bluuebunny/crossref_metadata_2025 huggingface dataset:
Programming finite-domain constraint propagators in Action Rules
Authors: ZHOU NENG-FA
Published: August 2006

In this paper, we propose a new language, called AR (Action Rules), and describe how various propagators for finite-domain constraints can be implemented in it. An action rule specifies a pattern for agents, an action that the agents can carry out, and an event pattern for events that can activate the agents. AR combines the goal-oriented execution model of logic programming with the event-driven execution model. This hybrid execution model facilitates programming constraint propagators. A propagator for a constraint is an agent that maintains the consistency of the constraint and is activated by the updates of the domain variables in the constraint. AR has a much stronger descriptive power than indexicals, the language widely used in the current finite-domain constraint systems, and is flexible for implementing not only interval-consistency but also arc-consistency algorithms. As examples, we present a weak arc-consistency propagator for the all_distinct constraint and a hybrid algorithm for n-ary linear equality constraints. B-Prolog has been extended to accommodate action rules. Benchmarking shows that B-Prolog as a CLP(FD) system significantly outperforms other CLP(FD) systems.
FORUM: THE IDEA OF THE SELF
Authors: LA VOPA ANTHONY J.
Published: August 2006

It is somehow fitting that Jerrold Seigel's The Idea of the Self, a triumph of rigorous and erudite intellectual labor, has me thinking about labor. And so I will come at the book through the meanings given to labor from the mid-seventeenth century to the early nineteenth. My skepticism is meant to serve a larger purpose: to begin mapping the research territories opened or resituated by Seigel's achievement.
FORUM: THE IDEA OF THE SELF
Authors: SURKIS JUDITH
Published: August 2006

The Idea of the Self is a book which really made me think. Within the history of selfhood that it sets forth (and within which it is inscribed), this is precisely what a book about the self should do. For, as Seigel explains, reflectivity—our ability as selves to think critically about our own positions—is a constitutive, and pre-eminent, aspect or dimension of our selfhood. His work raises important questions about the normative implications of the ways in which we think about selfhood and how we attempt to write its history. As someone whose work has both addressed and been influenced by thinkers (such as Emile Durkheim, Georges Bataille, Michel Foucault, and Jacques Derrida) that Seigel argues have an unsatisfying and overly abstract account of selfhood, these are provocative questions indeed. The Idea of the Self has, as a result, forced me to interrogate the normative assumptions that underlie my own research and writing.
Effekte des Sporttreibens auf die Entwicklung des Selbstkonzepts Jugendlicher
Authors: Burrmann Ulrike
Published: August 2006

Zusammenfassung. Der Beitrag befasst sich mit der Frage, ob die Beteiligung am Sport generell (Indikator: Häufigkeit des Sporttreibens) und speziell die Teilnahme am vereinsorganisierten Sport (Indikator: Sportvereinsmitgliedschaft) einen Beitrag zur Entwicklung eines positiven Selbst- und Körperkonzepts leisten kann. Datengrundlage bildet eine standardisierte Längsschnitterhebung von 219 Mädchen und 184 Jungen, die zum Zeitpunkt der Erstbefragung im Durchschnitt 12½ Jahre und zur zweiten Messung etwa 16 Jahre alt waren. Sportlich hoch aktive Jugendliche schätzen sich knapp vier Jahre später im Vergleich zu sportlich wenig aktiven Altersgleichen als sportlich fitter und kompetenter ein, und sie nehmen bei sich weniger Figurprobleme wahr. Die Entwicklung positiver Beziehungen zu Gleichaltrigen ist hingegen weniger von der Sportbeteiligung als vielmehr von dessen sozialer Rahmung abhängig, erfasst über die Sportvereinszugehörigkeit.
Unterschiede im Fertigkeitsniveau - ein qualitativer oder “nur” ein quantitativer Unterschied?
Authors: Büsch Dirk
Published: August 2006

Zusammenfassung. In einer feldexperimentellen Untersuchung mit 305 Probanden konnten Büsch, Hagemann und Thielke (2001) zeigen, dass die Anzahl der extrahierten Dimensionen in einer Faktorenanalyse durch das unterschiedliche Fertigkeitsniveau der untersuchten Stichprobe moderiert wird. Die Autoren schlagen eine Unterscheidung des Fertigkeitsniveaus in Ballsportler(innen) und Nicht-Ballsportler(innen) vor. Diese Differenzierung impliziert einen qualitativen Unterschied, der jedoch durch die Konfundierung von Aufgaben- und Personenmerkmalen in exploratorischen Faktorenanalysen mit eben diesen statistischen Verfahren nicht “entdeckt” werden kann. Die Re-Analyse der Daten mit klassifizierenden Verfahren, d. h. Latent-Class- und Mixed-Rasch-Modellen zeigt, dass unter formalen Gesichtspunkten entweder von einem Ein-Klassen-Modell mit quantitativen Personenunterschieden im Fertigkeitsniveau oder einem Zwei-Klassen-Modell mit qualitativen Personenunterschieden auszugehen ist. Das Ein-Klassen-Modell führt zur Annahme einer rein quantitativen Unterscheidung des Fertigkeitsniveaus. Das Zwei-Klassen-Modell korrespondiert jedoch nicht mit der Unterscheidung von Ballsportler(innen) und Nicht-Ballsportler(innen). Vielmehr kann begründet angenommen werden, dass Personen bei der Realisierung großmotorischer Zeitdruckaufgaben zwei unterschiedliche koordinative Strategien verwenden. Aufgrund der fehlenden hierarchischen Beziehung zwischen dem Ein- und Zwei-Klassen-Modell und der für beide Modelle theoretisch-inhaltlichen Plausibilität werden weiterführende Überlegungen und Untersuchungen für die differenzielle Motorikforschung diskutiert.
Effekte sozialer und dimensionaler Vergleichsinformationen im Sport
Authors: Tietjens Maike , Niewerth Jörg
Published: August 2006

