bluuebunny/crossref_metadata_2025 huggingface dataset:
The binary fraction and mass segregation in Alpha Persei open cluster
Authors: Sheikhi Najmeh , Hasheminia Maryam , Khalaj Pouria , Haghi Hosein , Zonoozi Akram Hasani , Baumgardt Holger
Published: January 2016

We have obtained membership probabilities of stars within a field of ${\sim }3\deg$ from the centre of the open cluster Alpha Persei using proper motions and photometry from the PPMXL and Wide-field Infrared Survey Explorer catalogues. We have identified 810 possible stellar members of Alpha Persei. We derived the global and radial present-day mass function (MF) of the cluster and found that they are well matched by two-stage power-law relations with different slopes at different radii. The global MF of Alpha Persei shows a turnover at m = 0.62 M⊙ with low- and high-mass slopes of αlow = 0.50 ± 0.09 (0.1 < m/ M⊙ < 0.62) and αhigh = 2.32 ± 0.14 (0.62 ≤ m/ M⊙ < 4.68), respectively. The high-mass slope of the cluster increases from 2.01 inside 1$_{.}^{\circ}$10 to 2.63 outside 2$_{.}^{\circ}$2, whereas the mean stellar mass decreases from 0.95 to 0.57 M⊙ in the same regions, signifying clear evidence of mass segregation in the cluster. From an examination of the high-quality colour–magnitude data of the cluster and performing a series of Monte Carlo simulations, we obtained a binary fraction of fbin = 34 ± 12 per cent for stars with 0.70 < m/ M⊙ < 4.68. This is significantly larger than the observed binary fraction, indicating that this open cluster contains a large population of unresolved binaries. Finally, we corrected the MF slopes for the effect of unresolved binaries and found low- and high-mass slopes of αlow = 0.89 ± 0.11 and αhigh = 2.37 ± 0.09 and a total cluster mass of 352 M⊙ for Alpha Persei.
X-ray flares in GRBs: general considerations and photospheric origin
Authors: Beniamini Paz , Kumar Pawan
Published: January 2016

Observations of X-ray flares from Gamma Ray Bursts imply strong constraints on possible physical models. We provide a general discussion of these. In particular, we show that in order to account for the relatively flat and weak optical flux during the X-ray flares, the size of the emitting region should be ≲3 × 1014cm. The bolometric luminosity of flares also strongly constrain the energy budget, and are inconsistent with late time activity of a central engine powered by the spin-down of a magnetar. We provide a simple toy model according to which flares are produced by an outflow of modest Lorentz factor (a few tens instead of hundreds) that is launched more or less simultaneously with the highly relativistic jet which produced the prompt gamma-ray emission. The ‘slower moving outflow produces the flare as it reaches its photosphere. If the X-ray flare jets are structured, the existence of such a component may naturally resolve the observational challenges imposed by flares, outlined in this work.
Creating a Cadre of Fellowship-Trained Medical Educators: A Qualitative Study of Faculty Development Program Leaders’ Perspectives and Advice
Authors: Coates Wendy C. , Runde Daniel P. , Yarris Lalena M. , Rougas Steven , Guth Todd A. , Santen Sally A. , Miller Jessica , Jordan Jaime
Published: January 2016

Purpose

Well-trained educators fill essential roles across the medical education continuum. Some medical schools offer programs for existing faculty to enhance teaching and scholarship. No standard postgraduate training model exists for residency graduates to attain competency as faculty members before their first academic appointment. The objective of this study is to inform the development of postgraduate medical education fellowships by exploring perceptions of educational leaders who direct well-established faculty development programs.

Method

The authors undertook a qualitative study, using purposeful sampling to recruit participants and a constant comparative approach to identify themes. They conducted semistructured telephone interviews with directors of faculty development fellowships using an interpretivist/constructivist paradigm (November 2013). Questions addressed curricular and fiscal structure, perceived benefits and challenges, and advice for starting a postgraduate fellowship.

Results

Directors reported institutional and participant benefits, notably the creation of a community of educators and pool of potential leaders. Curricular offerings focused on learning theory, teaching, assessment, leadership, and scholarship. Funding and protected time were challenges. Advice for new program directors included evaluating best practices, defining locally relevant goals; garnering sufficient, stable financial support; and rallying leaders’ endorsement.

Conclusions

Medical education fellowships cultivate leaders and communities of trained educators but require participants to balance faculty responsibilities with professional development. Advice of current directors can inform the development of postgraduate programs modeled after accredited clinical specialty fellowships. Programs with the support of strategic partners, financial stability, and well-defined goals may allow new faculty to begin their careers with existing competency in medical education skills.
Reducing Implicit Gender Leadership Bias in Academic Medicine With an Educational Intervention
Authors: Girod Sabine , Fassiotto Magali , Grewal Daisy , Ku Manwai Candy , Sriram Natarajan , Nosek Brian A. , Valantine Hannah
Published: January 2016

Purpose

One challenge academic health centers face is to advance female faculty to leadership positions and retain them there in numbers equal to men, especially given the equal representation of women and men among graduates of medicine and biological sciences over the last 10 years. The purpose of this study is to investigate the explicit and implicit biases favoring men as leaders, among both men and women faculty, and to assess whether these attitudes change following an educational intervention.

