bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo
Authors: Kur Ivan-Maximiliano , Prouvot Pierre-Hugues , Fu Ting , Fan Wei , Müller-Braun Felicia , Das Avash , Das Saumya , Deller Thomas , Roeper Jochen , Stroh Albrecht , Momma Stefan 
Published: August 2019

AbstractCommunication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are either by individual molecules such as cytokines carried by blood, by neural transmission, or in more severe pathologies, by entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs) but the parameters that determine their uptake are unknown. We show that transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object recognition. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.
Early eukaryotic origins and metazoan elaboration of MAPR family proteins
Authors: Hehenberger Elisabeth , Eitel Michael , Fortunato Sofia A.V. , Miller David J. , Keeling Patrick J. , Cahill Michael A. 
Published: August 2019

ABSTRACTBackgroundThe membrane-associated progesterone receptor (MAPR) family consists of heme-binding proteins containing a cytochrome b5(cytb5) domain characterized by the presence of a MAPR-specific interhelical insert region (MIHIR) between helices 3 and 4 of the canonical cytb5-domain fold. Animals possess three MAPR families (PGRMC-like, Neuferricin and Neudesin).ResultsHere we show that all animal MAPR families were already present in the common ancestor of the Opisthokonta (comprising animals and fungi as well as related protistan taxa). All three MAPR genes acquired extensions C-terminal to the cytb5domain, either before or with the evolution of animals. The archetypical MAPR protein, progesterone receptor membrane component 1 (PGRMC1), contains phosphorylated tyrosines Y139 and Y180. The combination of Y139/Y180 appeared in the common ancestor of Cnidaria and bilaterally symmetrical animals, along with an early embryological organizer and synapsed neurons, and is strongly conserved in all bilateral animals. A predicted protein interaction motif in the PGRMC1 MIHIR is potentially regulated by Y139 phosphorylation. A multilayered model of animal MAPR function acquisition includes some pre-metazoan functions (e.g., heme binding and cytochrome P450 interactions) and some acquired animal-specific functions that involve regulation of strongly conserved protein interaction motifs acquired by early-branching animals.ConclusionsThis study provides a conceptual framework for future studies, against which PGRMC1’s multiple functions can perhaps be stratified and functionally dissected. In accompanying papers we show that mutational perturbation of PGRMC1 phosphorylation status of the Y180 motif is associated with dramatic changes cell pasticity assayed by protein abundances, cell morphology, mitochondrial function, genomic stability, and epigenetic status, with pathways analysis associating Y180 mutation with processes related to organizer function. These combined works reveal previously unrecognized involvement of PGRMC1 in foundational animal processes of great relevance to disease.
Selective enhancement of object representations through multisensory integration
Authors: Tovar David A. , Murray Micah M. , Wallace Mark T. 
Published: August 2019

AbstractObjects are the fundamental building blocks of how we create a representation of the external world. One major distinction amongst objects is between those that are animate versus inanimate. Many objects are specified by more than a single sense, yet the nature by which multisensory objects are represented by the brain remains poorly understood. Using representational similarity analysis of human EEG signals, we show enhanced encoding of audiovisual objects when compared to their corresponding visual and auditory objects. Surprisingly, we discovered the often-found processing advantages for animate objects was not evident in a multisensory context due to greater neural enhancement of inanimate objects—the more weakly encoded objects under unisensory conditions. Further analysis showed that the selective enhancement of inanimate audiovisual objects corresponded with an increase in shared representations across brain areas, suggesting that neural enhancement was mediated by multisensory integration. Moreover, a distance-to-bound analysis provided critical links between neural findings and behavior. Improvements in neural decoding at the individual exemplar level for audiovisual inanimate objects predicted reaction time differences between multisensory and unisensory presentations during a go/no-go animate categorization task. Interestingly, links between neural activity and behavioral measures were most prominent 100 to 200ms and 350 to 500ms after stimulus presentation, corresponding to time periods associated with sensory evidence accumulation and decision-making, respectively. Collectively, these findings provide key insights into a fundamental process the brain uses to maximize information it captures across sensory systems to perform object recognition.Significance StatementOur world is filled with an ever-changing milieu of sensory information that we are able to seamlessly transform into meaningful perceptual experience. We accomplish this feat by combining different features from our senses to construct objects. However, despite the fact that our senses do not work in isolation but rather in concert with each other, little is known about how the brain combines the senses together to form object representations. Here, we used EEG and machine learning to study how the brain processes auditory, visual, and audiovisual objects. Surprisingly, we found that non-living objects, the objects which were more difficult to process with one sense alone, benefited the most from engaging multiple senses.
Radiation-Induced DNA Damage and Repair Effects on 3D Genome Organization
Authors: Sanders Jacob T. , Freeman Trevor F. , Xu Yang , Golloshi Rosela , Stallard Mary A. , Martin Rebeca San , Balajee Adayabalam S. , McCord Rachel Patton 
Published: August 2019