Zusammenfassung. Auf der Grundlage des Internal/External-frame of reference Modells (I/E-Modell) von Marsh (1986 , 1990 soll der Einfluss dimensionaler und sozialer Vergleiche im sportbezogenen Kontext geprüft werden. Das Modell basiert auf der Annahme, dass intraindividuelle/dimensionale Vergleiche der Leistungsfähigkeit in zwei Dimensionen (z. B. Schulfächern) einen Einfluss auf die Ausbildung selbstbezogener Kognitionen, Motivation und Emotion haben. Nach der Durchführung zweier sportmotorischer Tests erhielten (N = 72) die Probanden dimensionale und soziale Vergleiche in Form einer randomisierten schriftlichen Rückmeldung. Danach wurden die Auswirkungen auf das aufgabenspezifische Selbstkonzept, der Zufriedenheit mit der eigenen Leistung und das aufgabenbezogene Interesse erfasst. Bei dimensionalen und sozialen Abwärtsvergleichen gaben die Probanden eine höhere Zufriedenheit mit ihrer Leistung und eine höhere aufgabenspezifische Fähigkeitseinschätzung an als bei Aufwärtsvergleichen. Ein Einfluss auf die Leistung konnte nur bedingt nachgewiesen werden. Die Ergebnisse dieses Experiments zeigen, wie dimensionale Vergleiche die eigene Fähigkeitseinschätzung, die Zufriedenheit mit der eigenen Leistung und das Interesse mitbestimmen, dabei wird die relative Größe dieses Einflusses im Verhältnis zum Einfluss sozialer Vergleichsinformationen deutlich.
Anwendungen probabilistischer Modelle in der Sportpsychologie
Authors: Strauß Bernd , Büsch Dirk , Tenenbaum Gershon
Published: August 2006

Zusammenfassung. Ziel dieses Kurzbeitrags ist ein Überblick über die wichtigsten probabilistischen Testmodelle und ihre wichtigsten Anwendungen in der Sportpsychologie und Bewegungswissenschaft. Seit der Publikation des sogenannten eindimensionalen Rasch-Modells ( Rasch, 1960 ) sind zahlreiche probabilistische Modelle entwickelt worden, die es erlauben, auch komplexe Fragestellungen zu überprüfen.
NAO influence on sub‐decadal moisture variability over central North America
Authors: Fye Falko K. , Stahle David W. , Cook Edward R. , Cleaveland Malcolm K.
Published: August 2006

A strong statistically significant spectral peak with a frequency of 7–8 years is computed for tree‐ring reconstructed summer PDSI averaged at continental and regional scales over North America for the period 1645–1990. A similar, though non‐significant spectral peak is computed for instrumental summer PDSI averaged over North America for the shorter period from 1900–1990. The winter NAO index (1781–2002) has a very strong spectral signature at this same 7–8 year sub‐decadal frequency and is coherent with summer PDSI across a broad sector of the central U.S. Composite analyses confirm a PDSI response to extremes of the NAO over the central U.S., with drought prevalent during negative extremes, and wetness during positive extremes. The winter NAO index leads summer PDSI and a contingency table analysis indicates that extrema in the winter NAO index may have modest forecast value for the following spring‐summer moisture regimes over the central U.S.
Using uplifted Holocene beach berms for paleoseismic analysis on the Santa María Island, south‐central Chile
Authors: Bookhagen B. , Echtler H. P. , Melnick D. , Strecker M. R. , Spencer J. Q. G.
Published: August 2006

Major earthquakes (M > 8) have repeatedly ruptured the Nazca‐South America plate interface of south‐central Chile involving meter scale land‐level changes. Earthquake recurrence intervals, however, extending beyond limited historical records are virtually unknown, but would provide crucial data on the tectonic behavior of forearcs. We analyzed the spatiotemporal pattern of Holocene earthquakes on Santa María Island (SMI; 37°S), located 20 km off the Chilean coast and approximately 70 km east of the trench. SMI hosts a minimum of 21 uplifted beach berms, of which a subset were dated to calculate a mean uplift rate of 2.3 ± 0.2 m/ky and a tilting rate of 0.022 ± 0.002 °/ky. The inferred recurrence interval of strandline‐forming earthquakes is ∼180 years. Combining coseismic uplift and aseismic subsidence during an earthquake cycle, the net gain in strandline elevation in this environment is ∼0.4 m per event.
Controlling poly(p-phenylene vinylene)/poly(vinyl pyrrolidone) composite nanofibers in different morphologies by electrospinning
Authors: Xin Y. , Huang Z. H. , Yan E. Y. , Zhang W. , Zhao Q.
Published: August 2006

