bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient parsimony-based methods for phylogenetic network reconstruction
Authors: Jin Guohua , Nakhleh Luay , Snir Sagi , Tuller Tamir
Published: January 2007

Motivation: Phylogenies—the evolutionary histories of groups of organisms—play a major role in representing relationships among biological entities. Although many biological processes can be effectively modeled as tree-like relationships, others, such as hybrid speciation and horizontal gene transfer (HGT), result in networks, rather than trees, of relationships. Hybrid speciation is a significant evolutionary mechanism in plants, fish and other groups of species. HGT plays a major role in bacterial genome diversification and is a significant mechanism by which bacteria develop resistance to antibiotics. Maximum parsimony is one of the most commonly used criteria for phylogenetic tree inference. Roughly speaking, inference based on this criterion seeks the tree that minimizes the amount of evolution. In 1990, Jotun Hein proposed using this criterion for inferring the evolution of sequences subject to recombination. Preliminary results on small synthetic datasets. Nakhleh et al. (2005) demonstrated the criterion’s application to phylogenetic network reconstruction in general and HGT detection in particular. However, the naive algorithms used by the authors are inapplicable to large datasets due to their demanding computational requirements. Further, no rigorous theoretical analysis of computing the criterion was given, nor was it tested on biological data.

Results: In the present work we prove that the problem of scoring the parsimony of a phylogenetic network is NP-hard and provide an improved fixed parameter tractable algorithm for it. Further, we devise efficient heuristics for parsimony-based reconstruction of phylogenetic networks. We test our methods on both synthetic and biological data (rbcL gene in bacteria) and obtain very promising results.

Contact:  ssagi@math.berkeley.edu
Family relationships: should consensus reign?—consensus clustering for protein families
Authors: Nikolski Macha , Sherman David J.
Published: January 2007

Motivation: Reliable identification of protein families is key to phylogenetic analysis, functional annotation and the exploration of protein function diversity in a given phylogenetic branch. As more and more complete genomes are sequenced, there is a need for powerful and reliable algorithms facilitating protein families construction.

Results: We have formulated the problem of protein families construction as an instance of consensus clustering, for which we designed a novel algorithm that is computationally efficient in practice and produces high quality results. Our algorithm uses an election method to construct consensus families from competing clustering computations.

Our consensus clustering algorithm is tailored to serve the specific needs of comparative genomics projects. First, it provides a robust means to incorporate results from different and complementary clustering methods, thus avoiding the need for an a priori choice that may introduce computational bias in the results. Second, it is suited to large-scale projects due to the practical efficiency. And third, it produces high quality results where families tend to represent groupings by biological function.

Availability: This method has been used for Génolevures project to compute protein families of Hemiascomycetous yeasts. The data are available online at

Supplementary information: Supplementary data are available at

Contact:  macha@labri.fr
A structural alignment kernel for protein structures
Authors: Qiu Jian , Hue Martial , Ben-Hur Asa , Vert Jean-Philippe , Noble William Stafford
Published: January 2007

Motivation: This work aims to develop computational methods to annotate protein structures in an automated fashion. We employ a support vector machine (SVM) classifier to map from a given class of structures to their corresponding structural (SCOP) or functional (Gene Ontology) annotation. In particular, we build upon recent work describing various kernels for protein structures, where a kernel is a similarity function that the classifier uses to compare pairs of structures.

Results: We describe a kernel that is derived in a straightforward fashion from an existing structural alignment program, MAMMOTH. We find in our benchmark experiments that this kernel significantly out-performs a variety of other kernels, including several previously described kernels. Furthermore, in both benchmarks, classifying structures using MAMMOTH alone does not work as well as using an SVM with the MAMMOTH kernel.

Availability:  http://noble.gs.washington.edu/proj/3dkernel

Contact:  noble@gs.washington.edu
TreeQ-VISTA: an interactive tree visualization tool with functional annotation query capabilities
Authors: Gu Shengyin , Anderson Iain , Kunin Victor , Cipriano Michael , Minovitsky Simon , Weber Gunther , Amenta Nina , Hamann Bernd , Dubchak Inna
Published: January 2007

Summary: We describe a general multiplatform exploratory tool called TreeQ-Vista, designed for presenting functional annotations in a phylogenetic context. Traits, such as phenotypic and genomic properties, are interactively queried from a user-provided relational database with a user-friendly interface which provides a set of tools for users with or without SQL knowledge. The query results are projected onto a phylogenetic tree and can be displayed in multiple color groups. A rich set of browsing, grouping and query tools are provided to facilitate trait exploration, comparison and analysis.

Availability: The program, detailed tutorial and examples are available online (http:/genome.lbl.gov/vista/TreeQVista).

Contact:  vista@lbl.gov
A faster circular binary segmentation algorithm for the analysis of array CGH data
Authors: Venkatraman E. S. , Olshen Adam B.
Published: January 2007

Motivation: Array CGH technologies enable the simultaneous measurement of DNA copy number for thousands of sites on a genome. We developed the circular binary segmentation (CBS) algorithm to divide the genome into regions of equal copy number. The algorithm tests for change-points using a maximal t-statistic with a permutation reference distribution to obtain the corresponding P-value. The number of computations required for the maximal test statistic is O(N2), where N is the number of markers. This makes the full permutation approach computationally prohibitive for the newer arrays that contain tens of thousands markers and highlights the need for a faster algorithm.