ABSTRACTThe three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. Fibroblasts, lymphoblasts, and ATM-deficient fibroblasts were irradiated with 5 Gy X-rays and Hi-C was performed after 30 minutes, 24 hours, or 5 days after irradiation. 3D genome changes after irradiation were cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibited an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation was not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.
Massive parallel variant characterization identifiesNUDT15alleles associated with thiopurine toxicity
Authors: Suiter Chase C. , Moriyama Takaya , Matreyek Kenneth A. , Yang Wentao , Scaletti Emma Rose , Nishii Rina , Yang Wenjian , Hoshitsuki Keito , Singh Minu , Trehan Amita , Parish Chris , Smith Colton , Bhojwani Deepa , Yuen Liz YP , Li Chi-kong , Li Chak-ho , Yang Yung-li , Walker Gareth J , Goodhand James R , Kennedy Nicholas A , Klussmann Federico Antillon , Bhatia Smita , Relling Mary V. , Kato Motohiro , Hori Hiroki , Bhatia Prateek , Ahmad Tariq , Yoeh Allen E. J. , Stenmark Pål , Fowler Douglas M. , Yang Jun J. 
Published: August 2019

AbstractAs a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently,NUDT15deficiency was identified as a novel genetic cause of thiopurine toxicity, andNUDT15-informed preemptive dose reduction is quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine variants’ effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino-acid resolution. Functional effects forNUDT15variants accurately predicted toxicity risk alleles in 2,398 patients treated with thiopurines, with 100% sensitivity and specificity, in contrast with poor performance of bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,103 deleteriousNUDT15variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
Cryptococcus neoformansevades pulmonary immunity by modulating xylose precursor transport
Authors: Li Lucy X. , Hole Camaron R. , Rangel-Moreno Javier , Khader Shabaana A. , Doering Tamara L. 
Published: August 2019

ABSTRACTCryptococcus neoformansis a fungal pathogen that kills almost 200,000 people each year and is distinguished by abundant and unique surface glycan structures that are rich in xylose. A mutant strain ofC. neoformansthat cannot transport xylose precursors into the secretory compartment is severely attenuated in virulence in mice, yet surprisingly is not cleared. We found that this strain failed to induce the non-protective T helper cell type 2 (Th2) responses characteristic of wild-type infection, instead promoting sustained Interleukin (IL)-12p40 induction and increased IL-17A (IL-17) production. It also stimulated dendritic cells to release high levels of pro-inflammatory cytokines, a behavior we linked to xylose expression. We further discovered that inducible bronchus associated lymphoid tissue (iBALT) forms in response to infection with either wild-type cryptococci or the mutant strain with reduced surface xylose; although iBALT formation is slowed in the latter case, the tissue is better organized. Finally, our temporal studies suggest that lymphoid structures in the lung restrict the spread of mutant fungi for at least 18 weeks after infection, in contrast to ineffective control of the pathogen after infection with wild-type cells. These studies demonstrate the role of xylose in modulation of host response to a fungal pathogen and show that cryptococcal infection triggers iBALT formation.
The Plasmodium falciparum protein VCAP1 controls Maurer’s cleft morphology, knob architecture and PfEMP1 trafficking
Authors: McHugh Emma , Carmo Olivia , Blanch Adam , Looker Oliver , Liu Boyin , Tiash Snigdha , Andrew Dean , Batinovic Steven , Low J.Y Andy , McMillan Paul , Tilley Leann , Dixon Matthew W.A 
Published: August 2019

