bluuebunny/crossref_metadata_2025 huggingface dataset:
Large amplitude oscillation of magnetization in spin-torque oscillator stabilized by field-like torque
Authors: Taniguchi Tomohiro , Tsunegi Sumito , Kubota Hitoshi , Imamura Hiroshi
Published: February 2015

Oscillation frequency of spin torque oscillator with a perpendicularly magnetized free layer and an in-plane magnetized pinned layer is theoretically investigated by taking into account the field-like torque. It is shown that the field-like torque plays an important role in finding the balance between the energy supplied by the spin torque and the dissipation due to the damping, which results in a steady precession. The validity of the developed theory is confirmed by performing numerical simulations based on the Landau-Lifshitz-Gilbert equation.
Role of surface oxygen-to-metal ratio on the wettability of rare-earth oxides
Authors: Khan Sami , Azimi Gisele , Yildiz Bilge , Varanasi Kripa K.
Published: February 2015

Hydrophobic surfaces that are robust can have widespread applications in drop-wise condensation, anti-corrosion, and anti-icing. Recently, it was shown that the class of ceramics comprising the lanthanide series rare-earth oxides (REOs) is intrinsically hydrophobic. The unique electronic structure of the rare-earth metal atom inhibits hydrogen bonding with interfacial water molecules resulting in a hydrophobic hydration structure where the surface oxygen atoms are the only hydrogen bonding sites. Hence, the presence of excess surface oxygen can lead to increased hydrogen bonding and thereby reduce hydrophobicity of REOs. Herein, we demonstrate how surface stoichiometry and surface relaxations can impact wetting properties of REOs. Using X-ray Photoelectron Spectroscopy and wetting measurements, we show that freshly sputtered ceria is hydrophilic due to excess surface oxygen (shown to have an O/Ce ratio of ∼3 and a water contact angle of ∼15°), which when relaxed in a clean, ultra-high vacuum environment isolated from airborne contaminants reaches close to stoichiometric O/Ce ratio (∼2.2) and becomes hydrophobic (contact angle of ∼104°). Further, we show that airborne hydrocarbon contaminants do not exclusively impact the wetting properties of REOs, and that relaxed REOs are intrinsically hydrophobic. This study provides insight into the role of surface relaxation on the wettability of REOs.
Ductility and work hardening in nano-sized metallic glasses
Authors: Chen D. Z. , Gu X. W. , An Q. , Goddard W. A. , Greer J. R.
Published: February 2015

In-situ nano-tensile experiments on 70 nm-diameter free-standing electroplated NiP metallic glass nanostructures reveal tensile true strains of ∼18%, an amount comparable to compositionally identical 100 nm-diameter focused ion beam samples and ∼3 times greater than 100 nm-diameter electroplated samples. Simultaneous in-situ observations and stress-strain data during post-elastic deformation reveal necking and work hardening, features uncharacteristic for metallic glasses. The evolution of free volume within molecular dynamics-simulated samples suggests a free surface-mediated relaxation mechanism in nano-sized metallic glasses.
The linear tearing instability in three dimensional, toroidal gyro-kinetic simulations
Authors: Hornsby W. A. , Migliano P. , Buchholz R. , Kroenert L. , Weikl A. , Peeters A. G. , Zarzoso D. , Poli E. , Casson F. J.
Published: February 2015

Linear gyro-kinetic simulations of the classical tearing mode in three-dimensional toroidal geometry were performed using the global gyro-kinetic turbulence code, GKW. The results were benchmarked against a cylindrical ideal MHD and analytical theory calculations. The stability, growth rate, and frequency of the mode were investigated by varying the current profile, collisionality, and the pressure gradients. Both collisionless and semi-collisional tearing modes were found with a smooth transition between the two. A residual, finite, rotation frequency of the mode even in the absence of a pressure gradient is observed, which is attributed to toroidal finite Larmor-radius effects. When a pressure gradient is present at low collisionality, the mode rotates at the expected electron diamagnetic frequency. However, the island rotation reverses direction at high collisionality. The growth rate is found to follow a η1∕7 scaling with collisional resistivity in the semi-collisional regime, closely following the semi-collisional scaling found by Fitzpatrick. The stability of the mode closely follows the stability analysis as performed by Hastie et al. using the same current and safety factor profiles but for cylindrical geometry, however, here a modification due to toroidal coupling and pressure effects is seen.
Piezoresistive microcantilever aptasensor for ricin detection and kinetic analysis
Authors: Liu Zhi-Wei , Tong Zhao-Yang , Liu Bing , Hao Lan-Qun , Mu Xi-Hui , Zhang Jin-Ping , Gao Chuan
Published: February 2015