Highly fluorescent nanofibers were prepared by electrospinning the solutions containing poly(p-phenylene vinylene) (PPV) precursor and poly(vinyl pyrrolidone), followed by thermal conversion. Different morphologies from uniform helical to ultrathin straight ones were controllably prepared by adjusting the amount of PPV precursor in electrospinning solutions. The experimental data suggest that the viscosity and conductivity of electrospinning solution and the operating voltage are the main factors that affect the formation of the helical structures. These different nanofiber morphologies may be advantageous depending on the applications.
Biomolecular origin of the rate-dependent deformation of prismatic enamel
Authors: Zhou Jikou , Hsiung Luke L.
Published: August 2006

Penetration deformation of columnar prismatic enamel was investigated using instrumented nanoindentation testing that was carried out at three constant strain rates (0.05, 0.005, and 0.0005s−1). Enamel demonstrated better resistance to penetration deformation and greater elastic modulus values were measured at higher strain rates. The origin of rate-dependent deformation was rationalized to be the shear deformation of nanoscale protein matrix surrounding each hydroxyapatite crystal rod. The shear modulus of protein matrix was determined. It depends on strain rate in a format Gp=0.213+0.021lnε̇.
Surface-enhanced Raman scattering on nanoporous Au
Authors: Kucheyev S. O. , Hayes J. R. , Biener J. , Huser T. , Talley C. E. , Hamza A. V.
Published: August 2006

Colloidal solutions of metal nanoparticles are currently among the most studied substrates for sensors based on surface-enhanced Raman scattering (SERS). However, such substrates often suffer from not being cost-effective, reusable, or stable. Here, we develop nanoporous Au as a highly active, tunable, stable, biocompatible, and reusable SERS substrate. Nanoporous Au is prepared by a facile process of free corrosion of AgAu alloys followed by annealing. Results show that nanofoams with average pore widths of ∼250nm exhibit the largest SERS signal for 632.8nm excitation. This is attributed to the electromagnetic SERS enhancement mechanism with additional field localization within pores.
Patterning of metal nanowires by directed ion-induced dewetting
Authors: Zhao K. , Averback R. S. , Cahill David G.
Published: August 2006

Ion beam irradiation of thin Au and Pt lines on SiO2 substrates, 60–400nm wide and 8–25nm thick, led to the formation of nanowires by directed dewetting. Continued irradiation of these wires further resulted in the formation of a linear array of metal dots with spacings consistent with a Rayleigh instability. For metal lines wider than ≈250nm, dry patches nucleated in the interior of the lines, preventing nanowire formation. The height of the lines relative to the substrate surface could be controlled by anisotropic deformation of the underlying SiO2 substrate.
Legume nodulation: successful symbiosis through short- and long-distance signalling
Authors: Kinkema Mark , Scott Paul T. , Gresshoff Peter M.
Published: August 2006

Nodulation in legumes provides a major conduit of available nitrogen into the biosphere. The development of nitrogen-fixing nodules results from a symbiotic interaction between soil bacteria, commonly called rhizobia, and legume plants. Molecular genetic analysis in both model and agriculturally important legume species has resulted in the identification of a variety of genes that are essential for the establishment, maintenance and regulation of this symbiosis. Autoregulation of nodulation (AON) is a major internal process by which nodule numbers are controlled through prior nodulation events. Characterisation of AON-deficient mutants has revealed a novel systemic signal transduction pathway controlled by a receptor-like kinase. This review reports our present level of understanding on the short- and long-distance signalling networks controlling early nodulation events and AON.
Brassinosteroid-independent function of BRI1/CLV1 chimeric receptors
Authors: Diévart Anne , Hymes Matthew J. , Li Jianming , Clark Steven E.
Published: August 2006

CLAVATA1 (CLV1) and BRASSINOSTEROID INSENSITIVE 1 (BRI1) belong to the leucine-rich repeat receptor-like kinase (LRR-RLK) family, comprising more than 200 members in Arabidopsis thaliana (L.) Heynh. and playing important roles in development and defence responses in many plant species (Diévart and Clark 2003, 2004; Shiu and Bleecker 2001a, b). To dissect the mechanisms of receptor function, we assessed the ability of chimeric proteins containing regions from two different receptors to function in vivo. Using domains from the receptor-kinases CLAVATA1 and BRASSINOSTEROID INSENSITIVE1, we tested the ability of the resulting chimeric receptors to replace CLV1 function. Receptors with the BRI1 extracellular domain and CLV1 kinase domain were able to partially replace CLV1 function. Both loss-of-function and gain-of-function mutations within the BRI1 leucine-rich repeats (LRRs) altered the extent of rescue. Chimeric receptor function was unaffected by addition of either exogenous brassinosteroids (BR) or BR biosynthesis inhibitors, suggesting that the chimeric receptors function in a ligand-independent fashion. We propose that the BRI1 LRR domain drives chimeric receptor homodimerisation, and that the BRI1 LRR domain mutations influence homodimerisation efficiency independent of ligand binding.
Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy
Authors: Tsujita Yasuyuki , Muraski John , Shiraishi Isao , Kato Takahiro , Kajstura Jan , Anversa Piero , Sussman Mark A.
Published: August 2006

