich Christopher J. , Jans David A. , Sandrin Mauro S. , Browne Kylie A.
Published: January 2003

The 280-kD cation-independent mannose-6-phosphate receptor (MPR) has been shown to play a role in endocytic uptake of granzyme B, since target cells overexpressing MPR have an increased sensitivity to granzyme B–mediated apoptosis. On this basis, it has been proposed that cells lacking MPR are poor targets for cytotoxic lymphocytes that mediate allograft rejection or tumor immune surveillance. In the present study, we report that the uptake of granzyme B into target cells is independent of MPR. We used HeLa cells overexpressing a dominant-negative mutated (K44A) form of dynamin and mouse fibroblasts overexpressing or lacking MPR to show that the MPR/clathrin/dynamin pathway is not required for granzyme B uptake. Consistent with this observation, cells lacking the MPR/clathrin pathway remained sensitive to granzyme B. Exposure of K44A-dynamin–overexpressing and wild-type HeLa cells to granzyme B with sublytic perforin resulted in similar apoptosis in the two cell populations, both in short and long term assays. Granzyme B uptake into MPR-overexpressing L cells was more rapid than into MPR-null L cells, but the receptor-deficient cells took up granzyme B through fluid phase micropinocytosis and remained sensitive to it. Contrary to previous findings, we also demonstrated that mouse tumor allografts that lack MPR expression were rejected as rapidly as tumors that overexpress MPR. Entry of granzyme B into target cells and its intracellular trafficking to induce target cell death in the presence of perforin are therefore not critically dependent on MPR or clathrin/dynamin-dependent endocytosis.
Prospective Estimation of Recombination Signal Efficiency and Identification of Functional Cryptic Signals in the Genome by Statistical Modeling
Authors: Cowell Lindsay G. , Davila Marco , Yang Kaiyong , Kepler Thomas B. , Kelsoe Garnett
Published: January 2003

The recombination signals (RS) that guide V(D)J recombination are phylogenetically conserved but retain a surprising degree of sequence variability, especially in the nonamer and spacer. To characterize RS variability, we computed the position-wise information, a measure correlated with sequence conservation, for each nucleotide position in an RS alignment and demonstrate that most position-wise information is present in the RS heptamers and nonamers. We have previously demonstrated significant correlations between RS positions and here show that statistical models of the correlation structure that underlies RS variability efficiently identify physiologic and cryptic RS and accurately predict the recombination efficiencies of natural and synthetic RS. In scans of mouse and human genomes, these models identify a highly conserved family of repetitive DNA as an unexpected source of frequent, cryptic RS that rearrange both in extrachromosomal substrates and in their genomic context.
Expression of ICOS In Vivo Defines CD4+ Effector T Cells with High Inflammatory Potential and a Strong Bias for Secretion of Interleukin 10
Authors: Löhning Max , Hutloff Andreas , Kallinich Tilmann , Mages Hans Werner , Bonhagen Kerstin , Radbruch Andreas , Hamelmann Eckard , Kroczek Richard A.
Published: January 2003

The studies performed to date analyzed the overall participation of the inducible costimulator (ICOS) in model diseases, but did not yield information on the nature and function of ICOS-expressing T cells in vivo. We examined ICOS+ T cells in the secondary lymphoid organs of nonmanipulated mice, in the context of an “unbiased” immune system shaped by environmental antigens. Using single cell analysis, ICOSlow cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-γ. ICOSmedium cells, the large majority of ICOS+ T cells in vivo, were very tightly associated with the synthesis of the T helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatory effects in vivo. In contrast, ICOShigh T cells were highly and selectively linked to the anti-inflammatory cytokine IL-10. Overall, these data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties. Further in vivo functional experiments with in vitro–activated T cells strongly suggested that the ICOS+ population, although representing in vivo only around 10% of T cells bearing early or late activation markers, nevertheless encompasses virtually all effector T cells, a finding with major diagnostic and therapeutic implications.
Malaria Blood Stage Suppression of Liver Stage Immunity by Dendritic Cells
Authors: Ocaña-Morgner Carlos , Mota Maria M. , Rodriguez Ana
Published: January 2003

Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.
DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells
Authors: Chan Huei-Wei , Kurago Zoya B. , Stewart C. Andrew , Wilson Michael J. , Martin Maureen P. , Mace Brian E. , Carrington Mary , Trowsdale John , Lutz Charles T.
Published: January 2003

