bluuebunny/crossref_metadata_2025_split huggingface dataset:
The connectome is necessary but not sufficient for the spread of alpha-synuclein pathology in rats
Authors: Oliveira Miguel A.P. , Arreckx Sylvain , Di Monte Donato , Preciat German A. , Ulusoy Ayse , Fleming Ronan M.T. 
Published: April 2019

AbstractCertain neuronal populations are selectively vulnerable to alpha-synuclein pathology in Parkinson’s Disease, yet the reasons for this selectivity are unclear. Pathology affects neuronal populations that are anatomically connected although the contribution of neuronal connectivity remains to be quantitatively explored. Herein, we simulate the contribution of the connectome alone to the spread of arbitrary aggregates using a computational model of temporal spread within an abstract representation of the mouse mesoscale connectome. Our simulations are compared with the neuron-to-neuron spread of alpha-synuclein that has been observed with in vivo spreading experiments in rats. We find that neuronal connectivity appears to be compatible with the spreading pattern of alpha-synuclein pathology however, it may be per se insufficient to determine the anatomical pattern of protein spreading observed in experimental animals, suggesting a role of selective vulnerability of neuronal pathways to alpha-synuclein diffusion, accumulation and pathology.Graphical abstract
RICOPILI: Rapid Imputation for COnsortias PIpeLIne
Authors: Lam Max , Awasthi Swapnil , Watson Hunna J. , Goldstein Jackie , Panagiotaropoulou Georgia , Trubetskoy Vassily , Karlsson Robert , Frei Oleksander , Fan Chun-Chieh , De Witte Ward , Mota Nina R. , Mullins Niamh , Skarabis Nora , Huang Hailiang , Neale Benjamin , Daly Mark , Mattheissen Manuel , Walters Raymond , Ripke Stephan 
Published: April 2019

AbstractMotivationGenome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open sourced Perl-based pipeline was developed to address the challenges of rapidly processing large scale multi-cohort GWAS studies including quality control, imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing (HPC) environments.SummaryRICOPILI was created as the Psychiatric Genomics Consortium (PGC) pipeline for GWAS and has been adopted by other users. The pipeline features i) technical and genomic quality control in case-control and trio cohorts ii) genome-wide phasing and imputation iv) association analysis v) meta-analysis vi) polygenic risk scoring and vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all of the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work.Availability and ImplementationRICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL:https://sites.google.com/a/broadinstitute.org/RICOPILI/homeContactsripke@broadinstitute.orgSupplementary informationSupplementary data are available.
Molecular archaeology of the human brain
Authors: Kaczanowska Joanna , Ganglberger Florian , Galik Bence , Hess Andreas , Moodley Yoshan , Bühler Katja , Haubensak Wulf 
Published: April 2019

AbstractMapping the origin of human cognitive traits typically relies on comparing behavioral or neuroanatomical features in human phylogeny. However, such studies rely on inferences from comparative relationships and do not incorporate neurogenetic information, as these approaches are restricted to experimentally accessible species. Here, we fused evolutionary genomics with human functional neuroanatomy to reconstruct the neurogenetic evolution of human brain functions more directly and comprehensively. Projecting genome-wide selection pressure (dN/dS ratios) in sets of chronologically ordered mammalian species onto the human brain reference space unmasked spatial patterns of cumulative neurogenetic selection and co-evolving brain networks from task-evoked functional MRI and functional neuroanatomy. Importantly, this evolutionary atlas allowed imputing functional features to archaic brains from extinct hominin genomes. These data suggest accelerated neurogenetic selection for language and verbal communication across all hominin lineages. In addition, the predictions identified strategic thought and decision making as the dominant traits that may have separated anatomically modern humans (AMH) from archaic hominins.
Validity and reliability of extrastriatal [11C]raclopride binding quantification in the living human brain
Authors: Svensson Jonas E , Schain Martin , Plavén-Sigray Pontus , Cervenka Simon , Tiger Mikael , Nord Magdalena , Halldin Christer , Farde Lars , Lundberg Johan 
Published: April 2019

