bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishing cross-linguistic semantic relatedness through monolingual corpora
Authors: Defrancq Bart
Published: December 2008

Each instance of language comparison requires observations on semantic equivalence. Meaning is by far the most popular tertium comparationis in contrastive and typological research. However, the question of how semantic equivalence is to be determined remains extremely difficult to solve. This paper presents an approach to detect semantic relatedness between a limited range of lexical items from different languages on the basis of monolingual data. Applying distributional similarity (Dagan et al. 1999) cross-linguistically, it identifies semantically related verbs governing embedded interrogatives by looking at the frequency of the question words (i.e. wh-items) that are used in the embedded interrogatives in monolingual corpora. Convincing results are obtained for six different language pairs: English-French, English-Dutch, English-Spanish, French-Dutch, French-Spanish and Dutch-Spanish.
NOEnet–Use of NOE networks for NMR resonance assignment of proteins with known 3D structure
Authors: Stratmann Dirk , van Heijenoort Carine , Guittet Eric
Published: December 2008

Motivation: A prerequisite for any protein study by NMR is the assignment of the resonances from the 15N−1H HSQC spectrum to their corresponding atoms of the protein backbone. Usually, this assignment is obtained by analyzing triple resonance NMR experiments. An alternative assignment strategy exploits the information given by an already available 3D structure of the same or a homologous protein. Up to now, the algorithms that have been developed around the structure-based assignment strategy have the important drawbacks that they cannot guarantee a high assignment accuracy near to 100%.

Results: We propose here a new program, called NOEnet, implementing an efficient complete search algorithm that ensures the correctness of the assignment results. NOEnet exploits the network character of unambiguous NOE constraints to realize an exhaustive search of all matching possibilities of the NOE network onto the structural one. NOEnet has been successfully tested on EIN, a large protein of 28 kDa, using only NOE data. The complete search of NOEnet finds all possible assignments compatible with experimental data that can be defined as an assignment ensemble. We show that multiple assignment possibilities of large NOE networks are restricted to a small spatial assignment range (SAR), so that assignment ensembles, obtained from accessible experimental data, are precise enough to be used for functional proteins studies, like protein–ligand interaction or protein dynamics studies. We believe that NOEnet can become a major tool for the structure-based backbone resonance assignment strategy in NMR.

Availability: The NOEnet program will be available under: http://www.icsn.cnrs-gif.fr/download/nmr

Contact:  carine@icsn.cnrs-gif.fr; eric.guittet@icsn.cnrs-gif.fr

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Speed versus accuracy in decision-making ants: expediting politics and policy implementation
Authors: Franks Nigel R , Dechaume-Moncharmont François-Xavier , Hanmore Emma , Reynolds Jocelyn K
Published: December 2008

Compromises between speed and accuracy are seemingly inevitable in decision-making when accuracy depends on time-consuming information gathering. In collective decision-making, such compromises are especially likely because information is shared to determine corporate policy. This political process will also take time. Speed–accuracy trade-offs occur among house-hunting rock ants,Temnothorax albipennis. A key aspect of their decision-making is quorum sensing in a potential new nest. Finding a sufficient number of nest-mates, i.e. a quorum threshold (QT), in a potential nest site indicates that many ants find it suitable. Quorum sensing collates information. However, the QT is also used as a switch, from recruitment of nest-mates to their new home by slow tandem running, to recruitment by carrying, which is three times faster. Although tandem running is slow, it effectively enables one successful ant to lead and teach another the route between the nests. Tandem running creates positive feedback; more and more ants are shown the way, as tandem followers become, in turn, tandem leaders. The resulting corps of trained ants can then quickly carry their nest-mates; but carried ants do not learn the route. Therefore, the QT seems to set both the amount of information gathered and the speed of the emigration. Low QTs might cause more errors and a slower emigration—the worst possible outcome. This possible paradox of quick decisions leading to slow implementation might be resolved if the ants could deploy another positive-feedback recruitment process when they have used a low QT. Reverse tandem runs occur after carrying has begun and lead ants back from the new nest to the old one. Here we show experimentally that reverse tandem runs can bring lost scouts into an active role in emigrations and can help to maintain high-speed emigrations. Thus, in rock ants, although quick decision-making and rapid implementation of choices are initially in opposition, a third recruitment method can restore rapid implementation after a snap decision. This work reveals a principle of widespread importance: the dynamics of collective decision-making (i.e. the politics) and the dynamics of policy implementation are sometimes intertwined, and only by analysing the mechanisms of both can we understand certain forms of adaptive organization.
Conflicts of interest and the evolution of decision sharing
Authors: Conradt Larissa , Roper Timothy J
Published: December 2008