The serine/threonine kinase Akt regulates cellular survival, proliferation, gene transcription, protein translation, metabolism, and differentiation. Although Akt substrates are found throughout the cell, activated Akt normally accumulates in the nucleus, suggesting that biologically relevant targets are located there. Consequences of nuclear Akt signaling in cardiomyocytes were explored by using nuclear-targeted Akt (Akt-nuc). Accumulation of Akt-nuc did not provoke hypertrophy, unlike constitutively activated Akt. Instead, Akt-nuc inhibited hypertrophy concurrent with increased atrial natriuretic peptide (ANP) expression that depended upon phosphatidylinositol-3 kinase activity. Akt-nuc antihypertrophic effects were blocked by inhibition of either guanylyl cyclase A receptor or cyclic guanosine monophosphate-dependent protein kinase in cultured cardiomyocytes. Corroborating evidence showed blunted acute hypertrophic remodeling in Akt-nuc transgenic mice after transverse aortic constriction coincident with higher ANP expression and smaller myocyte volume. In addition, Akt-nuc expression improved systolic function and survival in the chronic phase of transverse aortic constriction-induced hypertrophy. Thus, Akt-nuc antagonizes certain aspects of hypertrophy through autocrine/paracrine stimulation of a phosphatidylinositol-3 kinase-dependent signaling cascade that promotes ANP expression, resulting in a unique combination of prosurvival coupled with antihypertrophic signaling.
Structural kinetic modeling of metabolic networks
Authors: Steuer Ralf , Gross Thilo , Selbig Joachim , Blasius Bernd
Published: August 2006

To develop and investigate detailed mathematical models of metabolic processes is one of the primary challenges in systems biology. However, despite considerable advance in the topological analysis of metabolic networks, kinetic modeling is still often severely hampered by inadequate knowledge of the enzyme–kinetic rate laws and their associated parameter values. Here we propose a method that aims to give a quantitative account of the dynamical capabilities of a metabolic system, without requiring any explicit information about the functional form of the rate equations. Our approach is based on constructing a local linear model at each point in parameter space, such that each element of the model is either directly experimentally accessible or amenable to a straightforward biochemical interpretation. This ensemble of local linear models, encompassing all possible explicit kinetic models, then allows for a statistical exploration of the comprehensive parameter space. The method is exemplified on two paradigmatic metabolic systems: the glycolytic pathway of yeast and a realistic-scale representation of the photosynthetic Calvin cycle.
Complementarity of ensemble and single-molecule measures of protein motion: A relaxation dispersion NMR study of an enzyme complex
Authors: Vallurupalli Pramodh , Kay Lewis E.
Published: August 2006

Single-molecule fluorescence experiments have shown that the conformation of the complex between
Escherichia coli
general NAD(P)H:flavin oxidoreductase (FRE) and flavin adenine dinucleotide (FAD) fluctuates over a range of timescales between 10
−4
and 1 s. Here we use
15
N and
13
C relaxation dispersion NMR methods to study millisecond-timescale dynamics in the complex. In this time regime, the protein is extremely flexible, with residues that undergo conformational exchange located throughout the molecule. Three distinct regions of dynamics are quantified, with two of them involving residues making contact to the donor (Tyr-35) and acceptor (FAD) sites that participate in the electron transfer reaction monitored in single-molecule experiments. Modulation of the donor–acceptor distance through these conformational exchange processes, occurring with rates of ≈400 and 1,200 s
−1
(22°C), affects the rate of electron transfer and partially accounts for the range of the observed dynamics monitored in the fluorescence experiments.
Genome-wide RNAi screening identifies protein damage as a regulator of osmoprotective gene expression
Authors: Lamitina Todd , Huang Chunyi George , Strange Kevin
Published: August 2006

The detection, stabilization, and repair of stress-induced damage are essential requirements for cellular life. All cells respond to osmotic stress-induced water loss with increased expression of genes that mediate accumulation of organic osmolytes, solutes that function as chemical chaperones and restore osmotic homeostasis. The signals and signaling mechanisms that regulate osmoprotective gene expression in animal cells are poorly understood. Here, we show that
gpdh-1
and
gpdh-2
, genes that mediate the accumulation of the organic osmolyte glycerol, are essential for survival of the nematode
Caenorhabditis elegans
during osmotic stress. Expression of GFP driven by the
gpdh-1
promoter (
P

gpdh-1

::
GFP
) is detected only during hypertonic stress but is not induced by other stressors. Using
P

gpdh-1

::
GFP
expression as a phenotype, we screened ≈16,000 genes by RNAi feeding and identified 122 that cause constitutive activation of
gpdh-1
expression and glycerol accumulation. Many of these genes function to regulate protein translation and cotranslational protein folding and to target and degrade denatured proteins, suggesting that the accumulation of misfolded proteins functions as a signal to activate osmoprotective gene expression and organic osmolyte accumulation in animal cells. Consistent with this hypothesis, 73% of these protein-homeostasis genes have been shown to slow age-dependent protein aggregation in
C. elegans
. Because diverse environmental stressors and numerous disease states result in protein misfolding, mechanisms must exist that discriminate between osmotically induced and other forms of stress-induced protein damage. Our findings provide a foundation for understanding how these damage-selectivity mechanisms function.
Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis
Authors: Li Mei , Hener Pierre , Zhang Zhikun , Kato Shigeaki , Metzger Daniel , Chambon Pierre
Published: August 2006