Abstract[11C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]raclopride: i) To assess the validity of extrastriatal [11C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [11C]raclopride BPND in temporal cortex (18±17% occupancy) and thalamus (20±17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51±4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [11C]raclopride PET is not a suitable tool for D2/3R binding quantification in extrastriatal regions.
Largest Complete Mitochondrial Genome of a Gymnosperm, Sitka Spruce (Picea sitchensis), Indicates Complex Physical Structure
Authors: Jackman Shaun D. , Coombe Lauren , Warren René L. , Kirk Heather , Trinh Eva , McLeod Tina , Pleasance Stephen , Pandoh Pawan , Zhao Yongjun , Coope Robin J. , Bousquet Jean , Bohlmann Joerg , Jones Steven J. M. , Birol Inanc 
Published: April 2019

AbstractPlant mitochondrial genomes vary widely in size. Although many plant mitochondrial genomes have been sequenced and assembled, the vast majority are of angiosperms, and few are of gymnosperms. Most plant mitochondrial genomes are smaller than a megabase, with a few notable exceptions. We have sequenced and assembled the 5.5 Mbp mitochondrial genome of Sitka spruce (Picea sitchensis), the largest complete mitochondrial genome of a gymnosperm. We sequenced the whole genome using Oxford Nanopore MinION, and then identified contigs of mitochondrial origin assembled from these long reads. The assembly graph shows a multipartite genome structure, composed of one smaller 168 kbp circular segment of DNA, and a larger 5.4 Mbp component with a branching structure. The assembly graph gives insight into a putative complex physical genome structure, and its branching points may represent active sites of recombination.
Integrated phylogenomic analyses reveal recurrent ancestral large-scale duplication events in mosses
Authors: Gao Bei , Chen Moxian , Li Xiaoshuang , Liang Yuqing , Zhang Daoyuan , Wood Andrew J. , Oliver Melvin J. , Zhang Jianhua 
Published: April 2019

SummaryMosses (Bryophyta) are a key group occupying important phylogenetic position for understanding land plant (embryophyte) evolution. The class Bryopsida represents the most diversified lineage and contains more than 95% of the modern mosses, whereas the other classes are by nature species-poor. The phylogeny of mosses remains elusive at present.Recurrent whole genome duplications have shaped the evolution trajectory of angiosperms, but little is known about the genome evolutionary history in mosses. It remains to be answered if there existed a historical genome duplication event associated with the species radiation of class Bryopsida.Here, the high-confidence moss phylogeny was generated covering major moss lineages. Two episodes of ancient genomic duplication events were elucidated by phylogenomic analyses, one in the ancestry of all mosses and another before the separation of the Bryopsida, Polytrichopsida and Tetraphidopsida, with estimated ages of the gene duplications clustered around 329 and 182 million year ago, respectively.The third episode of polyploidy event (termed ψ) was tightly associated with the early diversification of Bryopsida with an estimated age of ~87 million years. By scrutinizing the phylogenetic timing of duplicated syntelogs in Physcomitrella patens, the WGD1 and WGD2 events were confidently re-recognized as the ψ event and the Funarioideae duplication event (~65 mya), respectively. Together, our findings unveiled four episodes of polyploidy events in the evolutionary past of Physcomitrella patens.
Direct measurement of X-ray induced heating of microcrystals
Authors: Warren Anna J , Axford Danny , Owen Robin L 
Published: April 2019

AbstractTemperature control is a key aspect of macromolecular crystallography, with the technique of cryocooling routinely used to mitigate X-ray induced damage. Beam induced heating could cause the temperature of crystals to rise above the glass transition temperature, greatly increasing the rate of damage. X-ray induced heating of ruby crystals 20-40 microns in size has been quantified non-invasively by monitoring the emission wavelengths of X-ray induced fluorescence during exposure to the X-ray beam. For beamsizes and dose-rates typically used in macromolecular crystallography the temperature rises are of order 20 K. The temperature changes observed are compared with models in the literature and can be used as a validation tool for future models.SynopsisX-ray induced heating of micro-crystals is quantified through the temperature-dependent shift in X-ray induced fluorescence from ruby crystals.
ORF Capture-Seq: a versatile method for targeted identification of full-length isoforms
Authors: Sheynkman Gloria M. , Tuttle Katharine S. , Tseng Elizabeth , Underwood Jason G. , Yu Liang , Dong Da , Smith Melissa L. , Sebra Robert , Hao Tong , Calderwood Michael A. , Hill David E. , Vidal Marc 
Published: April 2019