Social animals regularly face consensus decisions whereby they choose, collectively, between mutually exclusive actions. Such decisions often involve conflicts of interest between group members with respect to preferred action. Conflicts could, in principle, be resolved, either by sharing decisions between members (‘shared decisions’) or by one ‘dominant’ member making decisions on behalf of the whole group (‘unshared decisions’). Both, shared and unshared decisions, have been observed. However, it is unclear as to what favours the evolution of either decision type. Here, after a brief literature review, we present a novel method, involving a combination of self-organizing system and game theory modelling, of investigating the evolution of shared and unshared decisions. We apply the method to decisions on movement direction. We find that both, shared and unshared, decisions can evolve without individuals having a global overview of the group's behaviour or any knowledge about other members' preferences or intentions. Selection favours unshared over shared decisions when conflicts are high relative to grouping benefits, and vice versa. These results differ from those of group decision models relating to activity timings. We attribute this to fundamental differences between collective decisions about modalities that are disjunct (here, space) or continuous (here, time) with respect to costs/benefits.
Voting patterns and alliance formation in the European Parliament
Authors: Hix Simon , Noury Abdul , Roland Gérard
Published: December 2008

Members of the European Parliament (MEPs) have voluntarily formed transnational political groups and invariably follow the voting instructions of these groups. This is intriguing as there are few obvious incentives for doing so. Unlike national parties, for example, the political groups in the European Parliament are not punished by the electorate if they are divided on key issues, as citizens know very little about what goes on inside the European Parliament. This paper pieces together an explanation of why the European political groups exist and why they have become so powerful by looking at the determinants of group cohesion and by undertaking a spatial analysis of voting in the European Parliament. MEPs who share preferences on a range of issues on the European Union policy agenda have an incentive to establish a division-of-labour contract and to share the costs of collecting information. Once internal party policy specialization and agenda setting has been established, MEPs have incentives to follow the voting instructions of their group owing to the advantages of cohesion in a context of repeated voting.
Reciprocity, culture and human cooperation: previous insights and a new cross-cultural experiment
Authors: Gächter Simon , Herrmann Benedikt
Published: December 2008

Understanding the proximate and ultimate sources of human cooperation is a fundamental issue in all behavioural sciences. In this paper, we review the experimental evidence on how people solve cooperation problems. Existing studies show without doubt that direct and indirect reciprocity are important determinants of successful cooperation. We also discuss the insights from a large literature on the role of peer punishment in sustaining cooperation. The experiments demonstrate that many people are ‘strong reciprocators’ who are willing to cooperate and punish others even if there are no gains from future cooperation or any other reputational gains. We document this in new one-shot experiments, which we conducted in four cities in Russia and Switzerland. Our cross-cultural approach allows us furthermore to investigate how the cultural background influences strong reciprocity. Our results show that culture has a strong influence on positive and in especially strong negative reciprocity. In particular, we find large cross-cultural differences in ‘antisocial punishment’ of pro-social cooperators. Further cross-cultural research and experiments involving different socio-demographic groups document that the antisocial punishment is much more widespread than previously assumed. Understanding antisocial punishment is an important task for future research because antisocial punishment is a strong inhibitor of cooperation.
Karrikins Discovered in Smoke Trigger Arabidopsis Seed Germination by a Mechanism Requiring Gibberellic Acid Synthesis and Light
Authors: Nelson David C. , Riseborough Julie-Anne , Flematti Gavin R. , Stevens Jason , Ghisalberti Emilio L. , Dixon Kingsley W. , Smith Steven M.
Published: December 2008

Discovery of the primary seed germination stimulant in smoke, 3-methyl-2H-furo[2,3-c]pyran-2-one (KAR1), has resulted in identification of a family of structurally related plant growth regulators, karrikins. KAR1 acts as a key germination trigger for many species from fire-prone, Mediterranean climates, but a molecular mechanism for this response remains unknown. We demonstrate that Arabidopsis (Arabidopsis thaliana), an ephemeral of the temperate northern hemisphere that has never, to our knowledge, been reported to be responsive to fire or smoke, rapidly and sensitively perceives karrikins. Thus, these signaling molecules may have greater significance among angiosperms than previously realized. Karrikins can trigger germination of primary dormant Arabidopsis seeds far more effectively than known phytohormones or the structurally related strigolactone GR-24. Natural variation and depth of seed dormancy affect the degree of KAR1 stimulation. Analysis of phytohormone mutant germination reveals suppression of KAR1 responses by abscisic acid and a requirement for gibberellin (GA) synthesis. The reduced germination of sleepy1 mutants is partially recovered by KAR1, which suggests that germination enhancement by karrikin is only partly DELLA dependent. While KAR1 has little effect on sensitivity to exogenous GA, it enhances expression of the GA biosynthetic genes GA3ox1 and GA3ox2 during seed imbibition. Neither abscisic acid nor GA levels in seed are appreciably affected by KAR1 treatment prior to radicle emergence, despite marked differences in germination outcome. KAR1 stimulation of Arabidopsis germination is light-dependent and reversible by far-red exposure, although limited induction of GA3ox1 still occurs in the dark. The observed requirements for light and GA biosynthesis provide the first insights into the karrikin mode of action.
FZR2/CCS52A1Expression Is a Determinant of Endoreduplication and Cell Expansion in Arabidopsis
Authors: Larson-Rabin Zachary , Li Ziyu , Masson Patrick H. , Day Christopher D.
Published: December 2008

