bluuebunny/crossref_metadata_2025 huggingface dataset:
Keeping them connected—reducing drug‐related harm in Australian schools from a Catholic perspective
Authors: NORDEN PETER
Published: June 2008

In this Harm Reduction Digest, Father Peter Norden of Jesuit Social Services (Australia) summarises the findings of a report of a consultation into how Catholic schools in Australia address substance use by school students. The report showed that while in the past the ‘zero tolerance’ approach had been the norm, more recently there had been a growing awareness in Catholic schools that it is possible to respond to the needs of drug‐using students while being respectful of the duty of care to other students. Moreover, harm reduction was accepted as a serious objective for drug policy and practice in Australian Catholic schools. The paper canvases the key issues that emerged from the consultation and suggests what ‘good practice’ looks like, providing useful guidance for both Catholic and non‐Catholic schools alike. For those of us outside the Catholic school system, the paper provides an enlightening read about how substance use can be best addressed within schools.
Political and legal institutions and their influence on drug policy: an Australian perspective
Authors: RYDER DAVID
Published: June 2008

Issues. Under a federal system of government, political power is separated and distributed between different institutions of government. The distribution of power to enact policies that influence alcohol and other drug use can impact on the associated harm.Approach. A description of the separation of powers under a federal system of government is followed by three case studies of alcohol and other drug policies which have been influenced by the use of power by different institutions of government.Key findings. Whether or not a policy is enacted depends upon who has the power to bring such a policy into being, who has the power to prevent its enactment and whether those with such power choose to use them.Conclusion. The enactment of policy is a political act, needing to be understood by those wishing to see evidence‐based policies brought into being. An understanding of the separation of powers under a federal system of government is one aspect of the political process that those who work in the alcohol and other drug field need to understand.
The size and mix of government spending on illicit drug policy in Australia
Authors: MOORE TIMOTHY J.
Published: June 2008

Aim. To estimate how much governments in Australia spend on reducing and dealing with illicit drug problems. Methods. Government documents and supplementary information sources were used to estimate drug‐related expenditure for the financial year 2002–03, in Australian dollars. Public sector expenditure on reducing drug problems (‘proactive expenditure’) was classified into four policy functions: prevention, treatment, harm reduction and enforcement. Expenditure related to the consequences of drug use (‘reactive expenditure’) was included as a separate category. Results. Spending by Australian governments in financial year 2002–03 on all drug‐related activities was estimated to be $3.2 billion. Proactive expenditure was estimated to be $1.3 billion, comprising 55% on enforcement, 23% on prevention, 17% on treatment, 3% on harm reduction and 1% on activities that span several of these functions. Expenditure on dealing with the consequences of drug use was estimated to be $1.9 billion, with the majority the result of crime‐related consequences. Conclusion. Several insights result from estimating these expenditures. First, law enforcement is the largest drug policy component, with Australian governments also spending significant amounts on treatment and prevention programmes. Secondly, apart from the prevention component, Australia's drug policy mix is strikingly similar to recent international estimates. Finally, expenditures associated with dealing with the consequences of illicit drugs are large and important for assessing drug‐related public sector expenditure.
Screening and brief interventions for alcohol: attitudes, knowledge and experience of community pharmacists in Auckland, New Zealand
Authors: SHERIDAN JANIE , WHEELER AMANDA , CHEN LUCY JU‐HSING , HUANG ANNIE CHEN‐YUN , LEUNG IRIS NGA‐YEE , TIEN KAREN YOW‐CHYI
Published: June 2008

Introduction. Screening and brief intervention (SBI) for alcohol consumption in primary care have been shown to be effective in reducing drinking. This role has not been taken up by community pharmacists. This study aimed to explore attitudes, knowledge, barriers and incentives towards involvement of community pharmacists in New Zealand with problem drinkers. Method. A postal survey (three mailshots) of community pharmacies was undertaken in Auckland, New Zealand, followed by a 10% random sample non‐responder‐follow‐up. Results. A response rate of 39.1% to the postal survey was obtained. In general, knowledge of alcohol content of drinks and recommended safe drinking limits was poor. Respondents were generally well motivated towards undertaking this role, but lacked knowledge, skills and confidence. On follow‐up, non‐responders were found to be less knowledgeable, but had similar attitudes to respondents, indicating potential for extrapolation with regard to beliefs and views on this subject. Discussion. This novel study has found that there is potential for involvement of community pharmacists in New Zealand in SBI for problem drinkers. Lack of knowledge can be remedied relatively easily; greater hurdles such as lack of skills, and lack of confidence may be offset by the high level of motivation of this group. This is an area where community pharmacists can further their professional scope of practice by being in an essential position to provide this service.
Ready to drinks are associated with heavier drinking patterns among young females
Authors: HUCKLE TAISIA , SWEETSUR PAUL , MOYES SIMON , CASSWELL SALLY
Published: June 2008

