bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing the 18 April 2002 storm‐time sawtooth events using ground magnetic data
Authors: Clauer C. Robert , Cai Xia , Welling Daniel , DeJong Anna , Henderson Michael G.
Published: April 2006

Beginning during the last half of the main phase and extending for over 12 hours, the 18 April 2002 magnetic storm is dominated by sawtooth oscillations. We examine the ground magnetic signatures of these events at both high latitudes and low latitudes. The first immediate observation is that the magnetic signatures from one sawtooth to another can show considerable variation. Thus the current systems associated with these events show considerable variation in location, pattern, and strength from one oscillation to the next. The characteristics of the magnetic disturbance for each sawtooth has little to distinguish it from the typical substorm expansion magnetic disturbance field except that some of the sawteeth disturbance profiles are broader in local time than observed during typical substorms. The injection region determined from the energetic particle flux measurements at geostationary orbit is generally broad, extending across the entire tail and past the terminators into the dayside. The injection region is usually wider than the magnetic disturbance profile at the peak of the dipolarization. There appears to be no relationship between the magnetic disturbance profile and the location and strength of the injection boundary. Finally, sawtooth events appear to be driven by a steady solar wind driver and to develop during a period of already enhanced ring current.
Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts
Authors: Petrov Andrei , Pirozhkova Iryna , Carnac Gilles , Laoudj Dalila , Lipinski Marc , Vassetzky Yegor S.
Published: April 2006

Fascioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder linked to partial deletion of integral numbers of a 3.3 kb polymorphic repeat, D4Z4, within the subtelomeric region of chromosome 4q. Although the relationship between deletions of D4Z4 and FSHD is well established, how this triggers the disease remains unclear. We have mapped the DNA loop domain containing the D4Z4 repeat cluster in human primary myoblasts and in murine–human hybrids. A nuclear matrix attachment site was found located in the vicinity of the repeat. Prominent in normal human myoblasts and nonmuscular human cells, this site is much weaker in muscle cells derived from FSHD patients, suggesting that the D4Z4 repeat array and upstream genes reside in two loops in nonmuscular cells and normal human myoblasts but in only one loop in FSHD myoblasts. We propose a model whereby the nuclear scaffold/matrix attached region regulates chromatin accessibility and expression of genes implicated in the genesis of FSHD.
The ILC and State Responsibility
Authors: Rosenstock Robert
Published: April 2006

The handling by the International Law Commission (ILC) of state responsibility, hazardous activities, and strict liability reveals in many ways the Commission’s strengths and limitations. This work also tells much about the development of international law and the extent to which there is—or is not—an international community. The Commission’s work on state responsibility in particular also illustrates the validity of Holmes’s immortal statement about logic and the life of the law, the utility of Occam’s razor, and the value of William James’s pragmatism. Even if Philip Allott were close to the mark—as he often is—in calling the draft articles, as they then were, “bland gruel,” it is hard to ignore the need for the articles or their contribution to the unification of international law. Both are witnessed by tribunals’ eagerness to cite the Commission’s texts even before their formal adoption. While this practice has upset some as premature, it reflects the symbiotic process that has evolved over time as both the Commission and courts and tribunals labor to clarify existing law. Codification of lex lata may be no less effective if contained in a paragraph of a report rather than in an article of a multilateral treaty.
Phagocytic NADPH Oxidase Overactivity Underlies Oxidative Stress in Metabolic Syndrome
Authors: Fortuño Ana , San José Gorka , Moreno María U. , Beloqui Oscar , Díez Javier , Zalba Guillermo
Published: April 2006

Oxidative stress plays a critical role in the pathogenesis of atherosclerosis in patients with metabolic syndrome. This study aimed to investigate whether a relationship exists between phagocytic NADPH oxidase activity and oxidative stress and atherosclerosis in metabolic syndrome patients. The study was performed in 56 metabolic syndrome patients (metabolic syndrome group), 99 patients with one or two cardiovascular risk factors (cardiovascular risk factor group), and 28 healthy subjects (control group). NADPH oxidase expression and activity was augmented (P < 0.05) in metabolic syndrome compared with cardiovascular risk factor and control groups. Insulin was enhanced (P < 0.05) in metabolic syndrome patients compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. Insulin stimulated NADPH oxidase activity; this effect was abolished by a specific protein kinase C inhibitor. Oxidized LDL and nitrotyrosine levels and carotid intima-media thickness were increased (P < 0.05) in the metabolic syndrome group compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. These findings suggest that phagocytic NADPH oxidase overactivity is involved in oxidative stress and atherosclerosis in metabolic syndrome patients. Our findings also suggest that hyperinsulinemia may contribute to oxidative stress in metabolic syndrome patients through activation of NADPH oxidase.
Adiponectin Multimeric Complexes and the Metabolic Syndrome Trait Cluster
Authors: Lara-Castro Cristina , Luo Nanlan , Wallace Penny , Klein Richard L. , Garvey W. Timothy
Published: April 2006