Results: We present a hybrid approach to obtain the P-value of the test statistic in linear time. We also introduce a rule for stopping early when there is strong evidence for the presence of a change. We show through simulations that the hybrid approach provides a substantial gain in speed with only a negligible loss in accuracy and that the stopping rule further increases speed. We also present the analyses of array CGH data from breast cancer cell lines to show the impact of the new approaches on the analysis of real data.

Availability: An R version of the CBS algorithm has been implemented in the “DNAcopy” package of the Bioconductor project. The proposed hybrid method for the P-value is available in version 1.2.1 or higher and the stopping rule for declaring a change early is available in version 1.5.1 or higher.

Contact:  venkatre@mskcc.org

Supplementary information: Supplementary data are available at Bioinformatics online.
Deleterious SNP prediction: be mindful of your training data!
Authors: Care Matthew A. , Needham Chris J. , Bulpitt Andrew J. , Westhead David R.
Published: January 2007

Motivation: To predict which of the vast number of human single nucleotide polymorphisms (SNPs) are deleterious to gene function or likely to be disease associated is an important problem, and many methods have been reported in the literature. All methods require data sets of mutations classified as ‘deleterious’ or ‘neutral’ for training and/or validation. While different workers have used different data sets there has been no study of which is best. Here, the three most commonly used data sets are analysed. We examine their contents and relate this to classifiers, with the aims of revealing the strengths and pitfalls of each data set, and recommending a best approach for future studies.

Results: The data sets examined are shown to be substantially different in content, particularly with regard to amino acid substitutions, reflecting the different ways in which they are derived. This leads to differences in classifiers and reveals some serious pitfalls of some data sets, making them less than ideal for non-synonymous SNP prediction.

Availability: Software is available on request from the authors.

Contact:  d.r.westhead@leeds.ac.uk

Supplementary information: Supplementary data are available at Bioinformatics online.
Dynamics of a stochastically perturbed two-body problem
Authors: Sharma Shambhu N , Parthasarathy H
Published: January 2007

In classical mechanics, the two-body problem has been well studied. The governing equations form a system of two-coupled second-order nonlinear differential equations for the radial and angular coordinates. The perturbation induced by the astronomical disturbance like ‘dust’ is normally not considered in the orbit dynamics. Distributed dust produces an additional random force on the orbiting particle, which can be modelled as a random force having ‘Gaussian statistics’. The estimation of accurate positioning of the orbiting particle is not possible without accounting for the stochastic perturbation felt by the orbiting particle. The objective of this paper is to use the stochastic differential equation (SDE) formalism to study the effect of such disturbances on the orbiting body. Specifically, in this paper, we linearize SDEs about the mean of the state vector. The linearization operation performed above, transforms the system of SDEs into another system of SDEs that resembles a bilinear system, as described in signal processing and control literature. However, the mean trajectory of the resulting bilinear stochastic differential model does not preserve the perturbation effect felt by the orbiting particle; only the variance trajectory includes the perturbation effect. For this reason, the effectiveness of the dust-perturbed model is examined on the basis of the bilinear and second-order approximations of the
system nonlinearity
. The bilinear and second-order approximations of the system nonlinearity allow substantial simplifications for the numerical implementation and preserve some of the properties of the original stochastically perturbed model. Most notably, this paper reveals that the Brownian motion process is accurate to model and study the effect of dust perturbation on the orbiting particle. In addition, analytical findings are supported with finite difference method-based numerical simulations.
Stress hormones and sociality: integrating social and environmental stressors
Authors: Rubenstein Dustin R
Published: January 2007

In cooperatively breeding species, reproductive decisions and breeding roles may be influenced by environmental (food resources) or social factors (reproductive suppression of subordinates by dominants). Studies of glucocorticoid stress hormones in cooperatively breeding species suggest that breeding roles and hormone levels are related to the relative costs of dominance and subordination, which are driven primarily by social interactions. Few studies, however, have considered how environmental factors affect glucocorticoid levels and breeding roles in cooperative breeders, even though environmental stressors modulate seasonal glucocorticoid release and often influence breeding roles. I examined baseline and stress-induced levels of the glucocorticoid corticosterone (CORT) across 4 years in the plural breeding superb starling,Lamprotornis superbus, to determine whether (i) environmental factors (namely rainfall) directly influence breeding roles or (ii) environmental factors influence social interactions, which in turn drive breeding roles. Chronic baseline and maximal stress-induced CORT changed significantly across years as a function of pre-breeding rainfall, but dominant and subordinate individuals responded differently. Pre-breeding rainfall was also correlated directly with breeding roles. The results are most consistent with the hypothesis that environmental conditions influenced the relative costs of dominance and subordination, which in turn affected the degree and intensity of social interactions and ultimately reproductive decisions and breeding roles.
Social transmission of face preferences among humans
Authors: Jones Benedict C , DeBruine Lisa M , Little Anthony C , Burriss Robert P , Feinberg David R
Published: January 2007