Method

The authors used a standardized, 20-minute educational intervention to educate faculty about implicit biases and strategies for overcoming them. Next, they assessed the effect of this intervention. From March 2012 through April 2013, 281 faculty members participated in the intervention across 13 of 18 clinical departments.

Results

The study assessed faculty members’ perceptions of bias as well as their explicit and implicit attitudes toward gender and leadership. Results indicated that the intervention significantly changed all faculty members’ perceptions of bias (P < .05 across all eight measures). Although, as expected, explicit biases did not change following the intervention, the intervention did have a small but significant positive effect on the implicit biases surrounding women and leadership of all participants regardless of age or gender (P = .008).

Conclusions

These results suggest that providing education on bias and strategies for reducing it can serve as an important step toward reducing gender bias in academic medicine and, ultimately, promoting institutional change, specifically the promoting of women to higher ranks.
Expression of segment polarity genes in brachiopods supports a non-segmental ancestral role ofengrailedfor bilaterians
Authors: Vellutini Bruno C. , Hejnol Andreas
Published: January 2016

The diverse and complex developmental mechanisms of segmentation have been more thoroughly studied in arthropods, vertebrates and annelids—distantly related animals considered to be segmented. Far less is known about the role of “segmentation genes” in organisms that lack a segmented body. Here we investigate the expression of the arthropod segment polarity genesengrailed,wnt1andhedgehogin the development of brachiopods—marine invertebrates without a subdivided trunk but closely related to the segmented annelids. We found that a stripe ofengrailedexpression demarcates the ectodermal boundary that delimits the anterior region ofTerebratalia transversaandNovocrania anomalaembryos. InT. transversa, thisengraileddomain is abutted by a stripe ofwnt1expression in a pattern similar to the parasegment boundaries of insects—except for the expression ofhedgehog, which is restricted to endodermal tissues of the brachiopod embryos. We found thatpax6andpax2/5/8, putative regulators ofengrailed, also demarcate the anterior boundary in the two species, indicating these genes might be involved in the anterior patterning of brachiopod larvae. In a comparative phylogenetic context, these findings suggest that bilaterians might share an ancestral, non-segmental domain ofengrailedexpression during early embryogenesis.
The Northern Arizona SNP Pipeline (NASP): accurate, flexible, and rapid identification of SNPs in WGS datasets
Authors: Sahl Jason W. , Lemmer Darrin , Travis Jason , Schupp James M. , Gillece John D. , Aziz Maliha , Driebe Elizabeth M. , Drees Kevin , Hicks Nathan , Williamson Charles H.D. , Hepp Crystal , Smith David , Roe Chandler , Engelthaler David M. , Wagner David M. , Keim Paul
Published: January 2016

Whole genome sequencing (WGS) of bacteria is becoming standard practice in many laboratories. Applications for WGS analysis include phylogeography and molecular epidemiology, using single nucleotide polymorphisms (SNPs) as the unit of evolution. The Northern Arizona SNP Pipeline (NASP) was developed as a reproducible pipeline that scales well with the large amount of WGS data typically used in comparative genomics applications. In this study, we demonstrate how NASP compares to other tools in the analysis of two real bacterial genomics datasets and one simulated dataset. Our results demonstrate that NASP produces comparable, and often better, results to other pipelines, but is much more flexible in terms of data input types, job management systems, diversity of supported tools, and output formats. We also demonstrate differences in results based on the choice of the reference genome and choice of inferring phylogenies from concatenated SNPs or alignments including monomorphic positions. NASP represents a source-available, version-controlled, unit-tested method and can be obtained from tgennorth.github.io/NASP.
Folding PDZ2 domain using the Molecular Transfer Model
Authors: Liu Zhenxing , Reddy Govardhan , Thirumalai D.
Published: January 2016

