bluuebunny/crossref_metadata_2025_split huggingface dataset:
Porcupine: a visual pipeline tool for neuroimaging analysis
Authors: van Mourik Tim , Snoek Lukas , Knapen Tomas , Norris David 
Published: September 2017

AbstractThe field of neuroimaging is rapidly adopting a more reproducible approach to data acquisition and analysis. Data structures and formats are being standardised and data analyses are getting more automated. However, as data analysis becomes more complicated, researchers often have to write longer analysis scripts, spanning different tools across multiple programming languages. This makes it more difficult to share or recreate code, reducing the reproducibility of the analysis. We present a tool, Porcupine, that constructs one’s analysis visually and automatically produces analysis code. The graphical representation improves understanding of the performed analysis, while retaining the flexibility of modifying the produced code manually to custom needs. Not only does Porcupine produce the analysis code, it also creates a shareable environment for running the code, in the form of a Docker image. Together, this forms a reproducible way of constructing, visualising and sharing one’s analysis. Currently, Porcupine links to Nipype functionalities, which in turn accesses most standard neuroimaging analysis tools. With Porcupine, we bridge the gap between a conceptual and an implementational level of analysis and thus create reproducible and shareable science. We give the researcher a better oversight of their pipeline, both while developing and communicating their work. This will reduce the threshold at which less expert users can generate reusable pipelines. We provide a wide range of examples and documentation, as well as installer files for all platforms on our website: https://timvanmourik.github.io/Porcupine. Porcupine is free, open source, andreleased under the GNU General Public License v3.0.Author SummaryThe neuroimaging community is fervently debating that its reproducibility and transparency should be improved, but it is a challenging problem as to how to accomplish this. We here propose a tool, Porcupine, to aid in this process by more easily creating shareable workflows for analysing neuroimaging data. The conceptual understanding of a pipeline is improved by means of the graphical interface, and it automatically produces the code to perform the analysis and to create a sharing environment. This retains full flexibility to modify the script afterwards but in principle produces readily executable code for an end-to-end analysis. Porcupine currently links to all Nipype functionality, but is designed to be extendable to other workflow packages in neuroimaging and beyond. Porcupine is free and is released under the GNU General Public License.
A Genome Scan for Genes Underlying Adult Body Size Differences between Central African Pygmies and their Non-Pygmy Neighbors
Authors: Pemberton Trevor J. , Verdu Paul , Becker Noémie S. , Willer Cristen J. , Hewlett Barry S. , Le Bomin Sylvie , Froment Alain , Rosenberg Noah A. , Heyer Evelyne 
Published: September 2017

AbstractBackgroundCentral African hunter-gatherer Pygmy populations have reduced body size compared with their often much larger agricultural non-Pygmy neighbors, potentially reflecting adaptation to the anatomical and physiological constraints of their lifestyle in tropical rainforests. Earlier studies investigating the genetics of the pygmy phenotype have focused on standing height, one aspect of this complex phenotype that is itself a composite of skeletal components with different growth patterns. Here, we extend the investigations of standing height to the variability and genetic architecture of sitting height and subischial leg length as well as body mass index (BMI) in a sample of 406 unrelated West Central African Pygmies and non-Pygmies.ResultsIn addition to their significantly reduced standing height compared with non-Pygmies, we find Pygmies to have significantly shorter sitting heights and subischial leg lengths as well as higher sitting/standing height ratios than non-Pygmies. However, while male Pygmies had significantly lower BMI compared with male non-Pygmies, the BMI of females were instead similar. Consistent with prior observations with standing height, sitting height and subischial leg length were strongly correlated with inferred levels of non-Pygmy genetic admixture while BMI was instead weakly correlated, likely reflecting the greater contribution of non-genetic factors to the determination of body weight compared with height. Using 196,725 SNPs on the Illumina Cardio-MetaboChip with genotypes on 358 Pygmy and 169 non-Pygmy individuals together with single-and multi-marker association approaches, we identified a single genomic region and seven genes associated with Pygmy/non-Pygmy categorization as well as 9, 10, 9, and 10 genes associated with standing and sitting height, sitting/standing height ratio, and subischial leg length, respectively. Many of the genes identified have putative functions consistent with a role in determining their associated trait as well as the complex Central African pygmy phenotype.ConclusionsThese findings highlight the potential of modestly sized datasets of Pygmies and non-Pygmies to detect biologically meaningful associations with traits contributing to the Central African pygmy phenotype. Moreover, they provide new insights into the phenotypic and genetic bases of the complex pygmy phenotype and offer new opportunities to facilitate our understanding of its complex evolutionary origins.
Precision genome-editing with CRISPR/Cas9 in human induced pluripotent stem cells
Authors: Budde John P. , Martinez Rita , Hsu Simon , Wen Natalie , Chen Jason A. , Coppola Giovanni , Goate Alison M. , Cruchaga Carlos , Karch Celeste M. 
Published: September 2017

