bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular dynamics simulation of the dielectric constant of water: The effect of bond flexibility
Authors: Raabe Gabriele , Sadus Richard J.
Published: June 2011

The role of bond flexibility on the dielectric constant of water is investigated via molecular dynamics simulations using a flexible intermolecular potential SPC/Fw [Y. Wu, H. L. Tepper, and G. A. Voth, J. Chem. Phys. 128, 024503 (2006)]. Dielectric constants and densities are reported for the liquid phase at temperatures of 298.15 K and 473.15 K and the supercritical phase at 673.15 K for pressures between 0.1 MPa and 200 MPa. Comparison with both experimental data and other rigid bond intermolecular potentials indicates that introducing bond flexibility significantly improves the prediction of both dielectric constants and pressure–temperature–density behavior. In some cases, the predicted densities and dielectric constants almost exactly coincide with experimental data. The results are analyzed in terms of dipole moments, quadrupole moments, and equilibrium bond angles and lengths. It appears that bond flexibility allows the molecular dipole and quadrupole moment to change with the thermodynamic state point, and thereby mimic the change of the intermolecular interactions in response to the local environment.
Trapping of implanted He at Cu/Nb interfaces measured by neutron reflectometry
Authors: Zhernenkov Mikhail , Jablin Michael S. , Misra Amit , Nastasi Michael , Wang Yongqiang , Demkowicz Michael J. , Baldwin Jon K. , Majewski Jarek
Published: June 2011

Neutron reflectometry is used to characterize physical vapor deposited [Cu/Nb]x/Si layered nanocomposites exposed to extreme helium ion doses. The effects of He ions on the interfacial roughness, layer swelling, and chemical mixing have been measured. Regions of high He concentration were localized at Cu/Nb interfaces while bulk Cu and Nb layers remained intact. This remarkable behavior is attributed to the efficient trapping and storage of He at interfaces as compared to bulk.
Tunable surface plasmon polaritons in Ag composite films by adding dielectrics or semiconductors
Authors: Lu Dylan , Kan Jimmy , Fullerton Eric E. , Liu Zhaowei
Published: June 2011

We demonstrate that the surface plasmon polariton (SPP) properties of the silver composite films can be tuned by modest additions of silicon oxide or silicon. The dispersion relations deviate from that of pure silver films, and exhibit the capability to shift the surface plasmon frequency and provide larger SPP wave vectors at longer wavelengths. The effective permittivities are modeled phenomenologically by taking into account both filling ratios and size effects. These types of tunable composite films have various useful applications in areas, such as superlens imaging, SPP based sensing, enhanced photoluminescence, and SPP based photovoltatics.
Light scattering assisted surface plasmon resonance at electrospun nanofiber-coated gold surfaces
Authors: Tsuboi Kazuma , Matsumoto Hidetoshi , Minagawa Mie , Tanioka Akihiko
Published: June 2011

This letter reports the polarized optical response of nanofiber-coated gold surfaces that originated from surface plasmon resonance (SPR). The reflection spectra of the poly(vinylpyrrolidone) nanofiber-coated gold surfaces prepared by electrospinning showed a clear polarization dependence. This indicates that the SPR at the air/gold interface was assisted by light scattering of the nanofibers. In addition, the optical response of the gold surface depends on the density of the coated nanofibers. This can be explained by the scattering and the interference of the surface plasmons in the pores between the nanofibers.
Structural principles within the human-virus protein-protein interaction network
Authors: Franzosa Eric A. , Xia Yu
Published: June 2011

General properties of the antagonistic biomolecular interactions between viruses and their hosts (
exogenous interactions
) remain poorly understood, and may differ significantly from known principles governing the cooperative interactions within the host (
endogenous interactions
). Systems biology approaches have been applied to study the combined interaction networks of virus and human proteins, but such efforts have so far revealed only low-resolution patterns of host-virus interaction. Here, we layer curated and predicted 3D structural models of human-virus and human-human protein complexes on top of traditional interaction networks to reconstruct the
human-virus structural interaction network
. This approach reveals atomic resolution, mechanistic patterns of host-virus interaction, and facilitates systematic comparison with the host’s endogenous interactions. We find that exogenous interfaces tend to overlap with and mimic endogenous interfaces, thereby competing with endogenous binding partners. The endogenous interfaces mimicked by viral proteins tend to participate in multiple endogenous interactions which are transient and regulatory in nature. While interface overlap in the endogenous network results largely from gene duplication followed by divergent evolution, viral proteins frequently achieve interface mimicry without any sequence or structural similarity to an endogenous binding partner. Finally, while endogenous interfaces tend to evolve more slowly than the rest of the protein surface, exogenous interfaces—including many sites of endogenous-exogenous overlap—tend to evolve faster, consistent with an evolutionary “arms race” between host and pathogen. These significant biophysical, functional, and evolutionary differences between host-pathogen and within-host protein-protein interactions highlight the distinct consequences of antagonism versus cooperation in biological networks.
Vectorial magnetometry using magnetooptic Kerr effect including first- and second-order contributions for thin ferromagnetic films
Authors: Kuschel T , Bardenhagen H , Wilkens H , Schubert R , Hamrle J , Pištora J , Wollschläger J
Published: June 2011

