bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetic nanoparticles with combined anisotropy
Authors: Usov N. A. , Barandiarán J. M.
Published: September 2012

We study the influence of the distribution of the particles' aspect ratio on the magnetostatic properties of an assembly of nanoparticles with cubic magnetocrystalline anisotropy, such as iron, nickel, iron oxides, and ferrites. Because of the large values of the dimensionless ratio Ms2/|Kc| for these particles, the shape anisotropy energy makes considerable contribution to the total nanoparticle energy even for relatively small shape distortions, with equivalent ellipsoids having aspect ratios ξ ≥ 1.1. As a result, the magnetostatic properties of a randomly oriented assembly of particles with combined anisotropy at ξ ≥ 1.1 are similar to those for an assembly of particles with purely uniaxial magnetic anisotropy. This conclusion is shown to be valid not only for the assembly hysteresis loops but also for the magnetic relaxation characteristics, at least in the high damping limit.
Study on the use of dielectrophoresis and electrothermal forces to produce on-chip micromixers and microconcentrators
Authors: Siva Kumar Gunda Naga , Bhattacharjee Subir , Mitra Sushanta K.
Published: September 2012

The present study uses the dielectrophoresis (DEP) and electrothermal (ET) forces to develop on-chip micromixers and microconcentrators. A microchannel with rectangular array of microelectrodes, patterned either on its bottom surface only or on both the top and the bottom surfaces, is considered for the analysis. A mathematical model to compute electrical field, temperature field, the fluid velocity, and the concentration distributions is developed. Both analytical and numerical solutions of standing wave DEP (SWDEP), traveling wave DEP (TWDEP), standing wave ET (SWET), and traveling wave ET (TWET) forces along the length and the height of the channel are compared. The effects of electrode size and their placement in the microsystem on micromixing and microconcentrating performance are studied and compared to velocity and concentration profiles. SWDEP forces can be used to collect the particles at different locations in the microchannel. Under positive and negative DEP effect, the particles are collected at electrode edges and away from the electrodes, respectively, irrespective of the position, size, and number of electrodes. The location of the concentration region can be shifted by changing the electrode position. SWET and TWET forces are used for mixing and producing concentration regions by circulating the fluid at a given location. The effect of forces can be changed with the applied voltage. The TWDEP method is the better method for mixing along the length of the channels among the four options explored in the present work. If two layers of particle suspension are placed side by side in the channel, triangular electrode configuration can be used to mix the suspensions. Triangular and rectangular electrode configurations can efficiently mix two layers of particle suspension placed side-by-side and one-atop-the-other, respectively. Hence, SWDEP forces can be successfully used to create microconcentrators, whereas TWDEP, SWET, and TWET can be used to produce efficient micromixers in a microfluidic chip.
Formation of manganese δ-doped atomic layer in wurtzite GaN
Authors: Shi Meng , Chinchore Abhijit , Wang Kangkang , Mandru Andrada-Oana , Liu Yinghao , Smith Arthur R.
Published: September 2012

We describe the formation of a δ-doped manganese layer embedded within c-plane wurtzite gallium nitride using a special molecular beam epitaxy growth process. Manganese is first deposited on the gallium-poor GaN (0001¯) surface, forming a 3×3−R30° reconstructed phase. This well-defined surface reconstruction is then nitrided using plasma nitridation, and gallium nitride is overgrown. The manganese content of the 3×3−R30° phase, namely one Mn per each 3×3−R30° unit cell, implies that the MnGaN alloy layer has a Mn concentration of up to 33%. The structure and chemical content of the surface are monitored beginning from the initial growth stage up through the overgrowth of 20 additional monolayers (MLs) of GaN. An exponential-like drop-off of the Mn signal with increasing GaN monolayers, as measured by Auger electron spectroscopy, indicates that the highly concentrated Mn layer remains at the δ-doped interface. A model of the resultant δ-doped structure is formulated based on the experimental data, and implications for possible spintronic applications are discussed.
Ni80Fe20/Ni binary nanomagnets for logic applications
Authors: Ding J. , Adeyeye A. O.
Published: September 2012

We demonstrate the functionality of Ni80Fe20/Ni binary nanostructures cells fabricated using self-aligned shadow deposition technique in logic applications. Depending on the magnetic ordering of the cells, distinct dynamic states probed by broadband ferromagnetic resonance spectroscopy are realized. We show that the magnetic ordering can be manipulated to achieve logic operations by controlling the amplitude and the orientation of reset fields. Magnetic force microscopy and micromagnetic simulations were used to validate our experimental results.
Low-order-mode harmonic multiplying gyrotron traveling-wave amplifier in W band
Authors: Yeh Y. S. , Hung C. L. , Chang T. H. , Chen C. H. , Yang S. J. , Lai C. H. , Lin T. Y. , Lo Y. C. , Hong J. W.
Published: September 2012