A major challenge in molecular simulations is to describe denaturant-dependent folding of proteins order to make direct comparisons within vitroexperiments. We use the molecular transfer model (MTM), which is currently the only method that accomplishes this goal albeit phenomenologically, to quantitatively describe urea-dependent folding of PDZ domain, which plays a significant role in molecular recognition and signaling. Experiments show that urea-dependent unfolding rates of the PDZ2 domain exhibit a downward curvature at high urea concentrations ([C]s), which has been interpreted by invoking the presence of a sparsely populated high energy intermediate. Simulations using the MTM and a coarse-grained Self-Organized Polymer (SOP) representation of PDZ2 are used to show that the intermediate (IEQ), which has some native-like character, is present in equilibrium both in the presence and absence of urea. The free energy profiles as a function of the structural overlap order parameter show that there are two barriers separating the folded and unfolded states. Structures of the transition state ensembles, (TSE1 separating the unfolded andIEQandTSE2 separatingIEQand the native state), determined using thePfoldmethod, show thatTSE1 is greatly expanded whileTSE2 is compact and native-like. Folding trajectories reveal that PDZ2 folds by parallel routes. In one pathway folding occurs exclusively throughI1, which resemblesIEQ. In a fraction of trajectories, constituting the second pathway, folding occurs through a combination ofI1and a kinetic intermediate. We establish that the radius of gyration () of the unfolded state is more compact (by ∼ 9%) under native conditions. Theory and simulations show that the decrease inoccurs on the time scale on the order of utmost ~ 20μβ.The modest decrease inand the rapid collapse suggest that high spatial and temporal resolution, currently beyond the scope of most small angle X-ray scattering experiments, are needed to detect compaction in finite-sized proteins. The present work further establishes that MTM is efficacious in producing nearly quantitative predictions for folding of proteins under conditions used to carry out experiments.
HASE: Framework for efficient high-dimensional association analyses
Authors: Roshchupkin G.V. , Adams H.H.H. , Vernooij M.W. , Hofman A. , Van Duijn C.M. , Ikram M.A. , Niessen W.J.
Published: January 2016

Large-scale data collection and processing have facilitated scientific discoveries in fields such as genomics and imaging, but cross-investigations between multiple big datasets remain impractical. Computational requirements of high-dimensional association studies are often too demanding for individual sites. Additionally, the sheer size of intermediate results is unfit for collaborative settings where summary statistics are exchanged for meta-analyses. Here we introduce the HASE framework to perform high-dimensional association studies with dramatic reduction in both computational burden and storage requirements of intermediate results. We implemented a novel meta-analytical method that yields identical power as pooled analyses without the need of sharing individual participant data. The efficiency of the framework is illustrated by associating 9 million genetic variants with 1.5 million brain imaging voxels in three cohorts (total N=4,034) followed by meta-analysis, on a standard computational infrastructure. These experiments indicate that HASE facilitates high-dimensional association studies enabling large multicenter association studies for future discoveries.
Genetic and environmental risk for chronic pain and the contribution of risk variants for psychiatric disorders. Results from Generation Scotland: Scottish Family Health Study and UK Biobank
Authors: McIntosh Andrew M , Hall Lynsey S , Zeng Yanni , Adams Mark James , Gibson Jude , Wigmore Ella , Pujils-Fernandez Maria , Campbell Archie I , Clarke Toni-Kim , Hayward Caroline , Haley Christopher , Porteous David , Deary Ian , Smith Daniel , Nicholl Barbara , Hinds David A , Jones Amy V , Scollen Serena , Meng Weihua , Smith Blair , Hocking Lynne J
Published: January 2016

Background Chronic pain is highly prevalent worldwide and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with psychiatric illness, and major depressive disorder (MDD) in particular, is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the UK Biobank study. Methods Using family-based mixed-model analyses, we examined the contribution of genetics and environment to chronic pain using spouse, sibling and household groups as measures of shared environment. We then examined the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic risk architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. Results Chronic pain is a moderately heritable trait (narrow sense heritability = 38.4%) which is more likely to be concordant in spouses and partners (variance explained 18.7%). Chronic pain is positively correlated with depression (rho = 0.13, p = 2.72x10-68) and it shows a tendency to cluster within families for genetic reasons (genetic correlation rho = 0.51, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, predicted chronic pain in both GS:SFHS (maximum = 6.18x10-2, p = 4.3x10-4) and UK Biobank (maximum = 5.68 x 10-2, p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum = 6.62x10-2, p = 4.3x10-4) and UK Biobank (maximum = 2.56x10-2, p < 3x10-4). Conclusions Genetic factors and chronic pain in a partner or spouse contribute substantially to the risk of chronic pain in the general population. Chronic pain is genetically correlated with MDD, has a polygenic architecture and is predicted by polygenic risk of MDD.
Features of ChIP-seq data peak calling algorithms with good operating characteristics
Authors: Thomas Reuben , Thomas Sean , Holloway Alisha K , Pollard Katherine S
Published: January 2016

Author description

Reuben Thomas is a Staff Research Scientist in the Bioinformatics Core at Gladstone Institutes

Sean Thomas is a Staff Research Scientist in the Bioinformatics Core at Gladstone Institutes

Alisha K Holloway is the Director of Bioinformatics at Phylos Biosciences, visiting scientist at Gladstone Institutes and Adjunct Assistant Professor in Biostatistics at the University of California, San Francisco.

Katherine S Pollard is a Senior Investigator at Gladstone Institutes and Professor of Biostatistics at University of California, San Francisco.