Previous studies demonstrating mate choice copying effects among females in non-human species have led many researchers to propose that social transmission of mate preferences may influence sexual selection for male traits. Although it has been suggested that social transmission may also influence mate preferences in humans, there is little empirical support for such effects. Here, we show that observing other women with smiling (i.e. positive) expressions looking at male faces increased women's preferences for those men to a greater extent than did observing women with neutral (i.e. relatively negative) expressions looking at male faces. By contrast, the reverse was true for male participants (i.e. observing women with neutral expressions looking at male faces increased male participant's preferences for those men to a greater extent than did observing women smiling at male faces). This latter finding suggests that within-sex competition promotes negative attitudes among men towards other men who are the target of positive social interest from women. Our findings demonstrate that social transmission of face preferences influences judgments of men's attractiveness, potentially demonstrating a mechanism for social transmission of mate preferences.
Is there a universal log law for turbulent wall-bounded flows?
Authors: George William K
Published: January 2007

The history and theory supporting the idea of a universal log law for turbulent wall-bounded flows are briefly reviewed. The original idea of justifying a log law from a constant Reynolds stress layer argument is found to be deficient. By contrast, it is argued that the logarithmic friction law and velocity profiles derived from matching inner and outer profiles for a pipe or channel flow are well-founded and consistent with the data. But for a boundary layer developing along a flat plate it is not, and in fact it is a power law theory that seems logically consistent. Even so, there is evidence for at least an empirical logarithmic fit to the boundary-friction data, which is indistinguishable from the power law solution. The value of
κ
≈0.38 obtained from a logarithmic curve fit to the boundary-layer velocity data, however, does not appear to be the same as for pipe flow for which 0.43 appears to be the best estimate. Thus, the idea of a universal log law for wall-bounded flows is not supported by either the theory or the data.
Composite asymptotic expansions and scaling wall turbulence
Authors: Panton Ronald L
Published: January 2007

In this article, the assumptions and reasoning that yield composite asymptotic expansions for wall turbulence are discussed. Particular attention is paid to the scaling quantities that are used to render the variables non-dimensional and of order one. An asymptotic expansion is proposed for the streamwise Reynolds stress that accounts for the active and inactive turbulence by using different scalings. The idea is tested with the data from the channel flows and appears to have merit.
Genetic interference reduces the evolvability of modular and non-modular visual neural networks
Authors: Calabretta Raffaele
Published: January 2007

The aim of this paper is to propose an interdisciplinary evolutionary connectionism approach for the study of the evolution of modularity. It is argued that neural networks as a model of the nervous system and genetic algorithms as simulative models of biological evolution would allow us to formulate a clear and operative definition of module and to simulate the different evolutionary scenarios proposed for the origin of modularity. I will present a recent model in which the evolution of primate cortical visual streams is possible starting from non-modular neural networks. Simulation results not only confirm the existence of the phenomenon of neural interference in non-modular network architectures but also, for the first time, reveal the existence of another kind of interference at the genetic level, i.e. genetic interference, a new population genetic mechanism that is independent from the network architecture. Our simulations clearly show that genetic interference reduces the evolvability of visual neural networks and sexual reproduction can at least partially solve the problem of genetic interference. Finally, it is shown that entrusting the task of finding the neural network architecture to evolution and that of finding the network connection weights to learning is a way to completely avoid the problem of genetic interference. On the basis of this evidence, it is possible to formulate a new hypothesis on the origin of structural modularity, and thus to overcome the traditional dichotomy between innatist and empiricist theories of mind.
Thermal Diffusivity Anisotropy of SiC/BN Composites
Authors: Ruh Robert , Bentsen Larry D. , Hasselman D. P. H.
Published: January 2007

The thermal diffusivity of hot‐pressed SiC /BN composites is shown to exhibit a high degree of anisotropy with respect to the hot‐pressing direction as a result of preferred orientation of the BN phase. This effect is particularly pronounced at the higher BN contents at both room and elevated temperatures.
Cation Valence in VOx
Authors: Hsieh Robert L. , Cohen Jerome B. , Georgopoulos Panayotis
Published: January 2007

By comparing the position of the K absorption edge of VOx to that of V metal, V2O4, and V2O5, it is concluded that the cation in VOx has the classical valence of 2 + only for oxygen‐rich compositions.
Growth of α‐Al2O3 Within a Transition Alumina Matrix
Authors: Morrissey Karen J. , Czanderna Karel K. , Carter C. B. , Merrill Robert P.
Published: January 2007

The growth of α‐Al2O3 from a planar specimen of thermally grown γ‐alumina on a molybdenum transmission electron microscope grid was studied. The α‐Al2O3 grows into the transition alumina matrix and then thickens via a ledge growth mechanism. Faceted Mo crystallites cause pinning of α‐Al2O3 ledges and are larger on α‐Al2O3 than on the transition alumina matrix.
Dielectric Properties of Lead‐Magnesium Niobate Ceramics
Authors: SWARTZ S. L. , SHROUT T. R. , SCHULZE W. A. , CROSS L. E.
Published: January 2007

Dielectric properties are reported for lead magnesium niobate (PbMg1/3Nb2/3/O3) ceramics which were prepared as single phase (i.e., without pyrochlore) with an improved technique. Dielectric constants of 18000 for pure PMN and 31000 for PMN with 10% PbTiO3 were achieved; these values are 50% larger than those reported in the literature. The dielectric constant of PMN ceramics was found to increase with both sintering temperature and excess MgO, and subsequent analysis of the microstructures confirmed that this was due to an increase in grain size. This grain‐size dependence is explained as a consequence of low‐permittivity grain boundaries.
Grain‐Oriented Glass‐Ceramics for Piezoelectric Devices
Authors: HALLIYAL A. , SAFARI A. , BHALLA A. S. , NEWNHAM R. E. , CROSS L. E.
Published: January 2007