Up to now, there has been no report on target molecules detection by a piezoresistive microcantilever aptasensor. In order to evaluate the test performance and investigate the response dynamic characteristics of a piezoresistive microcantilever aptasensor, a novel method for ricin detection and kinetic analysis based on a piezoresistive microcantilever aptasensor was proposed, where ricin aptamer was immobilised on the microcantilever surface by biotin-avidin binding system. Results showed that the detection limit of ricin was 0.04μg L−1 (S/N ≥ 3). A linear relationship between the response voltage and the concentration of ricin in the range of 0.2μg L−1-40μg L−1 was obtained, with the linear regression equation of ΔUe = 0.904C + 5.852 (n = 5, R = 0.991, p < 0.001). The sensor showed no response for abrin, BSA, and could overcome the influence of complex environmental disruptors, indicating high specificity and good selectivity. Recovery and reproducibility in the result of simulated samples (simulated water, soil, and flour sample) determination met the analysis requirements, which was 90.5∼95.5% and 7.85%∼9.39%, respectively. On this basis, a reaction kinetic model based on ligand-receptor binding and the relationship with response voltage was established. The model could well reflect the dynamic response of the sensor. The correlation coefficient (R) was greater than or equal to 0.9456 (p < 0.001). Response voltage (ΔUe) and response time (t0) obtained from the fitting equation on different concentrations of ricin fitted well with the measured values.
Controlled synthesis and magnetic properties of monodispersed ceria nanoparticles
Authors: Kumar Sumeet , Srivastava Manish , Singh Jay , Layek Samar , Yashpal Madhu , Materny Arnulf , Ojha Animesh K.
Published: February 2015

In the present study, monodispersed CeO2 nanoparticles (NPs) of size 8.5 ± 1.0, 11.4 ± 1.0 and 15.4 ± 1.0 nm were synthesized using the sol-gel method. Size-dependent structural, optical and magnetic properties of as-prepared samples were investigated by X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM), high resolution transmission electron microscopy (HR-TEM), ultra-violet visible (UV-VIS) spectroscopy, Raman spectroscopy and vibrating sample magnetometer (VSM) measurements. The value of optical band gap is calculated for each particle size. The decrease in the value of optical band gap with increase of particle size may be attributed to the quantum confinement, which causes to produce localized states created by the oxygen vacancies due to the conversion of Ce4+ into Ce3+ at higher calcination temperature. The Raman spectra showed a peak at ∼461 cm-1 for the particle size 8.5 nm, which is attributed to the 1LO phonon mode. The shift in the Raman peak could be due to lattice strain developed due to variation in particle size. Weak ferromagnetism at room temperature is observed for each particle size. The values of saturation magnetization (Ms), coercivity (Hc) and retentivity (Mr) are increased with increase of particle size. The increase of Ms and Mr for larger particle size may be explained by increase of density of oxygen vacancies at higher calcination temperature. The latter causes high concentrations of Ce3+ ions activate more coupling between the individual magnetic moments of the Ce ions, leading to an increase of Ms value with the particle size. Moreover, the oxygen vacancies may also produce magnetic moment by polarizing spins of f electrons of cerium (Ce) ions located around oxygen vacancies, which causes ferromagnetism in pure CeO2 samples.
Propagation of plasma bullet in U-shape tubes
Authors: Wu S. , Xu H. , Xian Y. , Lu Y. , Lu X.
Published: February 2015

In this work, to better understand the propagation mechanism of plasma bullets in capillary tubes, the propagation of plasma stream in a special designed U-shape tube is investigated. First, it’s observed that the smaller the distance d between the bended tubes is, the shorter the total length of the plasma stream is. Second, when d is reduced to 1 mm, the plasma stream in the lower part of the tube propagates along the upper inner surface of the tube rather than propagating in the whole tube uniformly. Third, high-speed photographs show that the plasma bullet starts to accelerate as soon as the secondary discharge is ignited, and propagating along the upper inner surface of the lower part of the tube. Such behavior is totally different with the propagation of plasma streams in straight tube. According to these results, we can conclude that the surface discharge plays an important role in the propagation of the plasma bullet and the conductivity of the plasma channel is relatively low, which is important for understanding the plasma bullet behavior.
Selenium semiconductor core optical fibers
Authors: Tang G. W. , Qian Q. , Peng K. L. , Wen X. , Zhou G. X. , Sun M. , Chen X. D. , Yang Z. M.
Published: February 2015

Phosphate glass-clad optical fibers containing selenium (Se) semiconductor core were fabricated using a molten core method. The cores were found to be amorphous as evidenced by X-ray diffraction and corroborated by Micro-Raman spectrum. Elemental analysis across the core/clad interface suggests that there is some diffusion of about 3 wt % oxygen in the core region. Phosphate glass-clad crystalline selenium core optical fibers were obtained by a postdrawing annealing process. A two-cm-long crystalline selenium semiconductor core optical fibers, electrically contacted to external circuitry through the fiber end facets, exhibit a three times change in conductivity between dark and illuminated states. Such crystalline selenium semiconductor core optical fibers have promising utility in optical switch and photoconductivity of optical fiber array.
Long non-coding RNA-DANCR in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis
Authors: Tong Xiang , Gu Peng-cheng , Xu San-zhong , Lin Xiang-jin
Published: February 2015

