bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cell cycle-coordinated nuclear compartment for Polymerase II transcription encompasses the earliest gene expression before global genome activation
Authors: Hadzhiev Yavor , Qureshi Haseeb K. , Wheatley Lucy , Cooper Ledean , Jasiulewicz Aleksandra , Nguyen Huy Van , Wragg Joseph , Poovathumkadavil Divyasree , Conic Sascha , Bajan Sarah , Sik Attila , Hutvàgner György , Tora Làszlò , Gambus Agnieszka , Fossey John S. , Müller Ferenc 
Published: July 2018

AbstractMost metazoan embryos commence development with rapid cleavages without zygotic gene expression and their genome activation is delayed until the mid-blastula transition (MBT). However, a set of genes escape global repression during the extremely fast cell cycles, which lack gap phases and their transcription is activated before the MBT. Here we describe the formation and the spatio-temporal dynamics of a distinct transcription compartment, which encompasses the earliest detectable transcription during the first wave of genome activation. Simultaneous 4D imaging of expression of pri-miR430 and zinc finger genes by a novel, native transcription imaging approach reveals a pair of shared transcription compartments regulated by homolog chromosome organisation. These nuclear compartments carry the majority of nascent RNAs and transcriptionally active Polymerase II, are depleted of compact chromatin and represent the main sites for detectable transcription before MBT. We demonstrate that transcription occurs in the S-phase of the cleavage cycles and that the gradual slowing of these cell cycles are permissive to transcription before global genome activation. We propose that the demonstrated transcription compartment is part of the regulatory architecture of nucleus organisation, and provides a transcriptionally competent, supporting environment to facilitate early escape from the general nuclear repression before global genome activation.
VarSome: The Human Genomic Variant Search Engine
Authors: Kopanos Christos , Tsiolkas Vasilis , Kouris Alexandros , Chapple Charles E. , Aguilera Monica Albarca , Meyer Richard , Massouras Andreas 
Published: July 2018

AbstractSummaryVarSome.com is a search engine, aggregator and impact analysis tool for human genetic variation and a community-driven project aiming at sharing global expertise on human variants.AvailabilityVarSome is freely available at http://varsome.com.
NG-meta-profiler: fast processing of metagenomes using NGLess, a domain-specific language
Authors: Coelho Luis Pedro , Alves Renato , Monteiro Paulo , Huerta-Cepas Jaime , Freitas Ana Teresa , Bork Peer 
Published: July 2018

AbstractNGLess is a domain specific language for describing next-generation sequence processing pipelines. It was developed with the goal of enabling user-friendly computational reproducibility.Using this framework, we developed NG-meta-profiler, a fast profiler for metagenomes which performs sequence preprocessing, mapping to bundled databases, filtering of the mapping results, and profiling (taxonomic and functional). It is significantly faster than either MOCAT2 or htseq-count and (as it builds on NGLess) its results are perfectly reproducible. These pipelines can easily be customized and extended with other tools.NGLess and NG-meta-profiler are open source software (under the liberal MIT licence) and can be downloaded from http://ngless.embl.de or installed through bioconda.
High cost of bias: Diminishing marginal returns on NIH grant funding to institutions
Authors: Wahls Wayne P. 
Published: July 2018

AbstractScientific output is not a linear function of amounts of federal grant support to individual investigators. As funding per investigator increases beyond a certain point, productivity decreases. This study reports that such diminishing marginal returns also apply for National Institutes of Health (NIH) research project grant funding to institutions. Analyses of data (2006–2015) for a representative cross-section of institutions, whose amounts of funding ranged from $3 million to $440 million per year, revealed robust inverse correlations between funding (per institution, per award, per investigator) and scientific output (publication productivity and citation impact productivity). Interestingly, prestigious institutions had on average 65% higher grant application success rates and 50% larger award sizes, whereas less-prestigious institutions produced 65% more publications and had a 35% higher citation impact per dollar of funding. These findings suggest that implicit biases and social prestige mechanisms (e.g., the Matthew effect) have a powerful impact on where NIH grant dollars go and the net return on taxpayers’ investments. They support evidence-based changes in funding policy geared towards a more equitable, more diverse and more productive distribution of federal support for scientific research. Success rate/productivity metrics developed for this study provide an impartial, empirically based mechanism to do so.
PhyloPi: an affordable, purpose built phylogenetic pipeline for the HIV drug resistance testing facility
Authors: Bester Phillip A , Vries Andrie De , Riekert SJPK , Steegen Kim , Zyl Gert van , Goedhals Dominique 
Published: July 2018