Killer immunoglobulin-like receptors (KIR) bind self–major histocompatibility complex class I molecules, allowing natural killer (NK) cells to recognize aberrant cells that have down-regulated class I. NK cells express variable numbers and combinations of highly homologous clonally restricted KIR genes, but uniformly express KIR2DL4. We show that NK clones express both 2DL4 alleles and either one or both alleles of the clonally restricted KIR 3DL1 and 3DL2 genes. Despite allele-independent expression, 3DL1 alleles differed in the core promoter by only one or two nucleotides. Allele-specific 3DL1 gene expression correlated with promoter and 5′ gene DNA hypomethylation in NK cells in vitro and in vivo. The DNA methylase inhibitor, 5-aza-2′-deoxycytidine, induced KIR DNA hypomethylation and heterogeneous expression of multiple KIR genes. Thus, NK cells use DNA methylation to maintain clonally restricted expression of highly homologous KIR genes and alleles.
T Cell Accumulation in B Cell Follicles Is Regulated by Dendritic Cells and Is Independent of B Cell Activation
Authors: Fillatreau Simon , Gray David
Published: January 2003

We investigated the mechanism of CD4 T cell accumulation in B cell follicles after immunization. Follicular T cell numbers were correlated with the number of B cells, indicating B cell control of the niche that T cells occupy. Despite this, we found no role for B cells in the follicular migration of T cells. Instead, T cells are induced to migrate into B cell follicles entirely as a result of interaction with dendritic cells (DCs). Migration relies on CD40-dependent maturation of DCs, as it did not occur in CD40-deficient mice but was reconstituted with CD40+ DCs. Restoration was not achieved by the activation of DCs with bacterial activators (e.g., lipopolysaccharide, CpG), but was by the injection of OX40L–huIgG1 fusion protein. Crucially, the up-regulation of OX40L (on antigen-presenting cells) and CXCR-5 (on T cells) are CD40-dependent events and we show that T cells do not migrate to follicles in immunized OX40-deficient mice.
Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4
Authors: Burns Kimberly , Janssens Sophie , Brissoni Brian , Olivos Natalia , Beyaert Rudi , Tschopp Jürg
Published: January 2003

Toll-like receptors (TLRs) and members of the proinflammatory interleukin 1 receptor (IL-1R) family are dependent on the presence of MyD88 for efficient signal transduction. The bipartite nature of MyD88 (N-terminal death domain [DD] and COOH-terminal Toll/IL-1 receptor [TIR] domain) allows it to link the TIR domain of IL-1R/TLR with the DD of the Ser/Thr kinase termed IL-1R–associated kinase (IRAK)-1. This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-κB. In contrast, expression of MyD88 short (MyD88s), an alternatively spliced form of MyD88 that lacks only the short intermediate domain separating the DD and TIR domains, leads to a shutdown of IL-1/lipopolysaccharide-induced NF-κB activation. Here, we provide the molecular explanation for this difference. MyD88 but not MyD88s strongly interacts with IRAK-4, a newly identified kinase essential for IL-1R/TLR signaling. In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-κB nor is ubiquitinated. Thus, MyD88s acts as a negative regulator of IL-1R/TLR/MyD88-triggered signals, leading to a transcriptionally controlled negative regulation of innate immune responses.
Joyce's Argument for Probabilism
Authors: Maher Patrick
Published: January 2003

James Joyce's ‘Nonpragmatic Vindication of Probabilism’ gives a new argument for the conclusion that a person's credences ought to satisfy the laws of probability. The premises of Joyce's argument include six axioms about what counts as an adequate measure of the distance of a credence function from the truth. This paper shows that (a) Joyce's argument for one of these axioms is invalid, (b) his argument for another axiom has a false premise, (c) neither axiom is plausible, and (d) without these implausible axioms Joyce's vindication of probabilism fails.
Interpreting Quantum Field Theory
Authors: Ruetsche Laura
Published: January 2003

The availability of unitarily inequivalent representations of the canonical commutation relations constituting a quantization of a classical field theory raises questions about how to formulate and pursue quantum field theory. In a minimally technical way, I explain how these questions arise and how advocates of the Hilbert space and of the algebraic approaches to quantum theory might answer them. Where these answers differ, I sketch considerations for and against each approach, as well as considerations which might temper their apparent rivalry.
In the Theater of Counterrevolution: Loyalist Association and Conservative Opinion in the 1790s
Authors: Gilmartin Kevin
Published: January 2003

