bluuebunny/crossref_metadata_2025 huggingface dataset:
Linear simulations of the cylindrical Richtmyer-Meshkov instability in magnetohydrodynamics
Authors: Bakhsh A. , Gao S. , Samtaney R. , Wheatley V.
Published: March 2016

Numerical simulations and analysis indicate that the Richtmyer-Meshkov instability (RMI) is suppressed in ideal magnetohydrodynamics (MHD) in Cartesian slab geometry. Motivated by the presence of hydrodynamic instabilities in inertial confinement fusion and suppression by means of a magnetic field, we investigate the RMI via linear MHD simulations in cylindrical geometry. The physical setup is that of a Chisnell-type converging shock interacting with a density interface with either axial or azimuthal (2D) perturbations. The linear stability is examined in the context of an initial value problem (with a time-varying base state) wherein the linearized ideal MHD equations are solved with an upwind numerical method. Linear simulations in the absence of a magnetic field indicate that RMI growth rate during the early time period is similar to that observed in Cartesian geometry. However, this RMI phase is short-lived and followed by a Rayleigh-Taylor instability phase with an accompanied exponential increase in the perturbation amplitude. We examine several strengths of the magnetic field (characterized by β=2pBr2) and observe a significant suppression of the instability for β ≤ 4. The suppression of the instability is attributed to the transport of vorticity away from the interface by Alfvén fronts.
Vlasov simulations of electron-ion collision effects on damping of electron plasma waves
Authors: Banks J. W. , Brunner S. , Berger R. L. , Tran T. M.
Published: March 2016

Collisional effects can play an essential role in the dynamics of plasma waves by setting a minimum damping rate and by interfering with wave-particle resonances. Kinetic simulations of the effects of electron-ion pitch angle scattering on Electron Plasma Waves (EPWs) are presented here. In particular, the effects of such collisions on the frequency and damping of small-amplitude EPWs for a range of collision rates and wave phase velocities are computed and compared with theory. Both the Vlasov simulations and linear kinetic theory find the direct contribution of electron-ion collisions to wave damping significantly reduced from that obtained through linearized fluid theory. To our knowledge, this simple result has not been published before. Simulations have been carried out using a grid-based (Vlasov) approach, based on a high-order conservative finite difference method for discretizing the Fokker-Planck equation describing the evolution of the electron distribution function. Details of the implementation of the collision operator within this framework are presented. Such a grid-based approach, which is not subject to numerical noise, is of particular interest for the accurate measurements of the wave damping rates.
Scattering, bound, and quasi-bound states of the generalized symmetric Woods-Saxon potential
Authors: Lütfüoğlu B. C. , Akdeniz F. , Bayrak O.
Published: March 2016

The exact analytical solutions of the Schrödinger equation for the generalized symmetrical Woods-Saxon potential are examined for the scattering, bound, and quasi-bound states in one dimension. The reflection and transmission coefficients are analytically obtained. Then, the correlations between the potential parameters and the reflection-transmission coefficients are investigated, and a transmission resonance condition is derived. Occurrence of the transmission resonance has been shown when incident energy of the particle is equal to one of the resonance energies of the quasi-bound states.
Ti3CrCu4: A possible 2-D ferromagnetic spin fluctuating system
Authors: Dhar S. K. , Provino A. , Manfrinetti P. , Kulkarni R. , Goyal Neeraj , Paudyal D.
Published: March 2016

Ti3CrCu4 is a new ternary compound which crystallizes in the tetragonal Ti3Pd5 structure type. The Cr atoms form square nets in the a-b plane (a = 3.124 Å) which are separated by an unusually large distance c = 11.228 Å along the tetragonal axis, thus forming a -2-D Cr-sublattice. The paramagnetic susceptibility is characterized by a low effective moment, μeff = 1.1 μB, a low paramagnetic Curie temperature θP (below 7 K) and a temperature independent χ0 = 6.7 x 10−4 emu/mol. The magnetization at 1.8 K increases rapidly with field nearly saturating to 0.2 μB/f.u. The zero field heat capacity C/T shows an upturn below 7 K (∼190 mJ/mol K2 at ∼0.1K) which is suppressed in applied magnetic fields and interpreted as suggesting the presence of spin fluctuations. The resistivity at low temperatures shows non-Fermi liquid behavior. Overall, the experimental data thus reveal an unusual magnetic state in Ti3CrCu4, which likely has its origin in the layered nature of the Cr sub-lattice and ferromagnetic spin fluctuations. Density functional theoretical calculations reveal a sharp Cr density of states peak just above the Fermi level, indicating the propensity of Ti3CrCu4 to become magnetic.
Thermal dynamics of thermoelectric phenomena from frequency resolved methods
Authors: García-Cañadas J. , Min G.
Published: March 2016