Endoreduplication, a modified cell cycle that allows cells to increase ploidy without subsequent cell division, is a key component of plant growth and development. In this work, we show that some, but not all, of the endoreduplication of Arabidopsis (Arabidopsis thaliana) is mediated by the expression of a WD40 gene, FIZZY-RELATED2 (FZR2). Loss-of-function alleles show reduced endoreduplication and reduced expansion in trichomes and other leaf cells. Misexpression of FZR2 is sufficient to drive ectopic or extra endoreduplication in leaves, roots, and flowers, leading to alteration of cell sizes and, sometimes, organ size and shape. Our data, which suggest that reduced cell size can be compensated by increased cell proliferation to allow normal leaf morphology, are discussed with respect to the so-called compensation mechanism of plant development.
Multiple protective activities of neuroglobin in cultured neuronal cells exposed to hypoxia re‐oxygenation injury
Authors: Duong Thi Thuy Hong , Witting Paul Kenneth , Antao Shane Tony , Parry Sarah Nicole , Kennerson Marina , Lai Barry , Vogt Stefan , Lay Peter Andrew , Harris Hugh Hamlyn
Published: December 2008

Oxidative stress is associated with the pathology of acute and chronic neurodegenerative disease. We have cloned a human neuroglobin (Nb) construct and over‐expressed this protein in cultured human neuronal cells to assess whether Nb ameliorates the cellular response to experimental hypoxia‐reoxygenation (H/R) injury. Parental cells transfected with a blank (pDEST40) vector responded to H/R injury with a significant decrease in cellular ATP at 5 and 24 h after insult. This was coupled with increases in the cytosolic Ca2+, and the transition metals iron (Fe), copper (Cu), and zinc (Zn) within the cell body, as monitored simultaneously using X‐ray fluorescence microprobe imaging. Parental cell viability decreased over the same time period with a ∼4 to 5‐fold increase in cell death (maximum ∼25%) matched by an increase in caspase 3/7 activation (peaking at a 15‐fold increase after 24 h) and condensation of β‐actin along axonal processes. Over‐expression of Nb inhibited ATP loss and except for significant decreases in the sulfur (S), chlorine (Cl), potassium (K) and Ca2+ contents, maintained cellular ion homeostasis after H/R insult. This resulted in increased cell viability, significantly diminished caspase activation and maintenance of the β‐actin cytoskeletal structure and receptor‐mediated endocytosis. These data indicate that bolstering the cellular content of Nb inhibits neuronal cell dysfunction promoted by H/R insult through multiple protective actions including: (i) maintenance of cellular bioenergetics; (ii) inhibition of Ca2+ influx; (iii) a reduction in cellular uptake of Fe, Cu and Zn at the expense of S, Cl and K; and (iv) an enhancement of cell viability through inhibiting necrosis and apoptosis.
HSP70 interacting protein prevents the accumulation of inclusions in polyglutamine disease1
Authors: Howarth Joanna L. , Glover Colin P. J. , Uney James B.
Published: December 2008

Heat shock proteins (HSPs) are associated with the proteinaceous inclusions that characterise many neurodegenerative diseases. This suggests they may be associated with disease aetiology and/or represents an attempt to remove abnormal protein aggregates. In this study the adenoviral mediated over‐expression of HSP70 interacting protein (HIP) alone was shown to significantly reduce inclusion formation in both an in vitro model of Spinal Bulbar Muscular Atrophy and a primary neuronal model of polyglutamine disease. Experiments to determine the mechanism of action showed that: denatured luciferase activity (a measure of protein refolding) was not increased in the presence of HIP alone but was increased when HIP was co‐expressed with HSP70 or Heat Shock cognate protein 70 (HSC70); the expression of polyglutamine inclusions in cortical neurons mediated an increase in the levels of HSC70 but not HSP70. Our data suggest that HIP may prevent inclusion formation by facilitating the constitutive HSC70 refolding cycle and possibly by preventing aggregation. HIP expression is not increased following stress and its over‐expression may therefore reduce toxic polyglutamine aggregation events and contribute to an effective therapeutic strategy.
Sept8 controls the binding of vesicle‐associated membrane protein 2 to synaptophysin
Authors: Ito Hidenori , Atsuzawa Kimie , Morishita Rika , Usuda Nobuteru , Sudo Kaori , Iwamoto Ikuko , Mizutani Kosuke , Katoh‐Semba Ritsuko , Nozawa Yoshinori , Asano Tomiko , Nagata Koh‐ichi
Published: December 2008

Septins, a conserved family of GTP/GDP‐binding proteins, are present in organisms as diverse as yeast and mammals. We analyzed the distribution of five septins, Sept6, Sept7, Sept8, Sept9 and Sept11, in various rat tissues by western blot analyses and found all septins to be expressed in brain. We also examined the developmental changes of expression of these septins in the rat brain and found that the level of Sept8 increased during post‐natal development. Morphological analyses revealed that Sept8 is enriched at pre‐synapses. Using yeast two‐hybrid screening, we identified vesicle‐associated membrane protein 2 (VAMP2), a soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE), as an interacting protein for Sept8. Synaptophysin is reported to associate with and recruit VAMP2 to synaptic vesicles and dissociate prior to forming the SNARE complex consisting of VAMP2, syntaxin and synaptosome‐associated protein of 25 kDa. We showed that Sept8 suppresses the interaction between VAMP2 and synaptophysin through binding to VAMP2. In addition, we found that Sept8 forms a complex with syntaxin1A, and the Sept8‐VAMP2 interaction is disrupted by synaptosome‐associated protein of 25 kDa. These results suggest that Sept8 may participate in the process of the SNARE complex formation and subsequent neurotransmitter release.
A Single Gene Causes Both Male Sterility and Segregation Distortion in
Drosophila
Hybrids
Authors: Phadnis Nitin , Orr H. Allen
Published: December 2008