Conservative movements have generally played a negative role in accounts of the history of political expression in Britain during the period of the French Revolution. Where E. P. Thompson and others on the Left tended to identify radicalism with the disenfranchised and with a struggle for the rights of free expression and public assembly, conservative activists have been associated with state campaigns of political repression and legal interference. Indeed, conservatism in this period is typically conceived in negative terms, as antiradicalism or counterrevolution. If this has been the view of hostile commentators, it is consistent with a more sympathetic mythology that sees nothing novel about the conservative principles that emerged in late eighteenth- and early nineteenth-century Britain. They represent an establishment response to alien challenges. Even where conservatives set about mobilizing the resources of print, opinion, and assembly in a constructive fashion, the reputation for interference has endured. John Reeves's Association for Preserving Liberty and Property against Republicans and Levellers is a useful case in point, since it managed in its brief but enterprising history to combine fierce anti-Jacobinism with the later eighteenth century's rising tide of voluntary civic activism. The association came together at the Crown and Anchor Tavern when a group of self-professed “private men” decided “to form ourselves into an Association” and announced their intentions through the major London newspapers in November and December of 1792. The original committee then called on others “to make similar exertions in their respective neighbourhoods,” forming energetic local associations that would be linked by regular correspondence with the central London committee. In this way, the loyalist movement grew with astonishing speed.
Bones of Contention: The Repatriation of the Remains of Roger Casement
Authors: Grant Kevin
Published: January 2003

This is a history of life after death—not the life of a disembodied soul, but of the body left behind in a prison yard, buried in quicklime. It is a history composed of family members, friends, politicians, and bureaucrats drawn into cooperation and conflict by the politics of rebellion, partition, and sexuality in Ireland and Great Britain. The deceased in dispute, Roger Casement, had been a controversial figure during the later years of his life, knighted by the British Crown in 1911 for his advocacy of humanitarian causes in Africa and South America and then hanged by the British government on 3 August 1916 for conspiring with Germany to mobilize and arm Irish separatists. Casement had requested that his body be buried at Murlough Bay, near his family's home in County Antrim in the province of Ulster. Instead, Casement's body was buried at Pentonville Prison in London, and for almost fifty years the British government rejected the appeals of Casement's family and supporters for the repatriation of his body to Ireland. In 1965, the body was finally exhumed and reinterred at Glasnevin Cemetery in Dublin, following a state funeral.

Why did the British government take over fifty years to disinter Casement's body from Pentonville, and why was his request to be buried at Murlough Bay not honored? In exploring the answers to these questions, I focus on negotiations between the British and Irish governments, and the terms of their final agreement over the present location of Casement's remains.
Aligning Multiple Research Techniques in Cognitive Neuroscience: Why Is It Important?
Authors: Bechtel William
Published: January 2003

The need to align multiple experimental procedures and produce converging results so as to demonstrate that the phenomenon under investigation is real and not an artifact is a commonplace both in scientific practice and discussions of scientific methodology (Campbell and Stanley 1963; Wimsatt 1981). Although sometimes this is the purpose of aligning techniques, often there is a different purpose—multiple techniques are sought to supply different perspectives on the phenomena under investigation that need to be integrated to answer the questions scientists are asking. After introducing this function, I will illustrate it by considering three of the major techniques in cognitive neuroscience for linking cognitive function with neural structure.
Model Selection, Simplicity, and Scientific Inference
Authors: Myrvold Wayne C. , Harper William L.
Published: January 2003

The Akaike Information Criterion can be a valuable tool of scientific inference. This statistic, or any other statistical method for that matter, cannot, however, be the whole of scientific methodology. In this paper some of the limitations of Akaikean statistical methods are discussed. It is argued that the full import of empirical evidence is realized only by adopting a richer ideal of empirical success than predictive accuracy, and that the ability of a theory to turn phenomena into accurate, agreeing measurements of causally relevant parameters contributes to the evidential support of the theory. This is illustrated by Newton's argument from orbital phenomena to the inverse-square law of gravitation.
A Rate of Incoherence Applied to Fixed-Level Testing
Authors: Schervish Mark J. , Seidenfeld Teddy , Kadane Joseph B.
Published: January 2003