Understanding the dynamics of thermoelectric (TE) phenomena is important for the detailed knowledge of the operation of TE materials and devices. By analyzing the impedance response of both a single TE element and a TE device under suspended conditions, we provide new insights into the thermal dynamics of these systems. The analysis is performed employing parameters such as the thermal penetration depth, the characteristic thermal diffusion frequency and the thermal diffusion time. It is shown that in both systems the dynamics of the thermoelectric response is governed by how the Peltier heat production/absorption at the junctions evolves. In a single thermoelement, at high frequencies the thermal waves diffuse semi-infinitely from the junctions towards the half-length. When the frequency is reduced, the thermal waves can penetrate further and eventually reach the half-length where they start to cancel each other and further penetration is blocked. In the case of a TE module, semi-infinite thermal diffusion along the thickness of the ceramic layers occurs at the highest frequencies. As the frequency is decreased, heat storage in the ceramics becomes dominant and starts to compete with the diffusion of the thermal waves towards the half-length of the thermoelements. Finally, the cancellation of the waves occurs at the lowest frequencies. It is demonstrated that the analysis is able to identify and separate the different physical processes and to provide a detailed understanding of the dynamics of different thermoelectric effects.
Sharpening of the 6.8 nm peak in an Nd:YAG laser produced Gd plasma by using a pre-formed plasma
Authors: Tian Yong , Song Xiaolin , Xie Zhuo , Gao Jian , Dou Yinping , Li Bochao , Lin Jingquan , Tomie Toshihisa
Published: March 2016

For effective use of a laser-produced-plasma (LPP) light source, an LPP is desired to emit a narrow spectral peak because the reflection spectrum of multilayer mirrors for guiding emission from the source is very narrow. While a Gd plasma has been studied extensively as an extreme ultraviolet (EUV) light source at around 6.8 nm, where La/B4C multilayer is reported to have a high reflectivity with a bandwidth of about 0.6 %, all previous works using an Nd:YAG laser reported very broad spectra. This paper reports the first narrowing of the 6.8 nm peak in the case of using an Nd:YAG laser to generate a Gd plasma by using a pre-pulse. The best peak narrowing is observed when a pre-formed plasma is heated by a 1064 nm main laser pulse with a duration of 10 ns at the irradiation density of 4x 1011 W/cm2 at a delay time of 50 ns after the pre-pulse irradiation. The observed spectral width of about 0.3 nm is about one fifth of the value for no pre-formed plasma. The peak wavelength of the 6.8 nm band shifted to a longer wavelength side and the peak was broadened both for lower and higher laser irradiation density. It is discussed that this robustness of the peak position of the 6.8 nm Gd peak against temperature change is suitable to achieve a narrow bandwidth from an LPP generated on solid. The observed spectra are compared with those previously reported in various conditions.
Functionality and genomics of selenium and vitamin E supplementation in ruminants
Authors: Chauhan S. S. , Liu F. , Leury B. J. , Cottrell J. J. , Celi P. , Dunshea F. R.
Published: March 2016

Selenium (Se) and vitamin E are essential micronutrients for animal health and production. The major function of both Se and vitamin E is to prevent the oxidative damage of biological membranes and they can influence growth, reproduction, immune function, health, and product quality in ruminants. Both Se and vitamin E are important for maintaining low cellular and systemic concentrations of reactive oxygen species and lipid hydroperoxides, to ensure optimum cellular function. Discovery of various selenoproteins and vitamin E-responsive genes has contributed significantly to improving our understanding about multiple functions of Se and vitamin E. There is evidence that these functions extend beyond the classical antioxidant properties to immunomodulation and intracellular cell signalling and gene regulation. Research in recent years has also shown that supranutritional supplementation of Se and vitamin E is required to improve the performance of ruminants under certain stressful conditions such as heat stress and during transition period. Considering the growing awareness among consumers of the benefits of antioxidant-rich food, there is a great opportunity for the livestock industries to focus on producing antioxidant-enriched milk and meat products or functional foods. The present review focuses on the recent developments in understanding multiple functions of Se and vitamin E at the cellular and molecular level and the effects of supranutritional supplementation on ruminant performance. In addition, the paper also articulates the potential opportunities to produce functional foods enriched with antioxidants, and underlines the need for optimum supplementation of these micronutrients for efficient ruminant production.
Effects of heat on dehiscence and germination in Eucalyptus globulus Labill.
Authors: Silva Joaquim S. , dos Santos Patrícia , Sério André , Gomes Filomena
Published: March 2016

Fire is a facilitating factor in the naturalisation of Eucalyptus globulus in countries where it has been introduced. In this study, we investigate the effect of heat on dehiscence and germination of free and encapsulated seeds. Twelve combinations of temperature (80, 150, 200°C) and heating exposure time (30, 60, 120, 300 s) were used and a corresponding heat index (H) was computed. Dehiscence was registered on a daily basis and germinability of encapsulated and free seeds was verified through germination tests. Results indicate that dehiscence was strongly dependent on individual trees, but no significant differences were found between the treatments applied, suggesting a direct effect of capsule desiccation rather than heat on seed shed. The percentage of germinated seeds was negatively influenced by the highest temperature and exposure times. The effect of capsule protection on seed germination was positive for 200°C at 60 and 150 s (H = 139 and 220 respectively), but negative at 150°C for 300 s (H = 269). No seeds germinated after treatment at 200°C for 300 s (H = 358). Given the estimated range of temperatures and residence times during wildfires in eucalypt plantations, our results help to explain the high levels of seedling recruitment observed in burned stands.
Necessity of capillary modes in a minimal model of nanoscale hydrophobic solvation
Authors: Vaikuntanathan Suriyanarayanan , Rotskoff Grant , Hudson Alexander , Geissler Phillip L.
Published: March 2016

