bluuebunny/crossref_metadata_2025 huggingface dataset:
Stochasticity in multi-phosphorylation and quasi steady state approximation in stochastic simulation
Authors: Das S. , Barik D.
Published: August 2018

Quantitative and qualitative nature of chemical noise propagation in a network of chemical reactions depend crucially on the topology of reaction networks. Multisite reversible phosphorylation-dephosphorylation of target proteins is one such recurrently found topology in various cellular networks regulating key functions in living cells. Here we analytically calculated the stochasticity in multistep reversible chemical reactions by determining variance of phosphorylated species at the steady state using linear noise approximation. We investigated the dependence of variance on the rate parameters in the reaction chain and the number of phosphorylation sites on the species. Assuming a quasi steady state approximation on the multistep reactions, originating from the disparity in time scales in the network, we propose a simulation scheme for coupled chemical reactions to improve the computational efficiency of stochastic simulation of the network. We performed case studies on signal transduction cascade and positive feedback loop with bistability to show the accuracy and efficiency of the method.
An algorithm for automated, noninvasive detection of cortical spreading depolarizations based on EEG simulations
Authors: Chamanzar Alireza , George Shilpa , Venkatesh Praveen , Chamanzar Maysamreza , Shutter Lori , Elmer Jonathan , Grover Pulkit
Published: August 2018

We present a novel signal processing algorithm for automated, noninvasive detection of Cortical Spreading Depolarizations (CSDs) using electroencephalography (EEG) signals and validate the algorithm on simulated EEG signals. CSDs are waves of neurochemical changes that suppress neuronal activity as they propagate across the brain’s cortical surface. CSDs are believed to mediate secondary brain damage after brain trauma and cerebrovascular diseases like stroke. We address key challenges in detecting CSDs from EEG signals: (i) decay of high spatial frequencies as they travel from the cortical surface to the scalp surface; and (ii) presence of sulci and gyri, which makes it difficult to track the CSD waves as they travel across the cortex. Our algorithm detects and tracks “wavefronts” of the CSD wave, and stitches together data across space and time to decide on the presence of a CSD wave. To test our algorithm, we provide different models and complex patterns of CSD waves, including different widths of CSD suppressions, and use these models to simulate scalp EEG signals using head models of 4 subjects from the OASIS dataset. Our results suggest that the average width of suppression that a low-density EEG grid of 40 electrodes can detect is 1.1 cm, which includes a vast majority of CSD suppressions, but not all. A higher density EEG grid having 340 electrodes can detect complex CSD patterns as thin as 0.43 cm (less than minimum widths reported in prior works), among which single-gyrus propagation is the hardest to detect because of its small suppression area.
Structures of the substrate-engaged 26S proteasome reveal the mechanisms for ATP hydrolysis-driven translocation
Authors: de la Peña Andres H. , Goodall Ellen A. , Gates Stephanie N. , Lander Gabriel C. , Martin Andreas
Published: August 2018

The 26S proteasome is the primary eukaryotic degradation machine and thus critically involved in numerous cellular processes. The hetero-hexameric ATPase motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core, while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. However, the mechanisms by which ATP hydrolysis drives the conformational changes responsible for these processes have remained elusive. Here we present the cryo-EM structures of four distinct conformational states of the actively ATP-hydrolyzing, substrate-engaged 26S proteasome. These structures reveal how mechanical substrate translocation accelerates deubiquitination, and how ATP-binding, hydrolysis, and phosphate-release events are coordinated within the AAA+ motor to induce conformational changes and propel the substrate through the central pore.
scMerge: Integration of multiple single-cell transcriptomics datasets leveraging stable expression and pseudo-replication
Authors: Lin Yingxin , Ghazanfar Shila , Wang Kevin , Gagnon-Bartsch Johann A. , Lo Kitty K. , Su Xianbin , Han Ze-Guang , Ormerod John T. , Speed Terence P. , Yang Pengyi , Hwa Yang Jean Yee
Published: August 2018

Concerted examination of multiple collections of single cell RNA-Seq (scRNA-Seq) data promises further biological insights that cannot be uncovered with individual datasets. However, such integrative analyses are challenging and require sophisticated methodologies. To enable effective interrogation of multiple scRNA-Seq datasets, we have developed a novel algorithm, named scMerge, that removes unwanted variation by combining stably expressed genes and utilizing pseudo-replicates across datasets. Analysis of large collections of publicly available datasets demonstrates that scMerge performs well in multiple scenarios and enhances biological discovery, including inferring cell developmental trajectories.
Dual role of Bnl/Fgf signaling in proliferation and endoreplication of Drosophila tracheal adult progenitor cells
Authors: Miguel Cristina de , Cruz Josefa , Martín David , Franch-Marro Xavier
Published: August 2018