AbstractPhylogenetic analysis plays a crucial role in quality control in the HIV drug resistance testing laboratory. If previous patient sequence data is available sample swaps can be detected and investigated. As Antiretroviral treatment coverage is increasing in many developing countries, so is the need for HIV drug resistance testing. In countries with multiple languages, transcription errors are easily made with patient identifiers. Here a self-contained blastn integrated phylogenetic pipeline can be especially useful. Even though our pipeline can run on any unix based system, a Raspberry Pi 3 is used here as a very affordable and integrated solution.The computational capability of this single board computer is demonstrated as well as the utility thereof in the HIV drug resistance laboratory. Benchmarking analysis against a large public database shows excellent time performance with minimal user intervention. This pipeline also contains utilities to find previous sequences as well as phylogenetic analysis and a graphical sequence mapping utility against the pol area of the HIV HXB2 reference genome. Sequence data from the Los Alamos HIV database was analyzed for inter- and intra-patient diversity and logistic regression was conducted on the calculated genetic distances. These findings show that allowable clustering and genetic distance between viral sequences from different patients is very dependent on subtype as well as the area of the viral genome being analyzed.The Raspberry Pi image for PhyloPi, source code of the pipeline, sequence data, bash-, python- and R-scripts for the logistic regression, benchmarking as well as helper scripts are available at http://scholar.ufs.ac.za:8080/xmlui/handle/11660/7638 and https://github.com/ArmandBester/phylopi.The PhyloPi image and the source code are published under the GPLv3 license. A demo version of the PhyloPi pipeline is available at http://phylopi.hpc.ufs.ac.za/.
Dispersal-dependent juvenile survival in a sexually dimorphic long-lived bird, the Greater FlamingoPhoenicopterus roseus
Authors: Souchay Guillaume , Barbraud Christophe , Germain Christophe , Béchet Arnaud 
Published: July 2018

AbstractThe viability and dynamics of spatially structured populations depend critically upon dispersal behaviour. Yet, in long lived species with delayed maturity, the fitness consequences of post-fledging dispersal, dispersal from the birthplace after independence and before first breeding attempt, are poorly understood although it is a critical determinant of natal dispersal.We aimed at estimating sex-specific variations of juvenile survival in a long-lived bird species with sexual size dimorphism, the greater flamingo, as a function of post fledging dispersal destination. Using capture-recapture models, we estimated the survivorship of flamingos ringed in the Camargue (south of France) and wintering in the Mediterranean.Dispersal probability from France was > 0.66 with important annual variations in preferred dispersal destinations. First-year survival increased along the winter temperature gradient with estimates below 0.50 ± 0.07 in France and above 0.60 ± 0.07 in African wetlands. The survival of flamingos wintering in France dropped by 30–50 % depending on sex between fall and spring of their first year.In African sites and in Italy, there was no detectable difference of survival between sexes suggesting favorable wintering conditions. Body condition at fledging did not explain variations in first-fall survival within genders. Males wintering in France had a better survival than females.These results show that sex and post-fledging dispersal destination affect juvenile survival, support theenergetichypothesis predicting an advantage of large body size to cope with cold temperatures and thecompetitionhypothesis, and suggest the existence of sex-specific post fledging dispersal tactics.
Dynamic Measurements of Bovine Serum Albumin Aggregation Using Small Angle Neutron Scattering
Authors: Austerberry James I , Belton Daniel J 
Published: July 2018

AbstractThe rapid and complex nature of protein aggregation makes the identification of aggregation mechanisms and their precursors challenging. Here we demonstrate the novel use of small-angle neutron scattering to perform dynamic real-time measurement and analysis of protein aggregation. Changes in bovine serum albumin monomer population and aggregate size are identified at several isothermal temperatures. Kratky plots indicate that the aggregation of BSA occurs through the partial unfolding of the monomer. Dual population modelling of the scattering data indicates that the protein nucleates and grows through a two stage mechanism; a rapid burst phase and a slower growth phase. Both stages are observed to follow Arrhenius behaviour between 70-80 °C.
Mapping In Vivo O-Glycoproteome Using Site-specific Extraction of O-linked glycopeptides (EXoO)
Authors: Yang Weiming , Ao Minghui , Hu Yingwei , Li Qing Kay , Zhang Hui 
Published: July 2018

AbstractProtein glycosylation is one of the most abundant post-translational modifications. However, detailed analysis ofin vivoO-linked glycosylation, a major type of protein glycosylation, has been severely impeded by the scarcity of suitable methodologies. Here, we present a chemoenzymatic method for the site-specificextractionofO-linked glycopeptides (EXoO), which enabled the unambiguous mapping of over 3,000 O-linked glycosylation sites and definition of their glycans on over 1,000 proteins in human kidney tissues, T cells and serum. This large-scale localization of O-linked glycosylation sites nearly doubles the number of previously identified sites, demonstrating that EXoO is the most effective method to-date for defining the site-specific O-linked glycoproteome in different types of sample. Detailed structural analysis of the sites identified revealed conserved motifs and topological orientations facing extracellular space, the cell surface, the lumen of the ER and the Golgi. EXoO was also able to reveal significant differences in thein vivoO-linked glycoproteome of tumor and normal kidney tissues pointing to its broader use in clinical diagnostics and therapeutics.
Expansion of a core regulon by transposable elements promotes Arabidopsis chemical diversity and pathogen defense
Authors: Barco Brenden , Kim Yoseph , Clay Nicole K. 
Published: July 2018