A new combination of different vectorial magnetometry techniques using magnetooptic Kerr effect is described. The processing of the experimental data contains the separation of linear and quadratic parts of the magnetization curves and determination of all three components of the magnetization vector in units of Kerr rotation without any normalization to the saturation values. The experimental procedure includes measurements with parallel and perpendicular polarized incident light and an external magnetic field parallel and perpendicular to the plane of incidence of light. The determination of the complex Kerr amplitude and the theoretic description of the data processing in assumption of small angles of incidence and also for larger angles of incidence using adequate scaling to the mean saturation value validate this vectorial magnetometry method. In the case of an absent out-of-plane component of the magnetization vector, the complete reversal process can easily be reconstructed and interpreted by monodomain states and domain splitting. The measurement procedure and the processing of the data are demonstrated for an ultra-thin epitaxial Fe film on MgO(0 0 1).
The images of non-commutative polynomials evaluated on 2×2 matrices
Authors: Kanel-Belov Alexey , Malev Sergey , Rowen Louis
Published: June 2011

Let

p
p

be a multilinear polynomial in several non-commuting variables with coefficients in a quadratically closed field

K
K

of any characteristic. It has been conjectured that for any

n
n

, the image of

p
p

evaluated on the set

M
n

(
K
)

M_n(K)

of

n
n

by

n
n

matrices is either zero, or the set of scalar matrices, or the set

s

l
n

(
K
)

sl_n(K)

of matrices of trace 0, or all of

M
n

(
K
)

M_n(K)

. We prove the conjecture for

n
=
2

n=2

, and show that although the analogous assertion fails for completely homogeneous polynomials, one can salvage the conjecture in this case by including the set of all non-nilpotent matrices of trace zero and also permitting dense subsets of

M
n

(
K
)

M_n(K)

.
Biogenesis of mitochondrial β-barrel proteins: the POTRA domain is involved in precursor release from the SAM complex
Authors: Stroud David A. , Becker Thomas , Qiu Jian , Stojanovski Diana , Pfannschmidt Sylvia , Wirth Christophe , Hunte Carola , Guiard Bernard , Meisinger Chris , Pfanner Nikolaus , Wiedemann Nils
Published: June 2011

The mitochondrial outer membrane contains proteinaceous machineries for the translocation of precursor proteins. The sorting and assembly machinery (SAM) is required for the insertion of β‑barrel proteins into the outer membrane. Sam50 is the channel-forming core subunit of the SAM complex and belongs to the BamA/Sam50/Toc75 family of proteins that have been conserved from Gram-negative bacteria to mitochondria and chloroplasts. These proteins contain one or more N-terminal polypeptide transport-associated (POTRA) domains. POTRA domains can bind precursor proteins, however, different views exist on the role of POTRA domains in the biogenesis of β-barrel proteins. It has been suggested that the single POTRA domain of mitochondrial Sam50 plays a receptor-like function at the SAM complex. We established a system to monitor the interaction of chemical amounts of β-barrel precursor proteins with the SAM complex of wild-type and mutant yeast in organello. We report that the SAM complex lacking the POTRA domain of Sam50 efficiently binds β-barrel precursors, but is impaired in the release of the precursors. These results indicate the POTRA domain of Sam50 is not essential for recognition of β-barrel precursors but functions in a subsequent step to promote the release of precursor proteins from the SAM complex.
The yeast p24 complex regulates GPI-anchored protein transport and quality control by monitoring anchor remodeling
Authors: Castillon Guillaume A. , Aguilera-Romero Auxiliadora , Manzano-Lopez Javier , Epstein Sharon , Kajiwara Kentaro , Funato Kouichi , Watanabe Reika , Riezman Howard , Muñiz Manuel
Published: June 2011

Glycosylphosphatidylinositol (GPI)-anchored proteins are secretory proteins that are attached to the cell surface of eukaryotic cells by a glycolipid moiety. Once GPI anchoring has occurred in the lumen of the endoplasmic reticulum (ER), the structure of the lipid part on the GPI anchor undergoes a remodeling process prior to ER exit. In this study, we provide evidence suggesting that the yeast p24 complex, through binding specifically to GPI-anchored proteins in an anchor-dependent manner, plays a dual role in their selective trafficking. First, the p24 complex promotes efficient ER exit of remodeled GPI-anchored proteins after concentration by connecting them with the COPII coat and thus facilitates their incorporation into vesicles. Second, it retrieves escaped, unremodeled GPI-anchored proteins from the Golgi to the ER in COPI vesicles. Therefore the p24 complex, by sensing the status of the GPI anchor, regulates GPI-anchored protein intracellular transport and coordinates this with correct anchor remodeling.
Generative probabilistic models for protein–protein interaction networks—the biclique perspective
Authors: Schweiger Regev , Linial Michal , Linial Nathan
Published: June 2011

Motivation: Much of the large-scale molecular data from living cells can be represented in terms of networks. Such networks occupy a central position in cellular systems biology. In the protein–protein interaction (PPI) network, nodes represent proteins and edges represent connections between them, based on experimental evidence. As PPI networks are rich and complex, a mathematical model is sought to capture their properties and shed light on PPI evolution. The mathematical literature contains various generative models of random graphs. It is a major, still largely open question, which of these models (if any) can properly reproduce various biologically interesting networks. Here, we consider this problem where the graph at hand is the PPI network of Saccharomyces cerevisiae. We are trying to distinguishing between a model family which performs a process of copying neighbors, represented by the duplication–divergence (DD) model, and models which do not copy neighbors, with the Barabási–Albert (BA) preferential attachment model as a leading example.

