bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing a macromolecular machine: Architecture and evolution of the F7 chemosensory system
Authors: Ortega Davi R. , Subramanian Poorna , Mann Petra , Kjær Andreas , Chen Songye , Watts Kylie J. , Pirbadian Sahand , Collins David A. , Kooger Romain , Kalyuzhnaya Marina G. , Ringgaard Simon , Briegel Ariane , Jensen Grant J. 
Published: May 2019

ABSTRACTHow complex, multi-component macromolecular machines evolved remains poorly understood. Here we reveal the evolutionary origins of the chemosensory machinery that controls flagellar motility inEscherichia coli. We first identified ancestral forms still present inVibrio cholerae, Pseudomonas aeruginosa, Shewanella oneidensisandMethylomicrobium alcaliphilum, characterizing their structures by electron cryotomography and finding evidence that they function in a stress response pathway. Using bioinformatics, we then traced the evolution of the system through γ-Proteobacteria, pinpointing key evolutionary events that led to the machine now seen inE. coli.Our results suggest that two ancient chemosensory systems with different inputs and outputs (F6 and F7) existed contemporaneously, with one (F7) ultimately taking over the inputs and outputs of the other (F6), which was subsequently lost.
Genomic diversity affects the accuracy of bacterial SNP calling pipelines
Authors: Bush Stephen J. , Foster Dona , Eyre David W. , Clark Emily L. , De Maio Nicola , Shaw Liam P. , Stoesser Nicole , Peto Tim E. A. , Crook Derrick W. , Walker A. Sarah 
Published: May 2019

AbstractBackgroundAccurately identifying SNPs from bacterial sequencing data is an essential requirement for using genomics to track transmission and predict important phenotypes such as antimicrobial resistance. However, most previous performance evaluations of SNP calling have been restricted to eukaryotic (human) data. Additionally, bacterial SNP calling requires choosing an appropriate reference genome to align reads to, which, together with the bioinformatic pipeline, affects the accuracy and completeness of a set of SNP calls obtained.This study evaluates the performance of 41 SNP calling pipelines using simulated data from 254 strains of 10 clinically common bacteria and real data from environmentally-sourced and genomically diverse isolates within the genera Citrobacter, Enterobacter, Escherichia and Klebsiella.ResultsWe evaluated the performance of 41 SNP calling pipelines, aligning reads to genomes of the same or a divergent strain. Irrespective of pipeline, a principal determinant of reliable SNP calling was reference genome selection. Across multiple taxa, there was a strong inverse relationship between pipeline sensitivity and precision, and the Mash distance (a proxy for average nucleotide divergence) between reads and reference genome. The effect was especially pronounced for diverse, recombinogenic, bacteria such as Escherichia coli, but less dominant for clonal species such as Mycobacterium tuberculosis.ConclusionsThe accuracy of SNP calling for a given species is compromised by increasing intra-species diversity. When reads were aligned to the same genome from which they were sequenced, among the highest performing pipelines was Novoalign/GATK. However, across the full range of (divergent) genomes, among the consistently highest-performing pipelines was Snippy.
Statistical learning attenuates visual activity only for attended stimuli
Authors: Richter David , de Lange Floris P. 
Published: May 2019

AbstractPerception and behavior can be guided by predictions, which are often based on learned statistical regularities. Neural responses to expected stimuli are frequently found to be attenuated after statistical learning. However, whether this sensory attenuation following statistical learning occurs automatically or depends on attention remains unknown. In the present fMRI study, we exposed human volunteers to sequentially presented object stimuli, in which the first object predicted the identity of the second object. We observed a strong attenuation of neural activity for expected compared to unexpected stimuli in the ventral visual stream. Crucially, this sensory attenuation was only apparent when stimuli were attended, and vanished when attention was directed away from the predictable objects. These results put important constraints on neurocomputational theories that cast perception as a process of probabilistic integration of prior knowledge and sensory information.
Identification of new therapeutic targets inCRLF2-overexpressing B-ALL through discovery of TF-gene regulatory interactions
Authors: Badri Sana , Carella Beth , Lhoumaud Priscillia , Castro Dayanne M. , Gibbs Claudia Skok , Raviram Ramya , Narang Sonali , Evensen Nikki , Watters Aaron , Carroll William , Bonneau Richard , Skok Jane A. 
Published: May 2019