AbstractMost human protein-coding genes are expressed as multiple isoforms. This in turn greatly expands the functional repertoire of the encoded proteome. While at least one reliable open reading frame (ORF) model has been assigned for every gene, the majority of alternative isoforms remains uncharacterized experimentally. This is primarily due to: i) vast differences of overall levels between different isoforms expressed from common genes, and ii) the difficulty of obtaining contiguous full-length ORF sequences. Here, we present ORF Capture-Seq (OCS), a flexible and cost-effective method that addresses both challenges for targeted full-length isoform sequencing applications using collections of cloned ORFs as probes. As proof-of-concept, we show that an OCS pipeline focused on genes coding for transcription factors increases isoform detection by an order of magnitude, compared to unenriched sample. In short, OCS enables rapid discovery of isoforms from custom-selected genes and will allow mapping of the full set of human isoforms at reasonable cost.
Endogenous TDP-43 prevents retrotransposons activation through Dicer-2 activity and the RNA silencing machinery in Drosophila neurons
Authors: Romano Giulia , Klima Raffaella , Feiguin Fabian 
Published: April 2019

ABSTRACTThe aberrant expression of retrotransposable elements (RTEs) was observed in different neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a terminal disorder characterized by functional alterations in the small RNA-binding protein TDP-43, suggesting that these events might be connected. Using genome wide gene expression profiles, we detected RTEs highly upregulated in TDP-43-null Drosophila heads while, the genetic rescue of TDP-43 function reverted these modifications. Furthermore, we found that TDP-43 modulates the small interfering RNA (siRNA) silencing machinery responsible for RTEs repression. Molecularly, we observed that TDP-43 regulates the expression levels of Dicer-2 by direct protein-mRNA interactionsin vivo. Accordingly, the genetic or pharmacological recovery of Dicer-2 activity was sufficient to repress retrotransposons activation and revert the neurodegeneration in TDP-43-null Drosophila motoneurons. Our results, describe a novel physiological role of endogenous TDP-43 in the prevention of RTEs-induced neurodegeneration through the modulation of Dicer-2 activity and the siRNA pathway.
Magnetic Resonance Fingerprinting with Combined Gradient- and Spin-echo Echo-planar Imaging: Simultaneous Estimation of T1, T2 and T2* with integrated-B1 Correction
Authors: Khajehim Mahdi , Christen Thomas , Chen J. Jean 
Published: April 2019

AbstractPurposeTo introduce a novel magnetic-resonance fingerprinting (MRF) framework with single-shot echo-planar imaging (EPI) readout to simultaneously estimate tissue T2, T1 and T2*, and integrate B1 correction.MethodsSpin-echo EPI is combined with gradient-echo EPI to achieve T2 estimation as well as T1 and T2* quantification. In the dictionary matching step, the GE-EPI data segment provides estimates of tissue T1 and T2* with additional B1 information, which are then incorporated into the T2-matching step that uses the SE-EPI data segment. In this way, biases in T2 and T2* estimates do not affect each other.ResultsAn excellent correspondence was found between our T1, T2, and T2* estimates and results obtained from standard approaches in both phantom and human scans. In the phantom scan, a linear relationship with R2>0.96 was found for all parameter estimates. The maximum error in the T2 estimate was found to be below 6%. In the in-vivo scan, similar contrast was noted between MRF and standard approaches, and values found in a small region of interest (ROI) located in the grey matter (GM) were in line with previous measurements (T2MRF=88±7ms vs T2Ref=89±11ms, T1MRF=1153±154ms vs T1Ref=1122±52ms, T2*MRF=56±4ms vs T2*Ref=53±3ms).ConclusionAdding a spin echo data segment to EPI based MRF allows accurate and robust measurements of T2, T1 and T2* relaxation times. This MRF framework is easier to implement than spiral-based MRF. It doesn’t suffer from undersampling artifacts and seems to require a smaller dictionary size that can fasten the reconstruction process.
A Two-Component System that Modulates Cyclic-di-GMP Metabolism PromotesLegionella pneumophilaDifferentiation and Viability in Low-Nutrient Conditions
Authors: Hughes Elisa D. , Byrne Brenda G. , Swanson Michele S. 
Published: April 2019