Harmonic multiplying gyrotron traveling-wave amplifiers (gyro-TWAs) allow for magnetic field reduction and frequency multiplication. To avoid absolute instabilities, this work proposes a W-band harmonic multiplying gyro-TWA operating at low-order modes. By amplifying a fundamental harmonic TE11 drive wave, the second harmonic component of the beam current initiates a TE21 wave to be amplified. Absolute instabilities in the gyro-TWA are suppressed by shortening the interaction circuit and increasing wall losses. Simulation results reveal that compared with Ka-band gyro-TWTs, the lower wall losses effectively suppress absolute instabilities in the W-band gyro-TWA. However, a global reflective oscillation occurs as the wall losses decrease. Increasing the length or resistivity of the lossy section can reduce the feedback of the oscillation to stabilize the amplifier. The W-band harmonic multiplying gyro-TWA is predicted to yield a peak output power of 111 kW at 98 GHz with an efficiency of 25%, a saturated gain of 26 dB, and a bandwidth of 1.6 GHz for a 60 kV, 7.5 A electron beam with an axial velocity spread of 8%.
Mg acceptor doping of In2O3 and overcompensation by oxygen vacancies
Authors: Bierwagen Oliver , Speck James S.
Published: September 2012

Mg-doped indium oxide (In2O3) thin films were grown by plasma-assisted molecular beam epitaxy with Mg-concentrations ranging from 1017 to 6×1020 cm−3. In this concentration range Mg was incorporated into In2O3 without discernable impediment nor formation of secondary phases. Despite the role of Mg as acceptor, the films were n-type conductive in the as-grown state or after annealing in vacuum. For Mg-concentrations well in excess of the unintentional donor concentration annealing in oxygen resulted in semi-insulating films without detectable p-type conductivity. These results strongly suggest oxygen vacancies to act as shallow donors in In2O3 that can overcompensate the Mg acceptors.
Heck Reactions in Aqueous Miniemulsions
Authors: Zayas Hazit A. , Valade David , Jia Zhongfan , Monteiro Michael J.
Published: September 2012

Carrying out organic reactions in water-based nanoreactors represents a ‘green’ method for the preparation of organic compounds. This process eliminates the need for solvents, thus reducing the effect of high volumes of solvent on the environment. In this work, we demonstrate a successful Heck cross-coupling reaction, one of the most used approaches to form C–C bonds using a palladium catalyst, in a miniemulsion. The miniemulsion droplet sizes were small (25 to 42 nm), and the reactions resulted in high conversions of three different products with high trans stereoisomers.
Molecular basis for Nup37 and ELY5/ELYS recruitment to the nuclear pore complex
Authors: Bilokapic Silvija , Schwartz Thomas U.
Published: September 2012

Nucleocytoplasmic transport is mediated by nuclear pore complexes (NPCs), enormous assemblies composed of multiple copies of ∼30 different proteins called nucleoporins. To unravel the basic scaffold underlying the NPC, we have characterized the species-specific scaffold nucleoporin Nup37 and ELY5/ELYS. Both proteins integrate directly via Nup120/160 into the universally conserved heptameric Y-complex, the critical unit for the assembly and functionality of the NPC. We present the crystal structure of
Schizosaccharomyces pombe
Nup37 in complex with Nup120, a 174-kDa subassembly that forms one of the two short arms of the Y-complex. Nup37 binds near the bend of the L-shaped Nup120 protein, potentially stabilizing the relative orientation of its two domains. By means of reconstitution assays, we pinpoint residues crucial for this interaction. In vivo and in vitro results show that ELY5 binds near an interface of the Nup120–Nup37 complex. Complementary biochemical and cell biological data refine and consolidate the interactions of Nup120 within the current Y-model. Finally, we propose an orientation of the Y-complex relative to the pore membrane, consistent with the lattice model.
Intrinsically disordered proteins aggregate at fungal cell-to-cell channels and regulate intercellular connectivity
Authors: Lai Julian , Koh Chuan Hock , Tjota Monika , Pieuchot Laurent , Raman Vignesh , Chandrababu Karthik Balakrishna , Yang Daiwen , Wong Limsoon , Jedd Gregory
Published: September 2012

Like animals and plants, multicellular fungi possess cell-to-cell channels (septal pores) that allow intercellular communication and transport. Here, using a combination of MS of Woronin body-associated proteins and a bioinformatics approach that identifies related proteins based on composition and character, we identify 17 septal pore-associated (SPA) proteins that localize to the septal pore in rings and pore-centered foci. SPA proteins are not homologous at the primary sequence level but share overall physical properties with intrinsically disordered proteins. Some SPA proteins form aggregates at the septal pore, and in vitro assembly assays suggest aggregation through a nonamyloidal mechanism involving mainly α-helical and disordered structures. SPA loss-of-function phenotypes include excessive septation, septal pore degeneration, and uncontrolled Woronin body activation. Together, our data identify the septal pore as a complex subcellular compartment and focal point for the assembly of unstructured proteins controlling diverse aspects of intercellular connectivity.
Long-range electron transport in
Geobacter sulfurreducens
biofilms is redox gradient-driven
Authors: Snider Rachel M. , Strycharz-Glaven Sarah M. , Tsoi Stanislav D. , Erickson Jeffrey S. , Tender Leonard M.
Published: September 2012