Aim. To report patterns of use of ready to drinks (RTDs) and to assess if RTD consumers have heavier drinking patterns. RTDs were introduced in 1995. Method. Data from a general population sample of 7201 respondents aged 14–65 years, in New Zealand in 2004, were modelled. Results. Nineteen per cent of respondents consumed RTDs. Respondents aged 14–17 and 18–24 years and females were the largest consumers of RTDs. Compared to beer, wine or spirits, being an RTD consumer predicted (1) higher typical occasion quantities for respondents aged 14–17, 18–24 and 25+ years and (2) heavier drinking for those aged 14–17 and 18–24 years. When amounts of beverages consumed were modelled, quantity of RTDs predicted higher typical occasion quantities among females of all ages. Among males beer was more predictive. Similar results were found for the heavier drinking measure. For 14–17‐year‐old females, RTDs consumption predicted higher annual frequency, but for the other females and males the amount of wine or beer consumed predicted higher frequency. Conclusion. RTDs were most popular among young people aged 14–17 years, and females. RTDs predicted higher typical occasion alcohol consumption and heavier drinking better than any other beverage for females aged 14–17 years. For the other age and gender groups, other beverages predicted higher quantity and frequency consumption.
Role of Thromboxane A2 Receptor on the Effects of Oxidized LDL on Microvascular Endothelium Nitric Oxide, Endothelin‐1, and IL‐6 Production
Authors: LUBRANO VALTER , BALDI SIMONA , FERRANNINI ELE , L'ABBATE ANTONIO , NATALI ANDREA
Published: June 2008

Objective: The aim of this study was to determine to what extent thromboxane A2 (TP) receptor mediates the effect of oxidated low‐density lipoprotein (LDL) on nitric oxide (NO), interleukin (IL)‐6, and endothelin‐1 (ET‐1) release by microvascular endothelial cells.

Methods: Endothelial nitric oxide synthase (eNOS), nitrites and nitrates (NO2/NO3), ET‐1, and IL‐6 production were measured following human microvascular endothelial cell 1 exposure to isoprostane‐8‐epi‐PGF2α (F2IP), a natural agonist of the TP receptor present in oxidized LDL, or native, low‐, or medium‐oxidized LDL either with the TP‐receptor blocker, SQ29.548, or its vehicle.

Results: F2IP and both native and oxidized LDL enhanced NO2/NO3. F2IP through the TP receptor stimulated eNOS (eight‐fold), while the oxidized LDL effect (two‐to five‐fold) was only partially prevented by SQ29.548. While LDL concentration and degree of oxidation synergistically and independent of SQ29.548 stimulated IL‐6, F2IP had no effect. F2IP induced a modest (+50%) increase in ET‐1. LDL, independent of concentration or degree of oxidation, stimulated (+120%) ET‐1 production, and this effect was only partially attenuated by SQ29.548.

Conclusions: In microvascular endothelial cells, LDL concentration and degree of oxidation synergistically stimulate NO and IL‐6 production, but only NO release is largely mediated by the TP receptor. LDL facilitates ET‐1 release independent of concentration and degree of oxidation; TP‐receptor stimulation is only partially responsible for this effect.
Modeling of Cellular Metabolism and Microcirculatory Transport
Authors: BEARD DANIEL A. , WU FAN , CABRERA MARCO E. , DASH RANJAN K.
Published: June 2008

Oxygen and other substrates, waste products, hormone messengers, and cells and other particles of the immune system are all transported in a closed‐loop circulatory system in vertebrates, within which pumped blood travels to within diffusion distances of practically every cell in the body. Exchange of oxygen and carbon dioxide in the pulmonary capillaries and absorption of nutrients in the gut provide the circulating blood with biochemical reactants to sustain bioenergetic processes throughout the body. Inputs and outputs transported by the microcirculation are necessary to drive the open‐system nonequilibrium chemical reactions of metabolism that are essential for cellular function. In turn, metabolically derived signals influence microcirculatory dynamics. Indeed, the microcirculation is the key system that ties processes at the whole‐body level of the cardiovascular system to subcellular phenomena. This tight integration between cellular metabolism and microcirculatory transport begs for integrative simulations that span the cell, tissue, and organ scales.
Energetic particles in magnetic confinement systems
Authors: Günter S.
Published: June 2008

Dominating α-particle heating will be the qualitatively new physics element of ITER. As it constitutes both a conceptually challenging as well as a practically highly relevant field, it has attracted the attention of a large and growing scientific community. Theoretical and diagnostic tools should be fully developed at the commencement of the thermonuclear operation of ITER. Fortunately effective methods exist to produce significant fractions of energetic ions already in present experiments. Although these populations differ qualitatively in their energy and pitch-angle spectra from those of fusion-alphas, they offer an excellent opportunity to test theoretical models and codes and to develop and benchmark diagnostic techniques. ITER itself will not mark the last stage in the development of fusion heating, and a comprehensive ab initio understanding of fast particle results on this device will be a necessary prerequisite for bridging the gap to DEMO. The study of the confinement properties of energetic particles, and in particular their interaction with the background plasma, is therefore a key element in the preparation for ITER and DEMO operation.