Adult progenitor cells activation is a key event in the formation of adult organs during development. The initiation of proliferation of these progenitor cells requires specific temporal signals, mostly of them still unknown. InDrosophila, formation of adult tracheal system depends on the activation of tracheal adult progenitors (tracheoblasts) of Tr4 and Tr5 tracheal metamers specific spiracular branches (SB) during the last larval stage. The mitotic activity of these tracheoblasts generate a pool of tracheal differentiated cells that migrate during pupal development along the larval trachea by the activation of the Branchless (Bnl)/Fibroblast growth factor (FGF) signaling to form the abdominal adult tracheal system. In here, we found that, in addition to migration, Bnl/FGF signaling, mediated by the transcription factor Pointed, is also required for adult progenitor cell proliferation in the SBs. Moreover, we found that tracheoblast proliferation in Tr4 and Tr5 SBs relies on the specific expression of the FGF ligandBnlin their nearby transverse connective branches. Finally, we also show that, in absence of the transcription factor Cut (Ct), Bnl/FGF signaling induces endoreplication of differentiated tracheoblast daughter cells by in part promotingFizzy-related(Fzr) expression. Altogether, our results suggest a dual role of Bnl/FGF signaling in tracheal adult progenitors, inducing both proliferation and endoreplication of tracheoblasts in late larval development, depending on the presence or absence of the transcription factorct, respectively.

Author summary

The generation of adult organs and tissue renewal are complex processes that depend on the proliferation and posterior differentiation of undifferentiated progenitor cells in a temporal coordinated manner. Although many signals that regulate the activity of progenitor cells have been identified, the characterization of the mechanisms underlying the temporal and spatial control of such events remain unknown. The tracheal system ofDrosophila, the respiratory organ, forms during embryogenesis and it is remodeled during metamorphosis from quiescent adult progenitor cells that proliferate. We have discovered that this proliferation depends on the activation of the FGF signaling as mutations that either inactivate or over-activate the pathway blocks cell division or induced over-proliferation of progenitor cells, respectively. Interestingly, we have found that the same signaling pathway also controls tracheal progenitor cells differentiation by promoting endoreplication. We found that this dual role of FGF signaling in adult progenitor cells, depends on the presence or absence of the transcription factor Cut. Altogether, our results, reveal the mechanism that control the division and differentiation of progenitor cells and open the possibility that analogous signaling pathway may play a similar role in vertebrate stem cell regulation and tumor growth.
Optimized Cas9 expression systems for highly efficient Arabidopsis genome editing facilitate isolation of complex alleles in a single generation
Authors: Ordon Jana , Bressan Mauro , Kretschmer Carola , Dall’Osto Luca , Marillonnet Sylvestre , Bassi Roberto , Stuttmann Johannes
Published: August 2018

Genetic resources for the model plant Arabidopsis comprise mutant lines defective in almost any single gene in reference accession Columbia. However, gene redundancy and/or close linkage often render it extremely laborious or even impossible to isolate a desired line lacking a specific function or set of genes from segregating populations. Therefore, we here evaluated strategies and efficiencies for the inactivation of multiple genes by Cas9-based nucleases and multiplexing. In first attempts, we succeeded in isolating a mutant line carrying a 70 kb deletion, which occurred at a frequency of ~1.6% in the T2 generation, through PCR-based screening of numerous individuals. However, we failed to isolate a line lacking Lhcb1 genes, which are present in five copies organized at two loci in the Arabidopsis genome. To improve efficiency of our Cas9-based nuclease system, regulatory sequences controlling Cas9 expression levels and timing were systematically compared. Indeed, use of DD45 and RPS5a promoters improved efficiency of our genome editing system by approximately 25-30-fold in comparison to the previous ubiquitin promoter. Using an optimized genome editing system with RPS5a promoter-driven Cas9, putatively quintuple mutant lines lacking detectable amounts of Lhcb1 protein represented approximately 30% of T1 transformants. These results show how improved genome editing systems facilitate the isolation of complex mutant alleles, previously considered impossible to generate, at high frequency even in a single (T1) generation.
The Relative Contribution of Color and Material in Object Selection
Authors: Radonjić Ana , Cottaris Nicolas P. , Brainard David H.
Published: August 2018

Information about color, material, texture and shape guide how we interact with objects. We developed a paradigm that quantifies how two object properties (color and material) combine in object selection. On each experimental trial, observers viewed three blob-shaped objects — the target and two tests — and selected the test that was more similar to the target. Across trials the target was fixed while the tests varied in color and material. We present a novel observer model that allows us to describe observers’ selection data in terms of (1) the underlying perceptual stimulus representation and (2) a color-material weight, which quantifies the relative importance of color vs. material in selection. We document large individual differences in the color-material weight. Furthermore, our analyses reveal limits on how precisely selection data simultaneously constrain perceptual representations and the color-material weight. These limits should guide future efforts towards understanding the multidimensional nature of object perception.
NucBreak: Location of structural errors in a genome assembly by using paired-end Illumina reads
Authors: Khelik Ksenia , Sandve Geir Kjetil , Nederbragt Alexander Johan , Rognes Torbjørn
Published: August 2018

Background

Advances in whole genome sequencing strategies have provided the opportunity for genomic and comparative genomic analysis of a vast variety of organisms. The analysis results are highly dependent on the quality of the genome assemblies used. Assessment of the assembly accuracy may significantly increase the reliability of the analysis results and is therefore of great importance.