AbstractGenome engineering in human induced pluripotent stem cells (iPSCs) represent an opportunity to examine the contribution of pathogenic and disease modifying alleles to molecular and cellular phenotypes. However, the practical application of genome-editing approaches in human iPSCs has been challenging. We have developed a precise and efficient genome-editing platform that relies on allele-specific guideRNAs (gRNAs) paired with a robust method for culturing and screening the modified iPSC clones. By applying an allele-specific gRNA design strategy, we have demonstrated greatly improved editing efficiency without the introduction of additional modifications of unknown consequence in the genome. Using this approach, we have modified nine independent iPSC lines at five loci associated with neurodegeneration. This genome-editing platform allows for efficient and precise production of isogenic cell lines for disease modeling. Because the impact of CRISPR/Cas9 on off-target sites remains poorly understood, we went on to perform thorough off-target profiling by comparing the mutational burden in edited iPSC lines using whole genome sequencing. The bioinformatically predicted off-target sites were unmodified in all edited iPSC lines. We also found that the numbers ofde novogenetic variants detected in the edited and unedited iPSC lines were similar. Thus, our CRISPR/Cas9 strategy does not specifically increase the mutational burden. Furthermore, our analyses of thede novogenetic variants that occur during iPSC culture and genome-editing indicate an enrichment ofde novovariants at sites identified in dbSNP. Taken together, we propose that this enrichment represents regions of the genome more susceptible to mutation. Herein, we present an efficient and precise method for allele-specific genome-editing in iPSC and an analyses pipeline to distinguish off-target events fromde novomutations occurring with culture.
Whole genome sequence-based haplotypes reveal single origin of the sickle allele during the Holocene Wet Phase
Authors: Shriner Daniel , Rotimi Charles N. 
Published: September 2017

ABSTRACTFive classical designations of sickle haplotypes are based on the presence/absence of restriction sites and named after ethnic groups or geographic regions from which patients originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation. We investigated the origins of the sickle mutation using whole genome sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. We defined a new haplotypic classification using 27 polymorphisms in linkage disequilibrium with rs334. Network analysis revealed a common haplotype that differed from the ancestral haplotype only by the derived sickle mutation at rs334 and correlated collectively with the Central African Republic/Bantu, Cameroon, and Arabian/Indian designations. Other haplotypes were derived from this haplotype and fell into two clusters, one comprised of haplotypes correlated with the Senegal designation and the other comprised of haplotypes correlated with both the Benin and Senegal designations. The near-exclusive presence of the original sickle haplotype in the Central African Republic, Kenya, Uganda, and South Africa is consistent with this haplotype predating the Bantu Expansion. Modeling of balancing selection indicated that the heterozygote advantage was 15.2%, an equilibrium frequency of 12.0% was reached after 87 generations, and the selective environment predated the mutation. The posterior distribution of the ancestral recombination graph yielded an age of the sickle mutation of 259 generations, corresponding to 7,300 years and the Holocene Wet Phase. These results clarify the origin of the sickle allele and improve and simplify the classification of sickle haplotypes.
FRONTAL EYE FIELD INACTIVATION DIMINISHES SUPERIOR COLLICULUS ACTIVITY, BUT DELAYED SACCADIC ACCUMULATION GOVERNS REACTION TIME INCREASES
Authors: Peel Tyler R. , Dash Suryadeep , Lomber Stephen G. , Corneil Brian D. 
Published: September 2017