Grain‐oriented glass‐ceramics of Li2Si2o5, fresnoite (Ba2TiSi2O8), and its isomorphs Sr2TiSi2O8, and Ba2TiGe2O8, were prepared by recrystallizing glasses in a temperature gradient. Electromechanical and hydrostatic piezoelectric properties of these glass‐ceramics were measured. Piezoelectric voltage coefficients g33 and hydrostatic voltage coefficient gh of these glass‐ceramics are comparable to those of polyvinylidene fluoride and an order of magnitude higher than the corresponding values of lead zirconate‐titanate. These glass‐ceramics seem to be attractive candidate materials for hydrophones and several piezoelectric devices. Hydrostatic piezoelectric properties of Ba2TiSi2O8 and Ba2TiGe2O8 single crystals were also measured. The unusually high values of gh in fresnoite single crystals and glass‐ceramics are supposed to be due to positive d31 in these materials. A composite model is proposed to explain the positive sign of d31 in fresnoite based on its crystal structure and internal Poisson's ratio stress.
Thermal Oxidation of Sputter‐Coated Reaction‐Bonded Silicon Nitride
Authors: GREGORY O. J. , RICHMAN M. H.
Published: January 2007

Ceramic coatings prepared by sputtering and reactive sputtering were applied to reaction‐bonded silicon nitride surfaces to prevent extensive oxidation of the underlying material. The high‐density nitride‐based coatings retard the oxidation of the substrate by forming an oxygen diffusion barrier which seals the open porosity while maintaining dimensional and thermal stability. The oxidation kinetics of the coated and uncoated reaction‐bonded silicon nitride substrates were compared at T =1000° to 1200°C. Oxidation of the underlying material in this temperature range was substantially reduced when suitable coatings were used and the crystalline oxidation product (cristobalite) was essentially eliminated.
Single‐Crystal Elastic Constants of Yttria‐Stabilized Zirconia in the Range 20° to 700°C
Authors: KANDIL H. M. , GREINER J. D. , SMITH J. F.
Published: January 2007

Elastic constants of single crystals of yttria‐stabilized zirconia were determined through the temperature range 20° to 700°C. Crystals containing 8.1, 11.1,12.1, 15.5, and 17.9 mol% Y203were measured. The elastic constant C11 was found to decrease and C12 and C44 to increase with increasing Y2O3 content; this appears to be due to decreasing coulombic interaction as Y3+ replaces Zr4+. Except for the 8.1 mol% Y2O3 crystal, the conventional elastic constants all showed normal monotonic decreases with increasing temperature. In the case of the 8.1 mol% Y2O3 crystal, measurements as a function of temperature were not reproducible, and it is likely that this composition at room temperature is below the composition limit of thermodynamic stability of the cubic fluorite phase.
Effect of Gas Percolation on Melting of Glass Batch
Authors: VISKANTA R. , WU X.
Published: January 2007

A model was developed to predict the temperature distribution, heat transfer, and melting time during unsteady heating and conversion of batch to glass. Percolation of gas through the blanket of batch and heat absorption during the decomposition of carbonates are accounted for in the model. In the glassmelt, heat was assumed to be transferred by combined conduction and radiation. The model equations were solved numerically using a finite‐difference method. The effects of several model parameters were investigated. The results of computations show that percolation of gas through the batch increases the time required to convert the batch to glass. Absorption of heat and release of gas in the batch due to decomposition of carbonates changed the temperature distribution in the batchiglass system and the melting times were affected relatively little as long as the total energy absorbed during the transformation process remained unaltered.
Tumor carbonic anhydrase 9 expression is associated with the presence of lymph node metastases in uterine cervical cancer
Authors: Lee Sun , Shin Hye‐Jin , Han In‐Oc , Hong Eun‐Kyung , Park Sang‐Yoon , Roh Ju‐Won , Shin Kyung H. , Kim Tae H. , Kim Joo‐Young
Published: January 2007

Tumor hypoxia has a pronounced effect on malignant progression and metastatic spread of human tumors. As carbonic anhydrases (CA) 9 and 12 are induced by the low‐oxygen environment within tumors, we investigated the relationship between the expression of these two CA and the presence of metastatic lymph nodes (LN) in uterine cervical cancer. CA9/CA12 expression was evaluated histochemically in primary cervical cancer tissues of 73 patients who underwent laparoscopic LN staging and two patients with clinical staging before definitive radiotherapy at the National Cancer Center, Korea. We also evaluated CA9 expression in 33 patients with pathologically confirmed metastatic LN. CA9 expression in the primary tumors was significantly associated with LN metastasis (P = 0.03) and poorer disease‐free survival (relative risk, 6.1; 95% confidence interval, 1.3–28.3, P = 0.02, multivariate analysis), whereas CA12 expression did not show such a relationship. In addition, 21 of 24 metastatic LN revealed similar CA9 expression (P = 0.001), suggesting that CA9‐expressing tumor cells had a higher metastatic potential. CA9 was expressed in 45 of 75 (60%) primary tumors, with positive tumor cells observed predominantly in the area away from the blood vessels. In contrast, CA12 expression was observed in only 29 of 74 primary tumors (39%), without a specific pattern. These findings indicate that expression of CA9, but not CA12, in tumors is associated with the presence of LN metastases and poorer prognosis. Selective application of new treatment modalities based on CA9 expression to prevent LN metastases may improve overall treatment outcome in patients with uterine cervical cancer. (Cancer Sci 2007; 98: 329–333)
The immortalized cell lines with differentiation potentials: Their establishment and possible application
Authors: Obinata Masuo
Published: January 2007