Osteoporosis is a common disease characterized by low bone mineral density (BMD) and low trauma fractures, mainly resulting from exceeding bone resorption by osteoclasts over bone formation by osteoblasts. Circulating monocytes are directly involved in osteoclastogenesis, and lncRNAs are believed to be involved in the osteoblast differentiation. However, no study has been conducted to identify the roles of lncRNA in circulating monocytes associated with human osteoporosis. In this study, we found significant upregulation of DANCR in the blood mononuclear cells (MNCs) from low-BMD patients with the qRT-PCR analyses. We further found that DANCR promoted the expression of IL6 and TNF-α at both mRNA level and protein level in MNCs. After deletion of DANCR with siRNAs, the levels of IL6 and TNF-α are decreased in the MNCs from low-BMD postmenopausal women. Moreover, DANCR level was correlated with IL6 and TNF-α in postmenopausal women with low BMD. Furthermore, we found that DANCR-induced IL6 and TNF-α in MNCs had bone-resorbing activity. These results indicate that DANCR is involved in the pathology of osteoporosis and may be as a biomarker for postmenopausal osteoporosis.
Psychotherapy: A Very Short Introduction
Authors: Burns Tom
Published: February 2015

Psychotherapy: A Very Short Introduction traces the development of psychotherapy from its origins in Freud’s psychoanalysis to the range of different approaches—counselling, cognitive behaviour therapy, other time-limited therapies, mindfulness, and group and family therapies. Describing the processes central to them all and highlighting their differences, it demonstrates what problems each therapy is best suited for. The principles behind the most commonly available types of psychotherapies are explained, and examples of what patients can expect when they seek such help are provided. This VSI concludes by examining the practice of psychotherapy: the types of psychotherapist training, the safeguards that exist to keep practice reliable, and how to choose a psychotherapist.
Umbilical cord occlusions in near-term ovine fetus induce increased beat-to-beat heart rate variability correlating to decreases in neuroinflammation: a case for the afferent cholinergic anti-inflammatory pathway?
Authors: Frasch M. G. , Szynkaruk M. , Prout A.P. , Nygard K. , Veldhuizen R. , Hammond R. , Richardson B.S
Published: February 2015

Supported by grants from the Canadian Institute of Health Research (CIHR) and Lawson Health Research Institute (LHRI) Internal Research Fund (MGF and BSR); CIHR, Fonds de la recherche en santé du Québec (FRSQ) (MGF). BSR is the recipient of the Canada Research Chair in Fetal and Neonatal Health and Development.

Neuroinflammationin uteromay contribute to brain injury resulting in life long neurological disabilities. The pivotal role of the efferent cholinergic anti-inflammatory pathway (CAP) in controlling inflammation has been described in adults, but its importance in the fetus is unknown. Moreover, it is unknown whether CAP may also exert anti-inflammatory effects on the brain via CAP’s afferent component of the vagus nerve. Based on multiple clinical studies in adults and our own work in fetal autonomic nervous system, we gauged the degree of CAP activityin vivousing heart rate variability measures reflecting fluctuations in vagus nerve activity. Measuring microglial activation in the ovine fetal brain near-term, we showin vivothat afferent fetal CAP may translate increased vagal cholinergic signaling into suppression of cerebral inflammation in response to near-term hypoxic acidemia as might occur during labour. Our findings suggest a new control mechanism of fetal neuroinflammation via the vagus nerve, providing novel possibilities for its non-invasive monitoringin uteroand for targeted treatment.
The positive inside rule is stronger when followed by a transmembrane helix
Authors: Virkki Minttu T. , Peters Christoph , Nilsson Daniel , Sörensen Therese , Cristobal Susana , Wallner Björn , Elofsson Arne
Published: February 2015

The translocon recognizes transmembrane helices with sufficient level of hydrophobicity and inserts them into the membrane. However, sometimes less hydrophobic helices are also recognized. Positive inside rule, orientational preferences of and specific interactions with neighboring helices have been shown to aid in the recognition of these helices, at least in artificial systems. To better understand how the translocon inserts marginally hydrophobic helices, we studied three naturally occurring marginally hydrophobic helices, which were previously shown to require the subsequent helix for efficient translocon recognition. We find no evidence for specific interactions when we scan all residues in the subsequent helices. Instead, we identify arginines located at the N-terminal part of the subsequent helices that are crucial for the recognition of the marginally hydrophobic transmembrane helices, indicating that the positive inside rule is important. However, in two of the constructs these arginines do not aid in the recognition without the rest of the subsequent helix, i.e. the positive inside rule alone is not sufficient. Instead, the improved recognition of marginally hydrophobic helices can here be explained as follows; the positive inside rule provides an orientational preference of the subsequent helix, which in turn allows the marginally hydrophobic helix to be inserted, i.e. the effect of the positive inside rule is stronger if positively charged residues are followed by a transmembrane helix. Such a mechanism can obviously not aid C-terminal helices and consequently we find that the terminal helices in multi-spanning membrane proteins are more hydrophobic than internal helices.
Cryptic and not-so-cryptic species in the complex “Holothuria (Thymiosycia) imaptiens” (Forsskål, 1775) (Echinodermata: Holothuroidea: Holothuriidae)
Authors: Michonneau François
Published: February 2015