ABSTRACTDuring its life cycle, the environmental pathogenLegionella pneumophilaalternates between a replicative and a transmissive cell type when cultured in broth, macrophages, or amoebae. Within a protozoan host,L. pneumophilafurther differentiates into the hardy cell type known as the Mature Infectious Form (MIF). The second messenger cyclic-di-GMP coordinates lifestyle changes in many bacterial species, but its role in theL. pneumophilalife cycle is less understood. Using anin vitrobroth culture model that approximates the intracellular transition from the replicative to transmissive form, here we investigate the contribution toL. pneumophiladifferentiation of a two-component system (TCS) that regulates cyclic-di-GMP metabolism. The TCS is encoded bylpg0278-lpg0277and is co-transcribed withlpg0279, which encodes a protein upregulated in MIF cells. Using agfp-reporter, we demonstrate that the promoter for this operon is RpoS-dependent and induced in nutrient-limiting conditions that do not support replication. The response regulator of the TCS (Lpg0277) is a bifunctional enzyme that both synthesizes and degrades cyclic-di-GMP. Using a panel of site-directed point mutants, we show that cyclic-di-GMP synthesis mediated by a conserved GGDEF domain promotes growth arrest of replicativeL. pneumophila, production of pigment and poly-3-hydroxybutyrate storage granules, and viability in nutrient-limiting conditions. Genetic epistasis tests predict that the MIF protein Lpg0279 acts upstream of the TCS as a negative regulator. Thus,L. pneumophilais equipped with a regulatory network in which cyclic-di-GMP stimulates the switch from a replicative to a resilient state equipped to survive in low-nutrient environments.IMPORTANCEAlthough an intracellular pathogen,L. pneumophilahas developed mechanisms to ensure long-term survival in low-nutrient aqueous conditions. Eradication ofL. pneumophilafrom contaminated water supplies has proven challenging, as outbreaks have been traced to previously remediated systems. Understanding the genetic determinants that supportL. pneumophilapersistence in low-nutrient environments can inform design of remediation methods. Here we characterize a genetic locus that encodes a two-component signaling system (lpg0278-lpg0277) and a putative regulator protein (lpg0279) that modulates production of the messenger molecule cyclic-di-GMP. We show that this locus promotes bothL. pneumophilacell differentiation and survival in nutrient-limiting conditions, thus advancing our understanding of the mechanisms that contribute toL. pneumophilaenvironmental resilience.
Genomic Analysis of Emerging Florfenicol-Resistant Campylobacter coli Isolated from the Intestinal Cecal Contents of Cattle in the United States
Authors: Zhao Shaohua , Mukherjee Sampa , Hsu Chih-Hao , Young Shenia , Li Cong , Tate Heather , Morales Cesar A. , Haro Jovita , Thitaram Sutawee , Tillman Glenn E. , Dessai Uday , McDermott Patrick 
Published: April 2019