Approximately 200 types of the cells are qualified as differentiated cells in the human body. If these different types of cells can be separated from each other (or cloned) and obtained in sufficient quantity, it will be beneficial for studying development, morphogenesis, tissue maintenance, cancer and aging, and for reconstructing functional tissues in vitro for regenerative medicine. We produced the transgenic mouse and rat harboring SV40 T‐antigen gene to make the immortalized cell lines in the primary tissue culture and succeeded in establishing many functionally active cell lines from various tissues. Many immortalized cell lines from various tissues are shown to exhibit the unique characteristics of tissue functions and they should be useful as an in vitro model of various tissues for physiological and pharmacological investigations. Future application of these cells to drug screening is discussed. (Cancer Sci 2007; 98: 275–283)
Assessment of potential ecological disruption based on heavy metal toxicity, accumulation and distribution in media of the Lagos Lagoon
Authors: Adebayo Otitoloju A. , Kio Don‐Pedro N. , Emmanuel Oyewo O.
Published: January 2007

Toxicity evaluations of heavy metals against three benthic animals, Tympanotonus fuscatus, Clibanarius africanus and Sesarma huzardi of the Lagos Lagoon were carried out under laboratory conditions. On the basis of the 96hLC50 values, Cd was found to be the most toxic metal tested followed by Cu, Zn and Pb, in a descending order of toxicity against T. fuscatus and S. huzardi; however, against C. africanus, Cu was the most toxic followed by Cd, Zn and Pb (least toxic). The determination of the metal concentrations in the water column and sediment of the Lagos Lagoon revealed that these media of the lagoon contained measurable concentrations of heavy metals but the levels were still several folds lower than the concentrations that will cause 50% mortality of exposed animals under laboratory conditions. The significance of the observed differences between the 96hLC50 values of the test metals, the concentration of heavy metals detected in tissues of field animals and ambient levels of the metals in the Lagos lagoon were discussed in relation to the protection of aquatic lives and potential public health risks. The need to verify the possibilities of synergistic interactions between the constituent metals when acting jointly against the exposed animals was recommended.
Maternal concerns during early parenthood
Authors: Kaitz M.
Published: January 2007

Background  Most research on maternal concerns has focused on their assessment during pregnancy and the early post‐partum period. The aim of this study was to identify primary concerns of mothers later in the first post‐partum year, changes over time, and factors that were associated with relatively intense concerns, including infant (difficult) temperament, hours employed out of the home and obstetrical complications during pregnancy or childbirth.

Method  Data were obtained from 366 first‐time (Israeli) mothers at 3 and 6 months post‐partum by employing a new tool, the Mothers' Concern Questionnaire, along with standardized questionnaires, administered by phone.

Results  Analyses revealed six dimensions of concerns (Family Health, Return to Work, Mother's Well‐being, Relationships/Support, Infant Care, and Spouse). Of these, issues related to returning to work and family health were of most concern, and ratings were higher at 3 months than at 6 months post‐partum. Women with higher‐than‐average total concern scores perceived their infant as more difficult, were more likely to have experienced an obstetric complication, and worked more hours out of the house than women with lower‐than‐average scores.

Conclusions  The findings afford a first look at the profile of normative maternal concerns outside of the immediate post‐partum period and identify factors that predict more intense concerns. These findings extend what we know about the issues of new mothers and can guide birth educators and help couples prepare themselves for parenthood.
Peroxisome proliferator‐activated receptor‐γ agonists inhibit respiratory syncytial virus‐induced expression of intercellular adhesion molecule‐1 in human lung epithelial cells
Authors: Arnold Ralf , Neumann Manfred , König Wolfgang
Published: January 2007

Respiratory syncytial virus (RSV) is the major causative agent of severe lower respiratory tract disease and death in infants worldwide. The epithelial cells of the airways are the target cells for RSV infection and the site of the majority of the inflammation associated with the disease. However, despite five decades of intensive RSV research there exist neither an effective active vaccine nor a promising antiviral and anti‐inflammatory therapy. Recently, peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), a member of the nuclear hormone receptor superfamily, has been shown to possess anti‐inflammatory properties. Therefore, we hypothesized whether the detrimental increase of intercellular adhesion molecule‐1 (ICAM‐1) on RSV‐infected lung epithelial cells (A549 and primary normal human bronchial epithelial cells (NHBE)) might be modulated by natural and synthetic PPAR‐γ agonists (15d‐PGJ2, ciglitazone, troglitazone, Fmoc‐Leu). Our data show that all PPAR‐γ agonists under study significantly down‐regulated the RSV‐induced expression of ICAM‐1 on A549‐ and NHBE cells in a dose‐dependent manner resulting in a reduced β2 integrin‐mediated adhesion of monocytic effector cells (U937) to RSV‐infected A549 cell monolayers. In contrast, the PPAR‐α agonist bezafibrate had no impact on the RSV‐induced ICAM‐1 expression. The reduced ICAM‐1 expression was associated with a diminished ICAM‐1 mRNA level and binding activity of nuclear factor‐κB (p65/p50) in A549 cells. These findings suggest that PPARγ agonists have beneficial effects in the suppression of the inflammatory response during RSV infection and therefore might have clinical efficacy in the course of severe RSV‐infection.
Bone morphogenetic protein‐2/4 signalling pathway components are expressed in the human thymus and inhibit early T‐cell development
Authors: Cejalvo Teresa , Sacedón Rosa , Hernández‐López Carmen , Diez Blanca , Gutierrez‐Frías Cruz , Valencia Jaris , Zapata Agustín G. , Varas Alberto , Vicente Angeles
Published: January 2007