AbstractThe malaria parasite, Plasmodium falciparum, traffics the virulence protein, P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurer’s clefts. We developed a method for efficient enrichment of Maurer’s clefts and profiled the protein composition of this trafficking organelle. We identified 13 previously uncharacterised or poorly characterised Maurer’s cleft proteins. We generated transfectants expressing GFP-fusions of 7 proteins and confirmed their Maurer’s cleft location. Using co-immunoprecipitation and mass spectrometry we have generated a protein interaction map of proteins at the Maurer’s clefts. We identified two key clusters that may function in the loading and unloading of PfEMP1 into and out of the Maurer’s clefts. We focus on a putative PfEMP1 loading complex that includes the newly characterised virulence complex assembly protein 1 (VCAP1). Disruption of VCAP1 causes Maurer’s cleft fragmentation, aberrant knobs, ablation of PfEMP1 surface expression and loss of the PfEMP1 directed adhesion. ΔVCAP1 parasite lines have a growth advantage compared to wildtype parasites; and the infected RBCs are more deformable and more osmotically fragile.ImportanceThe trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite infected RBCs is central to severe adhesion related pathologies such as cerebral and placental malaria. This work adds to our understanding of how PfEMP1 is trafficked to the RBC membrane by defining the protein-protein interaction networks that function at the Maurer’s clefts controlling PfEMP1 loading and unloading. This work adds significantly to our understanding of virulence protein trafficking and will provide crucial knowledge that will be required to determine the mechanisms underpinning parasite driven host cell remodelling, parasite survival within the host and virulence mechanisms.
A single-cell transcriptomics CRISPR-activation screen identifies new epigenetic regulators of zygotic genome activation
Authors: Alda-Catalinas Celia , Bredikhin Danila , Hernando-Herraez Irene , Kubinyecz Oana , Santos Fátima , Eckersley-Maslin Mélanie A. , Stegle Oliver , Reik Wolf 
Published: August 2019

AbstractZygotic genome activation (ZGA) is a crucial developmental milestone that remains poorly understood. This first essential transcriptional event in embryonic development coincides with extensive epigenetic reprogramming processes and is orchestrated, in part, by the interplay of transcriptional and epigenetic regulators. Here, we developed a novel high-throughput screening method that combines pooled CRISPR-activation (CRISPRa) with single-cell transcriptomics to systematically probe candidate regulators of ZGA. We screened 230 epigenetic and transcriptional regulators by upregulating their expression with CRISPRa in mouse embryonic stem cells (ESCs). Through single-cell RNA-sequencing (scRNA-seq) of CRISPRa-perturbed cells, we generated approximately 200,000 single-cell transcriptomes, each transduced with a unique short-guide RNA (sgRNA) targeting a specific candidate gene promoter. Using integrative dimensionality reduction of the perturbation scRNA-seq profiles, we characterized molecular signatures of ZGA and uncovered 44 factors that promote a ZGA-like response in ESCs, both in the coding and non-coding transcriptome. Upon upregulation of these factors, including the DNA binding protein Dppa2, the chromatin remodeller Smarca5 and the transcription factor Patz1, ESCs adopt an early embryonic-like state. Supporting their roles as ZGA regulators, Dppa2 and Smarca5 knock-out ESCs lose expression of ZGA genes, however, overexpression of Dppa2 in Smarca5 knock-out ESCs, but not vice versa, rescues ZGA-like expression, suggesting that Smarca5 regulates ZGA upstream and via Dppa2. Together, our single-cell transcriptomic profiling of CRISPRa-perturbed cells provides comprehensive system-level insights into the molecular mechanisms that orchestrate ZGA.HighlightsFirst large-scale screen combining pooled CRISPRa with scRNA-seq.Multi-omics factor analysis identifies a ZGA-like signature for 44 of the candidate regulators.Dppa2, Smarca5 and Patz1 were validated as strong inducers of ZGA gene expression.Smarca5 regulates zygotic genome activation in a Dppa2-dependent manner.
Transient primary cilia mediate robust Hedgehog pathway-dependent cell cycle control
Authors: Ho Emily K. , Tsai Anaïs E. , Stearns Tim 
Published: August 2019