Adiponectin circulates in human plasma mainly as a 180-kDa low molecular weight (LMW) hexamer and a high molecular weight (HMW) multimer of ∼360 kDa. We comprehensively examined the relationships between circulating levels of total adiponectin, adiponectin multimers, and the relative distribution (i.e., ratio) of multimeric forms with key features of the metabolic syndrome. Total adiponectin (r = 0.45), HMW (r = 0.47), LMW (r = 0.31), and HMW-to-total adiponectin ratio (r = 0.29) were significantly correlated with insulin-stimulated glucose disposal rate. Similarly, total (r = −0.30), HMW (r = −0.38), and HMW-to-total adiponectin ratio (r = −0.34) were correlated with central fat distribution but not with total fat mass or BMI. Regarding energy metabolism, although there were no effects on resting metabolic rate, total (r = 0.41) and HMW (r = 0.44) were associated with increasing rates of fat oxidation. HMW-to-total adiponectin ratio increased as a function of total adiponectin, and it was HMW quantity (not total or HMW-to-total adiponectin ratio or LMW) that was primarily responsible for all of these relationships. Impact on nuclear magnetic resonance lipoprotein subclasses was assessed. HMW and total adiponectin were correlated with decreases in large VLDL (r = −0.44 and −0.41); decreases in small LDL (r = −0.41 and −0.36) and increases in large LDL (r = 0.36 and 0.30) particle concentrations accompanied by increased LDL particle size (r = 0.47 and 0.39); and increases in large HDL (r = 0.45 and 0.37) and HDL particle size (r = 0.53 and 0.47). Most of these correlations persisted after adjustment for metabolic covariables. In conclusion, first, serum adiponectin is associated with increased insulin sensitivity, reduced abdominal fat, and high basal lipid oxidation; however, it is HMW quantity, not total or HMW-to-total adiponectin ratio, that is primarily responsible for these relationships. Second, reduced quantities of HMW independently recapitulate the lipoprotein subclass profile associated with insulin resistance after correcting for glucose disposal rate and BMI. Finally, HMW adiponectin is an important factor in explaining the metabolic syndrome.
A Randomized Comparison of Pioglitazone to Inhibit Restenosis After Coronary Stenting in Patients With Type 2 Diabetes
Authors: Nishio Kazuaki , Sakurai Masayuki , Kusuyama Taro , Shigemitsu Meiei , Fukui Tomoyasu , Kawamura Kitaro , Itoh Seiji , Konno Noburu , Katagiri Takashi
Published: April 2006

OBJECTIVE—Recent studies have demonstrated that the treatment with thiazolidinediones reduces in-stent restenosis. The aim of this study was to elucidate the mechanism of the efficacy of pioglitazone for preventing in-stent restenosis in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—We conducted a prospective, randomized trial involving 54 type 2 diabetic patients referred for coronary stenting who were randomly assigned to either the control or the pioglitazone group. Quantitative coronary angiography was performed at study entry and at 6 months follow-up. Endothelial nitric oxide synthase (eNOS), tumor necrosis factor α, interleukin-6, leptin, and adiponectin were measured at study entry and at 6 months follow-up.

RESULTS—A total of 28 patients were randomly assigned to the control group, and 26 patients were assigned to the pioglitazone group. There were no significant differences in glycemic control levels or in lipid levels in the two groups at baseline or at follow-up. Insulin, homeostasis model assessment of insulin resistance, eNOS, and leptin at follow-up were significantly reduced in the pioglitazone group compared with the control group. The late luminal loss and in-stent restenosis were significantly less in the pioglitazone group than in the control group. Leptin independently correlated with late luminal loss at multiple regression analysis.

CONCLUSIONS—The treatment with pioglitazone in type 2 diabetic patients significantly reduced leptin. This decreased leptin improved insulin resistance and endothelial function with the reduction of insulin. The improved endothelial function affected the reduction of in-stent restenosis.
Preliminary three‐dimensional analysis of the heliospheric response to the 28 October 2003 CME using SMEI white‐light observations
Authors: Jackson B. V. , Buffington A. , Hick P. P. , Wang X. , Webb D.
Published: April 2006

The Solar Mass Ejection Imager (SMEI) has recorded the inner heliospheric response in white‐light Thomson scattering to the 28 October 2003 coronal mass ejection (CME). This preliminary report shows the evolution of this particular event in SMEI observations, as we track it from a first measurement at approximately 20° elongation (angular distance) from the solar disk until it fades in the antisolar hemisphere in the SMEI 180° field of view. The large angle and spectrometric coronagraph (LASCO) images show a CME and an underlying bright ejection of coronal material that is associated with an erupting prominence. Both of these are seen by SMEI in the interplanetary medium. We employ a three‐dimensional (3‐D) reconstruction technique that derives its perspective views from outward flowing solar wind to reveal the shape and extent of the CME. This is accomplished by iteratively fitting the parameters of a kinematic solar wind density model to both SMEI white‐light observations and Solar‐Terrestrial Environment Laboratory (STELab), interplanetary scintillation (IPS) velocity data. This modeling technique separates the true heliospheric signal in SMEI observations from background noise and reconstructs the 3‐D heliospheric structure as a function of time. These reconstructions allow separation of the 28 October CME from other nearby heliospheric structure and a determination of its mass. The present results are the first utilizing this type of 3‐D reconstruction with the SMEI data. We determine an excess‐over‐ambient mass for the southward moving ejecta associated with the prominence material of 7.1 × 1016 g and a total mass of 8.9 × 1016 g. Preliminary SMEI white‐light calibration indicates that the total mass of this CME including possible associated nearby structures may have been as much as ∼2.0 × 1017 g spread over much of the earthward facing hemisphere.
Possible explanation linking 18.6‐year period nodal tidal cycle with bi‐decadal variations of ocean and climate in the North Pacific
Authors: Yasuda Ichiro , Osafune Satoshi , Tatebe Hiroaki
Published: April 2006