Geobacter
spp. can acquire energy by coupling intracellular oxidation of organic matter with extracellular electron transfer to an anode (an electrode poised at a metabolically oxidizing potential), forming a biofilm extending many cell lengths away from the anode surface. It has been proposed that long-range electron transport in such biofilms occurs through a network of bound redox cofactors, thought to involve extracellular matrix
c
-type cytochromes, as occurs for polymers containing discrete redox moieties. Here, we report measurements of electron transport in actively respiring
Geobacter sulfurreducens
wild type biofilms using interdigitated microelectrode arrays. Measurements when one electrode is used as an anode and the other electrode is used to monitor redox status of the biofilm 15 μm away indicate the presence of an intrabiofilm redox gradient, in which the concentration of electrons residing within the proposed redox cofactor network is higher farther from the anode surface. The magnitude of the redox gradient seems to correlate with current, which is consistent with electron transport from cells in the biofilm to the anode, where electrons effectively diffuse from areas of high to low concentration, hopping between redox cofactors. Comparison with gate measurements, when one electrode is used as an electron source and the other electrode is used as an electron drain, suggests that there are multiple types of redox cofactors in
Geobacter
biofilms spanning a range in oxidation potential that can engage in electron transport. The majority of these redox cofactors, however, seem to have oxidation potentials too negative to be involved in electron transport when acetate is the electron source.
Registration of Blood Exposure Accidents in the Netherlands by a Nationally Operating Call Center
Authors: Schneeberger Peter M. , Meiberg Annemarie E. , Warmelts Janet , Leenders Sander C. A. P. , van Wijk Paul T. L.
Published: September 2012

Objective.

Healthcare providers and other employees, especially those who do not work in a hospital, may not easily find help after the occurrence of a blood exposure accident. In 2006, a national call center was established in the Netherlands to fill this gap.

Methods.

All occupational blood exposure accidents reported to the 24-hours-per-day, 7-days-per-week call center from 2007, 2008, and 2009 were analyzed retrospectively for incidence rates, risk assessment, handling, and preventive measures taken.

Results.

A total of 2,927 accidents were reported. The highest incidence rates were reported for private clinics and hospitals (68.5 and 54.3 accidents per 1,000 person-years, respectively). Dental practices started reporting incidents frequently after the arrangement of a collective financial agreement with the call center. Employees of ambulance services, midwife practices, and private clinics reported mostly high-risk accidents, whereas penitentiaries frequently reported low-risk accidents. Employees in mental healthcare facilities, private clinics, and midwife practices reported accidents relatively late. The extent of hepatitis B vaccination in mental healthcare facilities, penitentiaries, occupational health services, and cleaning services was low (<70%).

Conclusions.

The national call center successfully organized the national registration and handling of blood exposure accidents. The risk of blood exposure accidents could be estimated on the basis of this information for several occupational branches. Targeted preventive measures for healthcare providers and other employees at risk can next be developed.

Infect Control Hosp Epidemiol 2012;33(10):1017-1023
Device-Associated Infection Rates, Device Utilization, and Antimicrobial Resistance in Long-Term Acute Care Hospitals Reporting to the National Healthcare Safely Network, 2010
Authors: Chitnis Amit S. , Edwards Jonathan R. , Ricks Phillip M. , Sievert Dawn M. , Fridkin Scott K. , Gould Carolyn V.
Published: September 2012

Objective.

To evaluate national data on healthcare-associated infections (HAIs), device utilization, and antimicrobial resistance in long-term acute care hospitals (LTACHs).

Design and Setting.

Comparison of data from LTACHs and from medical and medical-surgical intensive care units (ICUs) in short-stay acute care hospitals reporting to the National Healthcare Safety Network (NHSN) during 2010.

Methods.

Rates of central line–associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), and ventilator-associated pneumonia (VAP) as well as device utilization ratios were calculated. For each HAI, pathogen profiles and antimicrobial resistance prevalence were evaluated. Comparisons were made using Poisson regression and the Mood median and x2 tests.

Results.

In 2010, 104 LTACHs reported CLABSIs and 57 reported CAUTIs and VAP to the NHSN. Median CLABSI rates in LTACHs (1.25 events per 1,000 device-days reported; range, 0.0-5.96) were comparable to rates in major teaching ICUs and were higher than those in other ICUs. CAUTI rates in LTACHs (median, 2.61; range, 0.0-9.92) were higher and VAP rates (median, 0.0; range, 0.0-3.29) were generally lower than those in ICUs. Central line utilization in LTACHs was higher than that in ICUs, whereas urinary catheter and ventilator utilization was lower. Methicillin resistance among Staphylococcus aureus CLABSIs (83%) and vancomycin resistance among Enterococcus faecalis CAUTIs (44%) were higher in LTACHs than in ICUs. Multidrug resistance among Pseudomonas aeruginosa CAUTIs (25%) was higher in LTACHs than in most ICUs.

Conclusions.

CLABSIs and CAUTIs associated with multidrug-resistant organisms present a challenge in LTACHs. Continued HAI surveillance with pathogen-level data can guide prevention efforts in LTACHs.