A central goal of evolutionary biology is to identify the genes and evolutionary forces that cause speciation, the emergence of reproductive isolation between populations. Despite the identification of several genes that cause hybrid sterility or inviability—many of which have evolved rapidly under positive Darwinian selection—little is known about the ecological or genomic forces that drive the evolution of postzygotic isolation. Here, we show that the same gene,
Overdrive
, causes both male sterility and segregation distortion in F
1
hybrids between the Bogota and U.S. subspecies of
Drosophila pseudoobscura
. This segregation distorter gene is essential for hybrid sterility, a strong reproductive barrier between these young taxa. Our results suggest that genetic conflict may be an important evolutionary force in speciation.
Development of Chemically Defined Media Supporting High-Cell-Density Growth of Lactococci, Enterococci, and Streptococci
Authors: Zhang Guiying , Mills David A. , Block David E.
Published: December 2008

Lactococcus lactis
IL1403 was used as an experimental strain to develop a chemically defined medium for study of the physiology and metabolic pathways of lactococci. An experimental leave-one-out technique was employed to determine the necessity of each of the 57 chemical components used in medium development. A statistical experimental design approach including three fractional factorial designs and a central composite design was used to optimize the fermentation process with 21 variables composed of 19 nutritional factors grouped from the 57 components and two environmental factors (initial pH and temperature). For
L. lactis
IL1403, the maximum biomass concentrations obtained with the two optimal chemically defined media developed in this study (ZMB1 and ZMB2) were generally 3.5- to 4-fold higher than the maximum biomass concentrations obtained with the previously described best synthetic media (SA) and 50% to 68% higher than the maximum biomass concentrations obtained with M17, a complex medium commonly used for lactococci. The new chemically defined media support high-cell-density growth of numerous strains of
L. lactis
,
Enterococcus faecalis
, and
Streptococcus thermophilus
.
Incorporation of Ceramides intoSaccharomyces cerevisiaeGlycosylphosphatidylinositol-Anchored Proteins Can Be Monitored In Vitro
Authors: Bosson Régine , Guillas Isabelle , Vionnet Christine , Roubaty Carole , Conzelmann Andreas
Published: December 2008

After glycosylphosphatidylinositols (GPIs) are added to GPI proteins ofSaccharomyces cerevisiae, a fatty acid of the diacylglycerol moiety is exchanged for a C26:0fatty acid through the subsequent actions of Per1 and Gup1. In most GPI anchors this modified diacylglycerol-based anchor is subsequently transformed into a ceramide-containing anchor, a reaction which requires Cwh43. Here we show that the last step of this GPI anchor lipid remodeling can be monitored in microsomes. The assay uses microsomes from cells that have been grown in the presence of myriocin, a compound that blocks the biosynthesis of dihydrosphingosine (DHS) and thus inhibits the biosynthesis of ceramide-based anchors. Such microsomes, when incubated with [3H]DHS, generate radiolabeled, ceramide-containing anchor lipids of the same structure as made by intact cells. Microsomes fromcwh43Δ ormcd4Δ mutants, which are unable to make ceramide-based anchors in vivo, do not incorporate [3H]DHS into anchors in vitro. Moreover,gup1Δ microsomes incorporate [3H]DHS into the same abnormal anchor lipids asgup1Δ cells synthesize in vivo. Thus, the in vitro assay of ceramide incorporation into GPI anchors faithfully reproduces the events that occur in mutant cells. Incorporation of [3H]DHS into GPI proteins is observed with microsomes alone, but the reaction is stimulated by cytosol or bovine serum albumin, ATP plus coenzyme A (CoA), or C26:0-CoA, particularly if microsomes are depleted of acyl-CoA. Thus, [3H]DHS cannot be incorporated into proteins in the absence of acyl-CoA.
Regulation and Activity of a Zinc Uptake Regulator, Zur, in
Corynebacterium diphtheriae
Authors: Smith Kelsy F. , Bibb Lori A. , Schmitt Michael P. , Oram Diana M.
Published: December 2008

Regulation of metal ion homeostasis is essential to bacterial cell survival, and in most species it is controlled by metal-dependent transcriptional regulators. In this study, we describe a
Corynebacterium diphtheriae
ferric uptake regulator-family protein, Zur, that controls expression of genes involved in zinc uptake. By measuring promoter activities and mRNA levels, we demonstrate that Zur represses transcription of three genes (
zrg
,
cmrA
, and
troA
) in zinc-replete conditions. All three of these genes have similarity to genes involved in zinc uptake. Transcription of
zrg
and
cmrA
was also shown to be regulated in response to iron and manganese, respectively, by mechanisms that are independent of Zur. We demonstrate that the activity of the
zur
promoter is slightly decreased under low zinc conditions in a process that is dependent on Zur itself. This regulation of
zur
transcription is distinctive and has not yet been described for any other
zur
. An adjacent gene, predicted to encode a metal-dependent transcriptional regulator in the ArsR/SmtB family, is transcribed from a separate promoter whose activity is unaffected by Zur. A
C. diphtheriae zur
mutant was more sensitive to peroxide stress, which suggests that
zur
has a role in protecting the bacterium from oxidative damage. Our studies provide the first evidence of a zinc specific transcriptional regulator in
C. diphtheriae
and give new insights into the intricate regulatory network responsible for regulating metal ion concentrations in this toxigenic human pathogen.
Characterization of YvcJ, a Conserved P-Loop-Containing Protein, and Its Implication in Competence in
Bacillus subtilis
Authors: Luciano Jennifer , Foulquier Elodie , Fantino Jean-Raphael , Galinier Anne , Pompeo Frédérique
Published: December 2008