ABSTRACTAlthough genetic alterations are initial drivers of disease, aberrantly activated transcriptional regulatory programs are often responsible for the maintenance and progression of cancer.CRLF2-overexpression in B-ALL patients leads to activation of JAK-STAT, PI3K and ERK/MAPK signaling pathways and is associated with poor outcome. Although inhibitors of these pathways are available, there remains the issue of treatment-associated toxicities, thus it is important to identify new therapeutic targets. Using a network inference approach, we reconstructed a B-ALL specific transcriptional regulatory network to evaluate the impact ofCRLF2-overexpression on downstream regulatory interactions.Comparing RNA-seq fromCRLF2-High and other B-ALL patients (CRLF2-Low), we defined aCRLF2-High gene signature. Patient-specific chromatin accessibility was interrogated to identify altered putative regulatory elements that could be linked to transcriptional changes. To delineate these regulatory interactions, a B-ALL cancer-specific regulatory network was inferred using 868 B-ALL patient samples from the NCI TARGET database coupled with priors generated from ATAC-seq peak TF-motif analysis. CRISPRi, siRNA knockdown and ChIP-seq of nine TFs involved in the inferred network were analyzed to validate predicted TF-gene regulatory interactions.In this study, a B-ALL specific regulatory network was constructed using ATAC-seq derived priors. Inferred interactions were used to identify differential patient-specific transcription factor activities predicted to controlCRLF2-High deregulated genes, thereby enabling identification of new potential therapeutic targets.
The Crk adapter protein is essential forDrosophilaembryogenesis, where it regulates multiple actin-dependent morphogenic events
Authors: Spracklen Andrew J. , Thornton-Kolbe Emma M. , Bonner Alison N. , Florea Alexandru , Compton Peter J. , Fernandez-Gonzalez Rodrigo , Peifer Mark 
Published: May 2019

AbstractSmall SH2/SH3 adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The Crk family has tissue-specific roles in phagocytosis, cell migration and neuronal development, and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of theDrosophilagene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with shRNA and CRISPR technology to assess Crk’s function inDrosophilamorphogenesis. We found Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates levels of the Arp2/3 complex, its regulator SCAR, and F-actin in actin caps and pseudocleavage furrows. Crk loss leads to loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.
Identification of 3’ UTR motifs required for mRNA localization to myelin sheaths in vivo
Authors: Yergert Katie M. , O’Rouke Rebecca , Hines Jacob H. , Appel Bruce 
Published: May 2019

ABSTRACTMyelin is a specialized membrane produced by oligodendrocytes that insulates and supports axons. Oligodendrocytes extend numerous cellular processes, as projections of the plasma membrane, and simultaneously wrap multiple layers of myelin membrane around target axons. Notably, myelin sheaths originating from the same oligodendrocyte are variable in size, suggesting local mechanisms regulate myelin sheath growth. Purified myelin contains ribosomes and hundreds of mRNAs, supporting a model that mRNA localization and local protein synthesis regulate sheath growth and maturation. However, the mechanisms by which mRNAs are selectively enriched in myelin sheaths are unclear. To investigate how mRNAs are targeted to myelin sheaths, we tested the hypothesis that transcripts are selected for myelin enrichment through consensus sequences in the 3’ untranslated region (3’ UTR). Using methods to visualize mRNA in living zebrafish larvae, we identified candidate 3’ UTRs that were sufficient to localize mRNA to sheaths and enriched near growth zones of nascent membrane. We bioinformatically identified motifs common in 3’ UTRs from three myelin-enriched transcripts and determined that these motifs are required for mRNA transport to myelin sheaths. Finally, we show that one motif is highly enriched in the myelin transcriptome, suggesting that this sequence is a global regulator of mRNA localization during developmental myelination.
Transparency, a better camouflage than crypsis in cryptically coloured moths
Authors: Arias Mónica , Elias Marianne , Andraud Christine , Berthier Serge , Gomez Doris 
Published: May 2019