AbstractStochastic accumulator models provide a comprehensive framework for how neural activity could produce behavior. Neural activity within the frontal eye fields (FEF) and intermediate layers of the superior colliculus (iSC) support such models for saccade initiation, by relating variations in saccade reaction time (SRT) to variations in parameters such as baseline, rate of accumulation of activity, or threshold. Here, by recording iSC activity during reversible cryogenic inactivation of the FEF in non-human primates, we causally test which parameter(s) best explains concomitant increases in SRT. While FEF inactivation decreased all aspects of ipsilesional iSC activity, decreases in accumulation rate and threshold poorly predicted accompanying increases in SRT. Instead, SRT increases best correlated with delays in the onset of saccade-related accumulation. We conclude that FEF signals govern the onset of saccade-related accumulation within the iSC, and that the onset of accumulation is a relevant parameter for stochastic accumulation models of saccade initiation.Significance StatementThe superior colliculus (SC) and frontal eye fields (FEF) are two of the best-studied areas in the primate brain. Surprisingly, little is known about what happens in the SC when the FEF is temporarily inactivated. Here, we show that temporary FEF inactivation decreases all aspects of functionally-related activity in the SC. This combination of techniques also allowed us to relate changes in SC activity to concomitant increases in saccadic reaction time (SRT). Although stochastic accumulator models relate SRT increases to reduced rates of accumulation or increases in threshold, such changes were not observed in the SC. Instead, FEF inactivation delayed the onset of saccade-related accumulation, emphasizing the importance of this parameter in biologically-plausible models of saccade initiation.
EPAC1 regulates endothelial Annexin A2 cell surface translocation and plasminogen activation
Authors: Yang Wenli , Mei Fang C. , Cheng Xiaodong 
Published: September 2017

ABSTRACTAnnexins, a family of highly conserved calcium-and phospholipid-binding proteins, play important roles in a wide range of physiological functions. Among the twelve known annexins in human, Annexin A2 (AnxA2) is one of the most extensively studied and has been implicated in various human diseases. AnxA2 can exist as a monomer or a heterotetrameric complex with S100A10 (P11) and plays a critical role in many cellular processes including exocytosis/endocytosis and membrane organization. At the endothelial cell surface, (AnxA2•P11)2 tetramer, acting as a coreceptor for plasminogen and tissue plasminogen activator (t-PA), accelerates t-PA dependent activation of the fibrinolytic protease, plasmin, the enzyme responsible for thrombus dissolution and degradation of fibrin. This study shows that exchange proteins directly activated by cAMP isoform 1 (EPAC1) interacts with AnxA2 and regulates its biological functions by modulating its membrane translocation in endothelial cells. Using genetic and pharmacological approaches, it is demonstrated that EPAC1, acting through the PLCε-PKC pathway, inhibits AnxA2 surface translocation and plasminogen activation. These results suggest that EPAC1 plays a role in the regulation of fibrinolysis in endothelial cells and may represent a novel therapeutic target for disorders of fibrinolysis.
The lectin-specific activity ofToxoplasma gondiimicroneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming
Authors: Sardinha-Silva Aline , Mendonça-Natividade Flávia C. , Pinzan Camila F. , Lopes Carla D. , Costa Diego L. , Jacot Damien , Fernandes Fabricio F. , Zorzetto-Fernandes André L. V. , Gay Nicholas J. , Sher Alan , Jankovic Dragana , Soldati-Favre Dominique , Grigg Michael E. , Roque-Barreira Maria Cristina 
Published: September 2017