Results

Here, we present a new tool called NucBreak aimed at detecting structural errors in assemblies, including insertions, deletions, duplications, inversions, and different inter-and intra-chromosomal rearrangements. NucBreak analyses the alignments of reads properly mapped to an assembly and exploits information about the alternative read alignments. We have compared NucBreak with other existing assembly accuracy assessment tools, namely Pilon, REAPR, and FRCbam as well as with several structural variant detection tools, including BreakDancer, Lumpy, and Wham, by using both simulated and real datasets.

Conclusions

The benchmarking results have shown that NucBreak in general predicts assembly errors of different types and sizes with relatively high sensitivity and with higher precision than the other tools. Such a balance between sensitivity and precision makes NucBreak a good alternative to the existing assembly accuracy assessment tools and SV detection tools. NucBreak is freely available at https://github.com/uio-bmi/NucBreak under the MPL license.
Hierarchical Bayesian inference for concurrent model fitting and comparison for group studies
Authors: Piray Payam , Dezfouli Amir , Heskes Tom , Frank Michael J. , Daw Nathaniel D.
Published: August 2018

Computational modeling plays an important role in modern neuroscience research. Much previous research has relied on statistical methods, separately, to address two problems that are actually interdependent. First, given a particular computational model, Bayesian hierarchical techniques have been used to estimate individual variation in parameters over a population of subjects, leveraging their population-level distributions. Second, candidate models are themselves compared, and individual variation in the expressed model estimated, according to the fits of the models to each subject. The interdependence between these two problems arises because the relevant population for estimating parameters of a model depends on which other subjects express the model. Here, we propose a hierarchical Bayesian inference (HBI) framework for concurrent model comparison, parameter estimation and inference at the population level, combining previous approaches. We show that this framework has important advantages for both parameter estimation and model comparison theoretically and experimentally. The parameters estimated by the HBI show smaller errors compared to other methods. Model comparison by HBI is robust against outliers and is not biased towards overly simplistic models. Furthermore, the fully Bayesian approach of HBI enables researchers to quantify uncertainty in group parameter estimates, for each candidate model separately, and to perform statistical tests on parameters of a population.
The neural dynamics of familiar face recognition
Authors: Ambrus Géza Gergely , Kaiser Daniel , Cichy Radoslaw Martin , Kovács Gyula
Published: August 2018

In real-life situations, the appearance of a person’s face can vary substantially across different encounters, making face recognition a challenging task for the visual system. Recent fMRI decoding studies have suggested that face recognition is supported by identity representations located in regions of the occipito-temporal cortex. Here, we used EEG to elucidate the temporal emergence of these representations. Human participants (both sexes) viewed a set of highly variable face images of four highly familiar celebrities (two male, two female), while performing an orthogonal task. Univariate analyses of event-related EEG responses revealed a pronounced differentiation between male and female faces, but not between identities of the same sex. Using multivariate representational similarity analysis, we observed a gradual emergence of face identity representations, with an increasing degree of invariance. Face identity information emerged rapidly, starting shortly after 100ms from stimulus onset. From 400ms after onset and predominantly in the right hemisphere, identity representations showed two invariance properties: (1) they equally discriminated identities of opposite sexes and of the same sex, and (2) they were tolerant to image-based variations. These invariant representations may be a crucial prerequisite for successful face recognition in everyday situations, where the appearance of a familiar person can vary drastically.

Significance Statement

Recognizing the face of a friend on the street is a task we effortlessly perform in our everyday lives. However, the necessary visual processing underlying familiar face recognition is highly complex. As the appearance of a given person varies drastically between encounters, for example across viewpoints or emotional expressions, the brain needs to extract identity information that is invariant to such changes. Using multivariate analyses of EEG data, we characterize how invariant representations of face identity emerge gradually over time. After 400ms of processing, cortical representations reliably differentiated two similar identities (e.g., two famous male actors), even across a set of highly variable images. These representations may support face recognition under challenging real-life conditions.
Spatial Structure Can Decrease Symbiotic Cooperation
Authors: Vostinar Anya E. , Ofria Charles
Published: August 2018