Infect Control Hosp Epidemiol 2012;33(10):993-1000
The tyrosine phosphatase SHP2 regulates recovery of endothelial adherens junctions through control of β-catenin phosphorylation
Authors: Timmerman Ilse , Hoogenboezem Mark , Bennett Anton M. , Geerts Dirk , Hordijk Peter L. , van Buul Jaap D.
Published: September 2012

Impaired endothelial barrier function results in a persistent increase in endothelial permeability and vascular leakage. Repair of a dysfunctional endothelial barrier requires controlled restoration of adherens junctions, comprising vascular endothelial (VE)-cadherin and associated β-, γ-, α-, and p120-catenins. Little is known about the mechanisms by which recovery of VE-cadherin–mediated cell–cell junctions is regulated. Using the inflammatory mediator thrombin, we demonstrate an important role for the Src homology 2-domain containing tyrosine phosphatase (SHP2) in mediating recovery of the VE-cadherin–controlled endothelial barrier. Using SHP2 substrate-trapping mutants and an in vitro phosphatase activity assay, we validate β-catenin as a bona fide SHP2 substrate. SHP2 silencing and SHP2 inhibition both result in delayed recovery of endothelial barrier function after thrombin stimulation. Moreover, on thrombin challenge, we find prolonged elevation in tyrosine phosphorylation levels of VE-cadherin–associated β-catenin in SHP2-depleted cells. No disassembly of the VE-cadherin complex is observed throughout the thrombin response. Using fluorescence recovery after photobleaching, we show that loss of SHP2 reduces the mobility of VE-cadherin at recovered cell–cell junctions. In conclusion, our data show that the SHP2 phosphatase plays an important role in the recovery of disrupted endothelial cell–cell junctions by dephosphorylating VE-cadherin–associated β-catenin and promoting the mobility of VE-cadherin at the plasma membrane.
BICD2, dynactin, and LIS1 cooperate in regulating dynein recruitment to cellular structures
Authors: Splinter Daniël , Razafsky David S. , Schlager Max A. , Serra-Marques Andrea , Grigoriev Ilya , Demmers Jeroen , Keijzer Nanda , Jiang Kai , Poser Ina , Hyman Anthony A. , Hoogenraad Casper C. , King Stephen J. , Akhmanova Anna
Published: September 2012

Cytoplasmic dynein is the major microtubule minus-end–directed cellular motor. Most dynein activities require dynactin, but the mechanisms regulating cargo-dependent dynein–dynactin interaction are poorly understood. In this study, we focus on dynein–dynactin recruitment to cargo by the conserved motor adaptor Bicaudal D2 (BICD2). We show that dynein and dynactin depend on each other for BICD2-mediated targeting to cargo and that BICD2 N-terminus (BICD2-N) strongly promotes stable interaction between dynein and dynactin both in vitro and in vivo. Direct visualization of dynein in live cells indicates that by itself the triple BICD2-N–dynein–dynactin complex is unable to interact with either cargo or microtubules. However, tethering of BICD2-N to different membranes promotes their microtubule minus-end–directed motility. We further show that LIS1 is required for dynein-mediated transport induced by membrane tethering of BICD2-N and that LIS1 contributes to dynein accumulation at microtubule plus ends and BICD2-positive cellular structures. Our results demonstrate that dynein recruitment to cargo requires concerted action of multiple dynein cofactors.
Evolution of gene neighborhoods within reconciled phylogenies
Authors: Bérard Sèverine , Gallien Coralie , Boussau Bastien , Szöllősi Gergely J. , Daubin Vincent , Tannier Eric
Published: September 2012

Motivation: Most models of genome evolution integrating gene duplications, losses and chromosomal rearrangements are computationally intract able, even when comparing only two genomes. This prevents large-scale studies that consider different types of genome structural variations.

Results: We define an ‘adjacency phylogenetic tree’ that describes the evolution of an adjacency, a neighborhood relation between two genes, by speciation, duplication or loss of one or both genes, and rearrangement. We describe an algorithm that, given a species tree and a set of gene trees where the leaves are connected by adjacencies, computes an adjacency forest that minimizes the number of gains and breakages of adjacencies (caused by rearrangements) and runs in polynomial time. We use this algorithm to reconstruct contiguous regions of mammalian and plant ancestral genomes in a few minutes for a dozen species and several thousand genes. We show that this method yields reduced conflict between ancestral adjacencies. We detect duplications involving several genes and compare the different modes of evolution between phyla and among lineages.

Availability: C++ implementation using BIO++ package, available upon request to Sèverine Bérard.

Contact:  Severine.Berard@cirad.fr or Eric.Tannier@inria.fr

Supplementary information:  Supplementary material is available at Bioinformatics online.
An exome sequencing pipeline for identifying and genotyping common CNVs associated with disease with application to psoriasis
Authors: Coin Lachlan J.M. , Cao Dandan , Ren Jingjing , Zuo Xianbo , Sun Liangdan , Yang Sen , Zhang Xuejun , Cui Yong , Li Yingrui , Jin Xin , Wang Jun
Published: September 2012

Motivation: Despite the prevalence of copy number variation (CNV) in the human genome, only a handful of confirmed associations have been reported between common CNVs and complex disease. This may be partially attributed to the difficulty in accurately genotyping CNVs in large cohorts using array-based technologies. Exome sequencing is now widely being applied to case–control cohorts and presents an exciting opportunity to look for common CNVs associated with disease.