The papers contained in this special section are based on invited presentations at the 10th IAEA Technical Meeting on Energetic Particles in Magnetic Confinement Systems held in Kloster Seeon, Germany, 8–10 October 2007, hosted by the Max-Planck-Institut für Plasmaphysik, Garching. The main topics of the presentations at this meeting were experimental observations and theoretical results on instabilities driven by energetic ions in tokamaks and stellarators, recent diagnostic developments, runaway electrons, heating and current drive.

The papers presented here are devoted to the most challenging topics in energetic particle physics: the drive of instabilities via resonant interaction between energetic particles and plasma waves and the non-linear back-reaction on the confinement of the fast ions. Experimental observations in various magnetic confinement devices (tokamaks, spherical tokamaks, stellarators) are presented as well as theoretical investigations based on true ab initio physics models.
Damping and drive of low-frequency modes in tokamak plasmas
Authors: Lauber Ph. , Günter S.
Published: June 2008

The ability to predict the stability of fast-particle-driven Alfvén eigenmodes in burning fusion plasmas requires a detailed understanding of the dissipative mechanisms that damp these modes. In order to address this question, the linear gyro-kinetic, electromagnetic code LIGKA (Lauber 2003 Linear gyrokinetic description of fast particle effects on the MHD stability in tokamaks PhD Thesis Technical University München, Lauber et al 2007 J. Comp. Phys.
226 447) is employed to investigate their behaviour in realistic tokamak geometry.

Recently, the model and the implementation of LIGKA were extended in order to capture rigorously the coupling of the shear Alfvén wave to the drift and sound waves. This coupling becomes important for the investigation of low-frequency modes such as the Alfvén cascade modes (AC), the beta-induced Alfvén eigenmodes (BAEs), the geodesic acoustic modes (GAMs), the energetic particle modes (EPMs) and—at even lower frequencies—the resistive wall modes (RWMs).

The authors report on an effort to close the gap between high-n micro-scale turbulence codes (in their linear phase) and low-n global MHD codes. More precisely, the aim is to describe both regimes within the same framework of equations and with the same numerical implementation by improving the range of applicability and validity of LIGKA: an eigenvalue code allows one to explore both the local complex dispersion relations, e.g. kinetic Alfvén waves (electromagnetic), ion acoustic waves (electrostatic) or drift waves in realistic geometry and also their global eigenfunctions.

As an application of this extension, an investigation of the kinetic RWM damping mechanisms is carried out.
MHD induced neutral beam ion loss from NSTX plasmas
Authors: Darrow D.S. , Fredrickson E.D. , Gorelenkov N.N. , Roquemore A.L. , Shinohara K.
Published: June 2008

Bursts of ∼60 kHz activity on Mirnov coils, identified as energetic particle modes, occur frequently in NSTX plasmas and these are accompanied by bursts of neutral beam ion loss over a range in pitch angles. These losses have been measured with a scintillator type loss probe imaged with a high speed (> 10 000 frames s−1) video camera, giving the evolution of the energy and pitch angle distributions of the lost neutral beam ions over the course of the events. The instability occurs below the TAE frequency in NSTX (∼100 kHz) in high beta plasmas and may also be identified as a beta-induced Alfvén acoustic (BAAE) mode.

The data from one burst that causes a 13% reduction in the neutron rate have been studied extensively and have several interesting features. First, the burst begins with the mode having a purely n = 1 character, sweeping downwards in frequency. However, there is no change to the underlying loss signal during this time interval. This indicates there is no phase space transport of fast (80 keV D) ions into the loss cone seen by the probe from the frequency sweeping. As the burst evolves further in time, a concurrent n = 2 mode arises, followed quickly by a concurrent n = 3 mode. During this period when multiple modes are present, loss over a wide range of pitch angles is seen simultaneously, suggesting stochastization of the beam ion phase space. There is no evidence of any sweeping in pitch angle of the loss in either phase of the burst, at least not on the 100 µs time scale.
Local observations of fast ion responses to energetic particle modes using a directional probe in the Compact Helical System (CHS)
Authors: Nagaoka K. , Isobe M. , Toi K. , Goto K. , Ito T. , Todo Y. , Osakabe M. , Ohshima S. , Shimizu A. , Fujisawa A. , Nakano H. , Takeiri Y. , Watanabe K. Y. , Akiyama T. , Yoshimura Y. , Suzuki C. , Nishimura S. , Matsuoka K. , Okamura S.
Published: June 2008

Bursting energetic particle mode (EPM) and fast ion loss induced by the EPM have been observed and experimentally investigated in the Compact Helical System (CHS). A directional probe method was newly applied to neutral beam heated plasmas for fast ion measurement, and it successfully revealed fast ion behaviour inside the last closed flux surface (LCFS) during bursting EPMs. A convective oscillation was observed only inside the LCFS, and drives little loss of fast ions. An anomalous loss of fast ions produced by the phase difference between the fast ion oscillation and the EPM with m = 3/n = 2 was observed in the outward shifted configurations. Another anomalous loss of fast ions due to EPMs with m = 2/n = 1 was also observed in the inward shifted configuration. The characteristics of the fast-ion-loss flux are different from those observed in the outward shifted configurations, and the loss mechanism seems to be related to a mode mixture between the EPM and a low frequency mode.
Simulation studies on alpha-particle-driven current in tokamak reactors
Authors: Tani K. , Azumi M.
Published: June 2008