Mutualisms occur when at least two species provide a net fitness benefit to each other. These types of interactions are ubiquitous in nature, with more being discovered regularly. Mutualisms are vital to humankind: pollinators and soil microbes are critical in agriculture, bacterial microbiomes regulate our health, and domesticated animals provide us with food and companionship. Many hypotheses exist on how mutualisms evolve, however they are difficult to evaluate without bias due to the fragile and idiosyncratic systems most often investigated. Instead, we have created an artificial life simulation, Symbulation, that we use to examine mutualism evolution based on: 1) the probability of vertical transmission (symbiont being passed to offspring) and 2) the spatial structure of the environment. We found that spatial structure can lead to less mutualism at intermediate vertical transmission rates. We provide evidence that this effect is due to the ability of quasi-species to purge parasites, reducing the diversity of available symbionts. Our simulation is easily extended to test many additional hypotheses about the evolution of mutualism and serves as a general model to quantitatively compare how different environments affect the evolution of mutualism.
Ultrafast clustering of single-cell ow cytometry data using FlowGrid
Authors: Ye Xiaoxin , Ho Joshua W. K.
Published: August 2018

Flow cytometry is a popular technology for quantitative single-cell profiling of cell surface markers. It enables expression measurement of tens of cell surface protein markers in millions of single cells. It is a powerful tool for discovering cell sub-populations and quantifying cell population heterogeneity. Traditionally, scientists use manual gating to identify cell types, but the process is subjective and is not effective for large multidimensional data. Many clustering algorithms have been developed to analyse these data but most of them are not scalable to very large data sets with more than ten million cells.

Here, we present a new clustering algorithm that combines the advantages of density-based clustering algorithm DBSCAN with the scalability of grid-based clustering. This new clustering algorithm is implemented in python as an open source package, FlowGrid. FlowGrid is memory efficient and scales linearly with respect to the number of cells. We have evaluated the performance of FlowGrid against other state-of-the-art clustering programs and found that FlowGrid produces similar clustering results but with substantially less time. For example, FlowGrid is able to complete a clustering task on a data set of 23.6 million cells in less than 12 seconds, while other algorithms take more than 500 seconds or get into error.

FlowGrid is an ultrafast clustering algorithm for large single-cell flow cy-tometry data. The source code is available at https://github.com/VCCRI/FlowGrid.
A map of direct TF-DNA interactions in the human genome
Authors: Gheorghe Marius , Sandve Geir Kjetil , Khan Aziz , Chèneby Jeanne , Ballester Benoit , Mathelier Anthony
Published: August 2018

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is the most popular assay to identify genomic regions, called ChIP-seq peaks, that are bound in vivo by transcription factors (TFs). These regions are derived from direct TF-DNA interactions, indirect binding of the TF to the DNA (through a co-binding partner), nonspecific binding to the DNA, and noise/bias/artifacts. Delineating the bona fide direct TF-DNA interactions within the ChIP-seq peaks remains challenging. We developed a dedicated software, ChIP-eat, that combines computational TF binding models and ChIP-seq peaks to automatically predict direct TF-DNA interactions. Our work culminated with predicted interactions covering >4% of the human genome, obtained by uniformly processing 1,983 ChIP-seq peak data sets from the ReMap database for 232 unique TFs. The predictions were a posteriori assessed using protein binding microarray and ChIP-exo data, and were predominantly found in high quality ChIP-seq peaks. The set of predicted direct TF-DNA interactions suggested that high-occupancy target regions are likely not derived from direct binding of the TFs to the DNA. Our predictions derived co-binding TFs supported by protein-protein interaction data and defined cis-regulatory modules enriched for disease- and trait-associated SNPs. Finally, we provide this collection of direct TF-DNA interactions and cis-regulatory modules in the human genome through the UniBind web-interface (http://unibind.uio.no).
Evolutionary history of Alzheimer Disease causing protein family Presenilins with pathological implications
Authors: Khan Ammad Aslam , Mirza Bushra , Raja Hashim Ali
Published: August 2018

Presenilin proteins are type II transmembrane proteins. They make the catalytic component of Gamma secretase, a multiportion transmembrane protease. Amyloid protein, Notch and beta catenin are among more than 90 substrates of Presenilins. Mutations in Presenilins lead to defects in proteolytic cleavage of its substrate resulting in some of the most devastating pathological conditions including Alzheimer disease (AD), developmental disorders and cancer. In addition to catalytic roles, Presenilin protein is also shown to be involved in many non-catalytic roles i.e. calcium homeostasis, regulation of autophagy and protein trafficking etc. These proteolytic proteins are highly conserved, present in almost all the major eukaryotic groups. Studies on wide variety of organisms ranging from human to unicellular dictyostelium have shown the important catalytic and non-catalytic roles of Presenilins. In the current research project, we aimed to elucidate the phylogenetic history of Presenilins. We showed that Presenilins are the most ancient of the Gamma secretase proteins and might have their origin in last common eukaryotic ancestor (LCEA). We also demonstrated that these proteins have been evolving under strong purifying selection. Through evolutionary trace analysis, we showed that Presenilin protein sites which undergoes mutations in Familial Alzheimer Disease are highly conserved in metazoans. Finally, we discussed the evolutionary, physiological and pathological implication of our findings and proposed that evolutionary profile of Presenilins supports the loss of function hypothesis of AD pathogenesis.
RT States: systematic annotation of the human genome using cell type-specific replication timing programs
Authors: Poulet Axel , Li Ben , Dubos Tristan , Rivera-Mulia Juan Carlos , Gilbert David M. , Qin Zhaohui S
Published: August 2018