ABSTRACTInfection of host cells byToxoplasma gondiiis an active process, which is regulated by secretion of microneme (MICs) and rhoptry proteins (ROPs and RONs) from specialized organelles in the apical pole of the parasite. MIC1, MIC4 and MIC6 assemble into an adhesin complex, secreted on the parasite surface and function to promote infection competency. MIC1 and MIC4 are known to bind terminal sialic acid residues and galactose residues, respectively and to induce IL-12 production from splenocytes. Here we show that rMIC1- and rMIC4-stimulated dendritic cells and macrophages to produce proinflammatory cytokines, and they do so by engaging TLR2 and TLR4. This process depends on sugar recognition, since point mutations in the carbohydrate-recognition domains (CRD) of rMIC1 and rMIC4 inhibit innate immune cells activation. HEK cells transfected with TLR2 glycomutants were selectively unresponsive to MICs. Followingin vitroinfection, parasites lacking MIC1 or MIC4, as well as expressing MIC proteins with point mutations in their CRD, failed to induce wild-type (WT) levels of IL-12 secretion by innate immune cells. However, only MIC1 was shown to impact systemic levels of IL-12 and IFN-γin vivo. Together, our data show that MIC1 and MIC4 interact physically with TLR2 and TLR4 N-glycans to trigger IL-12 responses, and MIC1 is playing a significant rolein vivoby alteringT. gondiiinfection competency and murine pathogenesis.AUTHOR SUMMARYToxoplasmosis is caused by the protozoanToxoplasma gondii, belonging to the Apicomplexa phylum. This phylum comprises important parasites able to infect a broad diversity of animals, including humans. A particularity ofT. gondiiis its ability to invade virtually any nucleated cell of all warm-blooded animals through an active process, which depends on the secretion of adhesin proteins. These proteins are discharged by specialized organelles localized in the parasite apical region, and termed micronemes and rhoptries. We show in this study that two microneme proteins fromT. gondiiutilize their adhesion activity to stimulate innate immunity. These microneme proteins, denoted MIC1 and MIC4, recognize specific sugars on receptors expressed on the surface of mammalian immune cells. This binding activates these innate immune cells to secrete cytokines, which promotes efficient host defense mechanisms against the parasite and regulate their pathogenesis. This activity promotes a chronic infection by controlling parasite replication during acute infection.
Mobile nucleosomes and the accessibility of transcription factors to DNA: a modified dynamic equilibrium model
Authors: Khamis Hadeel , Rudnizky Sergei , Kaplan Ariel 
Published: September 2017

AbstractNucleosomes, the basic building block of chromatin, regulate the accessibility of the transcription machinery to DNA. Recent studies have revealed that the nucleosome's spontaneous, thermally driven positional dynamics are modulated by different factors, and exploited by the cell as a regulatory mechanism. In particular, enrichment of mobile nucleosomes at the promoters of genes suggests that the mobility of nucleosomes may affect the ability of transcription factors to bind DNA. However, a quantitative model describing the effect nucleosome mobility on the effective affinity of transcription factors is lacking. We present here a simple equilibrium model that captures the essence of the effect, and show that modulation of the nucleosome's mobility can be a potent and versatile regulator of transcription factor binding.
A note on the analysis of two-stage task results: how changes in task structure affect what model-free and model-based strategies predict about the effects of reward and transition on the stay probability
Authors: da Silva Carolina Feher , Hare Todd A. 
Published: September 2017