AbstractPredation is a ubiquitous and strong selective pressure on living organisms. Transparency is a predation defence widespread in water but rare on land. Some Lepidoptera display transparent patches combined with already cryptic opaque patches. While transparency has recently been shown to reduce detectability in conspicuous prey, we here test whether transparency decreases detectability in already cryptically-coloured terrestrial prey, by conducting field predation experiments with free avian predators and artificial moths. We monitored and compared survival of a fully opaque grey artificial form (cryptic), a form including transparent windows and a wingless artificial butterfly body. Survival of the transparent forms was similar to that of wingless bodies and higher than that of fully opaque forms, suggesting a reduction of detectability conferred by transparency. This is the first evidence that transparency decreases detectability in cryptic terrestrial prey. Future studies should explore the organisation of transparent and opaque patches on the animal body and their interplay on survival, as well as the costs and other potential benefits associated to transparency on land.
Doxorubicin-loaded human serum albumin nanoparticles overcome transporter-mediated drug resistance
Authors: Onafuye Hannah , Pieper Sebastian , Mulac Dennis , Cinatl Jindrich , Wass Mark N. , Langer Klaus , Michaelis Martin 
Published: May 2019

AbstractResistance to systemic drug therapies is a major reason for the failure of anti-cancer therapies. Here, we tested doxorubicin-loaded human serum albumin (HSA) nanoparticles in the neuroblastoma cell line UKF-NB-3 and its ABCB1-expressing sublines adapted to vincristine (UKF-NB-3rVCR1) and doxorubicin (UKF-NB-3rDOX20). Doxorubicin-loaded nanoparticles displayed increased anti-cancer activity in UKF-NB-3rVCR1and UKF-NB-3rDOX20cells relative to doxorubicin solution, but not in UKF-NB-3 cells. UKF-NB-3rVCR1cells were resensitised by nanoparticle-encapsulated doxorubicin to the level of UKF-NB-3 cells. UKF-NB-3rDOX20cells displayed a more pronounced resistance phenotype than UKF-NB-3rVCR1cells and were not re-sensitised by doxorubicin-loaded nanoparticles to the level of parental cells. ABCB1 inhibition using zosuquidar resulted in similar effects like nanoparticle incorporation, indicating that doxorubicin-loaded nanoparticles circumvent ABCB1-mediated drug efflux. The limited re-sensitisation of UKF-NB-3rDOX20cells to doxorubicin by circumvention of ABCB1-mediated efflux is probably due to the presence of multiple doxorubicin resistance mechanisms. So far, ABCB1 inhibitors have failed in clinical trials, probably because systemic ABCB1 inhibition results in a modified body distribution of its many substrates including drugs, xenobiotics, and other molecules. HSA nanoparticles may provide an alternative, more specific way to overcome transporter-mediated resistance.
Combinatorial prediction of marker panels from single-cell transcriptomic data
Authors: Delaney Conor , Schnell Alexandra , Cammarata Louis V. , Yao-Smith Aaron , Regev Aviv , Kuchroo Vijay K. , Singer Meromit 
Published: May 2019

AbstractSingle-cell transcriptomic studies are identifying novel cell populations with exciting functional roles in variousin vivocontexts, but identification of succinct gene-marker panels for such populations remains a challenge. In this work we introduce COMET, a computational framework for the identification of candidate marker panels consisting of one or more genes for cell populations of interest identified with single-cell RNA-seq data. We show that COMET outperforms other methods for the identification of single-gene panels, and enables, for the first time, prediction of multi-gene marker panels ranked by relevance. Staining by flow-cytometry assay confirmed the accuracy of COMET’s predictions in identifying marker-panels for cellular subtypes, at both the single- and multi-gene levels, validating COMET’s applicability and accuracy in predicting favorable marker-panels from transcriptomic input. COMET is a general non-parametric statistical framework and can be used as-is on various high-throughput datasets in addition to single-cell RNA-sequencing data. COMET is available for use via a web interface (http://www.cometsc.com) or a standalone software package (https://github.com/MSingerlab/COMETSC).
The onset time of balance control during walking is phase-independent, but the magnitude of the response is not
Authors: Reimann Hendrik , Fettrow Tyler , Grenet David , Thompson Elizabeth D. , Jeka John J. 
Published: May 2019