The replication timing (RT) program has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows to characterize the RT program in the entire human genome in a high-throughput and high-resolution fashion. These experiments suggest that RT changes dynamically during development in coordination with gene activity. Since RT is such a fundamental biological process, we believe that an effective quantitative profile of the local RT program from a diverse set of cell types in various developmental stages and lineages can provide crucial biological insights for a genomic locus. In the present study, we explored recurrent and spatially coherent combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We found that a Hidden Markov Model with 15 hidden states provide a good model to describe these genome-wide RT profiling data. Each of the hidden state represents a unique combination of RT profiles across different cell types which we refer to as “RT states”. To understand the biological properties of these RT states, we inspected their relationship with chromatin states, gene expression, functional annotation and 3D chromosomal organization. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.

AUTHOR SUMMARY

The replication timing (RT) program is an important cellular mechanism and has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows us to characterize the RT program in the entire human genome. Results from these experiments suggest that RT changes dynamically across different developmental stages. Since RT is such a fundamental biological process, we believe that the local RT program from a diverse set of cell types in various developmental stages can provide crucial biological insights for a genomic locus. In the present study, we explored combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We developed a statistical model consist of 15 “RT states” to describe these genome-wide RT profiling data. To understand the biological properties of these RT states, we inspected the relationship between RT states and other types of functional annotations of the genome. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.
Interrogating Mutant Allele Expression via Customized Reference Genomes to Define Influential Cancer Mutations
Authors: Grant Adam , Vail Paris , Padi Megha , Witkiewicz Agnieszka K. , Knudsen Erik S.
Published: August 2018

Genetic alterations are essential for cancer initiation and progression. However, differentiating mutations that drive the tumor phenotype from mutations that do not affect tumor fitness remains a fundamental challenge in cancer biology. To better understand the impact of a given mutation within cancer, RNA-sequencing data was used to categorize mutations based on their allelic expression. For this purpose, we developed the MAXX (Mutation Allelic Expression Extractor) software, which is highly effective at delineating the allelic expression of both single nucleotide variants and small insertions and deletions. Results from MAXX demonstrated that mutations can be separated into three groups based on their expression of the mutant allele, lack of expression from both alleles, or expression of only the wild-type allele. By taking into consideration the allelic expression patterns of genes that are mutated in PDAC, it was possible to increase the sensitivity of widely used driver mutation detection methods, as well as identify subtypes that have prognostic significance and are associated with sensitivity to select classes of therapeutic agents in cell culture. Thus, differentiating mutations based on their mutant allele expression via MAXX represents a means to parse somatic variants in tumor genomes, helping to elucidate of a gene’s respective role in cancer.
Decomposing cell identity for transfer learning across cellular measurements, platforms, tissues, and species
Authors: Stein-O’Brien Genevieve L. , Clark Brian S. , Sherman Thomas , Zibetti Cristina , Hu Qiwen , Sealfon Rachel , Liu Sheng , Qian Jiang , Colantuoni Carlo , Blackshaw Seth , Goff Loyal A. , Fertig Elana J.
Published: August 2018

New approaches are urgently needed to glean biological insights from the vast amounts of single cell RNA sequencing (scRNA-Seq) data now being generated. To this end, we propose that cell identity should map to a reduced set of factors which will describe both exclusive and shared biology of individual cells, and that the dimensions which contain these factors reflect biologically meaningful relationships across different platforms, tissues and species. To find a robust set of dependent factors in large-scale scRNA- Seq data, we developed a Bayesian non-negative matrix factorization (NMF) algorithm, scCoGAPS. Application of scCoGAPS to scRNA-Seq data obtained over the course of mouse retinal development identified gene expression signatures for factors associated with specific cell types and continuous biological processes. To test whether these signatures are shared across diverse cellular contexts, we developed projectR to map biologically disparate datasets into the factors learned by scCoGAPS. Because projecting these dimensions preserve relative distances between samples, biologically meaningful relationships/factors will stratify new data consistent with their underlying processes, allowing labels or information from one dataset to be used for annotation of the other—a machine learning concept called transfer learning. Using projectR, data from multiple datasets was used to annotate latent spaces and reveal novel parallels between developmental programs in other tissues, species and cellular assays. Using this approach we are able to transfer cell type and state designations across datasets to rapidly annotate cellular features in a new dataset without a priori knowledge of their type, identify a species-specific signature of microglial cells, and identify a previously undescribed subpopulation of neurosecretory cells within the lung. Together, these algorithms define biologically meaningful dimensions of cellular identity, state, and trajectories that persist across technologies, molecular features, and species.