We have demonstrated that cytokine thymic stromal lymphopoietin (TSLP), whose expression is rapidly induced upon keratinocyte-selective ablation of retinoid X receptors (RXRs) -α and -β in the mouse (RXRαβ
ep−/−
mice), plays a key role in initiating a skin and systemic atopic dermatitis-like phenotype. We show here that topical application of the physiologically active ligand [1α,25-(OH)
2
D
3
; calcitriol] of the vitamin D receptor, or of its low-calcemic analog MC903 (calcipotriol; Dovonex), induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome mimicking that seen in RXRαβ
ep−/−
mutants and transgenic mice overexpressing TSLP in keratinocytes. Furthermore, topical application of retinoic acid receptor RARγ-selective agonist BMS961 also induces TSLP expression either on its own or synergistically with 1α,25-(OH)
2
D
3
. Our data demonstrate that RXR/vitamin D receptor and RXR/retinoic acid receptor-γ heterodimers and their ligands cell-autonomously control the expression of TSLP in epidermal keratinocytes of the mouse. We propose molecular mechanisms through which vitamin D3 and retinoic acid signalings could be involved in the pathogenesis of atopic diseases.
Hotspots of transcription factor colocalization in the genome of
Drosophila melanogaster
Authors: Moorman Celine , Sun Ling V. , Wang Junbai , de Wit Elzo , Talhout Wendy , Ward Lucas D. , Greil Frauke , Lu Xiang-Jun , White Kevin P. , Bussemaker Harmen J. , van Steensel Bas
Published: August 2006

Regulation of gene expression is a highly complex process that requires the concerted action of many proteins, including sequence-specific transcription factors, cofactors, and chromatin proteins. In higher eukaryotes, the interplay between these proteins and their interactions with the genome still is poorly understood. We systematically mapped the
in vivo
binding sites of seven transcription factors with diverse physiological functions, five cofactors, and two heterochromatin proteins at ≈1-kb resolution in a 2.9 Mb region of the
Drosophila melanogaster
genome. Surprisingly, all tested transcription factors and cofactors show strongly overlapping localization patterns, and the genome contains many “hotspots” that are targeted by all of these proteins. Several control experiments show that the strong overlap is not an artifact of the techniques used. Colocalization hotspots are 1–5 kb in size, spaced on average by ≈50 kb, and preferentially located in regions of active transcription. We provide evidence that protein–protein interactions play a role in the hotspot association of some transcription factors. Colocalization hotspots constitute a previously uncharacterized type of feature in the genome of
Drosophila
, and our results provide insights into the general targeting mechanisms of transcription regulators in a higher eukaryote.
CD8 T cell competition for dendritic cellsin vivois an early event in activation
Authors: Willis Richard A. , Kappler John W. , Marrack Philippa C.
Published: August 2006

T cell responses against an antigen are often focused on a small fraction of potentially immunogenic determinants, a phenomenon known as immunodominance. Immunodominance can be established at several stages of antigen presentation, including antigen processing, binding of peptides to MHC, and competition between T cells for dendritic cells (DCs). The mechanism of this T cell competition is unclear, but may include competition for physical access to DCs, competition for limiting soluble DC-derived factors, or a suppressive effect of one T cell population on the other(s). To model DC-specific T cell competition, normal mice were injected with one or two T cell receptor transgenic CD8 T cell populations, each with high affinity for different peptides presented by different class I MHC complexes. These mice were immunized with DCs pulsed with peptides that are recognized by the transferred T cells. Competition was detectable when both T cell populations were transferred and their target peptides were present on the same DCs. The competition resulted in fewer cells entering the response, but had no effect on the level of activation of the cells that did respond. The effect was evident very early in the response, and in fact the competing T cells needed to be present in the first 5 h of the response for competition to occur. Thus, some aspect of DCs other than peptide/MHC complexes is limiting in the earliest stages of the CD8 T cell response. These results have implications for the design of multivalent vaccines.
Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model
Authors: Maines Taronna R. , Chen Li-Mei , Matsuoka Yumiko , Chen Hualan , Rowe Thomas , Ortin Juan , Falcón Ana , Hien Nguyen Tran , Mai Le Quynh , Sedyaningsih Endang R. , Harun Syahrial , Tumpey Terrence M. , Donis Ruben O. , Cox Nancy J. , Subbarao Kanta , Katz Jacqueline M.
Published: August 2006

Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian–human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait.
Identifying transcription factor functions and targets by phenotypic activation
Authors: Chua Gordon , Morris Quaid D. , Sopko Richelle , Robinson Mark D. , Ryan Owen , Chan Esther T. , Frey Brendan J. , Andrews Brenda J. , Boone Charles , Hughes Timothy R.
Published: August 2006

Mapping transcriptional regulatory networks is difficult because many transcription factors (TFs) are activated only under specific conditions. We describe a generic strategy for identifying genes and pathways induced by individual TFs that does not require knowledge of their normal activation cues. Microarray analysis of 55 yeast TFs that caused a growth phenotype when overexpressed showed that the majority caused increased transcript levels of genes in specific physiological categories, suggesting a mechanism for growth inhibition. Induced genes typically included established targets and genes with consensus promoter motifs, if known, indicating that these data are useful for identifying potential new target genes and binding sites. We identified the sequence 5′-TCACGCAA as a binding sequence for Hms1p, a TF that positively regulates pseudohyphal growth and previously had no known motif. The general strategy outlined here presents a straightforward approach to discovery of TF activities and mapping targets that could be adapted to any organism with transgenic technology.
Home‐based therapy for oedematous malnutrition with ready‐to‐use therapeutic food
Authors: Ciliberto Michael A. , Manary Mark J. , Ndekha MacDonald J. , Briend Andre , Ashorn Per
Published: August 2006

Background: Standard recommendations are that children with oedematous malnutrition receive inpatient therapy with a graduated feeding regimen. Aim: To investigate exclusive home‐based therapy for children with oedematous malnutrition. Methods: Children with oedematous malnutrition, good appetite and no complications were treated at home with ready‐to‐use therapeutic food (RUTF) and followed up fortnightly for up to 8 wk. Setting and participants: 219 children aged 1–5 y with oedema enrolled in one of two therapeutic nutritional studies in Malawi in 2003–2004. Results: The overall recovery rate was 83% (182/219), and the case‐fatality rate was 5% (11/219). For children with wasting and oedematous malnutrition, 65% (55/85) recovered and 7% (6/85) died. The average weight gain was 2.8±3.2 g/kg/d (mean±SD).

