bluuebunny/crossref_metadata_2025_split huggingface dataset:
Versatile proteome labelling in fruit flies with SILAF
Authors: Schober Florian A. , Atanassov Ilian , Moore David , Wedell Anna , Freyer Christoph , Wredenberg Anna 
Published: March 2019

ABSTRACTDrosophila melanogaster has been a working horse of genetics and cell biology for more than a century. However, proteomic-based methods have been limited due to technical obstacles, especially the lack of reliable labelling methods. Here, we advanced a chemically defined food source into stable-isotope labelling of amino acids in flies (SILAF). It allows for the rapid generation of a large number of flies with full incorporation of lysine-6. SILAF followed by fractionation and enrichment gave proteomic insights at a depth of 5,966 proteins and 7,496 phosphorylation sites, which substantiated metabolic regulation on enzymatic level. Furthermore, the label can be traced and predicts protein turnover rates during different developmental stages. The ease and versatility of the method actuates the fruit fly as an appealing model in proteomic and post-translational modification studies and it enlarges potential metabolic applications based on heavy amino acid diets.
High-Speed Automatic Characterization of Rare Events in Flow Cytometric Data
Authors: Qi Yuan , Fang Youhan , Sinclair David R. , Guo Shangqin , Alberich-Jorda Meritxell , Lu Jun , Tenen Daniel G. , Kharas Michael G. , Pyne Saumyadipta 
Published: March 2019

AbstractA new computational framework for FLow cytometric Analysis of Rare Events (FLARE) has been developed specifically for fast and automatic identification of rare cell populations in very large samples generated by platforms like multi-parametric flow cytometry. Using a hierarchical Bayesian model and information-sharing via parallel computation, FLARE rapidly explores the high-dimensional marker-space to detect highly rare populations that are consistent across multiple samples. Further it can focus within specified regions of interest in marker-space to detect subpopulations with desired precision.
Genetic sensitivity analysis: adjusting for genetic confounding in epidemiological associations
Authors: Pingault Jean-Baptiste , Rijsdijk Frühling , Schoeler Tabea , Choi Shing Wan , Selzam Saskia , Krapohl Eva , O’Reilly Paul F. , Dudbridge Frank 
Published: March 2019

AbstractAssociations between exposures and outcomes reported in epidemiological studies are typically unadjusted for genetic confounding. We propose a two-stage approach for estimating the degree to which such observed associations can be explained by genetic confounding. First, we assess attenuation of exposure effects in regressions controlling for increasingly powerful polygenic scores. Second, we use structural equation models to estimate genetic confounding using heritability estimates derived from both SNP-based and twin-based studies. We examine associations between maternal education and three developmental outcomes – child educational achievement, Body Mass Index, and Attention Deficit Hyperactivity Disorder. Polygenic scores explain between 14.3% and 23.0% of the original associations, while analyses under SNP- and twin-based heritability scenarios indicate that observed associations could be almost entirely explained by genetic confounding. Thus, caution is needed when interpreting associations from non-genetically informed epidemiology studies. Our approach, akin to a genetically informed sensitivity analysis can be applied widely.Author summaryAn objective shared across the life, behavioural, and social sciences is to identify factors that increase risk for a particular disease or trait. However, identifying true risk factors is challenging. Often, a risk factor is statistically associated with a disease even if it is not really relevant, meaning that even successfully improving the risk factor will not impact the disease. One reason for the existence of such misleading associations stems from genetic confounding. This is when genetic factors influence both the risk factor and the disease, which generates a statistical association even in the absence of a true effect of the risk factor. Here, we propose a method to estimate genetic confounding and quantify its effect on observed associations. We show that a large part of the associations between maternal education and three child outcomes - educational achievement, body mass index and Attention-Deficit Hyperactivity Disorder-is explained by genetic confounding. Our findings can be applied to better understand the role of genetics in explaining associations of key risk factors with diseases and traits.
Spatiotemporal Dynamics of Stream Fish Assemblages Over Four Decades
Authors: Zbinden Zachery D. 
Published: March 2019