The uncharacterized protein family UPF0042 of the Swiss-Prot database is predicted to be a member of the conserved group of bacterium-specific P-loop-containing proteins. Here we show that two of its members, YvcJ from
Bacillus subtilis
and YhbJ, its homologue from
Escherichia coli
, indeed bind and hydrolyze nucleotides. The cellular function of
yvcJ
was then addressed. In contrast to results recently obtained for
E. coli
, which indicated that
yhbJ
mutants strongly overproduced glucosamine-6-phosphate synthase (GlmS), comparison of the wild type with the
yvcJ
mutant of
B. subtilis
showed that GlmS expression was quite similar in the two strains. However, in mutants defective in
yvcJ
, the transformation efficiency and the fraction of cells that expressed competence were reduced. Furthermore, our data show that YvcJ positively controls the expression of late competence genes. The overexpression of
comK
or
comS
compensates for the decrease in competence of the
yvcJ
mutant. Our results show that even if YvcJ and YhbJ belong to the same family of P-loop-containing proteins, the deletion of corresponding genes has different consequences in
B. subtilis
and in
E. coli
.
Chromatin Organization and Radio Resistance in the Bacterium
Gemmata obscuriglobus
Authors: Lieber Arnon , Leis Andrew , Kushmaro Ariel , Minsky Abraham , Medalia Ohad
Published: December 2008

The organization of chromatin has a major impact on cellular activities, such as gene expression. For bacteria, it was suggested that the spatial organization of the genetic material correlates with transcriptional levels, implying a specific architecture of the chromosome within the cytoplasm. Accordingly, recent technological advances have emphasized the organization of the genetic material within nucleoid structures.
Gemmata obscuriglobus
, a member of the phylum
Planctomycetes
, exhibits a distinctive nucleoid structure in which chromatin is encapsulated within a discrete membrane-bound compartment. Here, we show that this soil and freshwater bacterium tolerates high doses of UV and ionizing radiation. Cryoelectron tomography of frozen hydrated sections and electron microscopy of freeze-substituted cells have indicated a more highly ordered condensed-chromatin organization in actively dividing and stationary-phase
G. obscuriglobus
cells. These three-dimensional analyses revealed a complex network of double membranes that engulf the condensed DNA. Bioinformatics analysis has revealed the existence of a putative component involved in nonhomologous DNA end joining that presumably plays a role in maintaining chromatin integrity within the bacterium. Thus, our observations further support the notion that packed chromatin organization enhances radiation tolerance.
Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation
Authors: Sodha Neel R. , Clements Richard T. , Boodhwani Munir , Xu Shu-Hua , Laham Roger J. , Bianchi Cesario , Sellke Frank W.
Published: December 2008

Coronary artery disease (CAD) is the leading cause of mortality in diabetic patients. Because of the diffuse nature of their disease, diabetic patients may be at risk for incomplete revascularization, highlighting a potential role for proangiogenic therapy in this group. This study investigates molecular mechanisms of angiogenesis in diabetic patients. Myocardial tissue was harvested from patients undergoing coronary artery bypass grafting [nondiabetic (ND) 11, type 2 diabetic (DM) 10]. Expression of angiostatin, endostatin, their precursors (plasminogen and collagen XVIII, respectively), enzymes leading to their production [matrix metalloprotease (MMP)-2 and -9, cathepsin L], and an inhibitor of MMPs (tissue inhibitor of metalloproteinase) was assessed with Western blotting. MMP activity was assessed. Coronary collateralization was graded by Rentrop scoring of angiograms. Plasminogen and collagen XVIII expression were similar between groups. Angiostatin expression trended to increase 1.24-fold ( P = 0.07), and endostatin expression increased 2.02-fold in DM patients relative to ND ( P = 0.02). MMP-9 expression was no different between groups, whereas MMP-2 expression decreased 1.8-fold in diabetics ( P = 0.003). MMP-2 and -9 activity decreased 1.33-fold ( P = 0.03) and 1.57-fold ( P = 0.04), respectively, in diabetic patients. Cathepsin L expression was 1.38-fold higher in diabetic patients ( P = 0.02). Coronary collateralization scores were ND 2.1 ± 0.37 vs. DM 1.0 ± 0.4 ( P = 0.05). Myocardial endostatin expression correlated strongly with the percentage of hemoglobin A1c ( r = 0.742, P = 0.0001). Myocardial expression of angiostatin and endostatin demonstrated significant negative linear correlations with coronary collateralization (angiostatin r = −0.531, P = 0.035, endostatin r = −0.794, P = 0.0002). Diabetic patients with CAD exhibit increased levels of the antiangiogenic proteins angiostatin and endostatin and differential regulation of the enzymes governing their production relative to ND patients. Myocardial levels of these proteins show significant correlation to coronary collateralization. These findings offer potential new therapeutic targets for enhancing proangiogenic therapy and insight into the angiogenic impairments seen in diabetes.
Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase
Authors: Farley K. S. , Wang L. , Mehta S.
Published: December 2008