AbstractThe human body is mechanically unstable during walking. Maintaining upright stability requires constant regulation of muscle force by the central nervous system to push against the ground and move the body mass in the desired way. Activation of muscles in the lower body in response to sensory or mechanical perturbations during walking is usually highly phase-dependent, because the effect any specific muscle force has on the body movement depends upon the body configuration. Yet the resulting movement patterns of the upper body after the same perturbations are largely phase-independent. This is puzzling, because any change of upper-body movement must be generated by parts of the lower body pushing against the ground. How do phase-dependent muscle activation patterns along the lower body generate phase-independent movement patterns of the upper body? We hypothesize that in response to a perceived threat to balance, the nervous system generates a functional response by pushing against the ground in any way possible with the current body configuration. This predicts that the changes in the ground reaction force patterns following a balance perturbation should be phase-independent. Here we test this hypothesis by disturbing upright balance using Galvanic vestibular stimulation at three different points in the gait cycle. We measure the resulting changes in whole-body center of mass movement and the location of the center of pressure of the ground reaction force. We find that the whole-body balance response is not phase-independent as expected: balance responses are initiated faster and are smaller following a disturbance late in the gait cycle. Somewhat paradoxically, the initial center of pressure changes are larger for perturbations late in the gait cycle. The onset of the center of pressure changes however, does not depend on the phase of the perturbation. The results partially support our hypothesis of a phase-independent functional balance response underlying the phase-dependent recruitment of different balance mechanisms at different points of the gait cycle. We conclude that the central nervous system recruits any available mechanism to push against the ground to maintain balance as fast as possible in response to a perturbation, but the different mechanisms do not have equal strength.
Neuron Geometry Underlies Universal Network Features in Cortical Microcircuits
Authors: Gal Eyal , Perin Rodrigo , Markram Henry , London Michael , Segev Idan 
Published: May 2019

ABSTRACTWhy do cortical microcircuits in a variety of brain regions express similar, highly nonrandom, network motifs? To what extent this structure is innate and how much of it is molded by plasticity and learning processes? To address these questions, we developed a general network science framework to quantify the contribution of neurons’ geometry and their embedding in cortical volume to the emergence of three-neuron network motifs. Applying this framework to a dense in silico reconstructed cortical microcircuits showed that the innate asymmetric neuron’s geometry underlies the universally recurring motif architecture. It also predicted the spatial alignment of cells composing the different triplets-motifs. These predictions were directly validated via in vitro 12-patch whole-cell recordings (7,309 triplets) from rat somatosensory cortex. We conclude that the local geometry of neurons imposes an innate, already structured, global network architecture, which serves as a skeleton upon which fine-grained structural and functional plasticity processes take place.
Dual Role of Jam3b in Early Hematopoietic and Vascular Development
Authors: Kobayashi Isao , Kobayashi-Sun Jingjing , Hirakawa Yuto , Ouchi Madoka , Yasuda Koyuki , Kamei Hiroyasu , Fukuhara Shigetomo , Yamaguchi Masaaki 
Published: May 2019

AbstractIn order to efficiently derive hematopoietic stem cells (HSCs) from pluripotent precursors, it is crucial to understand how mesodermal cells acquire hematopoietic or endothelial identity due to their close developmental connection. Although Npas4 has been recently identified as a conserved master regulator of hemato-vascular development, the molecular mechanisms underlying the cell fate divergence between hematopoietic and vascular endothelial cells are still unclear. Here, we show in zebrafish that the divergence of hematopoietic and vascular endothelial cells in mesodermal cells is regulated by Junctional adhesion molecule 3b (Jam3b) via two independent signaling pathways. Mutation ofjam3bled to the reduction ofnpas4lexpression in the posterior lateral plate mesoderm and defect of both hematopoietic and vascular development. Mechanistically, we uncover that Jam3b promotes endothelial specification by regulatingnpas4lexpression through the repression of the Rap1a-Erk signaling cascade. Jam3b subsequently promotes hematopoietic development including HSCs by regulatinglrrc15expression in endothelial precursors through the activation of an integrin-dependent signaling cascade. Our data provide insight into the divergent mechanisms for instructing hematopoietic or vascular fates from mesodermal cells.
Parallel accumulation – serial fragmentation combined with data-independent acquisition (diaPASEF): Bottom-up proteomics with near optimal ion usage
Authors: Meier Florian , Brunner Andreas-David , Frank Max , Ha Annie , Bludau Isabell , Voytik Eugenia , Kaspar-Schoenefeld Stephanie , Lubeck Markus , Raether Oliver , Aebersold Ruedi , Collins Ben C. , Röst Hannes L. , Mann Matthias 
Published: May 2019