Bi‐decadal climate variation is dominant over the North Pacific on inter‐decadal timescale; however the mechanism has not been fully understood. We here find that the bi‐decadal variations in the North Pacific climate and intermediate waters possibly relate to the 18.6‐year period modulation of diurnal tide. In the period of strong diurnal tide, tide‐induced diapycnal mixing makes surface salinity and density higher and the upper‐layer shallower along the Kuril Islands and the east coast of Japan. Simple model results suggest that the coastal depth adjustment by baroclinic Kelvin waves enhances the thermohaline circulation, the upper‐layer poleward western boundary current and associated heat transport by about 0.05PW. This could also explain the warmer SST in the Kuroshio‐Oyashio Extension regions, where positive feedback with Aleutian Low might amplify the bidecadal variations. The 18.6‐year tidal cycle hence could play a role as a basic forcing for the bi‐decadal ocean and climate variations.
Imaging the global solar wind flow in EUV
Authors: Gruntman Mike , Izmodenov Vlad , Pizzo Vic
Published: April 2006

We advance the original concept of imaging the three‐dimensional solar wind flow (Gruntman, 2001a) by characterizing expected heliospheric EUV signatures under assumptions of a realistic solar wind. Charge exchange collisions between the solar wind alpha particles and heliospheric atomic hydrogen produce unique emissions in the 30.4‐nm line. All‐sky images at 30.4 nm with high spectral resolution reveal the three‐dimensional flow properties of the solar wind, including the flow in the regions over the Sun's poles, and the variability of the global solar wind properties during the 11‐year solar cycle. We simulate global heliospheric images at 30.4 nm for a realistic three‐dimensional solar wind with the Sun's effective magnetic dipole tilted with respect to the spin axis, resulting in a complex flow pattern of the plasma. We show that the physical properties of the flow would permit averaging over several rotations of the Sun, thus realistically limiting the total number of all‐sky images to a few per year. This feature effectively establishes the sensitivity requirements for an experiment to image the global solar wind.
On the accuracy of HF radar measurement in the Tsushima Strait
Authors: Yoshikawa Y. , Masuda A. , Marubayashi K. , Ishibashi M. , Okuno A.
Published: April 2006

The accuracy of HF radar measurement in the Tsushima Strait is investigated. A comparison between radial velocities measured by HF radar and acoustic Doppler current profiler (ADCP), which provides an upper bound of HF radar measurement error, shows that the root‐mean‐square (RMS) velocity difference obtained from the principal component analysis is 6.62∼11.3 cm s−1. A comparison of velocities measured by two facing HF radars, which provides a lower bound of HF radar measurement error, shows that the variance error of hourly radial velocity is 5.75∼13.3 cm s−1. The bias error of HF radar measurement is also found to be reasonably small through a comparison of tidal ellipses estimated from 1 year of HF radar data with those from 5 years of ADCP data. These results suggest that the variance error of HF radar measurement is the dominant source of the velocity difference found between ADCP and HF radar.
Cenozoic contractional reactivation of Mesozoic extensional structures in the Eastern Cordillera of Colombia
Authors: Mora Andrés , Parra Mauricio , Strecker Manfred R. , Kammer Andreas , Dimaté Cristina , Rodríguez Fernando
Published: April 2006

The Eastern Cordillera of Colombia is key to understanding the role of inherited basement anisotropies in the evolution of active noncollisional mountain belts. In particular, the Rio Blanco–Guatiquía region of the Eastern Cordillera is exemplary in displaying a variety of phenomena that document the importance of the orientation, geometry, and segmentation of preorogenic anisotropies. We document the first unambiguous evidence that extensional basement structures played an important role in determining the locus of deformation during contractional reactivation in the Eastern Cordillera. Detailed structural field mapping and analysis of industry seismic reflection profiles have helped to identify the inherited San Juanito, Naranjal, and Servitá normal faults and associated transfer faults as important structures that were inverted during the Cenozoic Andean orogeny. Apparently, the more internal faults in the former rift basin were not properly oriented for an efficient reactivation in contraction. However, these faults have a fundamental role as strain risers, as folding is concentrated west of them. In contrast, reactivated normal faults such as the more external Servitá fault are responsible for uplifting the eastern flank of the Eastern Cordillera. In addition, these structures are adjacent and intimately linked to the development of thin‐skinned faults farther east. In part, the superimposed compression in this prestrained extensional region is compensated by lateral escape. The dominant presence of basement involved buckling and thrusting, and the restricted development of thin‐skinned thrusting in this inversion orogen makes the Eastern Cordillera a close analog to the intraplate Atlas Mountains of Morocco and other inverted sectors of the Andean orogen farther south.
Remote sensing of future competitors: Impacts on plant defenses
Authors: Izaguirre Miriam M. , Mazza Carlos A. , Biondini Mariela , Baldwin Ian T. , Ballaré Carlos L.
Published: April 2006