GRAPHICAL ABSTRACT
Efficient variant set mixed model association tests for continuous and binary traits in large-scale whole genome sequencing studies
Authors: Chen Han , Huffman Jennifer E. , Brody Jennifer A. , Wang Chaolong , Lee Seunggeun , Li Zilin , Gogarten Stephanie M. , Sofer Tamar , Bielak Lawrence F. , Bis Joshua C. , Blangero John , Bowler Russell P. , Cade Brian E. , Cho Michael H. , Correa Adolfo , Curran Joanne E. , Vries Paul S. de , Glahn David C. , Guo Xiuqing , Johnson Andrew D. , Kardia Sharon , Kooperberg Charles , Lewis Joshua P. , Liu Xiaoming , Mathias Rasika A. , Mitchell Braxton D. , O’Connell Jeffrey R. , Peyser Patricia A. , Post Wendy S. , Reiner Alex P. , Rich Stephen S. , Rotter Jerome I. , Silverman Edwin K. , Smith Jennifer A. , Vasan Ramachandran S. , Wilson James G. , Yanek Lisa R. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, Redline Susan , Smith Nicholas L. , Boerwinkle Eric , Borecki Ingrid B. , Cupples L. Adrienne , Laurie Cathy C. , Morrison Alanna C. , Rice Kenneth M. , Lin Xihong
Published: August 2018

With advances in Whole Genome Sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and Sequence Kernel Association Test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally-efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-Set Mixed Model Association Tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program. SMMAT tests share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be only fit once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMAT tests correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.
Butyrivibrio hungateiMB2003 competes effectively for soluble sugars released byButyrivibrio proteoclasticusB316Tfrom growth on xylan or pectin
Authors: Palevich Nikola , Kelly William J. , Ganesh Siva , Rakonjac Jasna , Attwood Graeme T.
Published: August 2018

Rumen bacterial species belonging to the generaButyrivibrioare important degraders of plant polysaccharides, particularly hemicelluloses (arabinoxylans) and pectin. Currently, four distinct species are recognized which have very similar substrate utilization profiles, but little is known about how these microorganisms are able to co-exist in the rumen. To investigate this question,Butyrivibrio hungatei(MB2003) andButyrivibrio proteoclasticus(B316T) were grown alone or in co-culture on the insoluble substrates, xylan or pectin, and their growth, release of sugars, fermentation end products and transcriptomes were examined. In single cultures, B316Twas able to degrade and grow well on xylan and pectin, whileB. hungateiMB2003 was unable to utilize either of these insoluble substrates to support significant growth. Co-cultures of B316Tgrown with MB2003 revealed that MB2003 showed almost equivalent growth to B316Twhen either xylan or pectin were supplied as substrates. The effect of co-culture on the transcriptomes of B316Tand MB2003 was very marked; B316Ttranscription was largely unaffected by the presence MB2003, but MB2003 expressed a wide range of genes encoding carbohydrate degradation/metabolism and oligosaccharide transport/assimilation in order to compete with B316Tfor the released sugars. These results suggest that B316Thas a role as an initiator of the primary solubilization of xylan and pectin, while MB2003 competes effectively as a scavenger for the released soluble sugars to enable its growth and maintenance in the rumen.

IMPORTANCE

Feeding a global population of nine billion people and climate change are the primary challenges facing agriculture today. Determining the roles of rumen microbes involved in plant polysaccharide breakdown is fundamental to understanding digestion and maximizing productivity of ruminant livestock.Butyrivibrioare abundant rumen bacteria and are a substantial source of polysaccharide-degrading enzymes with biotechnological applications for the depolymerization of lignocellulosic material. Our findings suggest that closely related species ofButyrivibriohave developed unique strategies for the degradation of plant fibre and the subsequent assimilation of carbohydrates in order to coexist in the competitive rumen environment. The identification of genes related to their enzymatic machinery by which these bacteria work in concert to degrade these different forms of polysaccharides contributes to our understanding of carbon flow in the rumen.
MaizeYABBY drooping leafgenes regulate floret development and floral meristem determinacy
Authors: Strable Josh , Vollbrecht Erik
Published: August 2018

Floret units in cereals produce grain, directly impacting yield. Here we report mutations in the maizeCRABS CLAW(CRC) co-orthologsdrooping leaf1(drl1) anddrl2alter the development of ear and tassel florets. Pistillate florets ofdrl1ears appear sterile and display ectopic unfused carpels that fail to enclose an expanded nucellus. Staminate florets ofdrl1tassels have extra stamens and retain fertile anthers. Natural variation and transposon alleles ofdrl2enhancedrl1floret phenotypes by reducing floral meristem (FM) determinacy. Thedrlparalogs are co-expressed in lateral floral organ primordia, but not within the FM. Together, the expression patterns and indeterminate mutant FMs suggest that thedrlgenes regulate FM activity and impose meristem determinacy by a non-cell autonomous signal. Genetic interaction analyses ofdrlmutants with maize floral mutants indicate that thedrlgenes are required throughout floret development, illustrating their importance for proper floret patterning in maize.
Fast Estimation of Recombination Rates Using Topological Data Analysis
Authors: Humphreys Devon P. , McGuirl Melissa R. , Miyagi Michael , Blumberg Andrew J.
Published: August 2018