SummaryThe regulation of proliferation is one of the primary functions of Hedgehog (Hh) signaling in development. Transduction of Hh signaling requires the primary cilium, a microtubule-based organelle that is necessary for several steps in the pathway (Corbit et al., 2005; Huangfu and Anderson, 2005; Huangfu et al., 2003; Liu et al., 2005; Rohatgi et al., 2007). Many cells only build a primary cilium upon cell cycle arrest in G0. In those proliferating cells that do make a cilium, it is a transient organelle, being assembled in G1 and disassembled sometime after, although exactly when is not well-characterized (Ford et al., 2018; Pugacheva et al., 2007; Wang and Dynlacht, 2018). Thus the requirement for primary cilia presents a conundrum: how are proliferative signals conveyed through an organelle that is present for only part of the cell cycle? Here we investigate this question in a mouse medulloblastoma cell line, SMB55, that requires cilium-mediated Hh pathway activity for proliferation (Zhao et al., 2015). We show that SMB55 cells are often ciliated beyond G1 into S phase, and the presence of the cilium determines the periods of Hh pathway activity. Using live imaging over multiple cell cycles, we define two windows of opportunity for Hh pathway activity, either of which is sufficient to effect cell cycle entry. The first is in the ciliated phase of the previous cell cycle, and the second is in G1 of the cell cycle in which the decision is made. We propose that the ability of cells to integrate Hh pathway activity from more than one cell cycle imparts robustness on Hh pathway control of proliferation and may have implications for other Hh-mediated events in development.
Evolution of the PRD1-adenovirus lineage: a viral tree of life incongruent with the cellular universal tree of life
Authors: Woo Anthony C. , Gaia Morgan , Guglielmini Julien , Da Cunha Violette , Forterre Patrick 
Published: August 2019

AbstractDouble-stranded DNA viruses of the PRD1-adenovirus lineage are characterized by homologous major capsid proteins containing one or two β-barrel domains known as the jelly roll folds. Most of them also share homologous packaging ATPases of the FtsK/HerA superfamily P-loop ATPases. Remarkably, members of this lineage infect hosts from the three domains of life, suggesting that viruses from this lineage could be very ancient and share a common ancestor. Here we analyzed the evolutionary history of these cosmopolitan viruses by inferring phylogenies based on single or concatenated genes. These viruses can be divided into two supergroups infecting either eukaryotes or prokaryotes. The latter can be further divided into two groups of bacterioviruses and one group of archaeoviruses. This viral tree is thus incongruent with the cellular tree of life in which Archaea are closer to Eukarya and more divergent from Bacteria. We discuss various evolutionary scenarios that could explain this paradox.
Mannose receptor is a restriction factor of HIV in macrophages and is counteracted by the accessory protein Vpr
Authors: Lubow Jay , Collins David R. , Mashiba Mike , Peterson Brian , Virgilio Maria , Collins Kathleen L 
Published: August 2019