Results: We developed ExoCNVTest: an exome sequencing analysis pipeline to identify disease-associated CNVs and to generate absolute copy number genotypes at putatively associated loci. Our method re-discovered the LCE3B_LCE3C CNV association with psoriasis (P-value = 5 × 10e−6) while controlling inflation of test statistics (λ < 1). ExoCNVTest-derived absolute CNV genotypes were 97.4% concordant with PCR-derived genotypes at this locus.

Availability and implementation: ExoCNVTest has been implemented in Java and R and is freely available from www1.imperial.ac.uk/medicine/people/l.coin/.

Contact:  wangj@genomics.org.cn or Lachlan.J.M.Coin@genomics.org.cn
Relating drug–protein interaction network with drug side effects
Authors: Mizutani Sayaka , Pauwels Edouard , Stoven Véronique , Goto Susumu , Yamanishi Yoshihiro
Published: September 2012

Motivation: Identifying the emergence and underlying mechanisms of drug side effects is a challenging task in the drug development process. This underscores the importance of system–wide approaches for linking different scales of drug actions; namely drug-protein interactions (molecular scale) and side effects (phenotypic scale) toward side effect prediction for uncharacterized drugs.

Results: We performed a large-scale analysis to extract correlated sets of targeted proteins and side effects, based on the co-occurrence of drugs in protein-binding profiles and side effect profiles, using sparse canonical correlation analysis. The analysis of 658 drugs with the two profiles for 1368 proteins and 1339 side effects led to the extraction of 80 correlated sets. Enrichment analyses using KEGG and Gene Ontology showed that most of the correlated sets were significantly enriched with proteins that are involved in the same biological pathways, even if their molecular functions are different. This allowed for a biologically relevant interpretation regarding the relationship between drug–targeted proteins and side effects. The extracted side effects can be regarded as possible phenotypic outcomes by drugs targeting the proteins that appear in the same correlated set. The proposed method is expected to be useful for predicting potential side effects of new drug candidate compounds based on their protein-binding profiles.

Supplementary information: Datasets and all results are available at http://web.kuicr.kyoto-u.ac.jp/supp/smizutan/target-effect/.

Availability: Software is available at the above supplementary website.

Contact:  yamanishi@bioreg.kyushu-u.ac.jp, or goto@kuicr.kyoto-u.ac.jp
Inferring duplications, losses, transfers and incomplete lineage sorting with nonbinary species trees
Authors: Stolzer Maureen , Lai Han , Xu Minli , Sathaye Deepa , Vernot Benjamin , Durand Dannie
Published: September 2012

Motivation: Gene duplication (D), transfer (T), loss (L) and incomplete lineage sorting (I) are crucial to the evolution of gene families and the emergence of novel functions. The history of these events can be inferred via comparison of gene and species trees, a process called reconciliation, yet current reconciliation algorithms model only a subset of these evolutionary processes.

Results: We present an algorithm to reconcile a binary gene tree with a nonbinary species tree under a DTLI parsimony criterion. This is the first reconciliation algorithm to capture all four evolutionary processes driving tree incongruence and the first to reconcile non-binary species trees with a transfer model. Our algorithm infers all optimal solutions and reports complete, temporally feasible event histories, giving the gene and species lineages in which each event occurred. It is fixed-parameter tractable, with polytime complexity when the maximum species outdegree is fixed. Application of our algorithms to prokaryotic and eukaryotic data show that use of an incomplete event model has substantial impact on the events inferred and resulting biological conclusions.

Availability: Our algorithms have been implemented in Notung, a freely available phylogenetic reconciliation software package, available at http://www.cs.cmu.edu/~durand/Notung.

Contact:  mstolzer@andrew.cmu.edu
The architecture of the gene regulatory networks of different tissues
Authors: Li Jie , Hua Xu , Haubrock Martin , Wang Jin , Wingender Edgar
Published: September 2012

Summary: The great variety of human cell types in morphology and function is due to the diverse gene expression profiles that are governed by the distinctive regulatory networks in different cell types. It is still a challenging task to explain how the regulatory networks achieve the diversity of different cell types. Here, we report on our studies of the design principles of the tissue regulatory system by constructing the regulatory networks of eight human tissues, which subsume the regulatory interactions between transcription factors (TFs), microRNAs (miRNAs) and non-TF target genes. The results show that there are in-/out-hubs of high in-/out-degrees in tissue networks. Some hubs (strong hubs) maintain the hub status in all the tissues where they are expressed, whereas others (weak hubs), in spite of their ubiquitous expression, are hubs only in some tissues. The network motifs are mostly feed-forward loops. Some of them having no miRNAs are the common motifs shared by all tissues, whereas the others containing miRNAs are the tissue-specific ones owned by one or several tissues, indicating that the transcriptional regulation is more conserved across tissues than the post-transcriptional regulation. In particular, a common bow-tie framework was found that underlies the motif instances and shows diverse patterns in different tissues. Such bow-tie framework reflects the utilization efficiency of the regulatory system as well as its high variability in different tissues, and could serve as the model to further understand the structural adaptation of the regulatory system to the specific requirements of different cell functions.