It has long been known that the practice of testing all hypotheses at the same level (such as 0.05), regardless of the distribution of the data, is not consistent with Bayesian expected utility maximization. According to de Finetti's “Dutch Book” argument, procedures that are not consistent with expected utility maximization are incoherent and they lead to gambles that are sure to lose no matter what happens. In this paper, we use a method to measure the rate at which incoherent procedures are sure to lose, so that we can distinguish slightly incoherent procedures from grossly incoherent ones. We present an analysis of testing a simple hypothesis against a simple alternative as a case-study of how the method can work.
Some Foundational Problems in the Scientific Study of Pain
Authors: Aydede Murat , Güzeldere Güven
Published: January 2003

This paper is an attempt to spell out what makes the scientific study of pain so distinctive from a philosophical perspective. Using the IASP definition of ‘pain’ (1986) as our guide, we raise a number of questions about the philosophical assumptions underlying the scientific study of pain. We argue that unlike the study of ordinary perception, the study of pain focuses from the very start on the experience itself and its qualities, without making deep assumptions about whether pain experiences are perceptual. This in turn puts scientific explanation in a curious position due to pain's inherently subjective epistemic nature. The reason for this focus on the experience itself and its qualities, we argue, has to do with pain's complex phenomenology involving an affective/motivational dimension. We argue for the scientific legitimacy of first-person phenomenological studies and attempts to correlate phenomenology with neural events. We argue that this methodological procedure is inevitable and has no anti-physicalist ontological implications when properly understood. We end the paper by commenting on a discussion between two prominent pain scientists in the field, Don Price and Howard Fields, about the need to distinguish more dimensions in the phenomenology of pain and how to classify them vis-à-vis the recent scientific findings. Our interest in this discussion is not only to introduce some clarifications but also to show how “neurophenomenology” has already been shaping the scientific research and to back our claim about why this methodology is inevitable with an example.
What Evidence in Evidence-Based Medicine?
Authors: Worrall John
Published: January 2003

Evidence-Based Medicine is a relatively new movement that seeks to put clinical medicine on a firmer scientific footing. I take it as uncontroversial that medical practice should be based on best evidence—the interesting questions concern the details. This paper tries to move towards a coherent and unified account of best evidence in medicine, by exploring in particular the EBM position on RCTs (randomized controlled trials).
Rethinking Mechanistic Explanation
Authors: Glennan Stuart
Published: January 2003

Philosophers of science typically associate the causal-mechanical view of scientific explanation with the work of Railton and Salmon. In this paper I shall argue that the defects of this view arise from an inadequate analysis of the concept of mechanism. I contrast Salmon's account of mechanisms in terms of the causal nexus with my own account of mechanisms, in which mechanisms are viewed as complex systems. After describing these two concepts of mechanism, I show how the complex-systems approach avoids certain objections to Salmon's account of causal-mechanical explanation. I conclude by discussing how mechanistic explanations can provide understanding by unification.
Logicism Lite
Authors: Jeffrey Richard
Published: January 2003

Logicism Lite counts number-theoretical laws as logical for the same sort of reason for which physical laws are counted as as empirical: because of the character of the data they are responsible to. In the case of number theory these are the data verifying or falsifying the simplest equations, which Logicism Lite counts as true or false depending on the logical validity or invalidity of first-order argument forms in which no numbertheoretical notation appears.
A comparison of normalization methods for high density
oligonucleotide array data based on variance and bias
Authors: Bolstad B.M. , Irizarry R.A , Åstrand M. , Speed T.P.
Published: January 2003

Motivation: When running experiments that involve multiple high density oligonucleotide arrays, it is important to remove sources of variation between arrays of non-biological origin. Normalization is a process for reducing this variation. It is common to see non-linear relations between arrays and the standard normalization provided by Affymetrix does not perform well in these situations.

Results: We present three methods of performing normalization at the probe intensity level. These methods are called complete data methods because they make use of data from all arrays in an experiment to form the normalizing relation. These algorithms are compared to two methods that make use of a baseline array: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure. Two publicly available datasets are used to carry out the comparisons. The simplest and quickest complete data method is found to perform favorably.

Availability: Software implementing all three of the complete data normalization methods is available as part of the R package Affy, which is a part of the Bioconductor project http://www.bioconductor.org.

Contact: bolstad@stat.berkeley.edu.