Far-red radiation (FR) reflected by green tissues is a key signal that plants use to detect the proximity of future competitors. Perception of increased levels of FR elicits a suite of responses collectively known as the shade-avoidance syndrome, which includes increased stem elongation, production of erect leaves, and reduced lateral branching. These responses improve the access to light for plants that occur in crowded populations. Responses to the proximity of competitors are known to affect the susceptibility to disease and predation in several organisms, including social animals. However, the impacts of warning signals of competition on the expression of defenses have not been explicitly investigated in plants. In the experiments reported here, we show that reflected FR induced a dramatic down-regulation of chemical defenses in wild tobacco (
Nicotiana longiflora
). FR altered the expression of several defense-related genes, inhibited the accumulation of herbivore-induced phenolic compounds, and augmented the performance of the specialist herbivore
Manduca sexta
. Complementary studies with tomato suggested that the effects of FR on defenses are mediated by the photoreceptor phytochrome B. The central implication of these results is that shade-intolerant species such as wild tobacco and tomato activate functional changes that affect their ability to cope with herbivore attack in response to phytochrome signals of future competition, even in the absence of real competition for resources. These findings suggest that competition overshadowed herbivory during the evolution of this group of species and add a new axis to the definition of the shade-avoidance syndrome.
Binding of 5′-GTP to the C-terminal FeS cluster of the radical
S
-adenosylmethionine enzyme MoaA provides insights into its mechanism
Authors: Hänzelmann Petra , Schindelin Hermann
Published: April 2006

The first step in molybdenum cofactor biosynthesis, the conversion of 5′-GTP to precursor Z, an oxygen-sensitive tetrahydropyranopterin is catalyzed by the
S
-adenosylmethionine (SAM)-dependent enzyme MoaA and the accessory protein MoaC. This reaction involves the radical-initiated intramolecular rearrangement of the guanine C8 atom. MoaA harbors an N-terminal [4Fe–4S] cluster, which is involved in the reductive cleavage of SAM and generates a 5′-deoxyadenosyl radical (5′-dA
•
), and a C-terminal [4Fe–4S] cluster presumably involved in substrate binding and/or activation. Biochemical studies identified residues involved in 5′-GTP binding and the determinants of nucleotide specificity. The crystal structure of MoaA in complex with 5′-GTP confirms the biochemical data and provides valuable insights into the subsequent radical reaction. MoaA binds 5′-GTP with high affinity and interacts through its C-terminal [4Fe–4S] cluster with the guanine N1 and N2 atoms, in a yet uncharacterized binding mode. The tightly anchored triphosphate moiety prevents the escape of radical intermediates. This structure also visualizes the
l
-Met and 5′-dA cleavage products of SAM. Rotation of the 5′-dA ribose and/or conformational changes of the guanosine are proposed to bring the 5′-deoxyadenosyl radical into close proximity of either the ribose C2′ and C3′ or the guanine C8 carbon atoms leading to hydrogen abstraction.
Histidines, heart of the hydrogen ion channel from influenza A virus: Toward an understanding of conductance and proton selectivity
Authors: Hu Jun , Fu Riqiang , Nishimura Katsuyuki , Zhang Li , Zhou Huan-Xiang , Busath David D. , Vijayvergiya Viksita , Cross Timothy A.
Published: April 2006

The heart of the H
+
conductance mechanism in the homotetrameric M2 H
+
channel from influenza A is a set of four histidine side chains. Here, we show that protonation of the third of these imidazoles coincides with acid activation of this transmembrane channel and that, at physiological pH, the channel is closed by two imidazole–imidazolium dimers, each sharing a low-barrier hydrogen bond. This unique construct succeeds in distributing a pair of charges over four rings and many atoms in a low dielectric environment to minimize charge repulsion. These dimers form with identical pK
a
s of 8.2 ± 0.2, suggesting cooperative H
+
binding and clearly illustrating high H
+
affinity for this channel. The protonation behavior of the histidine side chains has been characterized by using solid-state NMR spectroscopy on the M2 transmembrane domain in fully hydrated lipid bilayers where the tetrameric backbone structure is known. Furthermore, electrophysiological measurements of multichannel and single-channel experiments confirm that these protein constructs are functional.
Genomewide comparative analysis of alternative splicing in plants
Authors: Wang Bing-Bing , Brendel Volker
Published: April 2006