A significant role for alveolar macrophages (AM) in the pathophysiology of sepsis-induced acute lung injury (ALI) has been shown; however, the mechanisms behind AM-related lung injury remain relatively uncertain. We examined the role of AM nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in pulmonary endothelial cell septic injury. NADPH oxidase is one of the major sources of cellular reactive oxygen species and has been implicated in endothelial injury in ALI. Pulmonary microvascular endothelial cells (PMVEC) monolayers were grown on Transwell inserts and incubated with wild-type and NADPH oxidase-deficient AM in the presence or absence of cytomix (equimolar TNF-α, IL-1β, and IFN-γ). Injury to the monolayers was assessed by trans-PMVEC Evans blue (EB)-labeled albumin flux. We found AM under cytomix stimulation caused significant EB-albumin flux across the PMVEC monolayers, and this effect was attenuated by the genetic deletion of AM NADPH oxidase. The pharmacological inhibition of AM NADPH oxidase with apocynin and PR-39 also significantly reduced AM-dependent PMVEC injury. In the AM-PMVEC cocultures, we also assessed PMVEC injury through measurement of protein oxidation and lipid peroxidation. AM were shown to cause a significant increase in these markers of PMVEC injury, which was also attenuated by the inhibition of NADPH oxidase or through the use of NADPH oxidase-deficient AM. PMVEC NADPH oxidase was shown not to significantly contribute to PMVEC injury in our studies. From our findings we have concluded that AM NADPH oxidase is crucial for the septic increase in pulmonary vascular permeability.
The role of time and pressure on alveolar recruitment
Authors: Albert Scott P. , DiRocco Joseph , Allen Gilman B. , Bates Jason H. T. , Lafollette Ryan , Kubiak Brian D. , Fischer John , Maroney Sean , Nieman Gary F.
Published: December 2008

Inappropriate mechanical ventilation in patients with acute respiratory distress syndrome can lead to ventilator-induced lung injury (VILI) and increase the morbidity and mortality. Reopening collapsed lung units may significantly reduce VILI, but the mechanisms governing lung recruitment are unclear. We thus investigated the dynamics of lung recruitment at the alveolar level. Rats ( n = 6) were anesthetized and mechanically ventilated. The lungs were then lavaged with saline to simulate acute respiratory distress syndrome (ARDS). A left thoracotomy was performed, and an in vivo microscope was placed on the lung surface. The lung was recruited to three recruitment pressures (RP) of 20, 30, or 40 cmH2O for 40 s while subpleural alveoli were continuously filmed. Following measurement of microscopic alveolar recruitment, the lungs were excised, and macroscopic gross lung recruitment was digitally filmed. Recruitment was quantified by computer image analysis, and data were interpreted using a mathematical model. The majority of alveolar recruitment (78.3 ± 7.4 and 84.6 ± 5.1%) occurred in the first 2 s (T2) following application of RP 30 and 40, respectively. Only 51.9 ± 5.4% of the microscopic field was recruited by T2 with RP 20. There was limited recruitment from T2 to T40 at all RPs. The majority of gross lung recruitment also occurred by T2 with gradual recruitment to T40. The data were accurately predicted by a mathematical model incorporating the effects of both pressure and time. Alveolar recruitment is determined by the magnitude of recruiting pressure and length of time pressure is applied, a concept supported by our mathematical model. Such a temporal dependence of alveolar recruitment needs to be considered when recruitment maneuvers for clinical application are designed.
Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control
Authors: Bessac Bret F. , Jordt Sven-Eric
Published: December 2008

New studies have revealed an essential role for TRPA1, a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species, and noxious constituents of smoke and smog, initiating irritation and airway reflex responses. Together with TRPV1, the capsaicin receptor, TRPA1 may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome.
Item Response Theory With Estimation of the Latent Density Using Davidian Curves
Authors: Woods Carol M. , Lin Nan
Published: December 2008

Davidian-curve item response theory (DC-IRT) is introduced, evaluated with simulations, and illustrated using data from the Schedule for Nonadaptive and Adaptive Personality Entitlement scale. DC-IRT is a method for fitting unidimensional IRT models with maximum marginal likelihood estimation, in which the latent density is estimated, simultaneously with the item parameters of logistic item response functions, as a Davidian curve. Simulations compare DC-IRT with Ramsay-curve IRT (RC-IRT) and the empirical histogram method (EHM) for a normal, bimodal, or skewed latent distribution. When the latent density was nonnormal, any of the three density estimation methods improved on the normal model. Both DC-IRT and RC-IRT produced more-accurate results than did the EHM.
Mothers' Economic Hardship and Behavior Problems in Their Early Adolescents
Authors: Burrell Ginger Lockhart , Roosa Mark W.
Published: December 2008