Key Points

Peak-calling using Chip-seq data consists of two sub-problems: identifying candidate peaks and testing candidate peaks for statistical significance.

Twelve features of the two sub-problems of peak-calling methods are identified.

Methods that explicitly combine the signals from ChIP and input samples are less powerful than methods that do not.

Methods that use windows of different sizes to scan the genome for potential peaks are more powerful than ones that do not.

Methods that use a Poisson test to rank their candidate peaks are more powerful than those that use a Binomial test.

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is an important tool for studying gene regulatory proteins, such as transcription factors and histones. Peak calling is one of the first steps in analysis of these data. Peak-calling consists of two sub-problems: identifying candidate peaks and testing candidate peaks for statistical significance. We surveyed 30 methods and identified 12 features of the two sub-problems that distinguish methods from each other. We picked six methods (GEM, MACS2, MUSIC, BCP, TM and ZINBA) that span this feature space and used a combination of 300 simulated ChIP-seq data sets, 3 real data sets and mathematical analyses to identify features of methods that allow some to perform better than others. We prove that methods that explicitly combine the signals from ChIP and input samples are less powerful than methods that do not. Methods that use windows of different sizes are more powerful than ones that do not. For statistical testing of candidate peaks, methods that use a Poisson test to rank their candidate peaks are more powerful than those that use a Binomial test. BCP and MACS2 have the best operating characteristics on simulated transcription factor binding data. GEM has the highest fraction of the top 500 peaks containing the binding motif of the immunoprecipitated factor, with 50% of its peaks within 10 base pairs (bp) of a motif. BCP and MUSIC perform best on histone data. These findings provide guidance and rationale for selecting the best peak caller for a given application.
Chromes from Chromatin: Sonification of the Epigenome
Authors: Cittaro Davide , Lazarevic Dejan , Provero Paolo
Published: January 2016

The epigenetic modifications are organized in patterns determining the functional properties of the underlying genome. Such patterns, typically measured by ChIP-seq assays of histone modifications, can be combined and translated into musical scores, summarizing multiple signals into a single waveform. As music is recognized as a universal way to convey meaningful information (1), we wanted to investigate properties of music obtained by sonification of ChIP-seq data. We show that the music produced by such quantitative signals is perceived by human listener as more pleasant than that produced from randomized signals. Moreover, the waveform can be analyzed to predict phenotypic properties, such as differential gene expression.
Transcription factor loads tend to decrease the robustness of stable gene transcription networks
Authors: Mou Shaoshuai , Del Vecchio Domitilla
Published: January 2016

Robustness of a system’s behavior to changes in parameter values is a remarkable property of natural systems and especially desirable when designing de novo synthetic gene circuits. Loads on transcription factors resulting from binding to target promoters have been shown to significantly affect the effective time constants of gene transcription networks and to thus alter the overall system’s behavior. Here, we employ models that explicitly account for load effects to investigate how these impact the robustness of a stable gene transcription network to parameter perturbations. By employing a combination of sampling-based methods and analytical tools from control theory, we demonstrate that the presence of loading shrinks the region of parameter space where a gene circuit performs the desired function. A number of multi-module synthetic gene circuits are analyzed to demonstrate this point, including an event detector and a molecular signature classifier. These results indicate that for designing genetic circuits that are robust to parameter uncertainty it is highly desirable to find ways to mitigate the effects of transcription factor loading.

Author Summary

Efforts to understand how loads affect gene transcription networks have been underway in the past decade. Here we perform a numerical investigation on three synthetic gene circuits to show that loads tend to decrease the robustness of stable gene transcriptional networks. We complement the numerical findings with analytical derivations that employ the stability radius to compare the robustness of different networks to parameter perturbations near an equilibrium point. Consistent with the numerical finding, the analytical results support that systems with substantial transcription factor loading have smaller stability radius (less robustness) than systems without loading.
Stress affects the epigenetic marks added by natural transposable element insertions inDrosophila melanogaster
Authors: Guio Lain , Vieira Cristina , González Josefa
Published: January 2016

Transposable elements are emerging as an important source of cis-acting regulatory sequences and epigenetic marks that could influence gene expression. However, few studies have dissected the role of specific transposable element insertions on epigenetic gene regulation.Bari-Jhehis a natural transposon that mediates resistance to oxidative stress by adding cis-regulatory sequences that affect expression of nearby genes. In this work, we integrated publicly available data with chromatin immunoprecipitation experiments to get a more comprehensive picture ofBari-Jhehmolecular effects. We showed thatBari-Jhehwas enriched for H3K9me3 in nonstress conditions, and for H3K9me3, H3K4me3 and H3K27me3 in oxidative stress conditions, which is consistent with expression changes in adjacent genes. We further showed that under oxidative stress conditions, H3K4me3 and H3K9me3 spread to the promoter region ofJheh1gene. Finally, another insertion of theBari1family was associated with increased H3K27me3 in oxidative stress conditions suggesting thatBari1histone marks are copy-specific. We concluded that besides adding cis-regulatory sequences,Bari-Jhehinfluences gene expression by affecting the local chromatin state.
Search calls long duration puts the bat on the tympanate moth's radar. A new perspective on how Noctuoidea's auditory cells drive evasive manoeuvres
Authors: Thevenon Herve , Pfuhl Gerit
Published: January 2016