ABSTRACTFish assemblage structure was compared between 1974 and 2014 at 33 sampling locations in the Muddy Boggy River drainage, OK. The two main objectives for this comparison were to first quantify change in assemblage structure, and, second, to test for a relationship between compositional change and spatial scale. Spatial scale was manipulated by pooling assemblage data into groups ranging from K=33 pairs (i.e., local scale) to K=1 pair (i.e., global scale). Local assemblages varied in the degree of assemblage change over 4 decades (range=10-99% dissimilarity; mean=66%). The global assemblage remained quantitatively and qualitatively similar: most species persisted through time and those that did not were rare, and several diversity measures were not significantly different between time periods. Pooling assemblage data into consecutively larger groups and assessing the resultant compositional change revealed interesting patterns indicative of domains of spatial scaling. A discontinuity in the relationship between compositional change and spatial scale occurred at K=15, and this grouping is roughly the size of the headwater/tributary drainages of the Muddy Boggy system. This result suggests assemblages are more predictable when defined at scales larger than a stream reach, and a domain of higher predictability exists at a scale smaller than the entire drainage.
Co-occurrence of multiple CRISPRs andcasclusters suggests epistatic interactions
Authors: Bernheim Aude , Bikard David , Touchon Marie , Rocha Eduardo PC 
Published: March 2019

AbstractProkaryotes use CRISPR-Cas for adaptive immunity, but the reasons for the existence of multiple CRISPR andcasclusters remain poorly understood. We found that more than 40% of the genomes encoding a system show atypical genetic organizations. Their analysis revealed negative and positive epistatic interactions between Cas subtypes. The latter often result in one single complex locus with a shared adaptation module and diverse interference mechanisms, presumably to produce more effective immune systems. We typed CRISPRs that could not be unambiguously associated with acascluster and found that such complex loci tend to have unique type I repeats in multiple CRISPRs. In contrast, under-represented co-occurrences caused by functional interference or redundancy may lead to CRISPRs distant fromcasgenes. To investigate the origin of atypical CRISPR-Cas organizations, we analyzed plasmids and phages. Sets of nearly 2000 phages and 10000 prophages were almost devoid of CRISPR-Cas systems, but a sizeable fraction of plasmids had them. Isolated CRISPRs in plasmids were often compatible with the chromosomalcasclusters, suggesting that plasmids use CRISPRs to subvert host immunity. These results point to an important role for the interactions between multiple CRISPR and Cas in the function and evolution of bacterial immunity.
Drivers of amphibian population dynamics and asynchrony at local and continental scales
Authors: Cayuela Hugo , Griffiths Richard A. , Zakaria Nurul , Arntzen Jan W. , Priol Pauline , Léna Jean-Paul , Besnard Aurélien , Joly Pierre 
Published: March 2019

ABSTRACTIdentifying the drivers of population fluctuations in spatially distinct populations remains a significant challenge for ecologists. Whereas regional climatic factors may generate population synchrony (i.e., Moran effect), local factors including the level of density-dependence may reduce the level of synchrony. Although divergences in the scaling of population synchrony and spatial environmental variation have been observed, the regulatory factors that underlie such mismatches are poorly understood.No previous studies have investigated how density-dependent processes and population-specific responses to weather variation influence spatial synchrony at both local and continental scales. We addressed this issue in a pond-breeding amphibian, the great crested newt (Triturus cristatus). We used capture-recapture data collected through long-term surveys in fiveT. cristatuspopulations in Western Europe.We found a low level of demographic synchrony at both local and continental levels. Weather has weak and spatially variable effects on survival, recruitment and population growth rate. In contrast, density-dependence was a common phenomenon (at least for population growth) in almost all populations and subpopulations.Our findings support the idea that Moran’s effect is low in species where the population dynamics more closely depends on local factors (e.g. population density and habitat characteristics) than on large-scale environmental fluctuation (e.g. regional climatic variation). Those demographic feature likely have far-reaching consequences for the long-term viability of the spatially structured populations and their ability to response to large-scale climatic anomalies.
Differences in sodium channel densities in the apical dendrites of pyramidal cells of the electrosensory lateral line lobe
Authors: Motipally Sree I. , Allen Kathryne M. , Williamson Daniel K. , Marsat Gary 
Published: March 2019