Identifying accurately species is critical for our understanding of patterns of diversity and speciation. However, for many organisms with simple and variable morphological traits, the characters traditionally used by taxonomists to identify species might lead to a considerable under appreciation of their diversity. Recent advances in molecular-data based computational methods have considerably improved our ability to identify and test species limits. Here, we use an integrative approach to delineate species in a complex of sea cucumbers. We used a three-step approach to show that “Holothuria impatiens”, a common, shallow-water species, occurring across the Indo-Pacific, the Western Atlantic and the Mediterranean Sea, targeted locally by fisheries, is a complex of at least 13 species. (1) We used the Generalized Mixed Yule Coalescent (GMYC) model to identify putative species withouta priorihypotheses. In the process, we also show that the number of putative species estimated with GMYC can be affected considerably by the priors used to build the input tree. (2) We assessed based on coloration patterns and distributional information, the most relevant hypothesis. This approach allowed us to identify unambiguously 9 species. However, some of the lineages consistently assigned to belong to different species using GMYC, are occurring in sympatry and are not differentiated morphologically. (3) We used Bayes factors to compare competing models of species assignment using the multispecies coalescent as implemented in *BEAST. This approach allowed us to validate that the species identified using GMYC were likely reproductively isolated. Estimates of the timing of diversification also showed that these species diverged less than 2 Ma, which is the fastest case of closely related species occurring in sympatry for a marine metazoan. Our study demonstrates how clarifying species limits contribute to refining our understanding of speciation.
Partitioning heritability by functional category using GWAS summary statistics
Authors: Finucane Hilary K. , Bulik-Sullivan Brendan , Gusev Alexander , Trynka Gosia , Reshef Yakir , Loh Po-Ru , Anttilla Verneri , Xu Han , Zang Chongzhi , Farh Kyle , Ripke Stephan , Day Felix , Consortium ReproGen ,   Schizophrenia Working Group of the Psychiatric Genetics Consortium,   The RACI Consortium, Purcell Shaun , Stahl Eli , Lindstrom Sara , Perry John R.B. , Okada Yukinori , Raychaudhuri Soumya , Daly Mark , Patterson Nick , Neale Benjamin M. , Price Alkes L.
Published: February 2015

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.
Segmentation of Noisy Signals Generated By a Nanopore
Authors: Schreiber Jacob , Karplus Kevin
Published: February 2015

Nanopore-based single-molecule sequencing techniques exploit ionic current steps produced as biomolecules pass through a pore to reconstruct properties of the sequence. A key task in analyzing complex nanopore data is discovering the boundaries between these steps, which has traditionally been done in research labs by hand. We present an automated method of analyzing nanopore data, by detecting regions of ionic current corresponding to the translocation of a biomolecule, and then segmenting the region. The segmenter uses a divide-and-conquer method to recursively discover boundary points, with an implementation that works several times faster than real time and that can handle low-pass filtered signals.
Bayesian priors for tree calibration: Evaluating two new approaches based on fossil intervals
Authors: Norris Ryan W. , Strope Cory L. , McCandlish David M. , Stoltzfus Arlin
Published: February 2015

Background:

Studies of diversification and trait evolution increasingly rely on combining molecular sequences and fossil dates to infer time-calibrated phylogenetic trees. Available calibration software provides many options for the shape of the prior probability distribution of ages at a node to be calibrated, but the question of how to assign a Bayesian prior from limited fossil data remains open.

Results:

We introduce two new methods for generating priors based upon (1) the interval between the two oldest fossils in a clade, i.e., the penultimate gap (PenG), and (2) the ghost lineage length (GLin), defined as the difference between the oldest fossils for each of two sister lineages. We show that PenG and GLin/2 are point estimates of the interval between the oldest fossil and the true age for the node. Furthermore, given either of these quantities, we derive a principled prior distribution for the true age. This prior is log-logistic, and can be implemented approximately in existing software. Using simulated data, we test these new methods against some other approaches.

Conclusions:

When implemented as approaches for assigning Bayesian priors, the PenG and GLin methods increase the accuracy of inferred divergence times, showing considerably more precision than the other methods tested, without significantly greater bias. When implemented as approaches to post-hoc scaling of a tree by linear regression, the PenG and GLin methods exhibit less bias than other methods tested. The new methods are simple to use and can be applied to a variety of studies that call for calibrated trees.
Large-scale assessment of olfactory preferences and learning inDrosophila melanogaster: behavioral and genetic measures
Authors: Versace Elisabetta , Reisenberger Julia
Published: February 2015