Alternative splicing (AS) has been extensively studied in mammalian systems but much less in plants. Here we report AS events deduced from EST/cDNA analysis in two model plants:
Arabidopsis
and rice. In
Arabidopsis
, 4,707 (21.8%) of the genes with EST/cDNA evidence show 8,264 AS events. Approximately 56% of these events are intron retention (IntronR), and only 8% are exon skipping. In rice, 6,568 (21.2%) of the expressed genes display 14,542 AS events, of which 53.5% are IntronR and 13.8% are exon skipping. The consistent high frequency of IntronR suggests prevalence of splice site recognition by intron definition in plants. Different AS events within a given gene occur, for the most part, independently. In total, 36–43% of the AS events produce transcripts that would be targets of the non-sense-mediated decay pathway, if that pathway were to operate in plants as in humans. Forty percent of
Arabidopsis
AS genes are alternatively spliced also in rice, with some examples strongly suggesting a role of the AS event as an evolutionary conserved mechanism of posttranscriptional regulation. We created a comprehensive web-interfaced database to compile and visualize the evidence for alternative splicing in plants (Alternative Splicing in Plants, available at
www.plantgdb.org/ASIP
).
Long-term self-renewal and directed differentiation of human embryonic stem cells in chemically defined conditions
Authors: Yao Shuyuan , Chen Shuibing , Clark Julie , Hao Ergeng , Beattie Gillian M. , Hayek Alberto , Ding Sheng
Published: April 2006

Chemically defined medium (CDM) conditions for controlling human embryonic stem cell (hESC) fate will not only facilitate the practical application of hESCs in research and therapy but also provide an excellent system for studying the molecular mechanisms underlying self-renewal and differentiation, without the multiple unknown and variable factors associated with feeder cells and serum. Here we report a simple CDM that supports efficient self-renewal of hESCs grown on a Matrigel-coated surface over multiple passages. Expanded hESCs under such conditions maintain expression of multiple hESC-specific markers, retain the characteristic hESC morphology, possess a normal karyotype
in vitro
, as well as develop teratomas
in vivo
. Additionally, several growth factors were found to selectively induce monolayer differentiation of hESC cultures toward neural, definitive endoderm/pancreatic and early cardiac muscle cells, respectively, in our CDM conditions. Therefore, this CDM condition provides a basic platform for further characterization of hESC self-renewal and directed differentiation, as well as the development of novel therapies.
GAME: detecting cis-regulatory elements using a genetic algorithm
Authors: Wei Zhi , Jensen Shane T.
Published: April 2006

Motivation: Identification of a transcription factor binding sites is an important aspect of the analysis of genetic regulation. Many programs have been developed for the de novo discovery of a binding motif (collection of binding sites). Recently, a scoring function formulation was derived that allows for the comparison of discovered motifs from different programs [S.T. Jensen, X.S. Liu, Q. Zhou and J.S. Liu (2004) Stat. Sci., 19, 188–204.] A simple program, BioOptimizer, was proposed in [S.T. Jensen and J.S. Liu (2004) Bioinformatics, 20, 1557–1564.] that improved discovered motifs by optimizing a scoring function. However, BioOptimizer is a very simple algorithm that can only make local improvements upon an already discovered motif and so BioOptimizer can only be used in conjunction with other motif-finding software.

Results: We introduce software, GAME, which utilizes a genetic algorithm to find optimal motifs in DNA sequences. GAME evolves motifs with high fitness from a population of randomly generated starting motifs, which eliminate the reliance on additional motif-finding programs. In addition to using standard genetic operations, GAME also incorporates two additional operators that are specific to the motif discovery problem. We demonstrate the superior performance of GAME compared with MEME, BioProspector and BioOptimizer in simulation studies as well as several real data applications where we use an extended version of the GAME algorithm that allows the motif width to be unknown.

Availability:  

Contact:  zhiwei@mail.med.upenn.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
A simple implementation of a normal mixture approach to differential gene expression in multiclass microarrays
Authors: McLachlan G.J. , Bean R.W. , Jones L. Ben-Tovim
Published: April 2006

Motivation: An important problem in microarray experiments is the detection of genes that are differentially expressed in a given number of classes. We provide a straightforward and easily implemented method for estimating the posterior probability that an individual gene is null. The problem can be expressed in a two-component mixture framework, using an empirical Bayes approach. Current methods of implementing this approach either have some limitations due to the minimal assumptions made or with more specific assumptions are computationally intensive.

Results: By converting to a z-score the value of the test statistic used to test the significance of each gene, we propose a simple two-component normal mixture that models adequately the distribution of this score. The usefulness of our approach is demonstrated on three real datasets.

Availability: An R-program for implementing the approach is freely available at

Contact:  gjm@maths.uq.edu.au

Supplementary information:
GeneRecon—a coalescent based tool for fine-scale association mapping
Authors: Mailund Thomas , Schierup Mikkel H. , Pedersen Christian N. S. , Madsen Jesper N. , Hein Jotun , Schauser Leif
Published: April 2006

Summary: GeneRecon is a tool for fine-scale association mapping using a coalescence model. GeneRecon takes as input case–control data from phased or unphased SNP and microsatellite genotypes. The posterior distribution of disease locus position is obtained by Metropolis-Hastings sampling in the state space of genealogies. Input format, search strategy and the sampled statistics can be configured through the Guile Scheme programming language embedded in GeneRecon, making GeneRecon highly configurable.

Availability: The source code for GeneRecon, written in C++ and Scheme, is available under the GNU General Public License (GPL) at

Contact:  mailund@birc.au.dk
A probabilistic dynamical model for quantitative inference of the regulatory mechanism of transcription
Authors: Sanguinetti Guido , Rattray Magnus , Lawrence Neil D.
Published: April 2006

Motivation: Quantitative estimation of the regulatory relationship between transcription factors and genes is a fundamental stepping stone when trying to develop models of cellular processes. This task, however, is difficult for a number of reasons: transcription factors’ expression levels are often low and noisy, and many transcription factors are post-transcriptionally regulated. It is therefore useful to infer the activity of the transcription factors from the expression levels of their target genes.