Results: The observed property of the network is the distribution of maximal bicliques in the graph. This is a novel criterion to distinguish between models in this area. It is particularly appropriate for this purpose, since it reflects the graph's growth pattern under either model. This test clearly favors the DD model. In particular, for the BA model, the vast majority (92.9%) of the bicliques with both sides ≥4 must be already embedded in the model's seed graph, whereas the corresponding figure for the DD model is only 5.1%. Our results, based on the biclique perspective, conclusively show that a naïve unmodified DD model can capture a key aspect of PPI networks.

Contact:  regevs01@cs.huji.ac.il; michall@cc.huji.ac.il; nati@cs.huji.ac.il

Supplementary information:  Supplementary data are available at Bioinformatics online.
An enhanced Petri-net model to predict synergistic effects of pairwise drug combinations from gene microarray data
Authors: Jin Guangxu , Zhao Hong , Zhou Xiaobo , Wong Stephen T. C.
Published: June 2011

Motivation: Prediction of synergistic effects of drug combinations has traditionally been relied on phenotypic response data. However, such methods cannot be used to identify molecular signaling mechanisms of synergistic drug combinations. In this article, we propose an enhanced Petri-Net (EPN) model to recognize the synergistic effects of drug combinations from the molecular response profiles, i.e. drug-treated microarray data.

Methods: We addressed the downstream signaling network of the targets for the two individual drugs used in the pairwise combinations and applied EPN to the identified targeted signaling network. In EPN, drugs and signaling molecules are assigned to different types of places, while drug doses and molecular expressions are denoted by color tokens. The changes of molecular expressions caused by treatments of drugs are simulated by two actions of EPN: firing and blasting. Firing is to transit the drug and molecule tokens from one node or place to another, and blasting is to reduce the number of molecule tokens by drug tokens in a molecule node. The goal of EPN is to mediate the state characterized by control condition without any treatment to that of treatment and to depict the drug effects on molecules by the drug tokens.

Results: We applied EPN to our generated pairwise drug combination microarray data. The synergistic predictions using EPN are consistent with those predicted using phenotypic response data. The molecules responsible for the synergistic effects with their associated feedback loops display the mechanisms of synergism.

Availability: The software implemented in Python 2.7 programming language is available from request.

Contact:  stwong@tmhs.org
A novel computational framework for simultaneous integration of multiple types of genomic data to identify microRNA-gene regulatory modules
Authors: Zhang Shihua , Li Qingjiao , Liu Juan , Zhou Xianghong Jasmine
Published: June 2011

Motivation: It is well known that microRNAs (miRNAs) and genes work cooperatively to form the key part of gene regulatory networks. However, the specific functional roles of most miRNAs and their combinatorial effects in cellular processes are still unclear. The availability of multiple types of functional genomic data provides unprecedented opportunities to study the miRNA–gene regulation. A major challenge is how to integrate the diverse genomic data to identify the regulatory modules of miRNAs and genes.

Results: Here we propose an effective data integration framework to identify the miRNA–gene regulatory comodules. The miRNA and gene expression profiles are jointly analyzed in a multiple non-negative matrix factorization framework, and additional network data are simultaneously integrated in a regularized manner. Meanwhile, we employ the sparsity penalties to the variables to achieve modular solutions. The mathematical formulation can be effectively solved by an iterative multiplicative updating algorithm. We apply the proposed method to integrate a set of heterogeneous data sources including the expression profiles of miRNAs and genes on 385 human ovarian cancer samples, computationally predicted miRNA–gene interactions, and gene–gene interactions. We demonstrate that the miRNAs and genes in 69% of the regulatory comodules are significantly associated. Moreover, the comodules are significantly enriched in known functional sets such as miRNA clusters, GO biological processes and KEGG pathways, respectively. Furthermore, many miRNAs and genes in the comodules are related with various cancers including ovarian cancer. Finally, we show that comodules can stratify patients (samples) into groups with significant clinical characteristics.

Availability: The program and supplementary materials are available at http://zhoulab.usc.edu/SNMNMF/.

Contact:  xjzhou@usc.edu; zsh@amss.ac.cn

Supplementary information:  Supplementary data are available at Bioinformatics online.
IPknot: fast and accurate prediction of RNA secondary structures with pseudoknots using integer programming
Authors: Sato Kengo , Kato Yuki , Hamada Michiaki , Akutsu Tatsuya , Asai Kiyoshi
Published: June 2011

Motivation: Pseudoknots found in secondary structures of a number of functional RNAs play various roles in biological processes. Recent methods for predicting RNA secondary structures cover certain classes of pseudoknotted structures, but only a few of them achieve satisfying predictions in terms of both speed and accuracy.