Concerns about the heightened prevalence of behavior problems among adolescents from low-income families have prompted researchers to understand processes through which economic variables influence functioning within multiple domains. Guided by a stress process framework and social contextual theory, this study examines processes linking perceived economic hardship and adolescent problem behavior in a sample of urban families. It hypothesizes that stress process variables experienced by mothers contribute to adolescents' functioning within the family, academic, and peer domains, which ultimately predict behavior problems. Results show a good fit of the models to the data, suggesting that the integration of stress process and social contextual approaches may be of particular use for scholars interested in understanding economic influences on adolescent problem behaviors.
Improving Methods for Measuring Quality of Care
Authors: Bokhour Barbara G. , Pugh Mary Jo , Rao Jaya K. , Avetisyan Ruzan , Berlowitz Dan R. , Kazis Lewis E.
Published: December 2008

As health care systems seek to provide patient-centered care as a cornerstone of quality, how to measure this aspect of quality has become a concern. Previous development of quality indicators for treating individual chronic disease has rarely included patient perspectives on quality of care. Using epilepsy as an exemplar, the authors sought to develop an approach to measuring patient-centered quality of care. They conducted six focus groups with adults with epilepsy. Using qualitative methods, the authors initially identified 10 patient-generated quality indicators, 5 of which were subsequently rated, along with literature-based quality indicators, by an expert panel using a modified RAND appropriateness methodology. The authors discuss similarities and differences in aspects of care patients and providers value as essential for good quality. The process presented in this article may serve as a model for incorporating patient perceptions of quality into the future development of quality indicators for chronic diseases.
Expression and distribution of Toll-like receptors 11–13 in the brain during murine neurocysticercosis
Authors: Mishra Bibhuti B , Gundra Uma Mahesh , Teale Judy M
Published: December 2008

The functions of Toll-like receptors (TLRs) 11–13 in central nervous system (CNS) infections are currently unknown. Using a murine model of neurocysticercosis, we investigated the expression and distribution of TLRs 11–13 by using both gene specific real-time PCR analysis andin situimmunofluoresence microscopy in both control and neurocysticercosis brains. In the mock infected brain, mRNAs of TLRs 11–13 were constitutively expressed. Parasite infection caused an increase of both mRNAs and protein levels of all three TLRs by several fold. All three TLR proteins were present in both CNS and immune cell types. Among them TLR13 was expressed the most in terms of number of positive cells and brain areas expressing it, followed by TLR11 and TLR12 respectively. Among the nervous tissue cells, TLRs 11–13 protein levels appeared highest in neurons. However, TLR13 expression was also present in ependymal cells, endothelial cells of pial blood vessels, and astrocytes. In contrast, infiltrating CD11b and CD11c positive myeloid cells predominantly produced TLR11 protein, particularly early during infection at 1 wk post infection (~50% cells). TLRs 12 and 13 proteins were present on approximately 5% of infiltrating immune cells. The infiltrating cells positive for TLRs 11–13 were mostly of myeloid origin, CD11b+ cells. This report provides a comprehensive analysis of the expression of TLRs 11–13 in normal and parasite infected mouse brains and suggests a role for them in CNS infections.
CCR7-deficient mice develop atypically persistent germinal centers in response to thymus-independent type 2 antigens
Authors: Achtman Ariel H , Höpken Uta E , Bernert Carola , Lipp Martin
Published: December 2008

Thymus-independent type 2 (TI-2) antigens are repetitive antigens capable of eliciting antibody responses without T cell help. They are important in the immune response against encapsulated bacteria and as a rapid first line of defense against pathogens. TI-2 antigens induce strong proliferation in extrafollicular foci. However, any germinal centers forming in response to TI-2 antigens involute synchronously 5 days after immunization. This is thought to be caused by the lack of T cell help. Surprisingly, immunization of mice deficient for the homeostatic chemokine receptor CCR7 with TI-2 antigens resulted not only in the expected, vigorous extrafollicular plasma cell response but also in persisting splenic germinal centers. This was observed for two different TI-2 antigens, heat-killed Streptococcus pneumoniae and (4-hydroxy-3-nitrophenyl)acetyl-Ficoll (NP-Ficoll). Germinal centers induced by TI-2 and thymus-dependent (TD) antigens were located in the periarteriolar area of the white pulp in CCR7 knockout mice, corresponding to the T zone of wild-type (WT) mice. The TI-2-induced germinal centers contained peripheral rings of follicular dendritic cells and unusually for TI-2-induced germinal centers, T cells. The licensing responsible for their atypical persistence did not endow TI-2-induced germinal centers with the full range of characteristics of classic germinal centers induced by TD antigens. Thus, class-switching, affinity maturation, and memory B cell generation were not increased in CCR7-deficient mice. It seems unlikely that a defect in regulatory T cell (Treg) location was responsible for the atypical persistence of TI-2-induced germinal centers, as Tregs were comparably distributed in germinal centers of CCR7-deficient and WT mice.
The fully integrated biomedical engineering programme at Eindhoven University of Technology
Authors: Slaaf D W , van Genderen M H P
Published: December 2008