Accurate estimation of recombination rates is critical for studying the origins and maintenance of genetic diversity. Because the inference of recombination rates under a full evolutionary model is computationally expensive, an alternative approach using topological data analysis (TDA) has been proposed. Previous TDA methods used information contained solely in the first Betti number (β1)of the cloud of genomes, which relates to the number of loops that can be detected within a genealogy. While these methods are considerably less computationally intensive than current biological model-based methods, these explorations have proven difficult to connect to the theory of the underlying biological process of recombination, and consequently have unpredictable behavior under different perturbations of the data. We introduce a new topological feature with a natural connection to coalescent models, which we callψ. We show thatψandβ1are differentially affected by changes to the structure of the data and use them in conjunction to provide a robust, efficient, and accurate estimator of recombination rates, TREE. Compared to previous TDA methods, TREE more closely approximates of the results of commonly used model-based methods. These characteristics make TREE well suited as a first-pass estimator of recombination rate heterogeneity or hotspots throughout the genome. In addition, we present novel arguments relatingβ1to population genetic models; our work justifies the use of topological statistics as summaries of distributions of genome sequences and describes a new, unintuitive relationship between topological summaries of distance and the footprint of recombination on genome sequences.
The comparative biogeography of Philippine geckos challenges predictions from a paradigm of climate-driven vicariant diversification across an island archipelago
Authors: Oaks Jamie R. , Siler Cameron D. , Brown Rafe M.
Published: August 2018

A primary goal of biogeography is to understand how large-scale environmental processes, like climate change, affect diversification One often-invoked but seldom tested process is the “species-pump” model, in which repeated bouts of co-speciation are driven by oscillating climate-induced habitat connectivity cycles. For example, over the past three million years, the landscape of the Philippine Islands has repeatedly coalesced and fragmented due to sea-level changes associated with glacial cycles. This repeated climate-driven vicariance has been proposed as a model of speciation across evolutionary lineages codistributed throughout the islands. This model predicts speciation times that are temporally clustered around the times when interglacial rises in sea level fragmented the islands. To test this prediction, we collected comparative genomic data from 16 pairs of insular gecko populations. We analyze these data in a full-likelihood, Bayesian model-choice framework to test for shared divergence times among the pairs. Our results provide support against the species-pump model prediction in favor of an alternative interpretation, namely that each pair of gecko populations diverged independently. These results suggest the repeated bouts of climate-driven landscape fragmentation has not been an important mechanism of speciation for gekkonid lizards on the Philippine Islands.
Life-history traits inform on population trends when assessing the conservation status of a declining tiger shark population
Authors: Brown Christopher J. , Roff George
Published: August 2018

The assessment of the conservation status of wide ranging species depends on estimates of the magnitude of their population trends. The accuracy of trend estimates will depend on where and how many locations within a species’ range are sampled. We ask how the spatial extent of sampling interacts with non-linear patterns in long-term trends to affect estimates of decline in standardised catch of tiger sharks (Galeocerdo cuvier) on the east coast of Australia. We apply a Bayesian trend model that uses prior information on life-history traits to estimate trends where we use data from all regions versus spatial subsets of the data. As more regions were included in the model the trend estimates converged towards an overall decline of 71% over three generations. Trends estimated from data only from northern regions or southern regions underestimated and overestimated the regional decline, respectively. When a subset of regions was modelled, rather than the full data-set, the prior informed by life-history traits performed well, as did a weakly informed prior that allowed for high variation. The rate of decline in tiger sharks is consistent with a listing East Coast Australia tiger sharks as endangered under local legislation. Monitoring programs that aim to estimate population trends should attempt to cover the extremes and mid-points of a population’s range. Life-history information can be used to inform priors for population variation and may give more accurate estimates of trends that can be justified in debates about the status of threatened species, particularly when sampling is limited.
22kHz and 55kHz ultrasonic vocalizations differentially influence neural and behavioral outcomes: Implications for modeling anxiety via auditory stimuli in the rat
Authors: Demaestri Camila , Brenhouse Heather C. , Honeycutt Jennifer A.
Published: August 2018