AbstractObjectiveGenomic analyses were performed on florfenicol resistant (FFNR) Campylobacter coli (C. coli) isolated from cattle and the cfr(C) gene-associated multi-drug resistance (MDR) plasmid was characterized.MethodsSixteen FFNRC. coli isolates recovered between 2013-2018 from beef cattle were sequenced using MiSeq. Genomes and plasmids were closed for three of the isolates using the PacBio® system. Single nucleotide polymorphisms (SNPs) across the genome and the structures of MDR plasmids were investigated. Conjugation experiments were performed to determine the transferability of cfr(C) associated MDR plasmids. The spectrum of resistance encoded by the cfr(C) gene was further investigated by agar dilution antimicrobial susceptibility testing.ResultsAll 16 FFNR isolates were MDR and exhibited co-resistance to ciprofloxacin, nalidixic acid, clindamycin and tetracycline. All isolates shared the same resistance genotype, carrying aph(3’)-III, hph, ∆aadE (truncated), blaOXA-61, cfr(C), and tet(O) genes plus a mutation of GyrA T86I. The cfr(C), aph(3’)-III, hph ∆aadE, and tet(O) genes were co-located on transferable MDR plasmids with size 48-50 kb. These plasmids showed high sequence homology with the pTet plasmid, and carried several Campylobacter virulence genes, including virB2, virB4, virB5, VirB6, virB7, virB8, virb9, virB10, virB11 and virD4. The cfr(C) gene conferred resistance to florfenicol (8-32 µg/ml), clindamycin (512-1,024 µg/ml), linezolid (128-512 µg/ml), and tiamulin (1,024 µg/ml). Phylogenetic analysis showed SNP differences ranging from 11-2,248 among the 16 isolates.ConclusionsThe results showed that the cfr(C) gene located in the conjugative pTet MDR/virulence plasmid is present in diverse strains, where it confers high levels of resistance to several antimicrobials, including linezolid, a critical drug for treating Gram positive bacterial infections in humans. This study highlights the power of genomic antimicrobial resistance surveillance to uncover the intricacies of transmissible co-resistance and provides information that is needed for accurate risk assessment and mitigation strategies.
Spatio-temporal analysis of human preimplantation development reveals dynamics of epiblast and trophectoderm
Authors: Meistermann Dimitri , Loubersac Sophie , Reignier Arnaud , Firmin Julie , Campion Valentin Francois , Kilens Stéphanie , Lelièvre Yohann , Lammers Jenna , Feyeux Magalie , Hulin Phillipe , Nedellec Steven , Bretin Betty , Covin Simon , Castel Gael , Bihouée Audrey , Soumillon Magali , Mikkelsen Tarjei , Barrière Paul , Bourdon Jérémie , Fréour Thomas , David Laurent 
Published: April 2019

AbstractRecent technological advances such as single-cell RNAseq1-3and CRISPR-CAS9-mediated knock-out4have allowed an unprecedented access into processes orchestrating human preimplantation development5. However, the sequence of events which occur during human preimplantation development are still unknown. In particular, timing of first human lineage specification, the process by which the morula cells acquire a specific fate, remains elusive. Here, we present a human preimplantation development model based on transcriptomic pseudotime modelling of scRNAseq biologically validated by spatial information and precise time-lapse staging. In contrast to mouse, we show that trophectoderm (TE) / inner cell mass (ICM) lineage specification in human is only detectable at the transcriptomic level at the blastocyst stage, just prior to expansion. We validated the expression profile of novel markers enabling precise staging of human preimplantation embryos, such as IFI16 which highlights establishment of epiblast (EPI) and NR2F2 which appears at the transition from specified to mature TE. Strikingly, mature TE cells arise from the polar side, just after specification, supporting a model of polar TE cells driving TE maturation. Altogether, our study unravels the first lineage specification event in the human embryo and provides a browsable resource for mapping spatio-temporal events underlying human lineage specification.
Discovery of small-molecule inhibitors targeting the ribosomal peptidyl transferase center (PTC) ofM. tuberculosis
Authors: Tam Benjamin , Sherf Dror , Cohen Shira , Eisdorfer Sarah Adi , Perez Moshe , Soffer Adam , Vilenchik Dan , Akabayov Sabine Ruth , Wagner Gerhard , Akabayov Barak 
Published: April 2019

AbstractM. tuberculosis(Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of theMtbribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50values, which were significantly improved over standard antibiotic drugs.