Contact:  edgar.wingender@bioinf.med.uni-goettingen.de; jwang@nju.edu.cn

Supplementary information:  Supplementary data are available at Bioinformatics online.
Side-chain rotamer changes upon ligand binding: common, crucial, correlate with entropy and rearrange hydrogen bonding
Authors: Gaudreault Francis , Chartier Matthieu , Najmanovich Rafael
Published: September 2012

Motivation: Protein movements form a continuum from large domain rearrangements (including folding and restructuring) to side-chain rotamer changes and small rearrangements. Understanding side-chain flexibility upon binding is important to understand molecular recognition events and predict ligand binding.

Methods: In the present work, we developed a well-curated non-redundant dataset of 188 proteins in pairs of structures in the Apo (unbound) and Holo (bound) forms to study the extent and the factors that guide side-chain rotamer changes upon binding.

Results: Our analysis shows that side-chain rotamer changes are widespread with only 10% of binding sites displaying no conformational changes. Overall, at most five rotamer changes account for the observed movements in 90% of the cases. Furthermore, rotamer changes are essential in 32% of flexible binding sites. The different amino acids have a 11-fold difference in their probability to undergo changes. Side-chain flexibility represents an intrinsic property of amino acids as it correlates well with configurational entropy differences. Furthermore, on average b-factors and solvent accessible surface areas can discriminate flexible side-chains in the Apo form. Finally, there is a rearrangement of the hydrogen-bonding network upon binding primarily with a loss of H-bonds with water molecules and a gain of H-bonds with protein residues for flexible residues. Interestingly, only 25% of side chains capable of forming H-bonds do so with the ligand upon binding. In terms of drug design, this last result shows that there is a large number of potential interactions that may be exploited to modulate the specificity and sensitivity of inhibitors.

Contact:  rafael.najmanovich@usherbrooke.ca
Uncovering the co-evolutionary network among prokaryotic genes
Authors: Cohen Ofir , Ashkenazy Haim , Burstein David , Pupko Tal
Published: September 2012

Motivation: Correlated events of gains and losses enable inference of co-evolution relations. The reconstruction of the co-evolutionary interactions network in prokaryotic species may elucidate functional associations among genes.

Results: We developed a novel probabilistic methodology for the detection of co-evolutionary interactions between pairs of genes. Using this method we inferred the co-evolutionary network among 4593 Clusters of Orthologous Genes (COGs). The number of co-evolutionary interactions substantially differed among COGs. Over 40% were found to co-evolve with at least one partner. We partitioned the network of co-evolutionary relations into clusters and uncovered multiple modular assemblies of genes with clearly defined functions. Finally, we measured the extent to which co-evolutionary relations coincide with other cellular relations such as genomic proximity, gene fusion propensity, co-expression, protein–protein interactions and metabolic connections. Our results show that co-evolutionary relations only partially overlap with these other types of networks. Our results suggest that the inferred co-evolutionary network in prokaryotes is highly informative towards revealing functional relations among genes, often showing signals that cannot be extracted from other network types.

Availability and implementation: Available under GPL license as open source.

Contact:  talp@post.tau.ac.il.

Supplementary information:  Supplementary data are available at Bioinformatics online.
Genomic context analysis reveals dense interaction network between vertebrate ultraconserved non-coding elements
Authors: Dimitrieva Slavica , Bucher Philipp
Published: September 2012

Motivation: Genomic context analysis, also known as phylogenetic profiling, is widely used to infer functional interactions between proteins but rarely applied to non-coding cis-regulatory DNA elements. We were wondering whether this approach could provide insights about utlraconserved non-coding elements (UCNEs). These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic.

Results: In a special setting of genomic context analysis, we analyzed the fate of GRBs after a whole-genome duplication event in five fish genomes. We found that in most cases all UCNEs were retained together as a single block, whereas the corresponding target genes were often retained in two copies, one completely devoid of UCNEs. This ‘winner-takes-all’ pattern suggests that UCNEs of a GRB function in a highly cooperative manner. We propose that the multitude of interactions between UCNEs is the reason for their extreme sequence conservation.

Supplementary information:  Supplementary data are available at Bioinformatics online and at http://ccg.vital-it.ch/ucne/
SANS: high-throughput retrieval of protein sequences allowing 50% mismatches
Authors: Koskinen J. Patrik , Holm Liisa
Published: September 2012

Motivation: The genomic era in molecular biology has brought on a rapidly widening gap between the amount of sequence data and first-hand experimental characterization of proteins. Fortunately, the theory of evolution provides a simple solution: functional and structural information can be transferred between homologous proteins. Sequence similarity searching followed by k-nearest neighbor classification is the most widely used tool to predict the function or structure of anonymous gene products that come out of genome sequencing projects.

Results: We present a novel word filter, suffix array neighborhood search (SANS), to identify protein sequence similarities in the range of 50–100% identity with sensitivity comparable to BLAST and 10 times the speed of USEARCH. In contrast to these previous approaches, the complexity of the search is proportional only to the length of the query sequence and independent of database size, enabling fast searching and functional annotation into the future despite rapidly expanding databases.