ABSTRACTData independent acquisition (DIA) modes isolate and concurrently fragment populations of different precursors by cycling through segments of a predefined precursor m/z range. Although these selection windows collectively cover the entire m/z range, overall only a few percent of all incoming ions are sampled. Making use of the correlation of molecular weight and ion mobility in a trapped ion mobility device (timsTOF Pro), we here devise a novel scan mode that samples up to 100% of the peptide precursor ion current. We extend an established targeted data extraction workflow by including the ion mobility dimension for both signal extraction and scoring, thereby increasing the specificity for precursor identification. Data acquired from whole proteome digests and mixed organism samples demonstrate deep proteome coverage and a very high degree of reproducibility as well as quantitative accuracy, even from 10 ng sample amounts.
Identification of lumbrokinase by fibrin-plate method, fibrin-zymography and liquid chromatography mass spectrometry
Authors: Ke’ Bingbing , Xian Ruiqing , Jiang Hong , Guo Jianghong 
Published: May 2019

AbstractLumbrokinase, extracted from the cultured earthworm ofEisenia fetida, has been widely used as biochemical medicine in China to prevent or treat thrombosis. In the present study, the mechanism of lumbrokinase was investigated using the fibrin plate method. The results revealed that lumbrokinase contained both fibrinolytic and kinase components. The method of fibrin-zymography was used to show the existence and activity of lumbrokinase, and we proved that the fibrin-zymogram gel could be adopted as the identification method of earthworm. Subsequently, the components were identified by mass spectrometry. According to the results, fibrinolytic related components existed in the drug. These proteins were further compared with other serine proteins. The result showed that the identified proteins were similar to human trypsin and bovine trypsin. Besides, some also exhibited similar characteristics with human plasminogen activators. The mentioned results demonstrated that lumbrokinase products contained two major groups of protein components, suggesting two different functions.
The Dps4 fromNostoc punctiformeATCC 29133 is a member of His-type FOC containing Dps protein class that can be broadly found among cyanobacteria
Authors: Howe Christoph , Moparthi Vamsi K. , Ho Felix M. , Persson Karina , Stensjö Karin 
Published: May 2019

AbstractDps proteins (DNA-binding proteins from starved cells) have been found to detoxify H2O2. At their catalytic centers, the ferroxidase center (FOC), Dps proteins utilize Fe2+to reduce H2O2and therefore play an essential role in the protection against oxidative stress and maintaining iron homeostasis. Whereas most bacteria accommodate one or two Dps, there are five different Dps proteins inNostoc punctiforme, a phototrophic and filamentous cyanobacterium. This uncommonly high number of Dps proteins implies a sophisticated machinery for maintaining complex iron homeostasis and for protection against oxidative stress. Functional analyses and structural information on cyanobacterial Dps proteins are rare, but essential for understanding the function of each of the NpDps proteins. In this study, we present the crystal structure of NpDps4 in its metal-free, iron- and zinc-bound forms. The FOC coordinates either two iron atoms or one zinc atom. Spectroscopic analyses revealed that NpDps4 could oxidize Fe2+utilizing O2, but no evidence for its use of the oxidant H2O2could be found. We identified Zn2+to be an effective inhibitor of the O2-mediated Fe2+oxidation in NpDps4. NpDps4 exhibits a FOC that is very different from canonical Dps, but structurally similar to the atypical one from DpsA ofThermosynechococcus elongatus. Sequence comparisons among Dps protein homologs to NpDps4 within the cyanobacterial phylum led us to classify a novel FOC class: the His-type FOC. The features of this special FOC have not been identified in Dps proteins from other bacterial phyla and it might be unique to cyanobacterial Dps proteins.