Significance

Hydrophobic effects, which play a crucial role in many chemical and biological processes, originate in the statistics of microscopic density fluctuations in liquid water. Chandler has established the foundation for a simple and unified understanding of these effects, by identifying essential aspects of water’s intermolecular structure while accounting for its proximity to phase coexistence. Here, we show that coarse-grained models based on this perspective, when constructed to include the statistics of capillary waves at interfaces, can achieve remarkable agreement with results of atomistically detailed simulations. Highly efficient and lacking adjustable parameters, such models hold promise as powerful tools for studying multiscale problems in hydrophobic solvation.
Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing
Authors: Falaleeva Marina , Pages Amadis , Matuszek Zaneta , Hidmi Sana , Agranat-Tamir Lily , Korotkov Konstantin , Nevo Yuval , Eyras Eduardo , Sperling Ruth , Stamm Stefan
Published: March 2016

Significance

C/D box small nucleolar RNAs (SNORDs) are abundant, short, nucleoli-residing, noncoding RNAs that guide the methyltransferase fibrillarin to perform 2′-O-methylation of target RNAs. We identified 29 SNORDs present in a fibrillarin-containing fraction as well as a fibrillarin-free fraction enriched in spliceosomes. One of these SNORDs,SNORD27, directsrRNAmethylation and regulates alternative pre-mRNA splicing (AS) ofE2F7pre-mRNA, a transcriptional repressor of cell cycle-regulated genes.SNORD27likely regulatesE2F7pre-mRNA AS by masking splice sites through base pairing. This previously unidentified function of SNORDs increases the number of factors regulating AS, a critical step in the expression of the vast majority of human genes, and highlights a potential coupling between AS, cell cycle, proliferation, and ribosome biogenesis.
Atomic resolution probe for allostery in the regulatory thin filament
Authors: Williams Michael R. , Lehman Sarah J. , Tardiff Jil C. , Schwartz Steven D.
Published: March 2016

Significance

The cardiac thin filament (CTF) is a complex and highly dynamic multiprotein complex that regulates heart function at the molecular level. Mutations in proteins that comprise the thin filament cause cardiomyopathic remodeling that is due, in part, to dysregulation of Ca
2+
binding. Many of the known mutations in multiple thin filament proteins occur at a significant physical distance from the Ca
2+
binding domain; thus, the elucidation of molecular mechanisms has been challenging. We have developed and now apply an atomistic model of the CTF to this question and have obtained molecular insight that both provides disease mechanisms and facilitates future rational drug design. Finding the molecular cause of disease is the first step in designing molecular interventions.
Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease
Authors: Flach Anne-Christine , Litke Tanja , Strauss Judith , Haberl Michael , Gómez César Cordero , Reindl Markus , Saiz Albert , Fehling Hans-Jörg , Wienands Jürgen , Odoardi Francesca , Lühder Fred , Flügel Alexander
Published: March 2016

Significance

Although T cells are the main players in autoimmune CNS inflammation, the role of B cells is being increasingly appreciated. We here investigated possible scenarios of how B cells could participate in the initiation of autoimmune CNS disease. We show that myelin-reactive autoantibodies accumulate in CNS-resident phagocytes, thereby concentrating myelin antigens in these cells and increasing the cells’ capacity to present the autoantigen to invading myelin-reactive T cells. Consequently, these T cells are stimulated and more easily reach the threshold for clinically relevant reactivation within the CNS tissue. This previously unidentified mechanism is of potential clinical relevance because it provides a scientific explanation for immune processes leading to disease initiation and induction of relapses in multiple sclerosis and other autoimmune CNS disorders.
Influence of operational parameters on the TiO2 photocatalytic degradation of Methylene blue
Authors: Sohrabi H. , Mozafari A. , Sajjadnejad M. , Tabaian S. H. , Omidvar H.
Published: March 2016

Thin films of titanium oxide were obtained by dip-coating, using the sol–gel method. TiO2 powder (Degussa, P25) and polyethylene glycol (PEG) were added to enhance the photocatalytic properties of resulting films. Effects of experimental variables on the photocatalytic properties of the coatings were evaluated based on the degradation efficiency of the reference dye (Methylene blue). The photocatalytic activity of resulting TiO2 coatings was improved with the loading of TiO2 powder (Degussa, P25) and PEG in the sols. The electron-hole pair photogeneration increases with the energy of irradiation and improves photocatalytic efficiency. Increasing coating thickness leads to a rough surface with more reaction sites. Photodegradation conversion of Methylene blue (Mb) decreases with an increase in the initial concentration of Mb.
Microstructure evolution of GCr15 in cold ring rolling and following heat treatment
Authors: Lu B. H. , Hua L. , Han X. H. , Zhou G. H.
Published: March 2016