In the Evolve and Resequence method (E&R), experimental evolution and genomics are combined to investigate evolutionary dynamics and the genotype-phenotype link. This approach requires many replicates with large population sizes, which imposes severe restrictions on the analysis of behavioral phenotypes. Aiming to use E&R for investigating the evolution of behavior inDrosophila, we have developed a simple and effective method to assess spontaneous olfactory preferences and learning in large samples of fruit flies using a T-maze. We tested this procedure on (a) a large wild-caught population and (b) 11 isofemale lines ofDrosophila melanogaster. Compared to previous methods, this procedure reduces the environmental noise and allows for the analysis of large population samples. Consistent with previous results, we show that flies have a spontaneous preference for orange vs. apple odor. With our procedure wild-derived flies exhibit olfactory learning in the absence of previous laboratory selection. Furthermore, we find genetic differences in the olfactory learning with relatively high heritability. We propose this large-scale method as an effective tool for E&R and genome-wide association studies on olfactory preferences and learning.
DeDaL: Cytoscape 3.0 app for producing and morphing data-driven and structure-driven network layouts
Authors: Czerwinska Urszula , Calzone Laurence , Barillot Emmanuel , Zinovyev Andrei
Published: February 2015

Background

Visualization and analysis of molecular profiling data together with biological networks are able to provide new mechanistical insights into biological functions. Currently, high-throughput data are usually visualized on top of predefined network layouts which are not always adapted to a given data analysis task. We developed a Cytoscape app which allows to construct biological network layouts based on the data from molecular profiles imported as values of nodes attributes.

Results

DeDaL is a Cytoscape 3.0 app which uses linear and non-linear algorithms of dimension reduction to produce data-driven network layouts based on multidimensional data (typically gene expression). DeDaL implements several data pre-processing and layout post-processing steps such as continuous morphing between two arbitrary network layouts and aligning one network layout with respect to another one by rotating and mirroring. Combining these possibilities facilitates creating insightful network layouts representing both structural network features and the correlation patterns in multivariate data.

Conclusions

DeDaL is the first method allowing to construct biological network layouts from high-throughput data. DeDaL is freely available for downloading together with step-by-step tutorial athttp://bioinfo-out.curie.fr/projects/dedal/.
Evolution of Conditional Cooperativity Between HOXA11 and FOXO1 Through Allosteric Regulation
Authors: Nnamani Mauris C. , Ganguly Soumya , Lynch Vincent J. , Mizoue Laura S. , Tong Yingchun , Darling Heather L. , Fuxreiter Monika , Meiler Jens , Wagner Günter P.
Published: February 2015

Transcription factors (TFs) play multiple roles in different cells and stages of development. Given this multitude of functional roles it has been assumed that TFs are evolutionarily highly constrained. Here we investigate the molecular mechanisms for the origin of a derived functional interaction between two TFs that play a key role in mammalian pregnancy, HOXA11 and FOXO1. We have previously shown that the regulatory role of HOXA11 in mammalian endometrial stromal cells requires an interaction with FOXO1, and that the physical interaction between these proteins evolved long before their functional cooperativity. Through a combination of functional, biochemical, and structural approaches, we demonstrate that the derived functional cooperativity between HOXA11 and FOXO1 is due to derived allosteric regulation of HOXA11 by FOXO1. This study shows that TF function can evolve through changes affecting the functional output of a pre-existing protein complex.
Origins of cattle on Chirikof Island, Alaska elucidated from genome-wide SNP genotypes
Authors: Decker Jared E. , Taylor Jeremy F. , Cronin Matthew A. , Alexander Leeson J. , Kantanen Juha , Millbrooke Ann , Schnabel Robert D. , MacNeil Michael D.
Published: February 2015

Feral livestock may harbor genetic variation of commercial, scientific, historical or esthetic value. Origins and uniqueness of feral cattle on Chirikof Island, Alaska are uncertain. The island is now part of the Alaska Maritime Wildlife Refuge and Federal wildlife managers want grazing to cease, presumably leading to demise of the cattle. Here we characterize the Chirikof Island cattle relative to extant breeds and discern their origins. Our analyses support the inference that Russian cattle arrived first on Chirikof Island, then approximately 120 years ago the first European taurine cattle were introduced to the island, and finally a large wave of Hereford cattle were introduced on average 40 years ago. While clearly Bos taurus taurus, the Chirikof Island cattle appear at least as distinct as other recognized breeds. Further, this mixture of European and East-Asian cattle is unique compared to other North American breeds and we find evidence that natural selection in the relatively harsh environment of Chirikof Island has further impacted their genetic architecture. These results provide an objective basis for decisions regarding conservation of the Chirikof Island cattle.
Ca2+-activation kinetics modulate successive puff/spark amplitude, duration and inter-event-interval correlations in a Langevin model of stochastic Ca2+release
Authors: Wang Xiao , Hao Yan , Weinberg Seth H. , Smith Gregory D.
Published: February 2015