AbstractHeterogeneity of neural properties within a given neural class is ubiquitous in the nervous system and permits different sub-classes of neurons to specialize for specific purposes. This principle has been thoroughly investigated in the hindbrain of the weakly electric fishA. leptorhynchusin the primary electrosensory area, the Electrosensory Lateral Line lobe (ELL). The pyramidal cells that receive inputs from tuberous electroreceptors are organized in three maps in distinct segments of the ELL. The properties of these cells vary greatly across maps due to differences in connectivity, receptor expression, and ion channel composition. These cells are a seminal example of bursting neurons and their bursting dynamic relies on the presence of voltage-gated Na+channels in the extensive apical dendrites of the superficial pyramidal cells. Other ion channels can affect burst generation and their expression varies across ELL neurons and segments. For example, SK channels cause hyperpolarizing after-potentials decreasing the likelihood of bursting, yet bursting propensity is similar across segments. We question whether the depolarizing mechanism that generates the bursts presents quantitative differences across segments that could counterbalance other differences having the opposite effect. Although their presence and role are established, the distribution and density of the apical dendrites’ Na+channels have not been quantified and compared across ELL maps. Therefore, we test the hypothesis that Na+channel density varies across segment by quantifying their distribution in the apical dendrites of immunolabeled ELL sections. We found the Na+channels to be two-fold denser in the lateral segment than in the centro-medial segment, the centro-lateral segment being intermediate. Our results imply that this differential expression of voltage-gated Na+channels could counterbalance or interact with other aspects of neuronal physiology that vary across segments (e.g. SK channels). We argue that burst coding of sensory signals, and the way the network regulates bursting, should be influenced by these variations in Na+channel density.
Convergent genes shape budding yeast pericentromeres
Authors: Paldi Flora , Alver Bonnie , Robertson Daniel , Schalbetter Stephanie A. , Kerr Alastair , Kelly David A. , Neale Matthew J. , Baxter Jonathan , Marston Adele L. 
Published: March 2019

AbstractThe 3D architecture of the genome governs its maintenance, expression and transmission. The conserved ring-shaped cohesin complex organises the genome by topologically linking distant loci on either a single DNA molecule or, after DNA replication, on separate sister chromatids to provide the cohesion that resists the pulling forces of spindle microtubules during mitosis1,2. Cohesin is highly enriched in specialized chromosomal domains surrounding centromeres, called pericentromeres3-7. However, the structural organisation of pericentromeres and implications for chromosome segregation are unknown. Here we report the 3D structure of budding yeast pericentromeres and establish the relationship between genome organisation and function. We find that convergent genes mark pericentromere borders and, together with core centromeres, define their structure and function by positioning cohesin. Centromeres load cohesin and convergent genes at pericentromere borders trap it. Each side of the pericentromere is organised into a looped conformation, with border convergent genes at the base. Microtubule attachment extends a single pericentromere loop, size-limited by convergent genes at its borders. Re-orienting genes at borders into a tandem configuration repositions cohesin, enlarges the pericentromere and impairs chromosome biorientation in mitosis. Thus, the linear arrangement of transcriptional units together with targeted cohesin loading at centromeres shapes pericentromeres into a structure competent for chromosome segregation during mitosis. Our results reveal the architecture of the chromosomal region within which kinetochores are embedded and the re-structuring caused by microtubule attachment. Furthermore, we establish a direct, causal relationship between 3D genome organization of a specific chromosomal domain and cellular function.
Opposing chromatin remodelers control transcription initiation frequency and start site selection
Authors: Kubik Slawomir , Challal Drice , Bruzzone Maria Jessica , Dreos René , Mattarocci Stefano , Bucher Philipp , Libri Domenico , Shore David 
Published: March 2019