An asymmetry particle trapping caused by the finite banana width of alpha particles and a current produced by the resulting imbalance between transit particles with positive and negative velocities parallel to the magnetic field line (simply referred to as transit current) are numerically demonstrated by using an orbit-following Monte-Carlo code. The transit current is considerably enhanced by a collaborative effect of the finite-banana-width and a non-uniformity of the alpha particle source. The pitch-angle scattering is also very important for it. Banana-trapped particles drive a substantially negative current in the central region. Consequently, the positive transit current is degraded by the negative banana current and the net alpha current is almost flat near the plasma centre. The net alpha-driven total currents in an ITER-like normal aspect-ratio system (aspect ratio = 3.17) and in a low aspect-ratio system VECTOR (aspect ratio = 1.98) estimated with a conventional electron screening effect are about 0.4 MA and 1 MA, respectively. A low-aspect-ratio tokamak has an advantage over a normal or a large-aspect-ratio system in driving current by fusion-produced alpha particles.
Assessment and improvement of the Plasmodium yoelii yoelii genome annotation through comparative analysis
Authors: Vaughan Ashley , Chiu Sum-Ying , Ramasamy Gowthaman , Li Ling , Gardner Malcolm J. , Tarun Alice S. , Kappe Stefan H.I. , Peng Xinxia
Published: June 2008

Motivation: The sequencing of the Plasmodium yoelii genome, a model rodent malaria parasite, has greatly facilitated research for the development of new drug and vaccine candidates against malaria. Unfortunately, only preliminary gene models were annotated on the partially sequenced genome, mostly by in silico gene prediction, and there has been no major improvement of the annotation since 2002.

Results: Here we report on a systematic assessment of the accuracy of the genome annotation based on a detailed analysis of a comprehensive set of cDNA sequences and proteomics data. We found that the coverage of the current annotation tends to be biased toward genes expressed in the blood stages of the parasite life cycle. Based on our proteomic analysis, we estimate that about 15% of the liver stage proteome data we have generated is absent from the current annotation. Through comparative analysis we identified and manually curated a further 510 P. yoelii genes which have clear orthologs in the P. falciparum genome, but were not present or incorrectly annotated in the current annotation. This study suggests that improvements of the current P. yoelii genome annotation should focus on genes expressed in stages other than blood stages. Comparative analysis will be critically helpful for this re-annotation. The addition of newly annotated genes will facilitate the use of P. yoelii as a model system for studying human malaria.

Contact:  xinxia.peng@sbri.org; stefan.kappe@sbri.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
Differential variability analysis of gene expression and its application to human diseases
Authors: Ho Joshua W.K. , Stefani Maurizio , dos Remedios Cristobal G. , Charleston Michael A.
Published: June 2008

Motivation: Current microarray analyses focus on identifying sets of genes that are differentially expressed (DE) or differentially coexpressed (DC) in different biological states (e.g. diseased versus non-diseased). We observed that in many human diseases, some genes have a significantincrease or decrease in expression variability (variance). Asthese observed changes in expression variability may be caused by alteration of the underlying expression dynamics, such differential variability (DV) patterns are also biologically interesting.

Results: Here we propose a novel analysis for changes in gene expression variability between groups of amples, which we call differential variability analysis. We introduce the concept of differential variability (DV), and present a simple procedure for identifying DV genes from microarray data. Our procedure is evaluated with simulated and real microarray datasets. The effect of data preprocessing methods on identification of DV gene is investigated. The biological significance of DV analysis is demonstrated with four human disease datasets. The relationships among DV, DE and DC genes are investigated. The results suggest that changes in expression variability are associated with changes in coexpression pattern, which imply that DV is not merely stochastic noise, but informative signal.

Availability: The R source code for differential variability analysis is available from the contact authors upon request.

Contact:  joshua@it.usyd.edu.au; mcharleston@it.usyd.edu.au
Classification and feature selection algorithms for multi-class CGH data
Authors: Liu Jun , Ranka Sanjay , Kahveci Tamer
Published: June 2008

Recurrent chromosomal alterations provide cytological and molecular positions for the diagnosis and prognosis of cancer. Comparative genomic hybridization (CGH) has been useful in understanding these alterations in cancerous cells. CGH datasets consist of samples that are represented by large dimensional arrays of intervals. Each sample consists of long runs of intervals with losses and gains.

In this article, we develop novel SVM-based methods for classification and feature selection of CGH data. For classification, we developed a novel similarity kernel that is shown to be more effective than the standard linear kernel used in SVM. For feature selection, we propose a novel method based on the new kernel that iteratively selects features that provides the maximum benefit for classification. We compared our methods against the best wrapper-based and filter-based approaches that have been used for feature selection of large dimensional biological data. Our results on datasets generated from the Progenetix database, suggests that our methods are considerably superior to existing methods.