T‐cell differentiation is driven by a complex network of signals mainly derived from the thymic epithelium. In this study we demonstrate in the human thymus that cortical epithelial cells produce bone morphogenetic protein 2 (BMP2) and BMP4 and that both thymocytes and thymic epithelium express all the molecular machinery required for a response to these proteins. BMP receptors, BMPRIA and BMPRII, are mainly expressed by cortical thymocytes while BMPRIB is expressed in the majority of the human thymocytes. Some thymic epithelial cells from cortical and medullary areas express BMP receptors, being also cell targets for in vivo BMP2/4 signalling. The treatment with BMP4 of chimeric human–mouse fetal thymic organ cultures seeded with CD34+ human thymic progenitors results in reduced cell recovery and inhibition of the differentiation of human thymocytes from CD4− CD8− to CD4+ CD8+ cell stages. These results support a role for BMP2/4 signalling in human T‐cell differentiation.
Sleep architecture and the apnoea–hypopnoea index in children with obstructive‐sleep apnoea syndrome
Authors: MATSUMOTO E. , TANAKA E. , TABE H. , WAKISAKA N. , NAKATA Y. , UEDA H. , HORI T. , ABE T. , TANNE K.
Published: January 2007

summary  This study aimed to examine the sleep architecture and craniofacial morphology in a group of children divided by different levels of apnoea‐hypopnoea index (AHI), 5, 4·5, 4, 3·5, 3 and 2·5, and to determine an AHI threshold value at which sleep architecture is most affected. 23 children, who were selected from a preliminary questionnaire survey about sleep‐related breathing disorders, were evaluated with cephalometric radiographs and overnight polysomnography. The findings indicated that the children with AH1 ≥2·5 and ≥3 showed significantly larger numbers of waking (p < 0·005) and desaturation index (p < 0·01) than those with AHI <2·3 and <3, respectively. Significantly (p < 0·05) higher amounts of waking and lower amounts of REM as a percentage of total sleep time (TST) were also found in the children with AH1 ≥3. In the subgroups with AHI ≥3·5 and ≥4, only the percentage of REM was found to be significantly (p < 0·05) lower. No significant differences were found at the AHI threshold of 4·5 and 4. AHI correlated significantly (p < 0·05) with the number of awakenings, amount of waking as a percentage of TST, desaturation index and oxygen saturation nadir. Higher incidence of skeletal Class II pattern was found in children with AHI ≥2·5 and ≥3, and Class III in those with AHI <2·3 and <3, respectively. The effects on polysomnographic characteristics demonstrated to be the greatest on children at the AHI threshold of 3. In addition, the evaluation of oxygen saturation can be used to provide some information concerning the severity of sleep‐related breathing disorders.
Effect of a nociceptive trigeminal inhibitory splint on electromyographic activity in jaw closing muscles during sleep
Authors: BAAD‐HANSEN L. , JADIDI F. , CASTRILLON E. , THOMSEN P. B. , SVENSSON P.
Published: January 2007

summary  The nociceptive trigeminal inhibitory (NTI) splint has been claimed to decrease the electromyographic (EMG) activity of jaw‐closing muscles and relieve symptoms of various types of temporomandibular disorders (TMD) and bruxism. The present study was designed to address the question about EMG‐changes during sleep. Ten patients (age: 23–39 years) with a self‐report of tooth‐grinding during sleep were recruited. Patients were examined at baseline and after each treatment period with the use of the Research Diagnostic Criteria for TMD. A portable EMG‐device was used to record EMG‐activity from the masseter muscle during sleep. The patients received two 2‐week splint treatments in a randomized cross‐over fashion; an NTI splint and a standard flat occlusal splint (OS). EMG data were analysed according to published criteria. Using a 10% of maximum clenching EMG‐activity cut‐off threshold to determine the number of EMG‐events h−1 of sleep, the NTI splint was associated with a significant reduction (9·2 ± 3·2 events h−1) compared with baseline EMG (19·3 ± 4·0; anova: P = 0·004, Tukey post hoc: P = 0·006), whereas there were no differences between the OS (16·2 ± 4·7) and baseline EMG (19·2 ± 4·1; P = 0·716). There were no effects of either NTI or OS on clinical outcome measures (anovas: P > 0·194). This short‐term study indicated a strong inhibitory effect on EMG‐activity in jaw closing muscles during sleep of the NTI, but not the OS. However, the EMG‐activity was not directly related to clinical outcome. Further studies will be needed to determine long‐term effects and possible side effects of the NTI splint.
Inhibition of HCV subgenomic replicons by siRNAs derived from plasmids with opposing U6 and H1 promoters
Authors: Korf M. , Meyer A. , Jarczak D. , Beger C. , Manns M. P. , Krüger M.
Published: January 2007