The auditory stimulation method used in experiments on moth A cell(s) is generally believed to be adequate to characterise the encoding of echolocation signals. The stimulation method hosts, though, several bias. Their compounded effects can explain a range of discrepancies between the reported electrophysiological recordings and significantly alter the current interpretation. To test the hypothesis that the bias may significantly alter our current understanding of the moth’s auditory transducer characteristics, papers using the same auditory stimulation method and reporting on either spiking threshold or spiking activity of the moth’s A cells were analysed. The consistency of the reported data was assessed. A range of corrections issued from best practices and theoretical background were applied to the data in an attempt to re-interpret the data. We found that it is not possible to apply a posteriori corrections to all data and bias. However the corrected data indicates that the A cell’s spiking may be (i) independent of the repetition rate, (ii) maximum when detecting the long and low intensity pulses of the bat in searching mode, and (iii) steadily reduce as the bat closes on the moth. These observations raise the possibility that a fixed action pattern drives the moths’s erratic evasive manoeuvres until the final moment. In depth investigation of the potential bias also suggest that the auditory transducer’s response may be constant for a larger frequency range than thought so far, and provide clues to explain the negative taxis in response to the searching bats’s calls detection.
TreeToReads - a pipeline for simulating raw reads from phylogenies
Authors: McTavish Emily Jane , Pettengill James , Davis Steven , Rand Hugh , Strain Errol , Allard Marc , Timme Ruth E
Published: January 2016

Using genome-wide SNP-based methods for tracking pathogens has become standard practice in academia and public health agencies. There are multiple computational approaches available that perform a similar task: call variants by mapping short read data against a reference genome, quality filter these variants, then concatenate the variants into a sequence matrix for downstream phylogenetic analysis. However, there are no existing methods to validate the accuracy of these approaches despite the fact that we know there are parameters that can affect whether a SNP is called, or the correct tree is recovered. We present a simulation approach (TreeToReads) to generate raw read data from mutated genomes simulated under a known phylogeny. The user can vary parameters of interest at each step in the simulation (e.g., topology, model of sequence evolution, and read coverage) to assess the robustness of a given result, which is critical within both research and applied settings. Source code, examples, and a tutorial are available at \url{https://github.com/snacktavish/TreeToReads}.
Reference-free deconvolution of DNA methylation data and mediation by cell composition effects
Authors: Houseman E. Andres , Kile Molly L. , Christiani David C. , Ince Tan A. , Kelsey Karl T. , Marsit Carmen J.
Published: January 2016

We propose a simple method for reference-free deconvolution that provides both proportions of putative cell types defined by their underlying methylomes, the number of these constituent cell types, as well as a method for evaluating the extent to which the underlying methylomes reflect specific types of cells. We have demonstrated these methods in an analysis of 23 Infinium data sets from 13 distinct data collection efforts; these empirical evaluations show that our algorithm can reasonably estimate the number of constituent types, return cell proportion estimates that demonstrate anticipated associations with underlying phenotypic data; and methylomes that reflect the underlying biology of constituent cell types. Thus the methodology permits an explicit quantitation of the mediation of phenotypic associations with DNA methylation by cell composition effects. Although more work is needed to investigate functional information related to estimated methylomes, our proposed method provides a novel and useful foundation for conducting DNA methylation studies on heterogeneous tissues lacking reference data.
A method for identifying genetic heterogeneity within phenotypically-defined disease subgroups
Authors: Liley James , Todd John A , Wallace Chris
Published: January 2016

Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in the two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximising power in comparison to a standard variant by variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post-hoc identification of the contributing genetic variants.

We demonstrate the method on a range of simulated and test datasets where expected results are already known. We investigate subgroups of type 1 diabetes (T1D) cases defined by autoantibody positivity, establishing evidence for differential genetic architecture with thyroid peroxidase antibody positivity, driven generally by variants in known T1D associated regions.
Tagmentation-Based Mapping (TagMap) of Mobile DNA Genomic Insertion Sites
Authors: Stern David L.
Published: January 2016