Through theoretical analysis of the statistics of stochastic calcium (Ca2+) release (i.e., the amplitude, duration and inter-event interval of simulated Ca2+puffs and sparks), we show that a Langevin description of the collective gating of Ca2+channels may be a good approximation to the corresponding Markov chain model when the number of Ca2+channels per Ca2+release unit (CaRU) is in the physiological range. The Langevin description of stochastic Ca2+release facilitates our investigation of correlations between successive puff/spark amplitudes, durations and inter-spark intervals, and how such puff/spark statistics depend on the number of channels per release site and the kinetics of Ca2+-mediated inactivation of open channels. When Ca2+inactivation/de-inactivation rates are intermediate—i.e., the termination of Ca2+puff/sparks is caused by the recruitment of inactivated channels—the correlation between successive puff/spark amplitudes is negative, while the correlations between puff/spark amplitudes and the duration of the preceding or subsequent inter-spark interval are positive. These correlations are significantly reduced when inactivation/deinactivation rates are extreme (slow or fast) and puff/sparks terminate via stochastic attrition.
Ebola virus is evolving but not changing: no evidence for functional change in EBOV from 1976 to the 2014 outbreak
Authors: Olabode Abayomi S , Jiang Xiaowei , Robertson David L , Lovell Simon C
Published: February 2015

The Ebola epidemic is having a devastating impact in West Africa. Sequencing of Ebola viruses from infected individuals has revealed extensive genetic variation, leading to speculation that the virus may be adapting to the human host and accounting for the scale of the 2014 outbreak. We show that so far there is no evidence for adaptation of EBOV to humans. We analyze the putatively functional changes associated with the current and previous Ebola outbreaks, and find no significant molecular changes. Observed amino acid replacements have minimal effect on protein structure, being neither stabilizing nor destabilizing. Replacements are not found in regions of the proteins associated with known functions and tend to occur in disordered regions. This observation indicates that the difference between the current and previous outbreaks is not due to the observed evolutionary change of the virus. Instead, epidemiological factors must be responsible for the unprecedented spread of EBOV.
Modulating pathological oscillations by rhythmic non-invasive brain stimulation – a therapeutic concept?
Authors: Krawinkel LK , Engel AK , Hummel FC
Published: February 2015

A large amount of studies of the last decades revealed an association between human behaviour and oscillatory activity in the human brain. Alike, abnormalities of oscillatory activity were related with pathological behaviour in many neuropsychiatric disorders, such as in Parkinson’s disease (PD) or in schizophrenia (SCZ). As a therapeutic tool, non-invasive brain stimulation (NIBS) has demonstrated the potential to improve behavioural performance in patients suffering from neuropsychiatric disorders. Since evidence accumulates that NIBS might be able to modulate oscillatory activity and related behaviour in a scientific setting, this review focuses on discussing potential interventional strategies to target abnormalities in oscillatory activity in neuropsychiatric disorders. In particular, we will review oscillatory changes described in patients after stroke, with PD or suffering from SCZ. Potential ways of targeting interventionally the underlying pathological oscillations to improve related pathological behaviour will be further discussed.
Permutation Testing in the Presence of Polygenic Variation
Authors: Abney Mark
Published: February 2015

This article discusses problems with and solutions to performing valid permutation tests for quantitative trait loci in the presence of polygenic effects. Although permutation testing is a popular approach for determining statistical significance of a test statistic with an unknown distribution–for instance, the maximum of multiple correlated statistics or some omnibus test statistic for a gene, gene-set or pathway–naive application of permutations may result in an invalid test. The risk of performing an invalid permutation test is particularly acute in complex trait mapping where polygenicity may combine with a structured population resulting from the presence of families, cryptic relatedness, admixture or population stratification. I give both analytical derivations and a conceptual understanding of why typical permutation procedures fail and suggest an alternative permutation based algorithm, MVNpermute, that succeeds. In particular, I examine the case where a linear mixed model is used to analyze a quantitative trait and show that both phenotype and genotype permutations may result in an invalid permutation test. I provide a formula that predicts the amount of inflation of the type 1 error rate depending on the degree of misspecification of the covariance structure of the polygenic effect and the heritability of the trait. I validate this formula by doing simulations, showing that the permutation distribution matches the theoretical expectation, and that my suggested permutation based test obtains the correct null distribution. Finally, I discuss situations where naive permutations of the phenotype or genotype are valid and the applicability of the results to other test statistics.
Dynamics of preventive and reactive cancer control using low-impact treatments
Authors: Akhmetzhanov Andrei R. R. , Hochberg Michael E.
Published: February 2015