AbstractPlants synthesize hundreds of thousands of ecologically specialized, lineage-specific metabolites through biosynthetic gene duplication and functional specialization. However, the rewiring of duplicated genes into existing regulatory networks remains unclear. We show that the duplicated geneCYP82C2was recruited into the WRKY33 regulon and indole-3-carbonylnitrile (ICN) biosynthetic pathway through exaptation of a retroduplicated LINE retrotransposon (EPCOT3) into a novel enhancer. The stepwise development of a chromatin-accessible WRKY33-binding site onEPCOT3potentiated the regulatory neofunctionalization ofCYP82C2and the evolution of inducible defense metabolite 4-hydroxy-ICN inArabidopsis thaliana.Transposable elements (TEs) have long been recognized to have the potential to rewire regulatory networks; these results establish a more complete understanding of how duplicated genes and TEs contribute in concert to chemical diversity and pathogen defense.
CRISPR/Cas9 gene editing for the creation of an MGAT1 deficient CHO cell line to control HIV-1 vaccine glycosylation
Authors: Byrne Gabriel , O’Rourke Sara M. , Alexander David L. , Yu Bin , Doran Rachel C. , Wright Meredith , Chen Qiushi , Azadi Parastoo , Berman Phillip W. 
Published: July 2018

AbstractOver the last decade multiple broadly neutralizing monoclonal antibodies (bN-mAbs) to the HIV-1 envelope protein, gp120, have been described. Surprisingly many of these recognize epitopes consisting of both amino acid and glycan residues. Moreover, the glycans required for binding of these bN-mAbs are early intermediates in the N-linked glycosylation pathway. This type of glycosylation substantially alters the mass and net charge of HIV envelope (Env) proteins compared to molecules with the same amino acid sequence but possessing mature, complex (sialic acid containing) carbohydrates. Since cell lines suitable for biopharmaceutical production that limit N-linked glycosylation to mannose-5 (Man5) or earlier intermediates are not readily available, the production of vaccine immunogens displaying these glycan dependent epitopes has been challenging. Here we report the development of a stable suspension adapted CHO cell line that limits glycosylation to Man5and earlier intermediates. This cell line was created using the CRISPR/Cas9 gene editing system and contains a mutation that inactivates the gene encoding Mannosyl (Alpha-1,3-)-Glycoprotein Beta-1,2-N-Acetylglucosaminyltransferase (MGAT1). Monomeric gp120s produced in the MGAT1-CHO cell line exhibit improved binding to prototypic glycan dependent bN-mAbs directed to the V1/V2 domain (e.g. PG9) and the V3 stem (e.g. PGT128 and 10–1074) while preserving the structure of the important glycan independent epitopes (e.g. VRC01). The ability of the MGAT1-CHO cell line to limit glycosylation to early intermediates in the N-linked glycosylation pathway, without impairing the doubling time or ability to grow at high cell densities, suggest that it will be a useful substrate for the biopharmaceutical production of HIV-1 vaccine immunogens.
Fluoxetine effects on behavior and adult hippocampal neurogenesis in female C57BL/6J mice across the estrous cycle
Authors: Yohn Christine N. , Shifman Sophie , Garino Alexander , Diethorn Emma , Bokka Leshya , Ashamalla Sandra A. , Adam Samuels Benjamin 
Published: July 2018

AbstractSome mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle. Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-like behaviors and increase adult hippocampal neurogenesis in male rodents. However, very few studies have conclusively looked at the effects of antidepressants on behavior and neurogenesis across the estrous cycle in naturally cycling female rodents. Here we analyze the effects of chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all four phases of the estrous cycle. Interestingly, we find that the effects of fluoxetine on both behavior and adult hippocampal neurogenesis are driven by mice specifically in the estrus or diestrus phases of the estrous cycle. Taken together our data is the first to illustrate the impact of fluoxetine on brain and behavior across all four stages of the murine estrous cycle.HighlightsChronic fluoxetine reduces anxiety-like behaviors in naturally cycling female miceChronic fluoxetine increases adult hippocampal neurogenesis in naturally cycling female miceThe effects of chronic fluoxetine on behavior and adult hippocampal neurogenesis are driven by the estrus and diestrus phases of the estrous cycle
Replisome preservation by a single-stranded DNA gate in the CMG helicase
Authors: Wasserman Michael R. , Schauer Grant D. , O’Donnell Michael E. , Liu Shixin 
Published: July 2018