Multiple methods have been introduced over the past 30 years to identify the genomic insertion sites of transposable elements and other DNA elements that integrate into genomes. However, each of these methods suffer from limitations that can frustrate attempts to map multiple insertions in a single genome and to map insertions in genomes of high complexity that contain extensive repetitive DNA. I introduce a new method for transposon mapping that is simple to perform, can accurately map multiple insertions per genome, and generates long sequence “reads” that facilitate mapping to complex genomes. The method, called TagMap, forTagmentation-basedMapping, relies on a modified Tn5 tagmentation protocol with a single tagmentation adaptor followed by PCR using primers specific to the tranposable element and the adaptor sequence. Several minor modifications to normal tagmentation reagents and protocols allow easy and rapid preparation of TagMap libraries. Short read sequencing starting from the adaptor sequence generates oriented reads that flank and are oriented toward the transposable element insertion site. The convergent orientation of adjacent reads at the insertion site allows straightforward prediction of the precise insertion site(s). A Linux shell script is provided to identify insertion sites from fastq files.
Incorporating and compensating cerebrospinal fluid in surface-based forward models of magneto– and electroencephalography
Authors: Stenroos Matti , Nummenmaa Aapo
Published: January 2016

MEG/EEG source imaging is usually done using a three-shell (3-S) or a simpler head model. Such models omit cerebrospinal fluid (CSF) that strongly affects the volume currents. We present a four-compartment (4-C) boundary-element (BEM) model that incorporates the CSF and is computationally efficient and straightforward to build using freely available software. We propose a way for compensating the omission of CSF by decreasing the skull conductivity of the 3-S model, and study the robustness of the 4-C and 3-S models to errors in skull conductivity.

We generated dense boundary meshes using MRI datasets and automated SimNIBS pipeline. Then, we built a dense 4-C reference model using Galerkin BEM, and 4-C and 3-S test models using coarser meshes and both Galerkin and collocation BEMs. We compared field topographies of cortical sources, applying various skull conductivities and fitting conductivities that minimized the relative error in 4-C and 3-S models. When the CSF was left out from the EEG model, our compensated, unbiased approach improved the accuracy of the 3-S model considerably compared to the conventional approach, where CSF is neglected without any compensation (mean relative error < 20% vs. > 40%). The error due to the omission of CSF was of the same order in MEG and compensated EEG. EEG has, however, large overall error due to uncertain skull conductivity.

Our results show that a realistic 4-C MEG/EEG model can be implemented using standard tools and basic BEM, without excessive workload or computational burden. If the CSF is omitted, compensated skull conductivity should be used in EEG.
A comparison of ancestral state reconstruction methods for quantitative characters
Authors: Royer-Carenzi Manuela , Didier Gilles
Published: January 2016

Choosing an ancestral state reconstruction method among the alternatives available for quantitative characters may be puzzling. We present here a comparison of five of them, namely the maximum likelihood, restricted maximum likelihood, generalized least squares, phylogenetic independent contrasts and squared parsimony methods.

A review of the relations between these methods shows that the first three ones infer the same ancestral states and can only be distinguished by the distributions accounting for the reconstruction uncertainty which they provide.

The respective accuracy of the methods is assessed over character evolution simulated under a Brownian motion with (and without) drift. We start by giving the general form of ancestral state distributions conditioned on leaf states under the simulation model.

Ancestral distributions are used first, to give a theoretical lower bound of the expected reconstruction error, and second, to develop an original evaluation scheme which is more efficient than comparing the reconstructed and the simulated states.

Our simulations show that: (i) the methods do not perform well as the evolution drift increases; (ii) the maximum likelihood method is generally the most accurate and (iii) not all the distributions of the reconstruction uncertainty provided by the methods are equally relevant.
Identification and Functional Characterization of Muscle Satellite Cells in Drosophila
Authors: Chaturvedi Dhananjay , Reichert Heinrich , Gunage Rajesh , VijayRaghavan K.
Published: January 2016

Work on genetic model systems such as Drosophila and mouse has shown that the fundamental mechanisms of myogenesis are remarkably similar in vertebrates and invertebrates. Strikingly however, satellite cells, the adult muscle stem cells that are essential for the regeneration of damaged muscles in vertebrates, have not been reported in invertebrates. In this study we show that lineal descendants of muscle stem cells are present in adult muscle of Drosophila as small, unfused cells located superficially and in close proximity to the mature muscle fibers. Normally quiescent, following muscle fiber injury, we show that these cells express Zfh1- cells and engage in Notch-Delta dependent proliferative activity and generate lineal descendant populations, which fuse with the injured muscle fiber. In view of strikingly similar morphological and functional features, we consider these novel cells to be the Drosophila equivalent of vertebrate muscle satellite cells.
Using Genome Wide Estimates of Heritability to Examine the Relevance of Gene-Environment Interplay
Authors: Domingue Ben , Boardmani Jason
Published: January 2016

We use genome-wide data from the third generation respondents of the Framing-ham Heart Study to estimate heritability in body mass index using different quantities of the measured genotype. Heritability decreases rapidly when SNPs implicated by a genome-wide association study are removed but shows essentially no decline when SNPs implicated by a gene-environment interaction in a second genome-wide analysis are removed. This second result is highlighted by our additional finding that the SNPs which explain heritability amongst a subsample defined by higher educational attainment explain no heritability of the heritability in the lower education group, and vice-versa. Finally, we do find consistent heritability estimates when we compare family-based estimates versus those based on measured genotype.
How do metal ions direct ribozyme folding?
Authors: Denesyuk Natalia A. , Thirumalai D.
Published: January 2016