Availability: All software developed in this article can be downloaded from http://plaza.ufl.edu/junliu/feature.tar.gz

Contact:  juliu@cise.ufl.edu
A model of higher accuracy for the individual haplotyping problem based on weighted SNP fragments and genotype with errors
Authors: Xie Minzhu , Wang Jianxin , Chen Jianer
Published: June 2008

Motivation: In genetic studies of complex diseases, haplotypes provide more information than genotypes. However, haplotyping is much more difficult than genotyping using biological techniques. Therefore effective computational techniques have been in demand. The individual haplotyping problem is the computational problem of inducing a pair of haplotypes from an individual's aligned SNP fragments. Based on various optimal criteria and including different extra information, many models for the problem have been proposed. Higher accuracy of the models has been an important issue in the study of haplotype reconstruction.

Results: The current article proposes a highly accurate model for the single individual haplotyping problem based on weighted fragments and genotypes with errors. The model is proved to be NP-hard even with gapless fragments. Based on the characteristics of Single Nucleotide Polymorphism (SNP) fragments, a parameterized algorithm of time complexity O(nk22k2 + m log m + mk1) is developed, where m is the number of fragments, n is the number of SNP sites, k1 is the maximum number of SNP sites that a fragment covers (no more than n and usually smaller than 10) and k2 is the maximum number of the fragments covering a SNP site (usually no more than 19). Extensive experiments show that this model is more accurate in haplotype reconstruction than other models.

Availability: The program of the parameterized algorithm can be obtained by sending an email to the corresponding author.

Contact:  jxwang@mail.csu.edu.cn
Efficient inference of bacterial strain trees from genome-scale multilocus data
Authors: Than C. , Sugino R. , Innan H. , Nakhleh L.
Published: June 2008

Motivation: In bacterial evolution, inferring a strain tree, which is the evolutionary history of different strains of the same bacterium, plays a major role in analyzing and understanding the evolution of strongly isolated populations, population divergence and various evolutionary events, such as horizontal gene transfer and homologous recombination. Inferring a strain tree from multilocus data of these strains is exceptionally hard since, at this scale of evolution, processes such as homologous recombination result in a very high degree of gene tree incongruence.

Results: In this article we present a novel computational method for inferring the strain tree despite massive gene tree incongruence caused by homologous recombination. Our method operates in three phases, where in phase I a set of candidate strain-tree topologies is computed using the maximal cliques concept, in phase II divergence times for each of the topologies are estimated using mixed integer linear programming (MILP) and in phase III the optimal tree (or trees) is selected based on an optimality criterion. We have analyzed 1898 genes from nine strains of the Staphylococcus aureus bacteria, and identified a fully resolved (binary) strain tree with estimated divergence times, despite the high degrees of sequence identity at the nucleotide level and gene tree incongruence. Our method's efficiency makes it particularly suitable for analysis of genome-scale datasets, including those of strongly isolated populations which are usually very challenging to analyze.

Availability: We have implemented the algorithms in the PhyloNet software package, which is available publicly at http://bioinfo.cs.rice.edu/phylonet/

Contact:  nakhleh@cs.rice.edu
Inferring differentiation pathways from gene expression
Authors: Costa Ivan G. , Roepcke Stefan , Hafemeister Christoph , Schliep Alexander
Published: June 2008

Motivation: The regulation of proliferation and differentiation of embryonic and adult stem cells into mature cells is central to developmental biology. Gene expression measured in distinguishable developmental stages helps to elucidate underlying molecular processes. In previous work we showed that functional gene modules, which act distinctly in the course of development, can be represented by a mixture of trees. In general, the similarities in the gene expression programs of cell populations reflect the similarities in the differentiation path.

Results: We propose a novel model for gene expression profiles and an unsupervised learning method to estimate developmental similarity and infer differentiation pathways. We assess the performance of our model on simulated data and compare it with favorable results to related methods. We also infer differentiation pathways and predict functional modules in gene expression data of lymphoid development.

Conclusions: We demonstrate for the first time how, in principal, the incorporation of structural knowledge about the dependence structure helps to reveal differentiation pathways and potentially relevant functional gene modules from microarray datasets. Our method applies in any area of developmental biology where it is possible to obtain cells of distinguishable differentiation stages.

Availability: The implementation of our method (GPL license), data and additional results are available at http://algorithmics.molgen.mpg.de/Supplements/InfDif/

Contact:  filho@molgen.mpg.de, schliep@molgen.mpg.de

Supplementary information:  Supplementary data is available at Bioinformatics online.
Predicting functional transcription factor binding through alignment-free and affinity-based analysis of orthologous promoter sequences
Authors: Ward Lucas D. , Bussemaker Harmen J.
Published: June 2008

Motivation: The identification of transcription factor (TF) binding sites and the regulatory circuitry that they define is currently an area of intense research. Data from whole-genome chromatin immunoprecipitation (ChIP–chip), whole-genome expression microarrays, and sequencing of multiple closely related genomes have all proven useful. By and large, existing methods treat the interpretation of functional data as a classification problem (between bound and unbound DNA), and the analysis of comparative data as a problem of local alignment (to recover phylogenetic footprints of presumably functional elements). Both of these approaches suffer from the inability to model and detect low-affinity binding sites, which have recently been shown to be abundant and functional.