Summary.  Hepatitis C virus (HCV) is a main cause of chronic liver disease, which may lead to the development of liver cirrhosis and hepatocellular carcinoma. Therapeutic options are still limited in a significant proportion of patients. Small interfering RNAs (siRNAs) are an efficient tool to inhibit gene expression by RNA interference. As HCV RNA replicates in the cytoplasm of liver cells without integration into the genome, RNA‐directed antiviral strategies are likely to successfully block its replication cycle. In this study, a panel of siRNAs was used to target various important regions of the HCV genome [5′ untranslated region (UTR), NS3, NS4A, NS4B, NS5B, 3′ UTR]. Convergent opposing human H1 and U6 polymerase III promoters were used to generate siRNAs. Target genes in sense and antisense orientation were attached to a luciferase reporter system to test the inhibitory efficiency of both siRNA strands. Our data revealed effective RNA interference against the HCV(+)‐strand, the HCV(−)‐strand or both strands simultaneously up to 65%. Subsequently, active siRNAs were tested in HCV subgenomic replicon cells and suppression of HCV RNA and NS5B protein levels up to 75% was confirmed. Interestingly, siRNAs that were effective against the sense as well as the antisense strand revealed the greatest inhibitory effects on HCV subgenomic replicons. Additionally, combinations of siRNAs induced a greater inhibition of HCV subgenomic replication of up to 90% proving the potential of this combined antiviral approach.
Structural basis for operator and antirepressor recognition by Myxococcus xanthus CarA repressor
Authors: Navarro‐Avilés Gloria , Jiménez María Angeles , Pérez‐Marín Mari Cruz , González Carlos , Rico Manuel , Murillo Francisco Jose , Elías‐Arnanz Montserrat , Padmanabhan S.
Published: January 2007

Blue light induces carotenogenesis in Myxococcus xanthus. The carB operon encodes all but one of the structural genes involved, and its expression is regulated by the CarA‐CarS repressor‐antirepressor pair. In the dark, CarA‐operator binding represses carB. CarS, produced on illumination, interacts physically with CarA to dismantle the CarA‐operator complex and activate carB. Both operator and CarS bind to the autonomously folded N‐terminal domain of CarA, CarA(Nter), which in excess represses carB. Here, we report the NMR structure of CarA(Nter), and map residues that interact with operator and CarS by NMR chemical shift perturbations, and in vivo and in vitro analyses of site‐directed mutants. We show CarA(Nter) adopts the winged‐helix topology of MerR‐family DNA‐binding domains, and conserves the majority of the helix‐turn‐helix and wing contacts with DNA. Tellingly, helix α2 in CarA, a key element in operator DNA recognition, is also critical for interaction with CarS, implying that the CarA‐CarS protein‐protein and the CarA‐operator protein–DNA interfaces overlap. Thus, binding of CarA to operator and to antirepressor are mutually exclusive, and CarA may discern structural features in the acidic CarS protein that resemble operator DNA. Repressor inactivation by occluding the DNA‐binding region may be a recurrent mechanism of action for acidic antirepressors.
Smooth to rugose phase variation in Vibrio cholerae can be mediated by a single nucleotide change that targets c‐di‐GMP signalling pathway
Authors: Beyhan Sinem , Yildiz Fitnat H.
Published: January 2007

Microorganisms use phase variation to increase population diversity to maximize evolutionary success. One such variation is the smooth to rugose phenotype change in Vibrio cholerae. We determined that the variation between smooth and rugose phenotypes can be controlled by a single nucleotide change in a gene (vpvC) predicted to encode a diguanylate cyclase. The vpvC allele found in the rugose genetic background is more active at producing c‐di‐GMP while that in smooth genetic background is less active. In support of this finding, disruption of vpvC in the rugose genetic variant decreases cellular c‐di‐GMP levels, diminishes rugose‐associated phenotypes and yields a smooth variant. Furthermore, the frequency of phase variation decreases dramatically when the vpvC locus is deleted in the smooth genetic background. Evidence is presented that the rugose variant is less susceptible to phage infection than the smooth variant. As phage infection is known to control populations of V. cholerae and thus outbreaks of cholera, phase variation may increase the evolutionary success of the pathogen.
A novel interaction between N‐myristoylation and the 26S proteasome during cell morphogenesis
Authors: Lee Soo Chan , Shaw Brian D.
Published: January 2007