The communicative role of ultrasonic vocalizations (USVs) in rodents is well established, with distinct USVs indicative of different affective states. USVs in the 22kHz range are typically emitted by adult rats when in anxiety-or fear-provoking situations (e.g. predator odor, social defeat), while 55kHz range USVs are emitted in appetitive situations (e.g., play, anticipation of reward). Previous work indicates that USVs (real-time and playback) can effectively communicate these affective states and influence changes in behavior and neural activity of the receiver. Changes in cFos activation following 22kHz USVs have been seen in cortical and limbic regions involved in anxiety, including the basolateral amygdala (BLA). However, it is unknown how USV playback influences cFos activity within the basal nucleus of the stria terminalis (BNST), a region also thought to be critical in processing anxiety-related information. The present work sought to characterize distinct behavioral, physiological, and neural responses in rats presented with aversive (22kHz) compared to appetitive (55kHz) USVs or silence. Our findings show that rats exposed to 22kHz USVs: 1) engage in anxiety-like behaviors in the open field and elevated zero maze, and 2) show distinct patterns of cFos activation within the BLA and BNST that contrast those seen in 55kHz playback. Specifically, 22kHz USVs increased cFos density in the anterodorsal nuclei, while 55kHz playback increased cFos in the oval nucleus of the BNST. These results provide important groundwork for leveraging ethologically-relevant stimuli in the rat to improve our understanding of anxiety-related responses in both typical and pathological populations.
Automated Electrodes Detection during simultaneous EEG/fMRI
Authors: Fleury Mathis , Barillot Christian , Mano Marsel , Bannier Elise , Maurel Pierre
Published: August 2018

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The coupling of Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) enables the measure of brain activity at high spatial and temporal resolution. The localisation of EEG sources depends on several parameters including the knowledge of the position of the electrodes on the scalp. An accurate knowledge about this information is important for source reconstruction. Currently, when acquiring EEG and fMRI together, the position of the electrodes is generally estimated according to fiducial points by using a template. In the context of simultaneous EEG/fMRI acquisition, a natural idea is to use magnetic resonance (MR) images to localise EEG electrodes. However, most MR compatible electrodes are built to be almost invisible on MR Images. Taking advantage of a recently proposed Ultra short Echo Time (UTE) sequence, we introduce a fully automatic method to detect and label those electrodes in MR images. Our method was tested on 8 subjects wearing a 64-channel EEG cap. This automated method showed an average detection accuracy of 94% and the average position error was 3.1 mm. These results suggest that the proposed method has potential for determining the position of the electrodes during simultaneous EEG/fMRI acquisition with a very light cost procedure.
Human-specificARHGAP11Binduces hallmarks of neocortical expansion in developing ferret neocortex
Authors: Kalebic Nereo , Gilardi Carlotta , Albert Mareike , Namba Takashi , Long Katherine R. , Kostic Milos , Langen Barbara , Huttner Wieland B.
Published: August 2018

The evolutionary increase in size and complexity of the primate neocortex is thought to underlie the higher cognitive abilities of humans.ARHGAP11Bis a human-specific gene that, based on its expression pattern in fetal human neocortex and progenitor effects in embryonic mouse neocortex, has been proposed to have a key function in the evolutionary expansion of the neocortex. Here, we study the effects ofARHGAP11Bexpression in the developing neocortex of the gyrencephalic ferret. In contrast to its effects in mouse, ARHGAP11B markedly increases proliferative basal radial glia, a progenitor cell type thought to be instrumental for neocortical expansion, and results in extension of the neurogenic period and an increase in upper-layer neurons. As a consequence, the postnatal ferret neocortex exhibits an increased neuron density in the upper cortical layers and expands in the radial dimension. Thus, human-specific ARHGAP11B can elicit hallmarks of neocortical expansion in developing ferret neocortex.
The RNA helicase UPF1 associates with mRNAs co-transcriptionally and is required for the release of mRNAs from transcription sites
Authors: Singh Anand K. , Choudhury Subhendu Roy , De Sandip , Zhang Jie , Kissane Stephen , Dwivedi Vibha , Ramanathan Preethi , Orsini Luisa , Hebenstreit Daniel , Brogna Saverio
Published: August 2018

UPF1 is an RNA helicase that is required for efficient nonsense-mediated mRNA decay (NMD) in eukaryotes, and the predominant view is that UPF1 mainly operates on the 3’UTRs of mRNAs that are directed for NMD in the cytoplasm. Here we offer evidence, obtained fromDrosophila, that UPF1 constantly moves between the nucleus and cytoplasm and that it has multiple functions in the nucleus. It is associated, genome-wide, with nascent RNAs at most of the active Pol II transcription sites and at some Pol III-transcribed genes, as demonstrated microscopically on the polytene chromosomes of salivary gland and by ChIP-seq analysis in S2 cells. Intron recognition seems to interfere with association and translocation of UPF1 on nascent pre-mRNA transcripts, and cells depleted of UPF1 show defects in several nuclear processes essential to correct gene expression – most strikingly, the release of mRNAs from transcription sites and mRNA export from the nucleus.