Conclusion: This preliminary observation suggests that children with oedematous malnutrition and good appetite may be successfully treated with home‐based therapy; a randomized, controlled trial to evaluate this is warranted.
Plasma long‐chain fatty acids and the degree of obesity in Italian children
Authors: Scaglioni Silvia , Verduci Elvira , Salvioni Michela , Bruzzese Maria Grazia , Radaelli Giovanni , Zetterström Rolf , Riva Enrica , Agostoni Carlo
Published: August 2006

Aim: To examine whether the plasma levels of long‐chain polyunsaturated fatty acids (LC‐PUFAs) are associated with the degree of obesity in children. Methods: Sixty‐seven normolipidaemic obese children, aged 8–12 y, and 67 age‐ and sex‐matched normal‐weight children were included in the study. Obesity was defined in accordance with the International Obesity Task Force. BMI z‐scores were calculated. Fasting blood samples were analysed for insulin, glucose, lipid profile and fatty acid (FA) levels (expressed as % total FA). Insulin resistance was estimated by homeostatic model assessment (HOMA). Results: Compared with normal‐weight children, obese children exhibited lower mean plasma total PUFA (37.8% vs 39.7%), ω‐6 PUFAs (35.0% vs 36.8%) and C22:6 ω‐3‐to‐C18:3 ω‐3 ratio (5.52 vs 7.61), and higher total monounsaturated FA (26.6% vs 25.0%), C18:3 ω‐3 (0.28% vs 0.25%) and C20:5 ω‐3 (0.45% vs 0.39%). In obese children, the BMI z‐score was negatively related to plasma PUFA, ω‐3 PUFAs, C22:6 ω‐3, and the C22:6 ω‐3‐to‐C20:6 ω‐6 and C22:6 ω‐3‐to‐C18:3 ω‐3 ratios, and positively with total saturated FA and C20:3 ω‐9.

Conclusion: In obese children, plasma LC‐PUFA profile may be associated with the degree of obesity.
T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17
Authors: Rangachari Manu , Mauermann Nora , Marty René R. , Dirnhofer Stephan , Kurrer Michael O. , Komnenovic Vukoslav , Penninger Josef M. , Eriksson Urs
Published: August 2006

Experimental autoimmune myocarditis (EAM) appears after infectious heart disease, the most common cause of dilated cardiomyopathy in humans. Here we report that mice lacking T-bet, a T-box transcription factor required for T helper (Th)1 cell differentiation and interferon (IFN)-γ production, develop severe autoimmune heart disease compared to T-bet−/− control mice. Experiments in T-bet−/− IL-4−/− and T-bet−/− IL-4Rα−/− mice, as well as transfer of heart-specific Th1 and Th2 cell lines, showed that autoimmune heart disease develops independently of Th1 or Th2 polarization. Analysis of T-bet−/− IL-12Rβ1−/− and T-bet−/− IL-12p35−/− mice then identified interleukin (IL)-23 as critical for EAM pathogenesis. In addition, T-bet−/− mice showed a marked increase in production of the IL-23–dependent cytokine IL-17 by heart-infiltrating lymphocytes, and in vivo IL-17 depletion markedly reduced EAM severity in T-bet−/− mice. Heart-infiltrating T-bet−/− CD8+ but not CD8− T cells secrete IFN-γ, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet−/− CD8+ lymphocytes completely lost their capacity to release IFN-γ within the heart. Collectively, these data show that severe IL-17–mediated EAM can develop in the absence of T-bet, and that T-bet can regulate autoimmunity via the control of nonspecific CD8+ T cell bystander functions in the inflamed target organ.
An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues
Authors: Chakraverty Ronjon , Côté Daniel , Buchli Jennifer , Cotter Pete , Hsu Richard , Zhao Guiling , Sachs Teviah , Pitsillides Costas M. , Bronson Roderick , Means Terry , Lin Charles , Sykes Megan
Published: August 2006

Transfer of T cells to freshly irradiated allogeneic recipients leads to their rapid recruitment to nonlymphoid tissues, where they induce graft-versus-host disease (GVHD). In contrast, when donor T cells are transferred to established mixed chimeras (MCs), GVHD is not induced despite a robust graft-versus-host (GVH) reaction that eliminates normal and malignant host hematopoietic cells. We demonstrate here that donor GVH-reactive T cells transferred to MCs or freshly irradiated mice undergo similar expansion and activation, with similar up-regulation of homing molecules required for entry to nonlymphoid tissues. Using dynamic two-photon in vivo microscopy, we show that these activated T cells do not enter GVHD target tissues in established MCs, contrary to the dogma that activated T cells inevitably traffic to nonlymphoid tissues. Instead, we show that the presence of inflammation within a nonlymphoid tissue is a prerequisite for the trafficking of activated T cells to that site. Our studies help to explain the paradox whereby GVH-reactive T cells can mediate graft-versus-leukemia responses without inducing GVHD in established MCs.
Asymmetrical lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors
Authors: Lai Anne Y. , Kondo Motonari
Published: August 2006