AbstractHIV-1 Vpr is necessary to support HIV infection and spread in macrophages. Evolutionary conservation of Vpr suggests an important yet poorly understood role for macrophages in HIV pathogenesis. Vpr counteracts a previously unknown macrophage-specific restriction factor that targets and reduces the expression of HIV Env. Here, we report that the macrophage mannose receptor (MR), is the restriction factor targeting Env in primary human monocyte-derived macrophages. Vpr acts synergistically with HIV Nef to target distinct stages of the MR biosynthetic pathway and dramatically reduce MR expression. Silencing MR or deleting mannose residues on Env rescues Env expression in HIV-1-infected macrophages lacking Vpr. However, we also show that disrupting interactions between Env and MR reduces initial infection of macrophages by cell-free virus. Together these results reveal a Vpr-Nef-Env axis that hijacks a macrophage mannose-MR response system to facilitate infection while evading MR’s normal role, which is to trap and destroy mannose-expressing pathogens.
Global adaptation confounds the search for local adaptation
Authors: Booker Tom R. , Yeaman Sam , Whitlock Michael C. 
Published: August 2019

AbstractSpatially varying selection promotes variance in allele frequencies, increasing genetic differentiation between the demes of a metapopulation. For that reason, outliers in the genome wide distribution of summary statistics measuring genetic differentiation, such asFST, are often interpreted as evidence for alleles which contribute to local adaptation. However, in spatially structured populations, the spread of beneficial mutations with spatially uniform effects can also induce transient genetic differentiation and numerous theoretical studies have suggested that species-wide, or global, adaptation makes a substantial contribution to molecular evolution. In this study, we ask whether such global adaptation affects the genome-wide distribution ofFSTand generates statistical outliers which could be mistaken for local adaptation. Using forward-in-time population genetic simulations assuming parameters for the rate and strength of beneficial mutations similar to those that have been estimated for natural populations, we show the spread of globally beneficial in parapatric populations can readily generateFSToutliers, which may be misinterpreted as evidence for local adaptation. The spread of beneficial mutations causes selective sweeps at flanking sites, so the effects of global versus local adaptation may be distinguished by examining patterns of nucleotide diversity along withFST. Our study suggests that global adaptation should be considered in the interpretation of genome-scan results and the design of future studies aimed at understanding the genetic basis of local adaptation.
Genome of an iconic Australian bird: Chromosome-scale assembly and linkage map of the superb fairy-wren (Malurus cyaneus)
Authors: Peñalba Joshua V. , Deng Yuan , Fang Qi , Joseph Leo , Moritz Craig , Cockburn Andrew 
Published: August 2019

AbstractThe superb fairy-wren, Malurus cyaneus, is one of the most iconic Australian passerine species. This species belongs to an endemic Australasian clade, Meliphagides, which diversified early in the evolution of the oscine passerines. Today, the oscine passerines comprise almost half of all avian species diversity. Despite the rapid increase of available bird genome assemblies, this part of the avian tree has not yet been represented by a high-quality reference. To rectify that, we present the first chromosome-scale genome assembly of a Meliphagides representative: the superb fairy-wren. We combined Illumina shotgun and mate-pair sequences, PacBio long-reads, and a genetic linkage map from an intensively sampled pedigree of a wild population to generate this genome assembly. Of the final assembled 1.07Gb genome, 894Mb (84.8%) was anchored onto 25 chromosomes resulting in a final scaffold N50 of 68.11 Mb. This high-quality bird genome assembly is also one of only a handful which is also accompanied by a genetic map and recombination landscape. In comparison to other pedigree-based bird genetic maps, we find that the zebrafinch (Taeniopygia) genetic map more closely resembles the fairy-wren map rather than the map from the more closely-related Ficedula flycatcher. Lastly, we also provide a predictive gene and repeat annotation of the genome assembly. This new high quality, annotated genome assembly will be an invaluable resource not only to the superb fairy-wren species and relatives but also broadly across the avian tree by providing a new reference point for comparative genomic analyses.