Results: We propose IPknot, a novel computational method for predicting RNA secondary structures with pseudoknots based on maximizing expected accuracy of a predicted structure. IPknot decomposes a pseudoknotted structure into a set of pseudoknot-free substructures and approximates a base-pairing probability distribution that considers pseudoknots, leading to the capability of modeling a wide class of pseudoknots and running quite fast. In addition, we propose a heuristic algorithm for refining base-paring probabilities to improve the prediction accuracy of IPknot. The problem of maximizing expected accuracy is solved by using integer programming with threshold cut. We also extend IPknot so that it can predict the consensus secondary structure with pseudoknots when a multiple sequence alignment is given. IPknot is validated through extensive experiments on various datasets, showing that IPknot achieves better prediction accuracy and faster running time as compared with several competitive prediction methods.

Availability: The program of IPknot is available at http://www.ncrna.org/software/ipknot/. IPknot is also available as a web server at http://rna.naist.jp/ipknot/.

Contact:  satoken@k.u-tokyo.ac.jp; ykato@is.naist.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
Accurate estimation of heritability in genome wide studies using random effects models
Authors: Golan David , Rosset Saharon
Published: June 2011

Motivation: Random effects models have recently been introduced as an approach for analyzing genome wide association studies (GWASs), which allows estimation of overall heritability of traits without explicitly identifying the genetic loci responsible. Using this approach, Yang et al. (2010) have demonstrated that the heritability of height is much higher than the ~10% associated with identified genetic factors. However, Yang et al. (2010) relied on a heuristic for performing estimation in this model.

Results: We adopt the model framework of Yang et al. (2010) and develop a method for maximum-likelihood (ML) estimation in this framework. Our method is based on Monte-Carlo expectation-maximization (MCEM; Wei et al., 1990), an expectation-maximization algorithm wherein a Markov chain Monte Carlo approach is used in the E-step. We demonstrate that this method leads to more stable and accurate heritability estimation compared to the approach of Yang et al. (2010), and it also allows us to find ML estimates of the portion of markers which are causal, indicating whether the heritability stems from a small number of powerful genetic factors or a large number of less powerful ones.

Contact:  saharon@post.tau.ac.il
Identification of metabolic network models from incomplete high-throughput datasets
Authors: Berthoumieux Sara , Brilli Matteo , de Jong Hidde , Kahn Daniel , Cinquemani Eugenio
Published: June 2011

Motivation: High-throughput measurement techniques for metabolism and gene expression provide a wealth of information for the identification of metabolic network models. Yet, missing observations scattered over the dataset restrict the number of effectively available datapoints and make classical regression techniques inaccurate or inapplicable. Thorough exploitation of the data by identification techniques that explicitly cope with missing observations is therefore of major importance.

Results: We develop a maximum-likelihood approach for the estimation of unknown parameters of metabolic network models that relies on the integration of statistical priors to compensate for the missing data. In the context of the linlog metabolic modeling framework, we implement the identification method by an Expectation-Maximization (EM) algorithm and by a simpler direct numerical optimization method. We evaluate performance of our methods by comparison to existing approaches, and show that our EM method provides the best results over a variety of simulated scenarios. We then apply the EM algorithm to a real problem, the identification of a model for the Escherichia coli central carbon metabolism, based on challenging experimental data from the literature. This leads to promising results and allows us to highlight critical identification issues.

Contact:  sara.berthoumieux@inria.fr; eugenio.cinquemani@inria.fr

Supplementary information:  Supplementary data are available at Bioinformatics online.
Ontology patterns for tabular representations of biomedical knowledge on neglected tropical diseases
Authors: Santana Filipe , Schober Daniel , Medeiros Zulma , Freitas Fred , Schulz Stefan
Published: June 2011

Motivation: Ontology-like domain knowledge is frequently published in a tabular format embedded in scientific publications. We explore the re-use of such tabular content in the process of building NTDO, an ontology of neglected tropical diseases (NTDs), where the representation of the interdependencies between hosts, pathogens and vectors plays a crucial role.

Results: As a proof of concept we analyzed a tabular compilation of knowledge about pathogens, vectors and geographic locations involved in the transmission of NTDs. After a thorough ontological analysis of the domain of interest, we formulated a comprehensive design pattern, rooted in the biomedical domain upper level ontology BioTop. This pattern was implemented in a VBA script which takes cell contents of an Excel spreadsheet and transforms them into OWL-DL. After minor manual post-processing, the correctness and completeness of the ontology was tested using pre-formulated competence questions as description logics (DL) queries. The expected results could be reproduced by the ontology. The proposed approach is recommended for optimizing the acquisition of ontological domain knowledge from tabular representations.

Availability and implementation: Domain examples, source code and ontology are freely available on the web at http://www.cin.ufpe.br/~ntdo.

Contact:  fss3@cin.ufpe.br
From sets to graphs: towards a realistic enrichment analysis of transcriptomic systems
Authors: Geistlinger Ludwig , Csaba Gergely , Küffner Robert , Mulder Nicola , Zimmer Ralf
Published: June 2011

Motivation: Current gene set enrichment approaches do not take interactions and associations between set members into account. Mutual activation and inhibition causing positive and negative correlation among set members are thus neglected. As a consequence, inconsistent regulations and contextless expression changes are reported and, thus, the biological interpretation of the result is impeded.