Results: We have developed a method that discovers functional regulatory targets of TFs by predicting the total affinity of each promoter for those factors and then comparing that affinity across orthologous promoters in closely related species. At each promoter, we consider the minimum affinity among orthologs to be the fraction of the affinity that is functional. Because we calculate the affinity of the entire promoter, our method is independent of local alignment. By comparing with functional annotation information and gene expression data in Saccharomyces cerevisiae, we have validated that this biophysically motivated use of evolutionary conservation gives rise to dramatic improvement in prediction of regulatory connectivity and factor–factor interactions compared to the use of a single genome. We propose novel biological functions for several yeast TFs, including the factors Snt2 and Stb4, for which no function has been reported. Our affinity-based approach towards comparative genomics may allow a more quantitative analysis of the principles governing the evolution of non-coding DNA.

Availability: The MatrixREDUCE software package is available from http://www.bussemakerlab.org/software/MatrixREDUCE

Contact:  Harmen.Bussemaker@columbia.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Combinatorial influence of environmental parameters on transcription factor activity
Authors: Knijnenburg T.A. , Wessels L.F.A. , Reinders M.J.T.
Published: June 2008

Motivation: Cells receive a wide variety of environmental signals, which are often processed combinatorially to generate specific genetic responses. Changes in transcript levels, as observed across different environmental conditions, can, to a large extent, be attributed to changes in the activity of transcription factors (TFs). However, in unraveling these transcription regulation networks, the actual environmental signals are often not incorporated into the model, simply because they have not been measured. The unquantified heterogeneity of the environmental parameters across microarray experiments frustrates regulatory network inference.

Results: We propose an inference algorithm that models the influence of environmental parameters on gene expression. The approach is based on a yeast microarray compendium of chemostat steady-state experiments. Chemostat cultivation enables the accurate control and measurement of many of the key cultivation parameters, such as nutrient concentrations, growth rate and temperature. The observed transcript levels are explained by inferring the activity of TFs in response to combinations of cultivation parameters. The interplay between activated enhancers and repressors that bind a gene promoter determine the possible up- or downregulation of the gene. The model is translated into a linear integer optimization problem. The resulting regulatory network identifies the combinatorial effects of environmental parameters on TF activity and gene expression.

Availability: The Matlab code is available from the authors upon request.

Contact:  t.a.knijnenburg@tudelft.nl

Supplementary information:  Supplementary data are available at Bioinformatics online.
The EXACT description of biomedical protocols
Authors: Soldatova Larisa N. , Aubrey Wayne , King Ross D. , Clare Amanda
Published: June 2008

Motivation: Many published manuscripts contain experiment protocols which are poorly described or deficient in information. This means that the published results are very hard or impossible to repeat. This problem is being made worse by the increasing complexity of high-throughput/automated methods. There is therefore a growing need to represent experiment protocols in an efficient and unambiguous way.

Results: We have developed the Experiment ACTions (EXACT) ontology as the basis of a method of representing biological laboratory protocols. We provide example protocols that have been formalized using EXACT, and demonstrate the advantages and opportunities created by using this formalization. We argue that the use of EXACT will result in the publication of protocols with increased clarity and usefulness to the scientific community.

Availability: The ontology, examples and code can be downloaded from http://www.aber.ac.uk/compsci/Research/bio/dss/EXACT/

Contact: Larisa Soldatova lss@aber.ac.uk
The ontology of biological taxa
Authors: Schulz Stefan , Stenzhorn Holger , Boeker Martin
Published: June 2008

Motivation: The classification of biological entities in terms of species and taxa is an important endeavor in biology. Although a large amount of statements encoded in current biomedical ontologies is taxon-dependent there is no obvious or standard way for introducing taxon information into an integrative ontology architecture, supposedly because of ongoing controversies about the ontological nature of species and taxa.

Results: In this article, we discuss different approaches on how to represent biological taxa using existing standards for biomedical ontologies such as the description logic OWL DL and the Open Biomedical Ontologies Relation Ontology. We demonstrate how hidden ambiguities of the species concept can be dealt with and existing controversies can be overcome. A novel approach is to envisage taxon information as qualities that inhere in biological organisms, organism parts and populations.

Availability: The presented methodology has been implemented in the domain top-level ontology BioTop, openly accessible at http://purl.org/biotop. BioTop may help to improve the logical and ontological rigor of biomedical ontologies and further provides a clear architectural principle to deal with biological taxa information.