ABSTRACTThe eukaryotic replicative helicase CMG is assembled at replication origins and is thought to remain topologically closed until termination. Upon encountering a lesion, CMG must vacate a stalled fork to allow DNA repair. However, the fate of CMG under these stress conditions remains unclear. Here, using correlative single-molecule fluorescence and force microscopy, we show that when uncoupled from a DNA polymerase, CMG opens a single-stranded (ss) DNA gate to traverse a forked junction and reside on double-stranded (ds) DNA. Surprisingly, CMG undergoes rapid diffusion on dsDNA and can transition back onto ssDNA for continued fork progression. The accessory protein Mcm10 is required for robust ssDNA gating. These results reveal an Mcm10-induced pathway that preserves CMG on DNA and allows it to access a repaired fork for swift replication recovery.
Detecting adaptive differentiation in structured populations with genomic data and common gardens
Authors: Josephs Emily B. , Berg Jeremy J. , Ross-Ibarra Jeffrey , Coop Graham 
Published: July 2018

ABSTRACTAdaptation in quantitative traits often occurs through subtle shifts in allele frequencies at many loci, a process called polygenic adaptation. While a number of methods have been developed to detect polygenic adaptation in human populations, we lack clear strategies for doing so in many other systems. In particular, there is an opportunity to develop new methods that leverage datasets with genomic data and common garden trait measurements to systematically detect the quantitative traits important for adaptation. Here, we develop methods that do just this, using principal components of the relatedness matrix to detect excess divergence consistent with polygenic adaptation and using a conditional test to control for confounding effects due to population structure. We apply these methods to inbred maize lines from the USDA germplasm pool and maize landraces from Europe. Ultimately, these methods can be applied to additional domesticated and wild species to give us a broader picture of the specific traits that contribute to adaptation and the overall importance of polygenic adaptation in shaping quantitative trait variation.
PLUG (Pruning of Local Unrealistic Geometries) removes restrictions on biophysical modeling for protein design
Authors: Hallen Mark A. 
Published: July 2018

AbstractProtein design algorithms must search an enormous conformational space to identify favorable conformations. As a result, those that perform this search with guarantees of accuracy generally start with a conformational pruning step, such as dead-end elimination (DEE). However, the mathematical assumptions of DEE-based pruning algorithms have up to now severely restricted the biophysical model that can feasibly be used in protein design. To lift these restrictions, I propose to prune local unrealistic geometries (PLUG) using a linear programming-based method. PLUG’s biophysical model consists only of well-known lower bounds on interatomic distances. PLUG is intended as pre-processing for energy-based protein design calculations, whose biophysical model need not support DEE pruning. Based on 96 test cases, PLUG is at least as effective at pruning as DEE for larger protein designs—the type that most require pruning. When combined with the LUTE protein design algorithm, PLUG greatly facilitates designs that account for continuous entropy, large multistate designs with continuous flexibility, and designs with extensive continuous backbone flexibility and advanced non-pairwise energy functions. Many of these designs are tractable only with PLUG, either for empirical reasons (LUTE’s machine learning step achieves an accurate fit only after PLUG pruning), or for theoretical reasons (many energy functions are fundamentally incompatible with DEE).
Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer
Authors: Fregoso Santiago P. , Dwyer Brett E. , Franco Santos J. 
Published: July 2018

AbstractDuring neocortical development, neurons are produced by a diverse pool of neural progenitors. A subset of progenitors express theCux2gene and are fate-restricted to produce certain neuronal subtypes, but the upstream pathways that specify these progenitor fates remain unknown. To uncover the transcriptional networks that regulateCux2expression in the forebrain, we characterized a conservedCux2enhancer that we find recapitulatesCux2expression specifically in the cortical hem. Using a bioinformatic approach, we found several potential transcription factor (TF) binding sites for cortical hem-patterning TFs. We found that the homeobox transcription factor, Lmx1a, can activate theCux2enhancerin vitro. Furthermore, we show that multiple Lmx1a binding sites required for enhancer activity in the cortical hemin vivo. Mis-expression of Lmx1a in neocortical progenitors caused an increase inCux2+-lineage cells. Finally, we compared several conserved human enhancers with cortical hem-restricted activity and found that recurrent Lmx1a binding sites are a top shared feature. Uncovering the network of TFs involved in regulatingCux2expression will increase our understanding of the mechanisms pivotal in establishingCux2-lineage fates in the developing forebrain.Summary StatementAnalysis of a cortical hem-specificCux2enhancer reveals role forLmx1aas a critical upstream regulator ofCux2expression patterns in neural progenitors during early forebrain development.