Results: We analyzed established gene set enrichment methods and their result sets in a large-scale investigation of 1000 expression datasets. The reported statistically significant gene sets exhibit only average consistency between the observed patterns of differential expression and known regulatory interactions. We present Gene Graph Enrichment Analysis (GGEA) to detect consistently and coherently enriched gene sets, based on prior knowledge derived from directed gene regulatory networks. Firstly, GGEA improves the concordance of pairwise regulation with individual expression changes in respective pairs of regulating and regulated genes, compared with set enrichment methods. Secondly, GGEA yields result sets where a large fraction of relevant expression changes can be explained by nearby regulators, such as transcription factors, again improving on set-based methods. Thirdly, we demonstrate in additional case studies that GGEA can be applied to human regulatory pathways, where it sensitively detects very specific regulation processes, which are altered in tumors of the central nervous system. GGEA significantly increases the detection of gene sets where measured positively or negatively correlated expression patterns coincide with directed inducing or repressing relationships, thus facilitating further interpretation of gene expression data.

Availability: The method and accompanying visualization capabilities have been bundled into an R package and tied to a grahical user interface, the Galaxy workflow environment, that is running as a web server.

Contact:  Ludwig.Geistlinger@bio.ifi.lmu.de; Ralf.Zimmer@bio.ifi.lmu.de
Sequence-based prediction of protein crystallization, purification and production propensity
Authors: Mizianty Marcin J. , Kurgan Lukasz
Published: June 2011

Motivation: X-ray crystallography-based protein structure determination, which accounts for majority of solved structures, is characterized by relatively low success rates. One solution is to build tools which support selection of targets that are more likely to crystallize. Several in silico methods that predict propensity of diffraction-quality crystallization from protein chains were developed. We show that the quality of their predictions drops when applied to more recent crystallization trails, which calls for new solutions. We propose a novel approach that alleviates drawbacks of the existing methods by using a recent dataset and improved protocol to annotate progress along the crystallization process, by predicting the success of the entire process and steps which result in the failed attempts, and by utilizing a compact and comprehensive set of sequence-derived inputs to generate accurate predictions.

Results: The proposed PPCpred (predictor of protein Production, Purification and Crystallization) predict propensity for production of diffraction-quality crystals, production of crystals, purification and production of the protein material. PPCpred utilizes comprehensive set of inputs based on energy and hydrophobicity indices, composition of certain amino acid types, predicted disorder, secondary structure and solvent accessibility, and content of certain buried and exposed residues. Our method significantly outperforms alignment-based predictions and several modern crystallization propensity predictors. Receiver operating characteristic (ROC) curves show that PPCpred is particularly useful for users who desire high true positive (TP) rates, i.e. low rate of mispredictions for solvable chains. Our model reveals several intuitive factors that influence the success of individual steps and the entire crystallization process, including the content of Cys, buried His and Ser, hydrophobic/hydrophilic segments and the number of predicted disordered segments.

Availability:  http://biomine.ece.ualberta.ca/PPCpred/.

Contact:  lkurgan@ece.ualberta.ca

Supplementary information:  Supplementary data are available at Bioinformatics online.
Reconstruction of genealogical relationships with applications to Phase III of HapMap
Authors: Kyriazopoulou-Panagiotopoulou Sofia , Kashef Haghighi Dorna , Aerni Sarah J. , Sundquist Andreas , Bercovici Sivan , Batzoglou Serafim
Published: June 2011

Motivation: Accurate inference of genealogical relationships between pairs of individuals is paramount in association studies, forensics and evolutionary analyses of wildlife populations. Current methods for relationship inference consider only a small set of close relationships and have limited to no power to distinguish between relationships with the same number of meioses separating the individuals under consideration (e.g. aunt–niece versus niece–aunt or first cousins versus great aunt–niece).

Results: We present CARROT (ClAssification of Relationships with ROTations), a novel framework for relationship inference that leverages linkage information to differentiate between rotated relationships, that is, between relationships with the same number of common ancestors and the same number of meioses separating the individuals under consideration. We demonstrate that CARROT clearly outperforms existing methods on simulated data. We also applied CARROT on four populations from Phase III of the HapMap Project and detected previously unreported pairs of third- and fourth-degree relatives.

Availability: Source code for CARROT is freely available at http://carrot.stanford.edu.

Contact:  sofiakp@stanford.edu
Characterization and improvement of RNA-Seq precision in quantitative transcript expression profiling
Authors: Łabaj Paweł P. , Leparc Germán G. , Linggi Bryan E. , Markillie Lye Meng , Wiley H. Steven , Kreil David P.
Published: June 2011

Motivation: Measurement precision determines the power of any analysis to reliably identify significant signals, such as in screens for differential expression, independent of whether the experimental design incorporates replicates or not. With the compilation of large-scale RNA-Seq datasets with technical replicate samples, however, we can now, for the first time, perform a systematic analysis of the precision of expression level estimates from massively parallel sequencing technology. This then allows considerations for its improvement by computational or experimental means.