The mechanism of lineage commitment from hematopoietic stem cells (HSCs) is not well understood. Although commitment to either the lymphoid or the myeloid lineage is popularly viewed as the first step of lineage restriction from HSCs, this model of hematopoietic differentiation has recently been challenged. The previous identification of multipotent progenitors (MPPs) that can produce lymphocytes and granulocyte/macrophages (GMs) but lacks erythroid differentiation ability suggests the existence of an alternative HSC differentiation program. Contribution to different hematopoietic lineages by these MPPs under physiological conditions, however, has not been carefully examined. In this study, we performed a refined characterization of MPPs by subfractionating three distinct subsets based on Flt3 and vascular cell adhesion molecule 1 expression. These MPP subsets differ in their ability to give rise to erythroid and GM lineage cells but are equally potent in lymphoid lineage differentiation in vivo. The developmental hierarchy of these MPP subsets demonstrates the sequential loss of erythroid and then GM differentiation potential during early hematopoiesis. Our results suggest that the first step of lineage commitment from HSCs is not simply a selection between the lymphoid and the myeloid lineage.
Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help
Authors: Mandik-Nayak Laura , Racz Jennifer , Sleckman Barry P. , Allen Paul M.
Published: August 2006

In K/BxN mice, arthritis is induced by autoantibodies against glucose-6-phosphate-isomerase (GPI). To investigate B cell tolerance to GPI in nonautoimmune mice, we increased the GPI-reactive B cell frequency using a low affinity anti-GPI H chain transgene. Surprisingly, anti-GPI B cells were not tolerant to this ubiquitously expressed and circulating autoantigen. Instead, they were found in two functionally distinct compartments: an activated population in the splenic marginal zone (MZ) and an antigenically ignorant one in the recirculating follicular/lymph node (LN) pool. This difference in activation was due to increased autoantigen availability in the MZ. Importantly, the LN anti-GPI B cells remained functionally competent and could be induced to secrete autoantibodies in response to cognate T cell help in vitro and in vivo. Therefore, our study of low affinity autoreactive B cells reveals two distinct but potentially concurrent mechanisms for their activation, of which one is T cell dependent and the other is T cell independent.
Antiviral defense: interferons and beyond
Authors: Stetson Daniel B. , Medzhitov Ruslan
Published: August 2006

Mice lacking the adaptor protein that initiates an antiviral response downstream of the RNA helicases retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) have recently been described. These studies highlight the essential and nonredundant role of nucleic acid recognition in the induction of type I interferon production and raise important questions regarding the nature of cell-autonomous virus detection in coordinating the antiviral response.
OSIRIS: a tool for retrieving literature about sequence variants
Authors: Bonis Julio , Furlong Laura Inés , Sanz Ferran
Published: August 2006

Summary: Sequence variants, in particular single nucleotide polymorphisms (SNPs), are key elements for the identification of genes associated with complex diseases and with particular drug responses. The search for literature about sequence variation is hampered by the large number of allelic variants reported for many genes and by the variability in both gene and sequence variants nomenclatures. We describe OSIRIS, a search tool that integrates different sources of information with the aim to retrieve literature about sequence variation of a gene. In addition, it provides a method to link a dbSNP entry with the articles referring to it.

Availability: OSIRIS is available for public use at

Contact:  fsanz@imim.es

Supplementary information:  Supplementary data are available at Bioinformatics online.
Sebida: a database for the functional and evolutionary analysis of genes with sex-biased expression
Authors: Gnad Florian , Parsch John
Published: August 2006

Summary: We describe Sebida, a database of genes with sex-biased expression. The database integrates results from multiple, independent microarray studies comparing male and female gene expression in Drosophila melanogaster, Drosophila simulans and Anopheles gambiae. Sebida uses standard nomenclature, which allows individual genes to be compared across different microarray platforms and to be queried by gene name, symbol, or annotation number. In addition to ratios of male/female expression for each gene, Sebida also contains information useful for evolutionary studies, such as local recombination rate, degree of codon bias and interspecific divergence at synonymous and non-synonymous sites.

Availability: Sebida can be accessed at

Contact:  gnad@biochem.mpg.de
Ingestion of Caustic Substances: A 15‐Year Experience
Authors: Arévalo‐Silva Carlos , Eliashar Ron , Wohlgelernter Jay , Elidan Josef , Gross Menachem
Published: August 2006

Objective: The objective of this study was to analyze the circumstance, demographic features, clinical findings, and complications of caustic ingestion in relation to the type and amount of caustic substance.

Study Design: The authors conducted a retrospective cohort study in a tertiary medical center.

Methods: The authors reviewed medical records from 1988 to 2003 of patients with a history of caustic ingestion and clinical signs of injury to the aerodigestive tract. Parameters examined included age at presentation, gender, demographic status, nature of the caustic substance ingested, amount of substance, circumstance of the event, diagnostic tools, degree of injury, and anatomic distribution of the injury, early and late complications, and requirement for ventilatory support.