Ribozymes, which carry out phosphoryl transfer reactions, often require Mg2+ions for catalytic activity. The correct folding of the active site and ribozyme tertiary structure is also regulated by metal ions in a manner which is not fully understood. Here, we employ coarse-grained molecular simulations to show that individual structural elements of the group I ribozyme from the bacteriumAzoarcusform spontaneously in the unfolded ribozyme even at very low Mg2+concentrations, and are transiently stabilized by coordination of Mg2+ ions to specific nucleotides. However, competition for scarce Mg2+and topological constraints arising from chain connectivity prevent complete folding of the ribozyme. A much higher Mg2+concentration is required for complete folding of the ribozyme and stabilization of the active site. When Mg2+is replaced by Ca2+ the ribozyme folds but the active site remains unstable. Our results suggest that group I ribozymes utilize the same interactions with specific metal ligands for both structural stability and chemical activity.
“Validating silicon polytrodes with paired juxtacellular recordings: method and dataset”
Authors: Neto Joana P. , Lopes Gonçalo , Frazão João , Nogueira Joana , Lacerda Pedro , Baião Pedro , Aarts Arno , Andrei Alexandru , Musa Silke , Fortunato Elvira , Barquinha Pedro , Kampff Adam R.
Published: January 2016

Cross-validating new methods for recording neural activity is necessary to accurately interpret and compare the signals they measure. Here we describe a procedure for precisely aligning two probes forin vivo“paired-recordings” such that the spiking activity of a single neuron is monitored with both a dense extracellular silicon polytrode and a juxtacellular micro-pipette. Our new method allows for efficient, reliable, and automated guidance of both probes to the same neural structure with micron resolution. We also describe a new dataset of paired-recordings, which is available online. We propose that our novel targeting system, and ever expanding cross-validation dataset, will be vital to the development of new algorithms for automatically detecting/sorting single-units, characterizing new electrode materials/designs, and resolving nagging questions regarding the origin and nature of extracellular neural signals.
An In Silico Model to Simulate the Evolution of Biological Aging
Authors: Šajina A. , Valenzano D.R.
Published: January 2016

Biological aging is characterized by an age-dependent increase in the probability of death and by a decrease in the reproductive capacity. Individual age-dependent rates of survival and reproduction have a strong impact on population dynamics, and the genetic elements determining survival and reproduction are under different selective forces throughout an organism lifespan. Here we develop a highly versatile numerical model of genome evolution — both asexual and sexual — for a population of virtual individuals with overlapping generations, where the genetic elements affecting survival and reproduction rate at different life stages are free to evolve due to mutation and selection. Our model recapitulates several emerging properties of natural populations, developing longer reproductive lifespan under stable conditions and shorter survival and reproduction in unstable environments. Faster aging results as the consequence of the reduced strength of purifying selection in more unstable populations, which have large portions of the genome that accumulate detrimental mutations. Unlike sexually reproducing populations under constant resources, asexually reproducing populations fail to develop an age-dependent increase in death rates and decrease in reproduction rates, therefore escaping senescence. Our model provides a powerfulin silicoframework to simulate how populations and genomes change in the context of biological aging and opens a novel analytical opportunity to characterize how real populations evolve their specific aging dynamics.
Evolutionary inference across eukaryotes identifies multiple pressures favoring mitochondrial gene retention
Authors: Johnston Iain G. , Williams Ben P.
Published: January 2016

Since their endosymbiotic origin, mitochondria have lost most of their genes. Although many selective mechanisms underlying the evolution of mitochondrial genomes have been proposed, a data-driven exploration of these hypotheses is lacking, and a quantitatively supported consensus remains absent. We developed HyperTraPS, a methodology coupling stochastic modelling with Bayesian inference, to identify the ordering of evolutionary events and suggest their causes. Using 2015 complete mitochondrial genomes, we inferred evolutionary trajectories of mitochondrial DNA (mtDNA) gene loss across the eukaryotic tree of life. We find that proteins comprising the structural cores of the electron transport chain are preferentially encoded within mitochondrial genomes across eukaryotes. A combination of high GC content and high protein hydrophobicity is required to explain patterns of mtDNA gene retention; a model that accounts for these selective pressures can also predict the success of artificial gene transfer experiments in vivo. This work provides a general method for data-driven inference of the ordering of evolutionary and progressive events, here identifying the distinct features shaping mitochondrial genomes of present day species.
On Post-Acquisition Motion Compensation for Prostate Perfusion Analysis
Authors: Wollny Gert , Casanova Isabel , Ledesma-Carbayo María-J. , Santos Andrés
Published: January 2016