Results: We report on a comprehensive study of target identification and measurement precision, including their dependence on transcript expression levels, read depth and other parameters. In particular, an impressive recall of 84% of the estimated true transcript population could be achieved with 331 million 50 bp reads, with diminishing returns from longer read lengths and even less gains from increased sequencing depths. Most of the measurement power (75%) is spent on only 7% of the known transcriptome, however, making less strongly expressed transcripts harder to measure. Consequently, <30% of all transcripts could be quantified reliably with a relative error <20%. Based on established tools, we then introduce a new approach for mapping and analysing sequencing reads that yields substantially improved performance in gene expression profiling, increasing the number of transcripts that can reliably be quantified to over 40%. Extrapolations to higher sequencing depths highlight the need for efficient complementary steps. In discussion we outline possible experimental and computational strategies for further improvements in quantification precision.

Contact:  rnaseq10@boku.ac.at

Supplementary information:  Supplementary data are available at Bioinformatics online.
HiTRACE: high-throughput robust analysis for capillary electrophoresis
Authors: Yoon Sungroh , Kim Jinkyu , Hum Justine , Kim Hanjoo , Park Seunghyun , Kladwang Wipapat , Das Rhiju
Published: June 2011

Motivation: Capillary electrophoresis (CE) of nucleic acids is a workhorse technology underlying high-throughput genome analysis and large-scale chemical mapping for nucleic acid structural inference. Despite the wide availability of CE-based instruments, there remain challenges in leveraging their full power for quantitative analysis of RNA and DNA structure, thermodynamics and kinetics. In particular, the slow rate and poor automation of available analysis tools have bottlenecked a new generation of studies involving hundreds of CE profiles per experiment.

Results: We propose a computational method called high-throughput robust analysis for capillary electrophoresis (HiTRACE) to automate the key tasks in large-scale nucleic acid CE analysis, including the profile alignment that has heretofore been a rate-limiting step in the highest throughput experiments. We illustrate the application of HiTRACE on 13 datasets representing 4 different RNAs, 3 chemical modification strategies and up to 480 single mutant variants; the largest datasets each include 87 360 bands. By applying a series of robust dynamic programming algorithms, HiTRACE outperforms prior tools in terms of alignment and fitting quality, as assessed by measures including the correlation between quantified band intensities between replicate datasets. Furthermore, while the smallest of these datasets required 7–10 h of manual intervention using prior approaches, HiTRACE quantitation of even the largest datasets herein was achieved in 3–12 min. The HiTRACE method, therefore, resolves a critical barrier to the efficient and accurate analysis of nucleic acid structure in experiments involving tens of thousands of electrophoretic bands.

Availability: HiTRACE is freely available for download at http://hitrace.stanford.edu.

Contact:  sryoon@korea.ac.kr; rhiju@stanford.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Collaborative Analysis of Wheat Endosperm Compressive Material Properties
Authors: Morris Craig F. , Delwiche Stephen R. , Bettge Arthur D. , Mabille Frédéric , Abécassis Joël , Pitts Marvin J. , Dowell Floyd E. , Deroo Camille , Pearson Tom
Published: June 2011

The objective measurement of cereal endosperm texture, for wheat (Triticum spp. L.) in particular, is relevant to the milling, processing, and utilization of grain. The objective of this study was to evaluate the interlaboratory results of compression failure testing of wheat endosperm specimens of defined geometry. Parallelepipeds (bricks) and cylinders were prepared from individual soft and hard near‐isogenic wheat kernels and compressed in two orientations (parallel and perpendicular to the long brush‐to‐germ axis). Compression curves were used to derive failure stress, failure strain, work density (area under the curve), and Young's modulus. In all five laboratories, the ability to delineate hard from soft wheat endosperm material properties was quite high. Four laboratories compressed endosperm bricks in the same orientation, on edge; texture class (soft vs. hard) was consistently the greatest source of variation in analysis of variance models (F‐values from 417 to 1401, Young's modulus and failure stress, respectively). Failure stress was found to be the best overall means of measuring the difference in what is known in the vernacular as wheat hardness. Across laboratories, the absolute measures of all four material properties ranged on the order of about two‐ to threefold from low to high, although within a laboratory, results were highly consistent. Laboratory by texture class interaction was deemed to be of minor importance. Brick size and moisture content within the ranges tested were not major sources of variation, and cylinders prepared from endosperm produced results similar to those obtained from bricks. The results suggested that wheat endosperm might express some level of anisotropic behavior, as specimens compressed in the kernel orientation parallel to the long axis failed at lower strain and stress values, with lower work density, when compared with kernel orientation perpendicular to the long axis. A key feature of interlaboratory variation was identified as being instrument rigidity, a subject of ongoing research. In conclusion, the preparation of endosperm specimens of defined size and shape, in combination with compression failure testing at low moisture content (<18%), is useful for objectively delineating the phenomenon known as hardness. The study presented here will advance our ability to objectively measure cereal grain texture and the material properties of endosperm.
Delaying Selection for Fungicide Insensitivity by Mixing Fungicides at a Low and High Risk of Resistance Development: A Modeling Analysis
Authors: Hobbelen P. H. F. , Paveley N. D. , van den Bosch F.
Published: June 2011