The influences of deformation degrees on the microstructure evolution of GCr15 steel in cold ring rolling and following heat treatment (quenching and temper) are investigated in this paper. As the deformation is uneven, microstructure at the outer surface, middle place and inner surface on the cross-section of the ring is selected for the study. The microstructure is characterised by scanning electron microscopy, optical microscopy and X-ray diffraction. The [Formula: see text] transformation is studied with differential scanning calorimetry, and the hardness is examined by Vickers hardness tester. The results show that the deformation is severe on the outer surface but slight on the middle place and inner surface. A large degree of deformation leads to the acceleration of carbide dissolution, the grain refinement and the increase of hardness. In addition, the deformation results in the decrease of [Formula: see text] transformation temperature according to the differential scanning calorimetry data.
Preferences and Positivist Methodology in Economics
Authors: Clarke Christopher
Published: March 2016

I distinguish several doctrines that economic methodologists have found attractive, all of which have a positivist flavor. One of these is the doctrine that preference assignments in economics are just shorthand descriptions of agents’ choices. Although most of these doctrines are problematic, the latter doctrine about preference assignments is a respectable one, I argue. It does not entail any of the problematic doctrines, and indeed it is warranted independently of them.
Kohnen’s formula and a conjecture of Darmon and Tornaría
Authors: Longo Matteo , Mao Zhengyu
Published: March 2016

We generalize a result of W. Kohnen (1985) to explicit Waldspurger lifts constructed by E. M. Baruch and Z. Mao (2007). As an application, we prove a conjecture formulated by H. Darmon and G. Tornaría (2008).
Vinculin regulates directionality and cell polarity in two- and three-dimensional matrix and three-dimensional microtrack migration
Authors: Rahman Aniqua , Carey Shawn P. , Kraning-Rush Casey M. , Goldblatt Zachary E. , Bordeleau Francois , Lampi Marsha C. , Lin Deanna Y. , García Andrés J. , Reinhart-King Cynthia A.
Published: March 2016

During metastasis, cells can use proteolytic activity to form tube-like “microtracks” within the extracellular matrix (ECM). Using these microtracks, cells can migrate unimpeded through the stroma. To investigate the molecular mechanisms of microtrack migration, we developed an in vitro three-dimensional (3D) micromolded collagen platform. When in microtracks, cells tend to migrate unidirectionally. Because focal adhesions are the primary mechanism by which cells interact with the ECM, we examined the roles of several focal adhesion molecules in driving unidirectional motion. Vinculin knockdown results in the repeated reversal of migration direction compared with control cells. Tracking the position of the Golgi centroid relative to the position of the nucleus centroid reveals that vinculin knockdown disrupts cell polarity in microtracks. Vinculin also directs migration on two-dimensional (2D) substrates and in 3D uniform collagen matrices, as indicated by reduced speed, shorter net displacement, and decreased directionality in vinculin-deficient cells. In addition, vinculin is necessary for focal adhesion kinase (FAK) activation in three dimensions, as vinculin knockdown results in reduced FAK activation in both 3D uniform collagen matrices and microtracks but not on 2D substrates, and, accordingly, FAK inhibition halts cell migration in 3D microtracks. Together these data indicate that vinculin plays a key role in polarization during migration.
Expansion and concatenation of nonmuscle myosin IIA filaments drive cellular contractile system formation during interphase and mitosis
Authors: Fenix Aidan M. , Taneja Nilay , Buttler Carmen A. , Lewis John , Van Engelenburg Schuyler B. , Ohi Ryoma , Burnette Dylan T.
Published: March 2016

Cell movement and cytokinesis are facilitated by contractile forces generated by the molecular motor, nonmuscle myosin II (NMII). NMII molecules form a filament (NMII-F) through interactions of their C-terminal rod domains, positioning groups of N-terminal motor domains on opposite sides. The NMII motors then bind and pull actin filaments toward the NMII-F, thus driving contraction. Inside of crawling cells, NMIIA-Fs form large macromolecular ensembles (i.e., NMIIA-F stacks), but how this occurs is unknown. Here we show NMIIA-F stacks are formed through two non–mutually exclusive mechanisms: expansion and concatenation. During expansion, NMIIA molecules within the NMIIA-F spread out concurrent with addition of new NMIIA molecules. Concatenation occurs when multiple NMIIA-Fs/NMIIA-F stacks move together and align. We found that NMIIA-F stack formation was regulated by both motor activity and the availability of surrounding actin filaments. Furthermore, our data showed expansion and concatenation also formed the contractile ring in dividing cells. Thus interphase and mitotic cells share similar mechanisms for creating large contractile units, and these are likely to underlie how other myosin II–based contractile systems are assembled.
UniProt-DAAC: domain architecture alignment and classification, a new method for automatic functional annotation in UniProtKB
Authors: Doğan Tunca , MacDougall Alistair , Saidi Rabie , Poggioli Diego , Bateman Alex , O’Donovan Claire , Martin Maria J.
Published: March 2016

Motivation: Similarity-based methods have been widely used in order to infer the properties of genes and gene products containing little or no experimental annotation. New approaches that overcome the limitations of methods that rely solely upon sequence similarity are attracting increased attention. One of these novel approaches is to use the organization of the structural domains in proteins.