Cancer poses danger because of its unregulated growth, development of resistant subclones, and metastatic spread to vital organs. Although the major transitions in cancer development are increasingly well understood, we lack quantitative theory for how preventive measures and post-excision ('reactive') treatments are predicted to affect risks of obtaining a life threatening cancer or relapse, respectively. We employ analytical and numerical models to evaluate how continuous measures such as life style changes, and certain non-targeted and targeted treatments affect both neoplastic growth and the frequency of resistant clones. We find that preventive measures can have a negligible impact on pre-cancerous lesions and yet achieve considerable reductions in risk of invasive cancer. Importantly, our model, based on realistic parameter estimates, predicts that daily cancer cell arrest levels of 0.2-0.3% produce optimal outcomes for prevention, whereas for reaction the level is 0.3-0.4%. For similar cancer cell populations, prevention outcomes are, on average, always better than reactive ones. This is because reactive measures are more likely to select for faster growing subclones with higher probabilities of resistance, highlighting the difficulty in countering relapse regardless of therapeutic impact on cancer cell populations. We discuss these results and other important mitigating factors that need to be taken into consideration in a comparative understanding of preventive versus reactive treatments.
Multi-trait eco-evolutionary dynamics explain niche diversity and evolved neutrality in forests
Authors: Falster Daniel S , Brännström Åke , Westoby Mark , Dieckmann Ulf
Published: February 2015

An enduring challenge in ecology is to understand how diverse plant species coexist when competing for the same basic resources. Two candidate frameworks for meeting this challenge currently exist in forest ecology. Niche-based approaches succeed in describing successional dynamics in response to recurrent disturbances. Approaches based on Hubbell's neutral theory describe abundance patterns in highly diverse communities. Yet both theories are unsuccessful where their competitor is strong, highlighting an enduring need for reconciliation. In fact, the perception that niche and neutral processes are incompatible may have arisen because both types of models have lacked some critical features of real forests. Here we report a productive reconciliation that arises from extending niche models to include three ubiquitous features of vegetation: (1) plant growth under light competition, (2) multiple trait-mediated tradeoffs in plant function, and (3) evolutionary community assembly. We show that fitness equivalence – which neutral theory controversially takes as an assumption – naturally arises as a mechanistic outcome of niche differentiation, but only within a specific region of trait space, corresponding to shade-tolerant later-successional strategies. In this way, niche diversification can lead, via evolved neutrality, to a proliferation of shade-tolerant strategies, one of the phenomena that motivated the development of neutral theory. Earlier niche models focussed on a single growth-mortality trait and found no evolved neutrality. In contrast, the model introduced here includes a second trait, height at maturation, in addition to a growth-mortality trait in the form of leaf-construction cost. We show that fitness equivalence only emerges when diversifications include this second trait. We also demonstrate that our extended niche model generates markedly different forest types under different environmental conditions, recovering known biogeographic patterns. By evolving forests from first principles, our study constructively resolves the protracted debate about niche versus neutral dynamics for forest communities, and provides a platform for a synthetic theory of forest structure and diversity.
Transition densities and sample frequency spectra of diffusion processes with selection and variable population size
Authors: Živković Daniel , Steinrücken Matthias , Song Yun S. , Stephan Wolfgang
Published: February 2015

Advances in empirical population genetics have made apparent the need for models that simultaneously account for selection and demography. To address this need, we here study the Wright-Fisher diffusion under selection and variable effective population size. In the case of genic selection and piecewise-constant effective population sizes, we obtain the transition density function by extending a recently developed method for computing an accurate spectral representation for a constant population size. Utilizing this extension, we show how to compute the sample frequency spectrum (SFS) in the presence of genic selection and an arbitrary number of instantaneous changes in the effective population size. We also develop an alternate, efficient algorithm for computing the SFS using a method of moments. We apply these methods to answer the following questions: If neutrality is incorrectly assumed when there is selection, what effects does it have on demographic parameter estimation? Can the impact of negative selection be observed in populations that undergo strong exponential growth?
SWORD - a highly efficient protein database search
Authors: Vaser Robert , Pavlovi Dario , Korpar Matija , Sikic Mile
Published: February 2015

Motivation

Protein database search is one of the fundamental problems in bioinformatics. For decades, it has been explored and solved using different exact and heuristic approaches. However, exponential growth of data in size in recent years has brought significant challenges in improving already existing algorithms. BLASTP has been the most successful tool for protein database search, but is also becoming a bottleneck in many applications. Due to that, many different approaches have been developed to comple-ment or replace BLASTP. In this paper, we present SWORD, an efficient protein database search implementation that runs 3-4 faster than BLASTP in the sensitive mode and up to 18 faster in the fast and less accurate mode and also provides guaranteed optimal alignments for candidate sequences. SWORD is designed to be used in nearly all database search environments, but is especially suitable for large databases. Its sensitivity exceeds that of BLASTP for majority of input datasets.