Supplementary information: Additional figures may be found at http://www.stat.berkeley.edu/~bolstad/normalize/index.html

* To whom correspondence should be addressed.
SEGID: Identifying Interesting Segments in (Multiple) Sequence Alignments
Authors: Wang Lusheng , Xu Ying
Published: January 2003

Summary: SEGID is a tool for finding conserved regions (regions of high scores) for a given (multiple) sequence alignment. It takes a (multiple) sequence alignment as its input and converts the alignment into a sequence of numbers, where each number is the alignment score of a column. Three algorithms are used to identify regions of high scores. A graphical interface is provided to present those identified regions.

Availability: Free from http://www.cs.cityu.edu.hk/~lwang/segid/subject to copyright restrictions.

Contact: cswangl@cityu.edu.hk

* To whom correspondence should be addressed.
r8s: inferring absolute rates of molecular evolution and
divergence times in the absence of a molecular clock
Authors: Sanderson Michael J.
Published: January 2003

Summary: Estimating divergence times and rates of substitution from sequence data is plagued by the problem of rate variation between lineages. R8s version 1.5 is a program which uses parametric, nonparametric and semiparametric methods to relax the assumption of constant rates of evolution to obtain better estimates of rates and times. Unlike most programs for rate inference or phylogenetics, r8s permits users to convert results to absolute rates and ages by constraining one or more node times to be fixed, minimum or maximum ages (using fossil or other evidence). Version 1.5 uses truncated Newton nonlinear optimization code with bound constraints, offering superior performance over previous versions.

Results:

Availability: The linux executable, C source code, sample data sets and user manual are available free at http://ginger.ucdavis.edu/r8s.

Contact: mjsanderson@ucdavis.edu
Chimera: construction of chimeric sequences for
phylogenetic analysis
Authors: Leunissen Jack A.M.
Published: January 2003

Summary: Chimera allows the construction of chimeric protein or nucleic acid sequence files by concatenating sequences from two or more sequence files in PHYLIP formats. It allows the user to interactively select genes and species from the input files. The concatenated result is stored to one single output file in PHYLIP or NEXUS formats.

Availability: The computer program, including supporting files and example files, is available from http://www.dalicon.com/chimera/.

Contact: jackl@dalicon.com
G-language Genome Analysis Environment: a workbench for nucleotide sequence data mining
Authors: Arakawa K. , Mori K. , Ikeda K. , Matsuzaki T. , Kobayashi Y. , Tomita M.
Published: January 2003

Summary: G-language Genome Analysis Environment (G-language GAE) is an open source generic software package aimed for higher efficiency in bioinformatics analysis. G-language GAE has an interface as a set of Perl libraries for software development, and a graphical user interface for easy manipulation. Both Windows and Linux versions are available.

Availability: From http://www.g-language.org/ under GNU General Public License. CD-ROMs are distributed freely in major conferences.

Contact: info@g-language.org

* To whom correspondence should be addressed.
A profile hidden Markov model for signal peptides generated by HMMER
Authors: Zhang Zemin , Wood William I.
Published: January 2003

Summary: Although the HMMER package is widely used to produce profile hidden Markov models (profile HMMs) for protein domains, it has been difficult to create a profile HMM for signal peptides. Here we describe an approach for building a complex model of eukaryotic signal peptides by the standard HMMER package. Signal peptide prediction with this model gives a 95.6% sensitivity and 95.7% specificity.

Availability: The profile HMM for signal peptides, data sets, and the scripts for analyzing data are available for non-commercial use at http://share.gene.com/.

Contact: zemin@gene.com

* To whom correspondence should be addressed.
MPID: MHC-Peptide Interaction Database for
sequence-structure-function information on peptides binding to
MHC molecules
Authors: Govindarajan Kunde Ramamoorthy , Kangueane Pandjassarame , Tan Tin Wee , Ranganathan Shoba
Published: January 2003

Summary: Binding of short antigenic peptides to Major histocompatibility complex (MHC) proteins is the first step in T-cell mediated immune response. To understand the structural principles governing MHC-specific peptide recognition and binding, we have developed the MHC-Peptide Interaction Database (MPID), containing sequence-structure-function information. MPID (version 1.2) contains curated x-ray crystallographic data on 86 MHC peptide complexes, with precomputed interaction parameters (solvent accessibility, hydrogen bonds, gap volume and gap index). A user-friendly web interface and query tools will facilitate the development of predictive algorithms for MHC-peptide binding from a structural viewpoint.