Dynamic Contrast enhance magnetic resonance imaging has been established as an accurate method to detect and localize prostate cancer. Time series of three-dimensional datasets of the prostate are acquired and used to obtain per-voxel signal-intensity vs. time curves. These are then used to differentiate cancerous from non-cancerous tissue. However, rectal peristalsis and patient movement may result in spatial-mismatching of the serial datasets and therefore, incorrect enhancement curves. In this work, we discuss and test four methods based on image registration to compensate for these movements. These methods include a serial approach that uses the registration of consecutive images and the accumulation of the obtained transformations, an all-to one registration approach, an approach that first aligns a sub-set of images that are already closely aligned, and then uses synthetic references to register the remaining images, and an approach that usesindependent component analysis(ICA) to create synthetic references and register the images to these. We conclude that the method based on ICA does not provide a viable approach for motion compensation in prostate perfusion imaging, and that the serial approach fails when motion artifacts are present in the series. The other two approaches provide qualitatively pleasing results.
Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis
Authors: Vogel Robert , Erez Amir , Altan-Bonnet Grégoire
Published: January 2016

Despite progress in developing small molecule inhibitors, a quantitative understanding of drug action in the physiological context of cells is lacking. Here, we apply single-cell analysis of signal transduction and proliferation to probe cellular responses to small molecule inhibitors. We use the model of cellular activation of T lymphocytes responding to cytokines and antigens. We uncover two distinct modes of drug action, in terms of signaling inhibition: digital inhibition (e.g. when the fraction of activated cells diminishes upon drug treatment, but cells remaining active appear unperturbed), and analog inhibition (e.g. when the fraction of activated cells is unperturbed while their overall activation is diminished). We introduce a computational model of the signaling cascade in order to account for such dichotomy. We test the predictions of our model in terms of the phenotypic variability of cellular responses under drug inhibition. Finally, we demonstrate that the digital/analog dichotomy of cellular response as revealed on short timescales with signal transduction, translates into similar dichotomy on long timescales. Overall, our analysis of drug action at the single cell level illustrates the strength of quantitative approaches to translate the promise ofin vitropharmacology into functionally-relevant cellular settings.
Sex-dependent and sex-independent brain resting-state functional connectivity in children with autism spectrum disorder
Authors: Di Xin , Biswal Bharat B.
Published: January 2016

Background

Males are more likely to suffer from autism spectrum disorder (ASD) than females. As to whether females with ASD have similar brain alterations remain an open question. The current study aimed to examine sex-dependent as well as sex-independent alterations in resting-state functional connectivity in individuals with ASD compared with typically developing (TD) individuals.

Method

Resting-state functional MRI data were acquired from the Autism Brain Imaging Data Exchange (ABIDE). Subjects between 6 to 20 years of age were included for analysis. After matching the intelligence quotient between groups for each dataset, and removing subjects due to excessive head motion, the resulting effective sample contained 28 females with ASD, 49 TD females, 129 males with ASD, and 141 TD males, with a two (diagnosis) by two (sex) design. Functional connectivity among 153 regions of interest (ROIs) comprising the whole brain was computed. Two by two analysis of variance was used to identify connectivity that showed diagnosis by sex interaction or main effects of diagnosis.

Results

The main effects of diagnosis were found mainly between visual cortex and other brain regions, indicating sex-independent connectivity alterations. We also observed two connections whose connectivity showed diagnosis by sex interaction between the precuneus and medial cerebellum as well as the precunes and dorsal frontal cortex. While males with ASD showed higher connectivity in these connections compared with TD males, females with ASD had lower connectivity than their counterparts.

Conclusions

Both sex-dependent and sex-independent functional connectivity alterations are present in ASD.
DNA sequencing with stacked nanopores and exonuclease: a simulation-based analysis
Authors: Sampath G.
Published: January 2016

Experiments (Clarke et al.,Nat. Nanotech., 2009,4, 265-270) have shown that DNA could be sequenced using a nanopore-based electrolytic cell in which an exonuclease enzyme in thecischamber cleaves the leading base of a strand of DNA. The base is identified (with a reported accuracy that exceeds 99%) by the level of the current blockade it causes in the pore; a biological adapter inside slows down the base to lower the detection bandwidth required. This approach, which has been mathematically modeled, analyzed, and simulated (Reiner et al.,J. Chem. Phys.,2012,137, 214903; Brady and Reiner,ibid.,2015,143, 074904), is error-prone because bases may be lost to diffusion or enter the pore out of order. Here a modified cell with three stacked nanopores (UNP, MNP, and DNP) and the enzyme attached to thetransside of UNP is proposed. Translocation of a base is simulated with the random walk of a dimensionless particle; the results show that bases translocate through MNP and DNP in sequence order without loss. If this holds in practice then with a suitably designed adapter and compatible enzyme turnover rates base calling accuracy would be limited only by the accuracy of base discrimination. Potential implementation issues are discussed.