Availability

Sword is freely available for download fromhttps://github.com/rvaser/sword

Contact

robert.vaser@fer.hr,mile.sikic@fer.hr
Side-chain-directed model and map validation for 3D Electron Cryomicroscopy
Authors: Barad Benjamin A , Echols Nathaniel , Wang Ray Y-R , Cheng Yifan , DiMaio Frank , Adams Paul D , Fraser James S
Published: February 2015

Advances in electron cryomicroscopy allow for the building ofde novoatomic models into high resolution Coulomb potential maps. While established validation metrics independently assess map quality and model geometry, methods to assess the precise fitting of an atomic model into the map and to validate the interpretation of high resolution features are less well developed. Here, we present EMRinger, which tests model-to-map agreement using side-chain dihedral-directed map density measurements. These measurements reveal local map density peaks and show that peaks located at rotameric angles are a sensitive marker of whether the backbone is correctly positioned. The EMRinger Score can be improved by model refinement, suggesting its utility as an effective model-to-map validation metric. Additionally, EMRinger sampling identifies how radiation damage alters scattering from negatively charged amino acids during data collection. EMRinger will be useful in assessing how advances in cryo-EM increase the ability to resolve and model high-resolution features.
A mechanistic link between cellular trade-offs, gene expression and growth
Authors: Weiβe Andrea Y. , Oyarzún Diego A. , Danos Vincent , Swain Peter S.
Published: February 2015

Intracellular processes rarely work in isolation but continually, interact with the rest of the cell. In microbes, for example, we now know that gene expression across the whole genome typically changes with growth rate. The mechanisms driving such global regulation, however, are not well understood. Here we consider three trade-offs that because of limitations in levels of cellular energy, free ribosomes, and proteins are faced by all living cells and construct a mechanistic model that comprises these trade-offs. Our model couples gene expression with growth rate and growth rate with a growing population of cells. We show that the model recovers Monod's law for the growth of microbes and two other empirical relationships connecting growth rate to the mass fraction of ribosomes. Further, we can explain growth related effects in dosage compensation by paralogs and predict host-circuit interactions in synthetic biology. Simulating competitions between strains, we find that the regulation of metabolic pathways may have evolved not to match expression of enzymes to levels of extracellular substrates in changing environments but rather to balance a trade-off between exploiting one type of nutrient over another. Although coarse-grained, the trade-offs that the model embodies are fundamental, and, as such, our modelling framework has potentially wide application, including in both biotechnology and medicine.
dbSUPER: a database of super-enhancers in mouse and human genome
Authors: Khan Aziz , Zhang Xuegong
Published: February 2015

Super-enhancers are the clusters of transcriptional enhancers that can drive cell-type-specific gene expression and also crucial in cell identity. Many disease-associated sequence variations are enriched in super-enhancer regions of disease-relevant cell types. Thus, super-enhancers can be used as potential biomarkers for disease diagnosis and therapeutics. Current studies have identified super-enhancers in more than 100 cell types and demonstrated their functional importance. However, no centralized resource to integrate all these findings is available yet. We developed dbSUPER (http://bioinfo.au.tsinghua.edu.cn/dbsuper/), the first integrated and interactive database of super-enhancers, with the primary goal of providing a resource for assistance in further studies related to transcriptional control of cell identity and disease. dbSUPER provides a responsive and user-friendly web interface to facilitate efficient and comprehensive search and browsing. The data can be easily sent to Galaxy instances, GREAT and Cistrome web servers for downstream analysis, and can be visualized in UCSC genome browser while custom tracks added automatically. The data can be downloaded and exported in variety of formats. Further, dbSUPER lists genes associated with the super-enhancers and links to various other databases such as GeneCards, UniProt and Entrez. dbSUPER also provides an overlap analysis tool, to annotate user defined regions. We believe dbSUPER is a valuable resource for the biologists and genetic research communities.
Epistasis and Entropy
Authors: Crona Kristina
Published: February 2015

Epistasis is a key concept in the theory of adaptation. Indicators of epistasis are of interest for large system where systematic fitness measurements may not be possible. Some recent approaches depend on information theory. We show that considering shared entropy for pairs of loci can be misleading. The reason is that shared entropy does not imply epistasis for the pair. This observation holds true also in the absence of higher order epistasis. We discuss a refined approach for identifying pairwise interactions using entropy.
Global determinants of mRNA degradation rates inSaccharomyces cerevisiae
Authors: Neymotin Benjamin , Ettorre Victoria , Gresham David
Published: February 2015

Degradation of mRNA contributes to variation in transcript abundance. Studies of individual mRNAs show thatcisandtransfactors control mRNA degradation rates. However, transcriptome-wide studies have failed to identify global relationships between transcript properties and mRNA degradation. We investigated the contribution ofcisandtransfactors to transcriptome-wide degradation rate variation in the budding yeast,Saccharomyces cerevisiae, using multiple regression analysis. We find that multiple transcript properties are associated with mRNA degradation rates and that a model incorporating these factors explains ∼50% of the genome-wide variance. Predictors of mRNA degradation rates include transcript length, abundance, ribosome density, codon adaptation index (CAI) and GC content of the third position in codons. To validate these factors we studied individual transcripts expressed from identical promoters. We find that decreasing ribosome density by mutating the translational start site of theGAP1transcript increases its degradation rate. Using variants of GFP that differ at synonymous sites, we show that increased GC content of the third position of codons results in decreased mRNA degradation rate. Thus, in steady-state conditions, a large fraction of genome-wide variation in mRNA degradation rates is determined by inherent properties of transcripts related to protein translation rather than specific regulatory mechanisms.