Results: We propose a method for the automatic annotation of protein sequences in the UniProt Knowledgebase (UniProtKB) by comparing their domain architectures, classifying proteins based on the similarities and propagating functional annotation. The performance of this method was measured through a cross-validation analysis using the Gene Ontology (GO) annotation of a sub-set of UniProtKB/Swiss-Prot. The results demonstrate the effectiveness of this approach in detecting functional similarity with an average F-score: 0.85. We applied the method on nearly 55.3 million uncharacterized proteins in UniProtKB/TrEMBL resulted in 44 818 178 GO term predictions for 12 172 114 proteins. 22% of these predictions were for 2 812 016 previously non-annotated protein entries indicating the significance of the value added by this approach.

Availability and implementation: The results of the method are available at: ftp://ftp.ebi.ac.uk/pub/contrib/martin/DAAC/.

Contact:  tdogan@ebi.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Tally: a scoring tool for boundary determination between repetitive and non-repetitive protein sequences
Authors: Richard François D. , Alves Ronnie , Kajava Andrey V.
Published: March 2016

Motivation: Tandem Repeats (TRs) are abundant in proteins, having a variety of fundamental functions. In many cases, evolution has blurred their repetitive patterns. This leads to the problem of distinguishing between sequences that contain highly imperfect TRs, and the sequences without TRs. The 3D structure of proteins can be used as a benchmarking criterion for TR detection in sequences, because the vast majority of proteins having TRs in sequences are built of repetitive 3D structural blocks. According to our benchmark, none of the existing scoring methods are able to clearly distinguish, based on the sequence analysis, between structures with and without 3D TRs.

Results: We developed a scoring tool called Tally, which is based on a machine learning approach. Tally is able to achieve a better separation between sequences with structural TRs and sequences of aperiodic structures, than existing scoring procedures. It performs at a level of 81% sensitivity, while achieving a high specificity of 74% and an Area Under the Receiver Operating Characteristic Curve of 86%. Tally can be used to select a set of structurally and functionally meaningful TRs from all TRs detected in proteomes. The generated dataset is available for benchmarking purposes. Availability and implementation: Source code is available upon request. Tool and dataset can be accessed through our website: http://bioinfo.montp.cnrs.fr/?r=Tally.

Contact:  andrey.kajava@crbm.cnrs.fr

Supplementary information:  Supplementary data are available at Bioinformatics online.
The spatiotemporal order of signaling events unveils the logic of development signaling
Authors: Zhu Hao , Owen Markus R. , Mao Yanlan
Published: March 2016

Motivation: Animals from worms and insects to birds and mammals show distinct body plans; however, the embryonic development of diverse body plans with tissues and organs within is controlled by a surprisingly few signaling pathways. It is well recognized that combinatorial use of and dynamic interactions among signaling pathways follow specific logic to control complex and accurate developmental signaling and patterning, but it remains elusive what such logic is, or even, what it looks like.

Results: We have developed a computational model for Drosophila eye development with innovated methods to reveal how interactions among multiple pathways control the dynamically generated hexagonal array of R8 cells. We obtained two novel findings. First, the coupling between the long-range inductive signals produced by the proneural Hh signaling and the short-range restrictive signals produced by the antineural Notch and EGFR signaling is essential for generating accurately spaced R8s. Second, the spatiotemporal orders of key signaling events reveal a robust pattern of lateral inhibition conducted by Ato-coordinated Notch and EGFR signaling to collectively determine R8 patterning. This pattern, stipulating the orders of signaling and comparable to the protocols of communication, may help decipher the well-appreciated but poorly defined logic of developmental signaling.

Availability and implementation: The model is available upon request.

Contact:  hao.zhu@ymail.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
Assessing statistical significance in multivariable genome wide association analysis
Authors: Buzdugan Laura , Kalisch Markus , Navarro Arcadi , Schunk Daniel , Fehr Ernst , Bühlmann Peter
Published: March 2016

Motivation: Although Genome Wide Association Studies (GWAS) genotype a very large number of single nucleotide polymorphisms (SNPs), the data are often analyzed one SNP at a time. The low predictive power of single SNPs, coupled with the high significance threshold needed to correct for multiple testing, greatly decreases the power of GWAS.

Results: We propose a procedure in which all the SNPs are analyzed in a multiple generalized linear model, and we show its use for extremely high-dimensional datasets. Our method yields P-values for assessing significance of single SNPs or groups of SNPs while controlling for all other SNPs and the family wise error rate (FWER). Thus, our method tests whether or not a SNP carries any additional information about the phenotype beyond that available by all the other SNPs. This rules out spurious correlations between phenotypes and SNPs that can arise from marginal methods because the ‘spuriously correlated’ SNP merely happens to be correlated with the ‘truly causal’ SNP. In addition, the method offers a data driven approach to identifying and refining groups of SNPs that jointly contain informative signals about the phenotype. We demonstrate the value of our method by applying it to the seven diseases analyzed by the Wellcome Trust Case Control Consortium (WTCCC). We show, in particular, that our method is also capable of finding significant SNPs that were not identified in the original WTCCC study, but were replicated in other independent studies.

Availability and implementation: Reproducibility of our research is supported by the open-source Bioconductor package hierGWAS.