Availability and implementation: The software is freely available to non-commercial users from our website http://ekhidna.biocenter.helsinki.fi/downloads/sans.

Contact:  liisa.holm@helsinki.fi.
Impact of ontology evolution on functional analyses
Authors: Groß Anika , Hartung Michael , Prüfer Kay , Kelso Janet , Rahm Erhard
Published: September 2012

Motivation: Ontologies are used in the annotation and analysis of biological data. As knowledge accumulates, ontologies and annotation undergo constant modifications to reflect this new knowledge. These modifications may influence the results of statistical applications such as functional enrichment analyses that describe experimental data in terms of ontological groupings. Here, we investigate to what degree modifications of the Gene Ontology (GO) impact these statistical analyses for both experimental and simulated data. The analysis is based on new measures for the stability of result sets and considers different ontology and annotation changes.

Results: Our results show that past changes in the GO are non-uniformly distributed over different branches of the ontology. Considering the semantic relatedness of significant categories in analysis results allows a more realistic stability assessment for functional enrichment studies. We observe that the results of term-enrichment analyses tend to be surprisingly stable despite changes in ontology and annotation.

Contact:  gross@informatik.uni-leipzig.de

Supplementary information: Supplementary Data are available at Bioinformatics online.
HighSSR: high-throughput SSR characterization and locus development from next-gen sequencing data
Authors: Churbanov Alexander , Ryan Rachael , Hasan Nabeeh , Bailey Donovan , Chen Haofeng , Milligan Brook , Houde Peter
Published: September 2012

Motivation: Microsatellites are among the most useful genetic markers in population biology. High-throughput sequencing of microsatellite-enriched libraries dramatically expedites the traditional process of screening recombinant libraries for microsatellite markers. However, sorting through millions of reads to distill high-quality polymorphic markers requires special algorithms tailored to tolerate sequencing errors in locus reconstruction, distinguish paralogous loci, rarify raw reads originating from the same amplicon and sort out various artificial fragments resulting from recombination or concatenation of auxiliary adapters. Existing programs warrant improvement.

Results: We describe a microsatellite prediction framework named HighSSR for microsatellite genotyping based on high-throughput sequencing. We demonstrate the utility of HighSSR in comparison to Roche gsAssembler on two Roche 454 GS FLX runs. The majority of the HighSSR-assembled loci were reliably mapped against model organism reference genomes. HighSSR demultiplexes pooled libraries, assesses locus polymorphism and implements Primer3 for the design of PCR primers flanking polymorphic microsatellite loci. As sequencing costs drop and permit the analysis of all project samples on next-generation platforms, this framework can also be used for direct simple sequence repeats genotyping.

Availability: http://code.google.com/p/highssr/

Contact: alexander@big.ac.cn

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Genome-wide in silico prediction of gene expression
Authors: McLeay Robert C. , Lesluyes Tom , Cuellar Partida Gabriel , Bailey Timothy L.
Published: September 2012

Motivation: Modelling the regulation of gene expression can provide insight into the regulatory roles of individual transcription factors (TFs) and histone modifications. Recently, Ouyang et al. in 2009 modelled gene expression levels in mouse embryonic stem (mES) cells using in vivo ChIP-seq measurements of TF binding. ChIP-seq TF binding data, however, are tissue-specific and relatively difficult to obtain. This limits the applicability of gene expression models that rely on ChIP-seq TF binding data.

Results: In this study, we build regression-based models that relate gene expression to the binding of 12 different TFs, 7 histone modifications and chromatin accessibility (DNase I hypersensitivity) in two different tissues. We find that expression models based on computationally predicted TF binding can achieve similar accuracy to those using in vivo TF binding data and that including binding at weak sites is critical for accurate prediction of gene expression. We also find that incorporating histone modification and chromatin accessibility data results in additional accuracy. Surprisingly, we find that models that use no TF binding data at all, but only histone modification and chromatin accessibility data, can be as (or more) accurate than those based on in vivo TF binding data.

Availability and implementation: All scripts, motifs and data presented in this article are available online at http://research.imb.uq.edu.au/t.bailey/supplementary_data/McLeay2011a.

Contact:  t.bailey@imb.uq.edu.au

Supplementary information:  Supplementary data are available at Bioinformatics online.
A linear programming model for protein inference problem in shotgun proteomics
Authors: Huang Ting , He Zengyou
Published: September 2012

Motivation: Assembling peptides identified from tandem mass spectra into a list of proteins, referred to as protein inference, is an important issue in shotgun proteomics. The objective of protein inference is to find a subset of proteins that are truly present in the sample. Although many methods have been proposed for protein inference, several issues such as peptide degeneracy still remain unsolved.