Results: A total of 50 cases of caustic ingestion were identified (age range, 5 months‐71 years). A biphasic distribution of the patients was noted; half were children under 5 years old and the remainder was adults. The most common caustic agent ingested was alkaline (42%) followed by acidic (32%) and chlorine bleach (26%). The most frequent cause for ingestion was accidental (67%) as opposed to attempt suicide (33%). All cases of attempted suicide occurred in adults. Most of them reported ingestion of large amounts of caustic substance. In the pediatric group, an association between the caustic agent and ethnicity was observed. Among Jewish children, alkaline cleaning agents were the most common cause (82%). Acetic acid was the most common substance ingested by the Arab children (100%). The findings of rigid esophagoscopy in 36 patients were as follows: first‐degree esophageal injury in 16 (44%), second‐degree in 6 (17%), third‐degree in 7 (19%), fourth‐degree in 6 (17%), and one (3%) was normal. Mucosal injury to the esophagus was worse in the acidic ingestion group as compared with the alkaline substance ingestion group with marginally statistically significant difference in the median degree of injury between the three types of ingested substances (P = .054). Mucosal injury to the esophagus was worse among patients who attempted suicide as compared with accidental ingestion with a statistically significant difference in the median degree of injury between the two reasons for ingestion (P = .002).

Conclusion: Severity of injury from caustic ingestion damages depend on the type of ingested substance, which varies depending on ethnicity. Ingestion of caustic agents by children involves specific substances according to the season, cultural and religious festivals, and ethnicity. The majority of adult cases are intentional with more serious injuries and a higher rate of complications. In our series, ingestion of acidic substances and ingestion associated with suicide attempt had the most severe consequences.
Early Endoscopic Treatment of Acute Inflammatory Airway Lesions Improves the Outcome of Postintubation Airway Stenosis
Authors: Nouraei S A. Reza , Singh Arvind , Patel Anil , Ferguson Catriona , Howard David J. , Sandhu Guri S.
Published: August 2006

Objectives/Hypothesis: The objective of this study was to compare the results of treating acute postintubation stenotic airway lesions with the results of treating mature lesions and to assess whether early intervention improves the outcome.

Methods: Patients without previous surgery, treated for postintubation airway stenosis, were reviewed. Those with airway lesions presenting within weeks of intubation (n = 11) were treated with intralesional steroids, laser reduction, and balloon dilatation. Patients with mature airway lesions (n = 20) were initially treated with laser, balloon dilatation, and topical mitomycin C. Preoperative patient and lesion characteristics, details of the treatment, and intervention‐free intervals were recorded. Data were compared with unpaired Student t test or χ2 test as appropriate, and intervention‐free intervals were compared with log‐rank statistics. Cox regression was used to identify independent predictors of intervention‐free interval.

Results: There were 18 males and 13 females. The average age at presentation was 47 ± 2.7 years. The two groups were statistically comparable for demographic and lesion characteristics. Patients treated for acute injury required significantly fewer interventions (P < .03), the majority being treated with a single treatment. They had a significantly longer intervention‐free interval (P < .02; log‐rank analysis) and did not require external laryngotracheal reconstruction (P < .001) compared with patients treated for mature fibrotic scars leading to airway stenosis.

Conclusions: Early treatment of acute fibroinflammatory airway lesions has the potential to favorably modify the natural history of postintubation tracheal injury, raising the tantalizing possibility of an early cure. These findings have significant implications for early identification, referral, and treatment of postintubation tracheal stenosis and need to be confirmed with further studies.
Gleevec Suppresses p63 Expression in Head and Neck Squamous Cell Carcinoma Despite p63 Activation by DNA‐Damaging Agents
Authors: Ongkeko Weg M. , An Yi , Chu Theresa S. , Aguilera Joseph , Dang Christopher L. , Wang‐Rodriguez Jessica
Published: August 2006

Objectives: The objectives of this study were to determine the effects of Gleevec on p63 expression in head and neck squamous cell carcinoma (HNSCC) cell lines and to investigate the role of Gleevec in regulating p63 stabilization under DNA‐damaging conditions.

Methods: Immunohistochemical staining was performed to determine p63 expression in HNSCC tissue. Annexin V staining was used to assess the effects of p63 on early apoptosis. Immunoblotting was used to examine the effects of Gleevec on p63 protein levels in HNSCC cell lines in response to DNA damage. Immunofluorescence staining was performed to study the expression pattern of p63 and c‐Abl.

Results: In HNSCC, p63 protein levels are induced by DNA‐damaging agents, including ionizing radiation, doxorubicin, and ultraviolet light. We demonstrate that Gleevec reduces p63/ΔNp63 expression in a dose‐dependent manner in HNSCC and overrides the protein induction by DNA‐damaging agents. Overexpression of c‐Abl in the absence of Gleevec results in higher levels of p63 than those treated with Gleevec, implicating c‐Abl kinase activity as a regulator of p63 protein stability.

Conclusions: Gleevec downregulates p63/ΔNp63 levels in HNSCC in a dose‐dependent manner under both normal and DNA‐damaging conditions. This downregulation can be explained by Gleevec's inhibition of c‐Abl, which destabilizes p63. Based on our data, treating cancers with high expression of TAp63 with Gleevec may result in the unfavorable inhibition of a tumor suppressor, whereas downregulation of ΔNp63 would be advantageous. Further development of antibodies that can discriminate between TAp63 and ΔNp63 will be needed to determine the specific effects of Gleevec on p63 in HNSCC.