This study used mathematical modeling to predict whether mixtures of a high-resistance-risk and a low-risk fungicide delay selection for resistance against the high-risk fungicide. We used the winter wheat and Mycosphaerella graminicola host–pathogen system as an example, with a quinone outside inhibitor fungicide as the high-risk and chlorothalonil as the low-risk fungicide. The usefulness of the mixing strategy was measured as the “effective life”: the number of seasons that the disease-induced reduction of the integral of canopy green area index during the yield forming period could be kept <5%. We determined effective lives for strategies in which the dose rate (i) was constant for both the low-risk and high-risk fungicides, (ii) was constant for the low-risk fungicide but could increase for the high-risk fungicide, and (iii) was adjusted for both fungicides but their ratio in the mixture was fixed. The effective life was highest when applying the full label-recommended dose of the low-risk fungicide and adjusting the dose of the high-risk fungicide each season to the level required to maintain effective control. This strategy resulted in a predicted effective life of ≤12 years compared with 3 to 4 years when using the high risk fungicide alone.
Calcifications in human osteoarthritic articular cartilage:ex vivoassessment of calcium compounds using XANES spectroscopy. Addendum
Authors: Nguyen Christelle , Ea Hang Korng , Thiaudiere Dominique , Reguer Solenn , Hannouche Didier , Daudon Michel , Lioté Frédéric , Bazin Dominique
Published: June 2011

An acknowledgment is published for the paper by Nguyenet al.[(2011),J. Synchrotron Rad.18, 475–480].
Brain‐derived neurotrophic factor is increased in serum and skin levels of patients with chronic spontaneous urticaria
Authors: Rössing K. , Novak N. , Mommert S. , Pfab F. , Gehring M. , Wedi B. , Kapp A. , Raap U.
Published: June 2011

Background Chronic spontaneous urticaria is triggered by many direct and indirect aggravating factors including autoreactive/autoimmune mechanisms, infections, non‐allergic and pseudoallergic intolerance reactions. However, the role of neuroimmune mechanisms in chronic spontaneous urticaria so far is unclear.

Objective Thus, we wanted to address the regulation of the neurotrophin brain‐derived neurotrophic factor (BDNF) in serum and inflammatory skin of patients with chronic spontaneous urticaria in comparison to subjects with healthy skin.

Methods Fifty adult patients with chronic spontaneous urticaria and 23 skin‐healthy subjects were studied. Chronic spontaneous urticaria was defined as recurrent weals for more than 6 weeks. Autologous serum skin test was performed in all patients with chronic spontaneous urticaria and BDNF serum levels were analysed by enzyme immunoassay in all subjects. Furthermore, skin biopsies were taken from weals of eight patients with chronic spontaneous urticaria as well as from healthy skin of eight controls to evaluate the expression of BDNF and its receptors including tyrosine kinase (trk) B and pan‐neurotrophin receptor p75NTR by immunohistochemistry.

Results BDNF serum levels were detectable in all subjects studied. However, BDNF levels were significantly higher in patients with chronic spontaneous urticaria compared to non‐atopic skin‐healthy controls (P<0.001). Furthermore, epidermal and dermal expression of BDNF and epidermal expression of p75NTR was significantly higher in patients with chronic spontaneous urticaria compared with controls (P<0.05–0.001). There was no difference with regard to the expression of trkB between chronic spontaneous urticaria and controls and no difference in BDNF serum levels between autologous serum skin test‐positive (n=23) and ‐negative (n=27) patients with chronic spontaneous urticaria.

Conclusions and Clinical Relevance This study shows that BDNF is increased in serum and diseased skin of patients with chronic spontaneous urticaria, suggesting a role for neurotrophins in the pathophysiology of this chronic inflammatory skin disease. Further studies are needed to address the functional role of BDNF on key target effector cells in chronic spontaneous urticaria to establish new therapeutic implications.

Cite this as: K. Rössing, N. Novak, S. Mommert, F. Pfab, M. Gehring, B. Wedi, A. Kapp and U. Raap, Clinical & Experimental Allergy, 2011 (41) 1392–1399.
Multiparameter phenotyping of T‐cell subsets in distinct subgroups of patients with pulmonary sarcoidosis
Authors: Wikén M. , Grunewald J. , Eklund A. , Wahlström J.
Published: June 2011

Abstract.  Wikén M, Grunewald J, Eklund A, Wahlström J (Respiratory Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden). Multiparameter phenotyping of T‐cell subsets in distinct subgroups of patients with pulmonary sarcoidosis. J Intern Med 2012; 271: 90–103.

Objectives.  Sarcoidosis is an inflammatory disorder in which elevated numbers of activated T cells are found in the lung. HLA‐DRB1*0301pos (DR3pos) patients are characterized by good prognosis and an accumulation of lung CD4pos T cells expressing the T‐cell receptor (TCR) gene segment AV2S3. Our aim was to phenotype lung and blood T‐cell subsets in distinct patient groups to better understand the function of these subsets.

Design.  Bronchoalveolar lavage (BAL) fluid and whole blood were obtained from a total of 22 patients with sarcoidosis, of whom 11 were DR3pos. Using eight‐colour flow cytometry, phenotyping of T cells was performed with regard to CD3, CD4, CD8, CD25, CD27, CD45RO, CD57, CD69, CD103, FOXP3 and TCR AV2S3.