Contact:  stschulz@uni-freiburg.de
GenoQuery: a new querying module for functional annotation in a genomic warehouse
Authors: Lemoine Frédéric , Labedan Bernard , Froidevaux Christine
Published: June 2008

Motivation: We have to cope with both a deluge of new genome sequences and a huge amount of data produced by high-throughput approaches used to exploit these genomic features. Crossing and comparing such heterogeneous and disparate data will help improving functional annotation of genomes. This requires designing elaborate integration systems such as warehouses for storing and querying these data.

Results: We have designed a relational genomic warehouse with an original multi-layer architecture made of a databases layer and an entities layer. We describe a new querying module, GenoQuery, which is based on this architecture. We use the entities layer to define mixed queries. These mixed queries allow searching for instances of biological entities and their properties in the different databases, without specifying in which database they should be found. Accordingly, we further introduce the central notion of alternative queries. Such queries have the same meaning as the original mixed queries, while exploiting complementarities yielded by the various integrated databases of the warehouse.

We explain how GenoQuery computes all the alternative queries of a given mixed query. We illustrate how useful this querying module is by means of a thorough example.

Availability:  http://www.lri.fr/~lemoine/GenoQuery/

Contact:  chris@lri.fr, lemoine@lri.fr
Identifying functional modules in protein–protein interaction networks: an integrated exact approach
Authors: Dittrich Marcus T. , Klau Gunnar W. , Rosenwald Andreas , Dandekar Thomas , Müller Tobias
Published: June 2008

Motivation: With the exponential growth of expression and protein–protein interaction (PPI) data, the frontier of research in systems biology shifts more and more to the integrated analysis of these large datasets. Of particular interest is the identification of functional modules in PPI networks, sharing common cellular function beyond the scope of classical pathways, by means of detecting differentially expressed regions in PPI networks. This requires on the one hand an adequate scoring of the nodes in the network to be identified and on the other hand the availability of an effective algorithm to find the maximally scoring network regions. Various heuristic approaches have been proposed in the literature.

Results: Here we present the first exact solution for this problem, which is based on integer-linear programming and its connection to the well-known prize-collecting Steiner tree problem from Operations Research. Despite the NP-hardness of the underlying combinatorial problem, our method typically computes provably optimal subnetworks in large PPI networks in a few minutes. An essential ingredient of our approach is a scoring function defined on network nodes. We propose a new additive score with two desirable properties: (i) it is scalable by a statistically interpretable parameter and (ii) it allows a smooth integration of data from various sources.

We apply our method to a well-established lymphoma microarray dataset in combination with associated survival data and the large interaction network of HPRD to identify functional modules by computing optimal-scoring subnetworks. In particular, we find a functional interaction module associated with proliferation over-expressed in the aggressive ABC subtype as well as modules derived from non-malignant by-stander cells.

Availability: Our software is available freely for non-commercial purposes at http://www.planet-lisa.net.

Contact:  tobias.mueller@biozentrum.uni-wuerzburg.de
Biomolecular network motif counting and discovery by color coding
Authors: Alon Noga , Dao Phuong , Hajirasouliha Iman , Hormozdiari Fereydoun , Sahinalp S. Cenk
Published: June 2008

Protein–protein interaction (PPI) networks of many organisms share global topological features such as degree distribution, k-hop reachability, betweenness and closeness. Yet, some of these networks can differ significantly from the others in terms of local structures: e.g. the number of specific network motifs can vary significantly among PPI networks.

Counting the number of network motifs provides a major challenge to compare biomolecular networks. Recently developed algorithms have been able to count the number of induced occurrences of subgraphs with k≤ 7 vertices. Yet no practical algorithm exists for counting non-induced occurrences, or counting subgraphs with k≥ 8 vertices. Counting non-induced occurrences of network motifs is not only challenging but also quite desirable as available PPI networks include several false interactions and miss many others.

In this article, we show how to apply the ‘color coding’ technique for counting non-induced occurrences of subgraph topologies in the form of trees and bounded treewidth subgraphs. Our algorithm can count all occurrences of motif G′ with k vertices in a network G with n vertices in time polynomial with n, provided k=O(log n). We use our algorithm to obtain ‘treelet’ distributions for k≤ 10 of available PPI networks of unicellular organisms (Saccharomyces cerevisiae Escherichia coli and Helicobacter Pyloris), which are all quite similar, and a multicellular organism (Caenorhabditis elegans) which is significantly different. Furthermore, the treelet distribution of the unicellular organisms are similar to that obtained by the ‘duplication model’ but are quite different from that of the ‘preferential attachment model’. The treelet distribution is robust w.r.t. sparsification with bait/edge coverage of 70% but differences can be observed when bait/edge coverage drops to 50%.

Contact:  cenk@cs.sfu.ca
Designing succinct structural alphabets
Authors: Li Shuai Cheng , Bu Dongbo , Gao Xin , Xu Jinbo , Li Ming
Published: June 2008

Motivation: The 3D structure of a protein sequence can be assembled from the substructures corresponding to small segments of this sequence. For each small sequence segment, there are only a few more likely substructures. We call them the ‘structural alphabet’ for this segment. Classical approaches such as ROSETTA used sequence profile and secondary structure information, to predict structural fragments. In contrast, we utilize more structural information, such as solvent accessibility and contact capacity, for finding structural fragments.