AbstractPrecise nucleosome organization at eukaryotic promoters is thought to be generated by multiple chromatin remodeler (CR) enzymes and to affect transcription initiation. Using an integrated analysis of chromatin remodeler binding and nucleosome displacement activity following rapid remodeler depletion, we investigate the interplay between these enzymes and their impact on transcription in budding yeast. We show that many promoters are acted upon by multiple CRs that operate either cooperatively or in opposition to position the key transcription start site-associated +1 nucleosome. Functional assays suggest that +1 nucleosome positioning often reflects a trade-off between maximizing RNA Polymerase II recruitment and minimizing transcription initiation at incorrect sites. Finally, we show that nucleosome movement following CR inactivation usually results from the activity of another CR and that in the absence of any remodeling activity +1 nucleosomes maintain their positions. Our results provide a detailed picture of fundamental mechanisms linking promoter nucleosome architecture to transcription initiation.
Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders
Authors: Byrne Enda M , Zhu Zhihong , Qi Ting , Skene Nathan G , Bryois Julien , Pardinas Antonio F , Stahl Eli , Smoller Jordan W , Rietschel Marcella ,   Bipolar Working Group of the Psychiatric Genomics Consortium,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Owen Michael J , Walters James T.R. , O’Donovan Michael C , McGrath John G , Hjerling-Leffler Jens , Sullivan Patrick F , Goddard Michael E , Visscher Peter M , Yang Jian , Wray Naomi R 
Published: March 2019

AbstractSubstantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium – schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genom-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. In addition, we identified a number of variants that approached genome-wide significance in the original GWAS and have larger conditional effect sizes after conditioning on the other disorders. We show that decreased expression ofVPS29in the brain may increase risk to SCZ only and increased expression ofCSE1Lis associated with SCZ and MD, but not with BIP. Likewise, decreased expression ofPCDHA7in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.
A new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen injection as a proof of principle
Authors: Shen Hanyuan , Qu Zhipeng , Harata-Lee Yuka , Cui Jian , Aung Thazin Nwe , Wang Wei , Kortschak R. Daniel , Adelson David L. 
Published: March 2019

AbstractDrug-drug interactions (DDIs), especially with herbal medicines, are complex, making it difficult to identify potential molecular mechanisms and targets. We introduce a workflow to carry out DDI research using transcriptome analysis and interactions of a complex herbal mixture, Compound Kushen Injection (CKI), with cancer chemotherapy drugs, as a proof of principle. Using CKI combined with doxorubicin or 5-Fu on cancer cells as a model, we found that CKI enhanced the cytotoxic effects of doxorubicin on A431 cells while protecting MDA-MB-231 cells treated with 5-Fu. We generated and analysed transcriptome data from cells treated with single treatments or combined treatments and our analysis showed that opposite directions of regulation for pathways related to DNA synthesis and metabolism appeared to be the main reason for different effects of CKI when used in combination with chemotherapy drugs. We also found that pathways related to organic biosynthetic and metabolic processes might be potential targets for CKI when interacting with doxorubicin and 5-Fu. Through co-expression analysis correlated with phenotype results, we selected the MYD88 gene as a candidate major regulator for validation as a proof of concept for our approach. Inhibition of MYD88 reduced antagonistic cytotoxic effects between CKI and 5-Fu, indicating that MYD88 is an important gene in the DDI mechanism between CKI and chemotherapy drugs. These findings demonstrate that our pipeline is effective for the application of transcriptome analysis to the study of DDIs in order to identify candidate mechanisms and potential targets.
MARGO (Massively Automated Real-time GUI for Object-tracking), a platform for high-throughput ethology
Authors: Werkhoven Zach , Rohrsen Christian , Qin Chuan , Brembs Björn , de Bivort Benjamin 
Published: March 2019