Results.  DR3pos patients had fewer FOXP3pos (regulatory) CD45ROpos (memory) BAL T cells than DR3neg patients. Fewer AV2S3pos T cells were FOXP3pos, compared with AV2S3neg cells, thus indicating an effector function and not a regulatory role for this subset. Fewer lung and blood AV2S3pos T cells were CD25pos CD27pos, and more were CD25neg CD27neg and CD69pos, compared with AV2S3neg T cells, indicating a higher degree of differentiation and activation in both compartments.

Conclusion.  Our main findings were a lower proportion of regulatory T cells in DR3pos patients, together with the accumulation of AV2S3pos T cells with a highly activated effector phenotype in the lungs of these patients. This may provide for efficient elimination of a harmful antigen in DR3pos patients and could thus help to explain the spontaneous recovery typically seen in these patients.
Health utilities and psychometric quality of life in patients with early‐ and late‐stage hepatitis C virus infection
Authors: Hsu Priscilla C , Federico Carole A , Krajden Mel , Yoshida Eric M , Bremner Karen E , Anderson Frank H , Weiss Alan A , Krahn Murray D
Published: June 2011

Background and Aim:  Hepatitis C virus (HCV) infection is associated with impairment in health‐related quality of life (HRQOL). The purpose of this study was to evaluate HRQOL across the HCV disease spectrum using preference‐based (utility) and non‐preference‐based (psychometric) methods, adjusting for sociodemographic factors and co‐morbidity.

Methods:  Hepatitis C virus patients (n = 751) were recruited from several tertiary care settings in Vancouver, Canada for this observational, cross‐sectional cohort study. Patients completed the Health Utilities Index Mark 2/3, a self‐administered time trade‐off utility instrument, and the Hepatitis Quality of Life Questionnaire (SF‐36 with HCV‐specific items). We examined the association between HRQOL and disease stage using linear regression adjusting for age, education, marital status, income, and co‐morbidities.

Results:  Utility scores were low across disease stage and instrument, ranging from 0.51 to 0.80. On the SF‐36, the mean Physical Component Summary score ranged from 37.2 to 49.2 across disease stage, and the Mental Component Summary score ranged from 39.7 to 45.7 (United States norms = 50). In general, patients with viral clearance had the highest scores, and those with late‐stage disease (cirrhosis, liver cancer) had the lowest. Multivariable linear regression showed that the effect of disease stage was modest overall. Increasing age, lower income, unattached marital status, and high comorbidity were strongly associated with impairment in HRQOL.

Conclusions:  The effect of stage of disease on HRQOL is modest, although viral clearance is associated with higher HRQOL. HCV patients' HRQOL is strongly associated with concomitant illness and sociodemographic factors.
Factors influencing suicidal ideation among Japanese adults: From the national survey by the Cabinet Office
Authors: Aiba Miyuki , Matsui Yutaka , Kikkawa Takehiko , Matsumoto Toshihiko , Tachimori Hisateru
Published: June 2011

Aim:  Suicide prevention is of pressing importance in Japan, and grappling with this problem necessitates clarifying the causes of suicidal ideation. The purpose of the present study was to investigate several factors influencing suicidal ideation. This was done through analyzing factors examined in prior research and accessing suicide sites.

Methods:  A total of 1080 randomly selected adults were asked about stress, stress release, social support sources, depression, access of suicides sites, and suicidal ideation.

Results:  Around 6% of men in their 20s and 30s as well as 7% of people with suicide ideations had accessed suicide sites on the web. Those with suicide ideations were more likely to access suicide sites than those without. There was no sex difference in suicide ideations. The results concerning factors influencing past‐year suicide ideations revealed that there were age and sex differences in these factors.

Conclusion:  For men in their 20s through their 50s, accessing suicide sites influenced suicidal ideations through depression, and for women in the same age bracket, emotional support influenced suicidal ideations through depression. For men and women over the age of 60, depression strongly influenced suicidal ideations.
An assessment of scientific approaches towards species relocations in Australia
Authors: SHEEAN VICTORIA A. , MANNING ADRIAN D. , LINDENMAYER DAVID B.
Published: June 2011

Species relocation programmes are increasingly performed with the intention of establishing a self‐sustaining population of threatened or declining native species. However, the use of experimental quantitative approaches in species relocation programmes is still relatively uncommon, despite a number of international studies recommending clear guidelines and standards. This paper evaluates species relocation programmes conducted within Australia to assess how programmes performed in relation to such standards. The search techniques identified 54 species relocation programmes, the majority of which were reintroductions (52%) and supplementations (30%). Only 25 (46%) of the species relocation programmes claimed success, with a lack of effective predator control recognized as contributing to the failure of 14 programmes. There was considerable variation in the quality of species relocation programmes in relation to key features such as whether the programme integrated experimental approaches with testable hypotheses, whether there were explicit statements of criteria for success, whether suitable habitat was identified for the release site and whether long‐term monitoring was conducted. We propose guidelines to improve scientific rigour and success rates of species relocation programmes.