Results: We introduce a novel probabilistic model to infer transcription factor activities from microarray data when the structure of the regulatory network is known. The model is based on regression, retaining the computational efficiency to allow genome-wide investigation, but is rendered more flexible by sampling regression coefficients independently for each gene. This allows us to determine the strength with which a transcription factor regulates each of its target genes, therefore providing a quantitative description of the transcriptional regulatory network. The probabilistic nature of the model also means that we can associate credibility intervals to our estimates of the activities. We demonstrate our model on two yeast datasets. In both cases the network structure was obtained using chromatin immunoprecipitation data. We show how predictions from our model are consistent with the underlying biology and offer novel quantitative insights into the regulatory structure of the yeast cell.

Availability: MATLAB code is available from

Contact:  guido@dcs.shef.ac.uk

Supplementary information: Supplementary data are available on Bioinformatics online.
The Intracellular Fate of a Recombinant Protein Is Tissue Dependent
Authors: Drakakaki Georgia , Marcel Sylvain , Arcalis Elsa , Altmann Friedrich , Gonzalez-Melendi Pablo , Fischer Rainer , Christou Paul , Stoger Eva
Published: April 2006

Recombinant proteins directed to the secretory pathway in plants require a signal peptide for entry into the endoplasmic reticulum. In the absence of further targeting information, such proteins are generally secreted via the default pathway to the apoplast. This has been well documented in protoplasts and leaf tissue, but the trafficking of recombinant proteins in seeds and other storage tissues has rarely been investigated. We used Aspergillus niger phytase as a model glycoprotein to compare the intracellular fate of a recombinant protein in the leaves and seeds of rice (Oryza sativa). Using fluorescence and electron microscopy we showed that the recombinant protein was efficiently secreted from leaf cells as expected. In contrast, within endosperm cells it was retained in endoplasmic reticulum-derived prolamin bodies and protein storage vacuoles. Consistent with our immunolocalization data, the phytase produced in endosperm cells possessed oligomannose and vacuolar-type N-glycans [Man3(Xyl)(Fuc)GlcNAc2], whereas the phytase produced in leaves contained predominantly secretion-type N-glycans [GlcNAc2Man3(Xyl)(Fuc)GlcNAc2]. The latter could not be detected in preparations of the endosperm-derived phytase. Our results show that the intracellular deposition and modification of a recombinant protein is tissue dependent.
Glycinebetaine Counteracts the Inhibitory Effects of Salt Stress on the Degradation and Synthesis of D1 Protein during Photoinhibition in Synechococcus sp. PCC 7942
Authors: Ohnishi Norikazu , Murata Norio
Published: April 2006

Glycinebetaine (hereafter referred to as betaine) is a compatible solute that accumulates in certain plants and microorganisms in response to various types of stress. We demonstrated previously that when the cyanobacterium Synechococcus sp. PCC 7942 (hereafter Synechococcus) is transformed with the codA gene for choline oxidase, it can synthesize betaine from exogenously supplied choline, exhibiting enhanced tolerance to salt and cold stress. In this study, we examined the effects of salt stress and betaine synthesis on the photoinhibition of photosystem II (PSII). Salt stress due to 220 mm NaCl enhanced photoinhibition of PSII and betaine protected PSII against photoinhibition under these conditions. However, neither salt stress nor betaine synthesis affected photodamage to PSII. By contrast, salt stress inhibited repair of photodamaged PSII and betaine reversed this inhibitory effect of salt stress. Pulse-chase-labeling experiments revealed that salt stress inhibited degradation of D1 protein in photodamaged PSII and de novo synthesis of D1. By contrast, betaine protected the machinery required for degradation and synthesis of D1 under salt stress. Neither salt stress nor betaine affected levels of psbA transcripts. These observations suggest that betaine counteracts the inhibitory effects of salt stress, with resultant accelerated repair of photodamaged PSII.
Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy
Authors: Pillai Jyothish B. , Gupta Madhu , Rajamohan Senthilkumar B. , Lang Roberto , Raman Jai , Gupta Mahesh P.
Published: April 2006

Poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme, is activated by cell oxidative stress. Because oxidative stress is also considered a main component of angiotensin II-mediated cell signaling, it was postulated that PARP could be a downstream target of angiotensin II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin II-induced hypertrophy, we infused angiotensin II into wild-type (PARP+/+) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-to-tibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP+/+but not in PARP−/−mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP−/−cardiomyocytes, angiotensin II (1 μM) treatment significantly increased protein synthesis in PARP+/+myocytes, as measured by3H-leucine incorporation into total cell protein. Angiotensin II-mediated hypertrophy of myocytes was accompanied with increased poly-ADP-ribosylation of nuclear proteins and depletion of cellular NAD content. When cells were treated with cell death-inducing doses of angiotensin II (10–20 μM), robust myocyte cell death was observed in PARP+/+but not in PARP−/−myocytes. This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2α deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin II-mediated cell signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure.
COX-2 contributes to the maintenance of flow-induced dilation in arterioles of eNOS-knockout mice
Authors: Sun Dong , Liu Hong , Yan Changdong , Jacobson Azita , Ojaimi Caroline , Huang An , Kaley Gabor
Published: April 2006