AbstractMany studies that aim to detect model-free and model-based influences on behavior employ two-stage behavioral tasks of the type pioneered by Daw and colleagues in 2011. Such studies commonly modify existing two-stage decision paradigms in order to better address a given hypothesis, which is an important means of scientific progress. It is, however, critical to fully appreciate the impact of any modified or novel experimental design features on the expected results. Here, we use two concrete examples to demonstrate that relatively small changes in the two-stage task design can substantially change the pattern of actions taken by model-free and model-based agents as a function of the reward outcomes and transitions on previous trials. In the first, we show that, under specific conditions, purely model-free agents will produce the reward by transition interactions typically thought to characterize model-based behavior on a two-stage task. The second example shows that model-based agents’ behavior is driven by a main effect of transition-type in addition to the canonical reward by transition interaction whenever the reward probabilities of the final states do not sum to one. Together, these examples emphasize the task-dependence of model-free and model-based behavior and highlight the benefits of using computer simulations to determine what pattern of results to expect from both model-free and model-based agents performing a given two-stage decision task in order to design choice paradigms and analysis strategies best suited to the current question.
An ensemble code in medial prefrontal cortex links prior events to outcomes during learning
Authors: Maggi Silvia , Peyrache Adrien , Humphries Mark D. 
Published: September 2017

AbstractThe prefrontal cortex is implicated in learning the rules of an environment through trial and error. But it is unclear how such learning is related to the prefrontal cortex’s role in short-term memory. Here we ask if the encoding of short-term memory in prefrontal cortex is used by rats learning decision rules in a Y-maze task. We find that a similar pattern of neural ensemble activity is selectively recalled after reinforcement for a correct decision. This reinforcement-selective recall only reliably occurs immediately before the abrupt behavioural transitions indicating successful learning of the current rule, and fades quickly thereafter. We could simultaneously decode multiple, retrospective task events from the ensemble activity, suggesting the recalled ensemble activity has multiplexed encoding of prior events. Our results suggest that successful trial-and-error learning is dependent on reinforcement tagging the relevant features of the environment to maintain in prefrontal cortex short-term memory.
Predictive model identifies strategies to enhance TSP1-mediated apoptosis signaling
Authors: Wu Qianhui , Finley Stacey D. 
Published: September 2017

AbstractThis study explores strategies to enhance thrombospondin-1 (TSP1) induced apoptosis in endothelial cells, an important function that contributes to TSP1’s anti-angiogenic effect. We established a mathematical model of TSP1-mediated intracellular signaling via the CD36 receptor. This model was used to investigate the effects of several approaches to perturb the TSP1-CD36 signaling network. Model simulations predict the population-based response to strategies to enhance TSP1-mediated apoptosis, such as downregulating the apoptosis inhibitor XIAP and inhibiting phosphatase activity. The model also postulates a new mechanism of low dosage doxorubicin treatment in combination with TSP1 stimulation. Using computational analysis, we predict which cells will undergo apoptosis, based on the initial intracellular concentrations of particular signaling species. Overall, the modeling framework predicts molecular strategies that increase TSP1-mediated apoptosis, which is useful in many disease settings.
Dynamic contrast enhancement and flexible odor codes
Authors: Nizampatnam Srinath , Saha Debajit , Chandak Rishabh , Raman Baranidharan 
Published: September 2017

ABSTRACTSensory stimuli evoke spiking activities patterned across neurons and time that are hypothesized to encode information about their identity. Since the same stimulus can be encountered in a multitude of ways, how stable or flexible are these stimulus-evoked responses? Here, we examined this issue in the locust olfactory system. In the antennal lobe, we found that both spatial and temporal features of odor-evoked responses varied in a stimulus-history dependent manner. The response variations were not random, but allowed the antennal lobe circuit to enhance the uniqueness of the current stimulus. Nevertheless, information about the odorant identity became confounded due to this contrast-enhancement computation. Notably, a linear logical classifier (OR-of-ANDs) that can decode information distributed in flexible subsets of neurons generated predictions that matched results from our behavioral experiments. In sum, our results reveal a simple computational logic for achieving the stability vs. flexibility tradeoff in sensory coding.