The development of a fully integrated biomedical engineering programme (life sciences included from the start) is described. Details are provided about background, implementation, and didactic concept: design centred learning combined with courses. The curriculum has developed into a bachelor—master's programme with two different master's degrees: Master's Degree in Biomedical Engineering and Master's Degree in Medical Engineering. Recently, the programme has adopted semester programming, has included a major and minor in the bachelor's degree phase, and a true bachelor's degree final project. Details about the programme and data about where graduates find jobs are provided in this paper.
Towards a Dual‐Tip STM Application in Mesoscopic Electron Transport
Authors: Dana Rami , Kiruschev Irina , Tran Phong Dinh , Doppelt Pascal , Manassen Yishay
Published: December 2008

A new design for a dual‐tip scanning tunneling microscope (STM) is presented. The design is a variation on the mechanically controllable break‐junction with two electron beam‐induced deposition nano‐tips. The new design enables one to scan surfaces simultaneously with two probes having a nano‐gap separation. By collecting the lateral current flowing between the tips, the transconductance map can then be compared with the STM images for local characterizations of the electron transport. Since the lateral beam carries the property of the density of states of the surface at momentum space, the dispersion of the electronic structure should give an orientation and position dependence of the local transconductance current. In addition, the reduced terminal separation, on the order of the characteristic mesoscopic length scales, is likely to be sensitive to a variety of typically observed interactions and interference effects.
Corneal Limbal Microenvironment Can Induce Transdifferentiation of Hair Follicle Stem Cells into Corneal Epithelial-like Cells
Authors: Blazejewska Ewa Anna , Schlötzer-Schrehardt Ursula , Zenkel Matthias , Bachmann Björn , Chankiewitz Erik , Jacobi Christina , Kruse Friedrich E.
Published: December 2008

The aim of this study was to investigate the transdifferentiation potential of murine vibrissa hair follicle (HF) stem cells into corneal epithelial-like cells through modulation by corneal- or limbus-specific microenvironmental factors. Adult epithelial stem cells were isolated from the HF bulge region by mechanical dissection or fluorescence-activated cell sorting using antibodies to α6 integrin, enriched by clonal expansion, and subcultivated on various extracellular matrices (type IV collagen, laminin-1, laminin-5, fibronectin) and in different conditioned media derived from central and peripheral corneal fibroblasts, limbal stromal fibroblasts, and 3T3 fibroblasts. Cellular phenotype and differentiation were evaluated by light and electron microscopy, real-time reverse transcription-polymerase chain reaction, immunocytochemistry, and Western blotting, using antibodies against putative stem cell markers (K15, α6 integrin) and differentiation markers characteristic for corneal epithelium (K12, Pax6) or epidermis (K10). Using laminin-5, a major component of the corneo-limbal basement membrane zone, and conditioned medium from limbal stromal fibroblasts, clonally enriched HF stem and progenitor cells adhered rapidly and formed regularly arranged stratified cell sheets. Conditioned medium derived from limbal fibroblasts markedly upregulated expression of cornea-specific K12 and Pax6 on the mRNA and protein level, whereas expression of the epidermal keratinocyte marker K10 was strongly downregulated. These findings suggest that adult HF epithelial stem cells are capable of differentiating into corneal epithelial-like cells in vitro when exposed to a limbus-specific microenvironment. Therefore, the HF may be an easily accessible alternative therapeutic source of autologous adult stem cells for replacement of the corneal epithelium and restoration of visual function in patients with ocular surface disorders.
Evidence for Transcriptional Regulation of the Glucose-6-Phosphate Transporter by HIF-1α: Targeting G6PT with Mumbaistatin Analogs in Hypoxic Mesenchymal Stromal Cells
Authors: Lord-Dufour Simon , Copland Ian B. , Levros Louis-Charles , Post Martin , Das Abhirup , Khosla Chaitan , Galipeau Jacques , Rassart Eric , Annabi Borhane
Published: December 2008

Mesenchymal stromal cell (MSC) markers are expressed on brain tumor-initiating cells involved in the development of hypoxic glioblastoma. Given that MSCs can survive hypoxia and that the glucose-6-phosphate transporter (G6PT) provides metabolic control that contributes to MSC mobilization and survival, we investigated the effects of low oxygen (1.2% O2) exposure on G6PT gene expression. We found that MSCs significantly expressed G6PT and the glucose-6-phosphatase catalytic subunit β, whereas expression of the glucose-6-phosphatase catalytic subunit α and the islet-specific glucose-6-phosphatase catalytic subunit-related protein was low to undetectable. Analysis of the G6PT promoter sequence revealed potential binding sites for hypoxia inducible factor (HIF)-1α and for the aryl hydrocarbon receptor (AhR) and its dimerization partner, the AhR nuclear translocator (ARNT), AhR:ARNT. In agreement with this, hypoxia and the hypoxia mimetic cobalt chloride induced the expression of G6PT, vascular endothelial growth factor (VEGF), and HIF-1α. Gene silencing of HIF-1α prevented G6PT and VEGF induction in hypoxic MSCs whereas generation of cells stably expressing HIF-1α resulted in increased endogenous G6PT gene expression. A semisynthetic analog of the polyketide mumbaistatin, a potent G6PT inhibitor, specifically reduced MSC-HIF-1α cell survival. Collectively, our data suggest that G6PT may account for the metabolic flexibility that enables MSCs to survive under conditions characterized by hypoxia and could be specifically targeted within developing tumors.