Availability: Freely accessible from http://surya.bic.nus.edu.sg/mpid.

Contact: shoba@bic.nus.edu.sg

* To whom correspondence should be addressed.
DPX: for the analysis of the protein core
Authors: Pintar Alessandro , Carugo Oliviero , Pongor Sándor
Published: January 2003

Summary: In order to obtain an accurate description of the protein interior, we describe a simple and fast algorithm that measures the depth of each atom in a protein (dpx), defined as its distance (Å) from the closest solvent accessible atom. The program reads a PDB file containing the atomic solvent accessibility in the B-factor field, and writes a file in the same format, where the B-factor field now contains the dpx value. Output structure files can be thus directly displayed with molecular graphics programs like RASMOL, MOLMOL, Swiss-PDB View and colored according to dpx values.

Availability: The algorithm is implemented in a standalone program written in C and its source is freely available at ftp.icgeb.trieste.it/pub/DPX or on request from the authors.

Contact: pintar@icgeb.org; carugo@icgeb.org; pongor@icgeb.org

* To whom correspondence should be addressed.
The Advent of Internet Surveys for Political Research: A Comparison of Telephone and Internet Samples
Authors: Berrens Robert P. , Bohara Alok K. , Jenkins-Smith Hank , Silva Carol , Weimer David L.
Published: January 2003

The Internet offers a number of advantages as a survey mode: low marginal cost per completed response, capabilities for providing respondents with large quantities of information, speed, and elimination of interviewer bias. Those seeking these advantages confront the problem of representativeness both in terms of coverage of the population and capabilities for drawing random samples. Two major strategies have been pursued commercially to develop the Internet as a survey mode. One strategy, used by Harris Interactive, involves assembling a large panel of willing respondents who can be sampled. Another strategy, used by Knowledge Networks, involves using random digit dialing (RDD) telephone methods to recruit households to a panel of Web-TV enabled respondents. Do these panels adequately deal with the problem of representativeness to be useful in political science research? The authors address this question with results from parallel surveys on global climate change and the Kyoto Protocol administered by telephone to a national probability sample and by Internet to samples of the Harris Interactive and Knowledge Networks panels. Knowledge and opinion questions generally show statistically significant but substantively modest difference across the modes. With inclusion of standard demographic controls, typical relational models of interest to political scientists produce similar estimates of parameters across modes. It thus appears that, with appropriate weighting, samples from these panels are sufficiently representative of the U.S. population to be reasonable alternatives in many applications to samples gathered through RDD telephone surveys.
Interpreting the Coefficient of Party Influence: Comment on Krehbiel
Authors: Groseclose Tim , Snyder James M.
Published: January 2003

Keith Krehbiel (2003) provides a thoughtful note that explains why the estimation strategy we proposed in Snyder and Groseclose (2000) cannot distinguish between majority-party influence and minority-party influence theories. We agree with Krehbiel's major points. In this note, we explain our disagreement with some of his minor points, and we suggest an additional assumption under which our method can distinguish between majority-party influence and minority-party influence.
Subject Acquisition for Web-Based Surveys
Authors: Alvarez R. Michael , Sherman Robert P. , VanBeselaere Carla
Published: January 2003

This article provides a basic report about subject recruitment processes for Web-based surveys. Using data from our ongoing Internet Survey of American Opinion project, two different recruitment techniques (banner advertisement and subscription campaigns) are compared. This comparison, together with a typology of Web-based surveys, provides insight into the validity and generalizability of Internet survey data. The results from this analysis show that, although Internet survey respondents differ demographically from the American population, the relationships among variables are similar across recruitment methods and match those implied by substantive theory. Thus, our research documents the basic methodology of subject acquisition for Web-based surveys, which, as we argue in our conclusion, may soon become the survey interview mode of choice for social scientists.
A Consensus on Second-Stage Analyses in Ecological Inference Models
Authors: Adolph Christopher , King Gary , Herron Michael C. , Shotts Kenneth W.
Published: January 2003

Since Herron and Shotts (2003a; hereinafter HS), Adolph and King (2003; hereinafter AK), and Herron and Shotts (2003b; hereinafter HS2), the four of us have iterated many more times, learned a great deal, and arrived at a consensus on this issue. This paper describes our joint recommendations for how to run second-stage ecological regressions, and provides detailed analyses to back up our claims.