Our previous studies demonstrated that, in gracilis muscle arterioles of male mice deficient in the gene for endothelial nitric oxide synthase (eNOS), flow-induced dilation (FID) is mediated by endothelial PGs. Thus the present study aimed to identify the specific isoform of cyclooxygenase (COX) responsible for the compensatory mediation of FID in arterioles of eNOS-knockout (KO) mice. Experiments were conducted on gracilis muscle arterioles of male eNOS-KO and wild-type (WT) mice. Basal tone and magnitude of FID of arterioles were comparable in the two strains of mice. A role for COX isoforms in the mediation of the responses was assessed by use of valeryl salicylate (3 mM) and NS-398 (10 μM), inhibitors of COX-1 and COX-2, respectively. In eNOS-KO arterioles, valeryl salicylate or NS-398 alone inhibited FID (at maximal flow rate) by ∼51% and ∼58%, respectively. Administration of both inhibitors eliminated the dilation. In WT arterioles, inhibition of COX-2 did not significantly affect FID, whereas inhibition of COX-1 decreased the dilation by ∼57%. The residual portion of the response was abolished by additional administration of Nω-nitro-l-arginine methyl ester. Western blot analysis indicated a comparable content of COX-1 protein in arterioles of WT and eNOS-KO mice. COX-2 protein, which was not detectable in arterioles of WT mice, was strongly expressed in arterioles of eNOS-KO mice, together with an upregulation of COX-2 gene expression. Immunohistochemical staining confirmed the presence of COX-2 in the endothelium of eNOS-KO arterioles. In conclusion, COX-2-derived PGs are the mediators responsible for maintenance of FID in arterioles of eNOS-deficient mice.
Nucleotides induce IL-6 release from human airway epithelia via P2Y2and p38 MAPK-dependent pathways
Authors: Douillet Christelle D. , Robinson William P. , Milano Peter M. , Boucher Richard C. , Rich Preston B.
Published: April 2006

Extracellular nucleotides can mediate a variety of cellular functions via interactions with purinergic receptors. We previously showed that mechanical ventilation (MV) induces airway IL-6 and ATP release, modifies luminal nucleotide composition, and alters lung purinoceptor expression. Here we hypothesize that extracellular nucleotides induce secretion of IL-6 by small airway epithelial cells (SAEC). Human SAEC were stimulated with nucleotides in the presence or absence of inhibitors. Supernatants were analyzed for IL-6 and lysates for p38 MAPK activity by ELISA. RNA was analyzed by real-time RT-PCR. Rats ( n = 51) were randomized to groups as follows: control, small-volume MV, large-volume MV, large-volume MV-intratracheal apyrase, or small-volume MV-intratracheal adenosine 5′- O-(3-thiotriphosphate) (ATPγS). After 1 h of MV, bronchoalveolar lavage fluid was analyzed for ATP and IL-6 by luminometry and ELISA. ATP and ATPγS increased SAEC IL-6 secretion in a time- and dose-dependent manner, an effect inhibited by apyrase. Agonists were ranked in the following order: ATPγS > ATP = UTP > ADP = adenosine > 2-methylthio-ADP = control. SB-203580, but not U-0126 or JNK1 inhibitor, decreased nucleotide effects. Additionally, nucleotides induced p38 MAPK phosphorylation. Inhibitors of Ca2+signaling, phospholipase C, transcription, and translation decreased IL-6 release. Furthermore, nucleotides increased IL-6 expression. In vivo, large-volume MV increased airway ATP and IL-6 concentrations. IL-6 release was decreased by apyrase and increased by ATPγS. Extracellular nucleotides induce P2Y2-mediated secretion of IL-6 by SAEC via Ca2+, phospholipase C, and p38 MAPK-dependent pathways. This effect is dependent on transcription and translation. Our findings were confirmed in an in vivo model, thus demonstrating a novel mechanism of nucleotide-induced IL-6 secretion by airway epithelia.
Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways
Authors: Abdulnour Raja-Elie E. , Peng Xinqi , Finigan Jay H. , Han Eugenia J. , Hasan Emile J. , Birukov Konstantin G. , Reddy Sekhar P. , Watkins James E. , Kayyali Usamah S. , Garcia Joe G. N. , Tuder Rubin M. , Hassoun Paul M.
Published: April 2006