Contact:  peter.buehlmann@stat.math.ethz.ch

Supplementary information:  Supplementary data are available at Bioinformatics online.
Dynamic software design for clinical exome and genome analyses: insights from bioinformaticians, clinical geneticists, and genetic counselors
Authors: Shyr Casper , Kushniruk Andre , van Karnebeek Clara D.M. , Wasserman Wyeth W.
Published: March 2016

Background The transition of whole-exome and whole-genome sequencing (WES/WGS) from the research setting to routine clinical practice remains challenging.

Objectives With almost no previous research specifically assessing interface designs and functionalities of WES and WGS software tools, the authors set out to ascertain perspectives from healthcare professionals in distinct domains on optimal clinical genomics user interfaces.

Methods A series of semi-scripted focus groups, structured around professional challenges encountered in clinical WES and WGS, were conducted with bioinformaticians (n = 8), clinical geneticists (n = 9), genetic counselors (n = 5), and general physicians (n = 4).

Results Contrary to popular existing system designs, bioinformaticians preferred command line over graphical user interfaces for better software compatibility and customization flexibility. Clinical geneticists and genetic counselors desired an overarching interactive graphical layout to prioritize candidate variants—a “tiered” system where only functionalities relevant to the user domain are made accessible. They favored a system capable of retrieving consistent representations of external genetic information from third-party sources. To streamline collaboration and patient exchanges, the authors identified user requirements toward an automated reporting system capable of summarizing key evidence-based clinical findings among the vast array of technical details.

Conclusions Successful adoption of a clinical WES/WGS system is heavily dependent on its ability to address the diverse necessities and predilections among specialists in distinct healthcare domains. Tailored software interfaces suitable for each group is likely more appropriate than the current popular “one size fits all” generic framework. This study provides interfaces for future intervention studies and software engineering opportunities.
Bayesian Networks and Boundedly Rational Expectations *
Authors: Spiegler Ran
Published: March 2016

I present a framework for analyzing decision making under imperfect understanding of correlation structures and causal relations. A decision maker (DM) faces an objective long-run probability distribution p over several variables (including the action taken by previous DMs). The DM is characterized by a subjective causal model, represented by a directed acyclic graph over the set of variable labels. The DM attempts to fit this model to p , resulting in a subjective belief that distorts p by factorizing it according to the graph via the standard Bayesian network formula. As a result of this belief distortion, the DM’s evaluation of actions can vary with their long-run frequencies. Accordingly, I define a ”personal equilibrium” notion of individual behavior. The framework enables simple graphical representations of causal-attribution errors (such as coarseness or reverse causation), and provides tools for checking rationality properties of the DM’s behavior. I demonstrate the framework’s scope of applications with examples covering diverse areas, from demand for education to public policy.
Genome-Wide Association Study Identifies Novel Candidate Genes for Aggressiveness, Deoxynivalenol Production, and Azole Sensitivity in Natural Field Populations ofFusarium graminearum
Authors: Talas Firas , Kalih Rasha , Miedaner Thomas , McDonald Bruce A.
Published: March 2016

Genome-wide association studies can identify novel genomic regions and genes that affect quantitative traits. Fusarium head blight is a destructive disease caused by Fusarium graminearum that exhibits several quantitative traits, including aggressiveness, mycotoxin production, and fungicide resistance. Restriction site–associated DNA sequencing was performed for 220 isolates of F. graminearum. A total of 119 isolates were phenotyped for aggressiveness and deoxynivalenol (DON) production under natural field conditions across four environments. The effective concentration of propiconazole that inhibits isolate growth in vitro by 50% was calculated for 220 strains. Approximately 29,000 single nucleotide polymorphism markers were associated to each trait, resulting in 50, 29, and 74 quantitative trait nucleotides (QTNs) that were significantly associated to aggressiveness, DON production, and propiconazole sensitivity, respectively. Approximately 41% of these QTNs caused nonsynonymous substitutions in predicted exons, while the remainder were synonymous substitutions or located in intergenic regions. Three QTNs associated with propiconazole sensitivity were significant after Bonferroni correction. These QTNs were located in genes not previously associated with azole sensitivity. The majority of the detected QTNs were located in genes with predicted regulatory functions, suggesting that nucleotide variation in regulatory genes plays a major role in the corresponding quantitative trait variation.
Development of a Greenhouse Screening Method for Adult Plant Response in Wheat to Stem Rust
Authors: Bender C. M. , Prins R. , Pretorius Z. A.
Published: March 2016