N‐myristoylation is a protein lipidation event in which myristate is covalently linked to the N‐terminal glycine of target proteins. In Aspergillus nidulans, the N‐myristoylation deficient swoF1 mutant was previously shown to lose cell polarity during the early morphogenic event of germ tube emergence. To further investigate this defect, we mutagenized swoF1 and recovered six partial suppressors designated ssf (suppressor of swoF1). The secondary mutations enabled swoF1 to partially bypass its growth defect. We characterized a frame‐shift mutation in ssfA1, which encodes an alpha subunit of the 20S core particle of the 26S proteasome. Fewer ubiquitinated proteins accumulated in the swoF1 mutant compared with wild‐type. In contrast, the swoF1;ssfA1 mutant accumulated higher levels of ubiquitinated proteins than wild‐type. The swoF1 mutant was bypassed in the presence of the proteasome inhibitor, MG132. These results demonstrate that the swoF1 phenotype was caused, at least in part, by an increased activity of 26S proteasome‐dependent proteolysis and suppression occurred by attenuating the 26S proteasome activity. This is the first report linking N‐myristoylation and ubiquitin–proteasome‐dependent proteolysis during morphogenesis.
A novel phospholipase from Trypanosoma brucei
Authors: Richmond Gregory S. , Smith Terry K.
Published: January 2007

Phospholipase A1 activities have been detected in most cells where they have been sought and yet their characterization lags far behind that of the phospholipases A2, C and D. The study presented here details the first cloning and characterization of a cytosolic PLA1 that exhibits preference for phosphatidylcholine (GPCho) substrates. Trypanosoma brucei phospholipase A1 (TbPLA1) is unique from previously identified eukaryotic PLA1 because it is evolutionarily related to bacterial secreted PLA1. A T. brucei ancestor most likely acquired the PLA1 from a horizontal gene transfer of a PLA1 from Sodalis glossinidius, a bacterial endosymbiont of tsetse flies. Nano‐electrospray ionization tandem mass spectrometry analysis of TbPLA1 mutants established that the enzyme functions in vivo to synthesize lysoGPCho metabolites containing long‐chain mostly polyunsaturated and highly unsaturated fatty acids. Analysis of purified mutated recombinant forms of TbPLA1 revealed that this enzyme is a serine hydrolase whose catalytic mechanism involves a triad consisting of the amino acid residues Ser‐131, His‐234 and Asp‐183. The TbPLA1 homozygous null mutants generated here constitute the only PLA1 double knockouts from any organism.
AtNHX8, a member of the monovalent cation:proton antiporter‐1 family in Arabidopsis thaliana, encodes a putative Li+/H+ antiporter
Authors: An Rui , Chen Qi‐Jun , Chai Mao‐Feng , Lu Ping‐Li , Su Zhao , Qin Zhi‐Xiang , Chen Jia , Wang Xue‐Chen
Published: January 2007

The Arabidopsis monovalent cation:proton antiporter‐1 (CPA1) family includes eight members, AtNHX1–8. AtNHX1 and AtNHX7/SOS1 have been well characterized as tonoplast and plasma membrane Na+/H+ antiporters, respectively. The proteins AtNHX2–6 have been phylogenetically linked to AtNHX1, while AtNHX8 appears to be related to AtNHX7/SOS1. Here we report functional characterization of AtNHX8. AtNHX8 T‐DNA insertion mutants are hypersensitive to lithium ions (Li+) relative to wild‐type plants, but not to the other metal ions such as sodium (Na+), potassium (K+) and caesium (Cs+). AtNHX8 overexpression in a triple‐deletion yeast mutant AXT3 that exhibits defective Na+/Li+ transport specifically suppresses sensitivity to Li+, but does not affect Na+ sensitivity. Likewise, AtNHX8 overexpression complemented sensitivity to Li+, but not Na+, in sos1‐1 mutant seedlings, and increased Li+ tolerance of both the sos1‐1 mutant and wild‐type seedlings. Results of Li+ and K+ measurement of loss‐of‐function and gain‐of‐function mutants indicate that AtNHX8 may be responsible for Li+ extrusion, and may be able to maintain K+ acquisition and intracellular ion homeostasis. Subcellular localization of the AtNHX8–enhanced green fluorescent protein (EGFP) fusion protein suggested that AtNHX8 protein is targeted to the plasma membrane. Taken together, our findings suggest that AtNHX8 encodes a putative plasma membrane Li+/H+ antiporter that functions in Li detoxification and ion homeostasis in Arabidopsis.
Comparison of orthologous loci from small grass genomes Brachypodium and rice: implications for wheat genomics and grass genome annotation
Authors: Bossolini Eligio , Wicker Thomas , Knobel Philip A. , Keller Beat
Published: January 2007

Brachypodium sylvaticum and Brachypodium distachyon were recently proposed as new model plants because of their small genomes and their phylogenetic position between rice and Triticeae crops. We sequenced a 371‐kb region in B. sylvaticum, the largest genomic sequence available so far from this species, providing quantitative data on gene conservation, collinearity and phylogeny. We compared it with orthologous regions from rice and wheat. Brachypodium and wheat show perfect macro‐collinearity of genetic markers, whereas rice contains an approximately 220‐kb inversion. Rice contains almost twice as many genes as Brachypodium in the region studied, whereas wheat has about 40% more. Through comparative annotation, we identified alternative transcripts and improved the annotation for several rice genes, indicating that approximately 15% of rice genes might require re‐annotation. Surprisingly, our data suggest that 10–15% of functional sequences in small grass genomes may not encode any proteins. From available genomic and expressed sequence tag sequences, we estimated Brachypodium to have diverged from wheat about 35–40 Mya, significantly more recently than the divergence of rice and wheat. However, our data also indicate that orthologous regions from Brachypodium and wheat differ considerably in gene content, thus the Brachypodium genome sequence probably cannot replace genomic studies in the large Triticeae genomes.