Xanthine oxidoreductase (XOR) plays a prominent role in acute lung injury because of its ability to generate reactive oxygen species. We investigated the role of XOR in ventilator-induced lung injury (VILI). Male C57BL/6J mice were assigned to spontaneous ventilation (sham) or mechanical ventilation (MV) with low (7 ml/kg) and high tidal volume (20 ml/kg) for 2 h after which lung XOR activity and expression were measured and the effect of the specific XOR inhibitor allopurinol on pulmonary vascular leakage was examined. In separate experiments, rat pulmonary microvascular endothelial cells (RPMECs) were exposed to cyclic stretch (5% and 18% elongation, 20 cycles/min) for 2 h before intracellular XOR activity measurement. Lung XOR activity was significantly increased at 2 h of MV without changes in XOR expression. There was evidence of p38 MAP kinase, ERK1/2, and ERK5 phosphorylation, but no change in JNK phosphorylation. Evans blue dye extravasation and bronchoalveolar lavage protein concentration were significantly increased in response to MV, changes that were significantly attenuated by pretreatment with allopurinol. Cyclic stretch of RPMECs also caused MAP kinase phosphorylation and a 1.7-fold increase in XOR activity, which was completely abrogated by pretreatment of the cells with specific MAP kinase inhibitors. We conclude that XOR enzymatic activity is significantly increased by mechanical stress via activation of p38 MAP kinase and ERK and plays a critical role in the pathogenesis of pulmonary edema associated with VILI.
Physiological effects of oxidized exogenous surfactant in vivo: effects of high tidal volume and surfactant protein A
Authors: Bailey Timothy C. , Maruscak Adam A. , Petersen Anne , White Sarah , Lewis James F. , Veldhuizen Ruud A. W.
Published: April 2006

Oxidative damage to surfactant can decrease lung function in vivo. In the current study, our two objectives were: 1) to examine whether the adverse effects of oxidized surfactant would be accentuated in animals exposed to high tidal volume ventilation, and 2) to test whether supplementation with surfactant protein A (SP-A) could improve the function of oxidized surfactant in vivo. The first objective was addressed by evaluating the response of surfactant-deficient rats administered normal or oxidized surfactant and then subjected to low tidal volume (6 ml/kg) or high tidal volume (12 ml/kg) mechanical ventilation. Under low tidal volume conditions, rats administered oxidized surfactant had impaired lung function, as determined by lung compliance and arterial blood gas analysis, compared with nonoxidized controls. Animals subjected to high tidal volume ventilation had impaired lung function compared with low tidal volume groups, regardless of the oxidative status of the surfactant. The second experiment demonstrated a significantly superior physiological response in surfactant-deficient rats receiving SP-A containing oxidized surfactant compared with oxidized surfactant. Lavage analysis at the end of the in vivo experimentation showed no differences in the recovery of oxidized surfactant compared with nonoxidized surfactant. We conclude that minimizing excessive lung stretch during mechanical ventilation is important in the context of exogenous surfactant supplementation and that SP-A has an important biophysical role in surfactant function in conditions of oxidative stress. Furthermore, the oxidative status of the surfactant does not appear to affect the alveolar metabolism of this material.
Job's Wife as Hero: A Feminist-forensic Reading of the Book of Job
Authors: Magdalene F. Rachel
Published: April 2006

This article offers a new reading of the role of Job's wife in the trial of Job, based on feminist hermeneutics, legal hermeneutics, and comparative legal historical analysis. The article proposes that the book of Job explores the problem of the violence and oppression of God's law as manifested through human suffering. Mrs. Job offers Job the best means available for resisting a violent, oppressive legal system, that is, martyrdom. Although Job does not use that strategy directly, he does employ it in an indirect fashion to exercise another form of legal resistance against God's violence in order that the case might be resolved. Consequently, God settles the matter with Job. The article demonstrates that Mrs. Job is a more important and more powerful figure in the book than prior readings have allowed. She is both heroic and wise.
Determination of biaxial stress–strain diagram for gas pressure superplastic forming
Authors: Dutta A. , Kumar A.
Published: April 2006

The success of a gas pressure superplastic forming operation depends on accurate formulation of a pressure–time diagram which in turn needs an accurate stress–strain relationship evaluated preferably under multiaxial or biaxial conditions. The present analysis describes a technique of generating such curves from gas pressure cone forming tests and subsequent manipulation of the data. The method also includes an innovative technique of online monitoring of strain during the forming process by measuring the volume of displaced air from the die during progress of forming.
Operon information improves gene expression estimation for cDNA microarrays
Authors: Xiao Guanghua , Martinez-Vaz Betsy , Pan Wei , Khodursky Arkady B
Published: April 2006

Background

In prokaryotic genomes, genes are organized in operons, and the genes within an operon tend to have similar levels of expression. Because of co-transcription of genes within an operon, borrowing information from other genes within the same operon can improve the estimation of relative transcript levels; the estimation of relative levels of transcript abundances is one of the most challenging tasks in experimental genomics due to the high noise level in microarray data. Therefore, techniques that can improve such estimations, and moreover are based on sound biological premises, are expected to benefit the field of microarray data analysis

Results

In this paper, we propose a hierarchical Bayesian model, which relies on borrowing information from other genes within the same operon, to improve the estimation of gene expression levels and, hence, the detection of differentially expressed genes. The simulation studies and the analysis of experiential data demonstrated that the proposed method outperformed other techniques that are routinely used to estimate transcript levels and detect differentially expressed genes, including the sample mean and SAM t statistics. The improvement became more significant as the noise level in microarray data increases.

Conclusion

By borrowing information about transcriptional activity of genes within classified operons, we improved the estimation of gene expression levels and the detection of differentially expressed genes.