Screening for adult plant resistance in wheat to stem rust, caused by Puccinia graminis f. sp. tritici, is generally conducted in field plots. Although such evaluations are successful if managed properly, field ratings are time consuming, expensive, weather dependent, and open to inoculum of unwanted races or other confounding diseases. The objective of this study was to develop a dependable system of screening the response of adult plants to stem rust under greenhouse conditions. A comparison of inoculation methods and incubation environments showed that plants inoculated with urediniospores suspended in water, followed by a 24 h dew period in a plastic chamber constructed in a greenhouse, gave the most consistent results. Measurements of response type, stem rust severity, and frequency in follow-up experiments indicated that the most reliable infection was obtained when plants sprayed with 1.25 mg urediniospores per ml water were incubated in the plastic chamber. Using the optimized protocol, a Kariega × Avocet S doubled haploid population was inoculated with two P. graminis f. sp. tritici races. Depending on the race, composite interval mapping showed flag leaf infection type to be significantly influenced by regions on chromosomes 6A, 6D, and 7D. Stem rust severity and reaction type mapped to chromosomes 6D and/or 6A. The Lr34/Yr18/Sr57 gene derived from Kariega on chromosome 7D affected the rust response on flag leaves but not on stems of greenhouse-grown plants. This study showed that phenotyping and genetic analysis of especially major effect stem rust resistance in adult wheat plants is possible and reproducible under controlled conditions in a greenhouse.
Cercosporin From Pseudocercosporella capsellae and its Critical Role in White Leaf Spot Development
Authors: Gunasinghe Niroshini , You Ming Pei , Cawthray Gregory R. , Barbetti Martin J.
Published: March 2016

Pseudocercosporella capsellae, the causative agent of white leaf spot disease in Brassicaceae, can produce a purple-pink pigment on artificial media resembling, but not previously confirmed as, the toxin cercosporin. Chemical extraction with ethyl acetate from growing hyphae followed by quantitative (thin-layer chromatography [TLC] and high-performance liquid chromatography [HPLC]) and qualitative methods showed an identical absorption spectrum, with similar retardation factor (Rf) values on TLC papers and an identical peak with the same retention time in HPLC as for a standard for cercosporin. We believe this is the first report to confirm that the purple-pink pigment produced by P. capsellae is cercosporin. Confocal microscopy detected green autofluorescence of cercosporin-producing hyphae, confirming the presence of cercosporin inside hyphae. The highly virulent UWA Wlra-7 isolate of P. capsellae produced the greatest quantity of cercosporin (10.69 mg g−1). The phytotoxicity and role of cercosporin in disease initiation across each of three Brassicaceae host species (Brassica juncea, B. napus, and Raphanus raphanistrum) was also studied. Culture filtrates containing cercosporin were phytotoxic to all three host plant species, producing large, white lesions on highly sensitive B. juncea, only water-soaked areas on least sensitive R. raphanistrum, and intermediate lesions on B. napus. It is noteworthy that sensitivity to cercosporin of these three host species was analogous to their susceptibility to the pathogen, viz., B. juncea the most susceptible, R. raphanistrum the least susceptible, and B. napus intermediate. The presence of cercosporin in the inoculum significantly increased disease severity on the highly cercosporin-sensitive B. juncea. We believe that this is the first study to demonstrate that P. capsellae produces cercosporin in liquid culture rather than agar media. Finally, this study highlights an important role of cercosporin as a pathogenicity factor in white leaf spot disease on Brassicaceae as evidenced by the ability of the cercosporin-rich culture filtrate to reproduce white leaf spot lesions on host plants and by the enhanced virulence of P. capsellae in the presence of cercosporin.
Overexpression of OsOSM1 Enhances Resistance to Rice Sheath Blight
Authors: Xue X. , Cao Z. X. , Zhang X. T. , Wang Y. , Zhang Y. F. , Chen Z. X. , Pan X. B. , Zuo S. M.
Published: March 2016

Sheath blight (SB), caused by Rhizoctonia solani, is one of the most destructive rice diseases worldwide. It has been difficult to generate SB-resistant varieties through conventional breeding because of the quantitative nature of rice resistance to SB. In this study, we found that overexpression of the OsOSM1 gene, encoding an osmotin protein belonging to the pathogenesis-related protein 5 family, is able to improve rice resistance to SB in field tests. Although there are two osmotin genes in rice, OsOSM1 is the one mainly expressed in leaf sheath at the booting stage, coinciding with the critical stage of SB development in the field. In addition, OsOSM1 expression is strongly induced by R. solani in SB-resistant rice variety YSBR1 but not in susceptible varieties, suggesting its involvement in SB resistance. Overexpression of OsOSM1 (OsOSM1ox) in susceptible variety Xudao 3 significantly increases resistance to SB in transgenic rice. The OsOSM1 mRNA levels in different transgenic lines are found to be positively correlated with their SB resistance levels. Intriguingly, although extremely high levels of OsOSM1 were detrimental to rice development, appropriately elevated levels of OsSOM1 were obtained that enhanced rice SB resistance without affecting rice development or grain yield. The OsSOM1 protein is localized on plasma membrane. OsOSM1 is upregulated by jasmonic acid (JA); furthermore, JA-responsive marker genes are induced in OsOSM1ox lines. These results suggest that the activation of JA signaling pathway may account for the increased resistance in transgenic OsOSM1ox lines. Taken together, our results demonstrate that OsOSM1 plays an important role in defense against rice SB disease and provides a new target for engineering resistance to SB.
Systemic Hypersensitive Resistance to Turnip mosaic virus in Brassica juncea is Associated With Multiple Defense Responses, Especially Phloem Necrosis and Xylem Occlusion
Authors: Nyalugwe Eviness P. , Barbetti Martin J. , Clode Peta L. , Jones Roger A. C.
Published: March 2016