Results: Integer linear programming technique is applied to derive the best combination of these sequence and structural information items. This approach generates significantly more accurate and succinct structural alphabets with more than 50% improvement over the previous accuracies. With these novel structural alphabets, we are able to construct more accurate protein structures than the state-of-art ab initio protein structure prediction programs such as ROSETTA. We are also able to reduce the Kolodny's library size by a factor of 8, at the same accuracy.

Availability: The online FRazor server is under construction

Contact:  scli@uwaterloo.ca,mli@uwaterloo.ca, j3xu@tti-c.org
Predicting protein thermostability changes from sequence upon multiple mutations
Authors: Montanucci Ludovica , Fariselli Piero , Martelli Pier Luigi , Casadio Rita
Published: June 2008

Motivation: A basic question in protein science is to which extent mutations affect protein thermostability. This knowledge would be particularly relevant for engineering thermostable enzymes. In several experimental approaches, this issue has been serendipitously addressed. It would be therefore convenient providing a computational method that predicts when a given protein mutant is more thermostable than its corresponding wild-type.

Results: We present a new method based on support vector machines that is able to predict whether a set of mutations (including insertion and deletions) can enhance the thermostability of a given protein sequence. When trained and tested on a redundancy-reduced dataset, our predictor achieves 88% accuracy and a correlation coefficient equal to 0.75. Our predictor also correctly classifies 12 out of 14 experimentally characterized protein mutants with enhanced thermostability. Finally, it correctly detects all the 11 mutated proteins whose increase in stability temperature is >10°C.

Availability: The dataset and the list of protein clusters adopted for the SVM cross-validation are available at the web site http://lipid.biocomp.unibo.it/~ludovica/thermo-meso-MUT.

Contact:  casadio@alma.unibo.it
Contact replacement for NMR resonance assignment
Authors: Xiong Fei , Pandurangan Gopal , Bailey-Kellogg Chris
Published: June 2008

Motivation: Complementing its traditional role in structural studies of proteins, nuclear magnetic resonance (NMR) spectroscopy is playing an increasingly important role in functional studies. NMR dynamics experiments characterize motions involved in target recognition, ligand binding, etc., while NMR chemical shift perturbation experiments identify and localize protein–protein and protein–ligand interactions. The key bottleneck in these studies is to determine the backbone resonance assignment, which allows spectral peaks to be mapped to specific atoms. This article develops a novel approach to address that bottleneck, exploiting an available X-ray structure or homology model to assign the entire backbone from a set of relatively fast and cheap NMR experiments.

Results: We formulate contact replacement for resonance assignment as the problem of computing correspondences between a contact graph representing the structure and an NMR graph representing the data; the NMR graph is a significantly corrupted, ambiguous version of the contact graph. We first show that by combining connectivity and amino acid type information, and exploiting the random structure of the noise, one can provably determine unique correspondences in polynomial time with high probability, even in the presence of significant noise (a constant number of noisy edges per vertex). We then detail an efficient randomized algorithm and show that, over a variety of experimental and synthetic datasets, it is robust to typical levels of structural variation (1–2 AA), noise (250–600%) and missings (10–40%). Our algorithm achieves very good overall assignment accuracy, above 80% in α-helices, 70% in β-sheets and 60% in loop regions.

Availability: Our contact replacement algorithm is implemented in platform-independent Python code. The software can be freely obtained for academic use by request from the authors.

Contact:  gopal@cs.purdue.edu; cbk@cs.dartmouth.edu
A computational framework to empower probabilistic protein design
Authors: Fromer Menachem , Yanover Chen
Published: June 2008

Motivation: The task of engineering a protein to perform a target biological function is known as protein design. A commonly used paradigm casts this functional design problem as a structural one, assuming a fixed backbone. In probabilistic protein design, positional amino acid probabilities are used to create a random library of sequences to be simultaneously screened for biological activity. Clearly, certain choices of probability distributions will be more successful in yielding functional sequences. However, since the number of sequences is exponential in protein length, computational optimization of the distribution is difficult.

Results: In this paper, we develop a computational framework for probabilistic protein design following the structural paradigm. We formulate the distribution of sequences for a structure using the Boltzmann distribution over their free energies. The corresponding probabilistic graphical model is constructed, and we apply belief propagation (BP) to calculate marginal amino acid probabilities. We test this method on a large structural dataset and demonstrate the superiority of BP over previous methods. Nevertheless, since the results obtained by BP are far from optimal, we thoroughly assess the paradigm using high-quality experimental data. We demonstrate that, for small scale sub-problems, BP attains identical results to those produced by exact inference on the paradigmatic model. However, quantitative analysis shows that the distributions predicted significantly differ from the experimental data. These findings, along with the excellent performance we observed using BP on the smaller problems, suggest potential shortcomings of the paradigm. We conclude with a discussion of how it may be improved in the future.

Contact:  fromer@cs.huji.ac.il