Results: In this article, we present a linear programming model for protein inference. In this model, we use a transformation of the joint probability that each peptide/protein pair is present in the sample as the variable. Then, both the peptide probability and protein probability can be expressed as a formula in terms of the linear combination of these variables. Based on this simple fact, the protein inference problem is formulated as an optimization problem: minimize the number of proteins with non-zero probabilities under the constraint that the difference between the calculated peptide probability and the peptide probability generated from peptide identification algorithms should be less than some threshold. This model addresses the peptide degeneracy issue by forcing some joint probability variables involving degenerate peptides to be zero in a rigorous manner. The corresponding inference algorithm is named as ProteinLP. We test the performance of ProteinLP on six datasets. Experimental results show that our method is competitive with the state-of-the-art protein inference algorithms.

Availability: The source code of our algorithm is available at: https://sourceforge.net/projects/prolp/.

Contact:  zyhe@dlut.edu.cn

Supplementary information:  Supplementary data are available at Bioinformatics Online.
Comb-p: software for combining, analyzing, grouping and correcting spatially correlatedP-values
Authors: Pedersen Brent S. , Schwartz David A. , Yang Ivana V. , Kechris Katerina J.
Published: September 2012

Summary:  comb-p is a command-line tool and a python library that manipulates BED files of possibly irregularly spaced P-values and (1) calculates auto-correlation, (2) combines adjacent P-values, (3) performs false discovery adjustment, (4) finds regions of enrichment (i.e. series of adjacent low P-values) and (5) assigns significance to those regions. In addition, tools are provided for visualization and assessment. We provide validation and example uses on bisulfite-seq with P-values from Fisher’s exact test, tiled methylation probes using a linear model and Dam-ID for chromatin binding using moderated t-statistics. Because the library accepts input in a simple, standardized format and is unaffected by the origin of the P-values, it can be used for a wide variety of applications.

Availability:  comb-p is maintained under the BSD license. The documentation and implementation are available at https://github.com/brentp/combined-pvalues.

Contact:  bpederse@gmail.com
Quantification of heterosubtypic immunity between avian influenza subtypes H3N8 and H4N6 in multiple avian host species
Authors: Pepin K. M. , VanDalen K. K. , Mooers N. L. , Ellis J. W. , Sullivan H. J. , Root J. J. , Webb C. T. , Franklin A. B. , Shriner S. A.
Published: September 2012

Low-pathogenicity avian influenza virus (LPAIV) can lead to epizootics that cause economic losses in poultry or the emergence of human-infectious strains. LPAIVs experience a complex immunity landscape as they are endemic in numerous host species, and many antigenically distinct strains co-circulate. Prevention and control of emergence of detrimental strains requires an understanding of infection/transmission characteristics of the various subtypes in different hosts, including interactions between subtypes. In order to develop analytical frameworks for examining control efficacy, quantification of heterosubtypic immunity interactions is fundamental. However, these data are scarce, especially for wild avian subtypes in natural hosts. Consequently, in this study, three host species (mallards, quail and pheasants) were infected with two LPAIV subtypes isolated from wild birds: H3N8 and H4N6. The recovered hosts were also reinfected with the alternate subtype to measure the effects of heterosubtypic immunity. Oropharyngeal and cloacal swabs were collected and viral RNA load was quantified by real-time RT-PCR. For secondary infections in recovered hosts, peak viral load was up to four orders of magnitude lower and shedding length was up to 4 days shorter. However, both the magnitude and presence of heterosubtypic immunity varied across specific host species/subtype combinations. Using a mathematical model of virus replication, the variation in virus replication dynamics due to host individuals was quantified. It was found that accounting for individual heterogeneity is important for drawing accurate conclusions about treatment effects. These results are relevant for developing epidemiological models to inform control practices and for analysing virus replication data.
Comparative analysis of the fusion efficiency elicited by the envelope glycoprotein V1–V5 regions derived from human immunodeficiency virus type 1 transmitted perinatally
Authors: Guo Hongyan , Abrahamyan Levon G. , Liu Chang , Waltke Mackenzie , Geng Yunqi , Chen Qimin , Wood Charles , Kong Xiaohong
Published: September 2012

Understanding the properties of viruses preferentially establishing infection during perinatal transmission of human immunodeficiency virus type 1 (HIV-1) is critical for the development of effective measures to prevent transmission. A previous study demonstrated that the newly transmitted viruses (in infants) of chronically infected mother–infant pairs (MIPs) were fitter in terms of growth, which was imparted by their envelope (Env) glycoprotein V1–V5 regions, than those in the corresponding chronically infected mothers. In order to investigate whether the higher fitness of transmitted viruses was conferred by their higher entry efficiency directed by the V1–V5 regions during perinatal transmission, the fusogenicity of Env containing V1–V5 regions derived from transmitted and non-tranmsmitted viruses of five chronically infected MIPs and two acutely infected MIPs was analysed using two different cell–cell fusion assays. The results showed that, in one chronically infected MIP, a higher fusion efficiency was induced by the infant Env V1–V5 compared with that of the corresponding mother. Moreover, the V4–V5 regions played an important role in discriminating the transmitted and non-transmitted viruses in this pair. However, neither a consistent pattern nor significant differences in fusogenicity mediated by the V1–V5 regions between maternal and infant variants was observed in the other MIPs. This study suggests that there is no consistent and significant correlation between viral fitness selection and entry efficiency directed by the V1–V5 regions during perinatal transmission. Other factors such as the route and timing of transmission may also be involved.