Systemic hypersensitive resistance (SHR) caused by Turnip mosaic virus (TuMV) was studied by light microscopy and histochemical analysis in stem cross sections of Brassica juncea (Indian mustard) plants. Ten TuMV isolates were inoculated to leaves of susceptible line JM 06006, cv. Oasis CI, which carries TuMV systemic hypersensitivity gene TuRBJU 01, and F3 progeny plants obtained from a cross between them. Systemic mosaic (SM) symptoms were induced by all 10 isolates in plants of JM 06006, and by resistance-breaking isolate NSW-3 in all cv. Oasis CI and F3 plants. With the other nine isolates, cv. Oasis CI plants developed SHR while F3 progeny plants segregated for both phenotypes; mock-inoculated control plants never became infected. Presence of SHR did not delay systemic invasion as this commenced within 2 hours after inoculation (hai) and was almost complete by 72 hai regardless of whether plants subsequently developed SHR or SM. When stem cross sections sampled 9 to 12 days after inoculation were examined for the plant defense responses, phloem necrosis, hydrogen peroxide accumulation, and additional lignin deposition, sections from plants with SHR demonstrated all of these characteristics, but sections from plants with SM or mock-inoculation did not. Based on consolidated data from all isolates except NSW-3, stems developing SHR had significantly more occluded xylem vessels (P < 0.001) compared with stems from plants developing SM or mock-inoculated plants. Both light microscopy and histochemical tests with phloroglucinol-HCl and toluidine blue O indicated that the xylem occlusions could be gels. Thus, phloem necrosis, xylem occlusion, lignification, and hydrogen peroxide accumulation were all associated with the SHR in B. juncea plants carrying TuMV hypersensitivity gene TuRBJU 01. In addition, virus inclusion bodies were fewer in sections from plants with SHR. Phloem necrosis was apparently acting as the primary cause of SHR and xylem occlusion as an important secondary cause.
The Role for Virtual Patients in the Future of Medical Education
Authors: Berman Norman B. , Durning Steven J. , Fischer Martin R. , Huwendiek Soren , Triola Marc M.
Published: March 2016

The medical education community is working—across disciplines and across the continuum—to address the current challenges facing the medical education system and to implement strategies to improve educational outcomes. Educational technology offers the promise of addressing these important challenges in ways not previously possible. The authors propose a role for virtual patients (VPs), which they define as multimedia, screen-based interactive patient scenarios. They believe VPs offer capabilities and benefits particularly well suited to addressing the challenges facing medical education. Well-designed, interactive VP-based learning activities can promote the deep learning that is needed to handle the rapid growth in medical knowledge. Clinically oriented learning from VPs can capture intrinsic motivation and promote mastery learning. VPs can also enhance trainees’ application of foundational knowledge to promote the development of clinical reasoning, the foundation of medical practice. Although not the entire solution, VPs can support competency-based education. The data created by the use of VPs can serve as the basis for multi-institutional research that will enable the medical education community both to better understand the effectiveness of educational interventions and to measure progress toward an improved system of medical education.
Prognostic Significance of Hyponatremia in Acute Intracerebral Hemorrhage: Pooled Analysis of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Studies*
Authors: Carcel Cheryl , Sato Shoichiro , Zheng Danni , Heeley Emma , Arima Hisatomi , Yang Jie , Wu Guojun , Chen Guofang , Zhang Shihong , Delcourt Candice , Lavados Pablo , Robinson Thompson , Lindley Richard I. , Wang Xia , Chalmers John , Anderson Craig S.
Published: March 2016

Objectives:

To determine the association of hyponatremia at presentation with clinical and imaging outcomes in patients with acute intracerebral hemorrhage.

Design:

Retrospective pooled analysis of prospectively collected data from 3,243 participants of the pilot and main phases of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials 1 and 2 (international, multicenter, open, blinded endpoint, randomized controlled trials designed to assess the effects of early intensive blood pressure lowering in patients with acute intracerebral hemorrhage).

Setting:

Clinical hospital sites in 21 countries.

Patients:

Patients with predominantly mild-moderate severity of spontaneous intracerebral hemorrhage within 6 hours of onset and elevated systolic blood pressure (150–220 mm Hg) were included in the study.

Interventions:

Patients were assigned to receive intensive (target systolic blood pressure, < 140 mm Hg within 1 hr) or guideline-recommended (target systolic blood pressure, < 180 mm Hg) blood pressure–lowering therapy.

Measurements and Main Results:

Presentation hyponatremia was defined as serum sodium less than 135 mEq/L. The primary outcome was death at 90 days. Multivariable logistic regression was used to assess the association of hyponatremia with important clinical events. Of 3,002 patients with available data, 349 (12%) had hyponatremia. Hyponatremia was associated with death (18% vs 11%; multivariable-adjusted odds ratio, 1.81; 95% CI, 1.28–2.57; p < 0.001) and larger baseline intracerebral hemorrhage volume (multivariable adjusted, p = 0.046) but not with baseline perihematomal edema volume nor with growth of intracerebral hemorrhage or perihematomal edema during the initial 24 hours.

Conclusions:

Hyponatremia at presentation is associated with increased mortality in patients with predominantly deep and modest volume intracerebral hemorrhage through mechanisms that seem independent of growth in intracerebral hemorrhage or perihematomal edema.