AbstractFast object tracking in real time allows convenient tracking of very large numbers of animals and closed-loop experiments that control stimuli for multiple animals in parallel. We developed MARGO, a real-time animal tracking suite for custom behavioral experiments. We demonstrated that MARGO can rapidly and accurately track large numbers of animals in parallel over very long timescales. We incorporated control of peripheral hardware, and implemented a flexible software architecture for defining new experimental routines. These features enable closed-loop delivery of stimuli to many individuals simultaneously. We highlight MARGO’s ability to coordinate tracking and hardware control with two custom behavioral assays (measuring phototaxis and optomotor response) and one optogenetic operant conditioning assay. There are currently several open source animal trackers. MARGO’s strengths are 1) robustness, 2) high throughput, 3) flexible control of hardware and 4) real-time closed-loop control of sensory and optogenetic stimuli, all of which are optimized for large-scale experimentation.
Increased molecular plasticity along the septotemporal axis of the hippocampus is associated with network functioning
Authors: Sotiriou Evangelos , Angelatou Fevronia , Papatheodoropoulos Costas 
Published: March 2019

AbstractMolecular plasticity crucially supports adaptive cellular and network functioning in the brain. Variations in molecular plasticity may yield important differences in neuronal network dynamics between discrete brain subregions. In the present study we show that the gradual development of sharp waves (SPWs), a spontaneous network activity that is organized under normalin vitroconditions in the CA1 field of ventral but not dorsal hippocampal slices, is associated with region selective molecular reorganization. In particular, increased levels of mRNAs for specific GABAAreceptor subunits (α1, β2, γ2) occurred in ventral hippocampal CA1 field during the development of SPWs. These mRNA changes were followed by a clear increase in GABAAreceptor number in ventral hippocampus, as shown by [3H]muscimol binding. An increase in mRNAs was also observed in dorsal slices for α2 and α5 subunits, not followed by quantitative GABAAreceptor changes. Furthermore, full development of SPWs in the CA1 field (at 3 hours of slice maintenancein vitro) was followed by increased expression of immediate early genes c-fos and zif-268 in ventral hippocampal slices (measured at 5 hoursin vitro). No change in c-fos and zif-268 levels is observed in the CA1 field of dorsal slices, which do not develop spontaneous activity. These results suggest that generation of SPWs could trigger specific molecular reorganization in the VH that may be related to the functional roles of SPWs. Correspondingly, the revealed increased potentiality of the ventral hippocampus for molecular reorganization may provide a clue to mechanisms that underlie the regulated emergence of SPWs along the longitudinal axis of the hippocampus. Furthermore, the present evidence suggests that dynamic tuning between spontaneous neuronal activity and molecular organization may importantly contribute to the functional segregation/heterogeneity seen along the hippocampus.
CGGBP1 regulates chromatin barrier activity and CTCF occupancy at repeats
Authors: Patel Divyesh , Patel Manthan , Singh Umashankar 
Published: March 2019

ABSTRACTCGGBP1 is a repeat-binding protein with diverse functions in regulation of gene expression, cytosine methylation, repeat silencing and genomic integrity. CGGBP1 has also been identified as a cooperator factor in histone modifying complexes and as a component of protein complexes that form the enhancer-promoter loops. Here we report that the occupancy of CTCF at repeats and the chromatin barrier function of these repeat sequences depends on CGGBP1. Using ChIP-sequencing for CTC we describe CTCF binding on repetitive DNA. Our results show that CGGBP1 determines the CTCF occupancy preference for repeats over canonical CTCF-motif. By combining CTCF ChIP-sequencing results with ChIP-sequencing for three different kinds of histone modifications (H3K4me3, H3K9me3 and H3K27me3) we uncover insulator-like chromatin barrier activities of the repeat-rich CTCF-binding sites. This work shows that CGGBP1 is a regulator of CTCF occupancy and posits it as a regulator of barrier functions of CTCF-binding sites.