Investigation of cross-cylinder responses under conditions of real and simulated distance

Investigation of cross-cylinder responses under conditions of real and simulated distanc

A GO catalogue of human DNA-binding transcription factors

To control gene transcription, DNA-binding transcription factors recognise specific sequence motifs in gene regulatory regions. A complete and reliable GO annotation of all DNA-binding transcription factors is key to investigating the delicate balance of gene regulation in response to environmental and developmental stimuli. The need for such information is demonstrated by the many lists of transcription factors that have been produced over the past decade. The COST Action Gene Regulation Ensemble Effort for the Knowledge Commons (GREEKC) Consortium brought together experts in the field of transcription with the aim of providing high quality and interoperable gene regulatory data. The Gene Ontology (GO) Consortium provides strict definitions for gene product function, including factors that regulate transcription. The collaboration between the GREEKC and GO Consortia has enabled the application of those definitions to produce a new curated catalogue of over 1400 human DNA-binding transcription factors, that can be accessed at https://www.ebi.ac.uk/QuickGO/targetset/dbTF. This catalogue has facilitated an improvement in the GO annotation of human DNA-binding transcription factors and led to the GO annotation of almost sixty thousand DNA-binding transcription factors in over a hundred species. Thus, this work will aid researchers investigating the regulation of transcription in both biomedical and basic science

A GO catalogue of human DNA-binding transcription factors

DNA-binding transcription factors recognise genomic addresses, specific sequence motifs in gene regulatory regions, to control gene transcription. A complete and reliable catalogue of all DNA-binding transcription factors is key to investigating the delicate balance of gene regulation in response to environmental and developmental stimuli. The need for such a catalogue of proteins is demonstrated by the many lists of DNA-binding transcription factors that have been produced over the past decade. The COST Action Gene Regulation Ensemble Effort for the Knowledge Commons (GREEKC) Consortium brought together experts in the field of transcription with the aim of providing high quality and interoperable gene regulatory data. The Gene Ontology (GO) Consortium provides strict definitions for gene product function, including factors that regulate transcription. The collaboration between the GREEKC and GO Consortia has enabled the application of those definitions to produce a new curated catalogue of human DNA-binding transcription factors, that can be accessed at https://www.ebi.ac.uk/QuickGO/targetset/dbTF. In addition, this curation effort has led to the GO annotation of almost sixty thousand DNA-binding transcription factors in over a hundred species. Thus, this work will aid researchers investigating the regulation of transcription in both biomedical and basic science

JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release

New miniPromoter Ple345 (NEFL) drives strong and specific expression in retinal ganglion cells of mouse and primate retina.

Retinal gene therapy is leading the neurological gene therapy field, with 32 ongoing clinical trials of recombinant adeno-associated virus (rAAV)-based therapies. Importantly, over 50% of those trials are using restricted promoters from human genes. Promoters that restrict expression have demonstrated increased efficacy and can limit the therapeutic to the target cells thereby reducing unwanted off-target effects. Retinal ganglion cells are a critical target in ocular gene therapy; they are involved in common diseases such as glaucoma, rare diseases such as Leber's hereditary optic neuropathy, and in revolutionary optogenetic treatments. Here, we used computational biology and mined the human genome for the best genes from which to develop a novel minimal promoter element(s) designed for expression in restricted cell types (MiniPromoter) to improve the safety and efficacy of retinal ganglion cell gene therapy. Gene selection included the use of the first available droplet-based single-cell RNA sequencing (Drop-seq) dataset, and promoter design was bioinformatically driven and informed by a wide range of genomics datasets. We tested seven promoter designs from four genes in rAAV for specificity and quantified expression strength in retinal ganglion cells in mouse, and then the single best in nonhuman primate retina. Thus, we developed a new human-DNA MiniPromoter, Ple345 (NEFL), which in combination with intravitreal delivery in rAAV9 showed specific and robust expression in the retinal ganglion cells of the nonhuman-primate rhesus macaque retina. In mouse, we also developed MiniPromoters expressing in retinal ganglion cells, the hippocampus of the brain, a pan neuronal pattern in the brain, and peripheral nerves. As single-cell transcriptomics such as Drop-seq become available for other cell types, many new opportunities for additional novel restricted MiniPromoters will present

Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells

Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses.info:eu-repo/semantics/publishedVersio

Advances in infrastructures and tools for multiagent systems

In the last few years, information system technologies have focused on solving challenges in order to develop distributed applications. Distributed systems can be viewed as collections of service-provider and ser vice-consumer components interlinked by dynamically defined workflows (Luck and McBurney 2008).Alberola Oltra, JM.; Botti Navarro, VJ.; Such Aparicio, JM. (2014). Advances in infrastructures and tools for multiagent systems. Information Systems Frontiers. 16:163-167. doi:10.1007/s10796-014-9493-6S16316716Alberola, J. M., Búrdalo, L., Julián, V., Terrasa, A., & García-Fornes, A. (2014). An adaptive framework for monitoring agent organizations. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9478-x .Alfonso, B., Botti, V., Garrido, A., & Giret, A. (2014). A MAS-based infrastructure for negotiation and its application to a water-right market. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9443-8 .Andrighetto, G., Castelfranchi, C., Mayor, E., McBreen, J., López-Sánchez, M., & Parsons, S. (2013). (Social) norm dynamics. In G. Andrighetto, G. Governatori, P. Noriega, & L. W. van der Torre (Eds.), Normative multi-agent systems (pp. 135–170). Dagstuhl: Schloss Dagstuhl--Leibniz-Zentrum fuer Informatik.Baarslag, T., Fujita, K., Gerding, E. H., Hindriks, K., Ito, T., Jennings, N. R., et al. (2013). Evaluating practical negotiating agents: results and analysis of the 2011 international competition. Artificial Intelligence, 198, 73–103.Boissier, O., Bordini, R. H., Hübner, J. F., Ricci, A., & Santi, A. (2013). Multi-agent oriented programming with JaCaMo. Science of Computer Programming, 78(6), 747–761.Campos, J., Esteva, M., López-Sánchez, M., Morales, J., & Salamó, M. (2011). Organisational adaptation of multi-agent systems in a peer-to-peer scenario. Computing, 91(2), 169–215.Carrera, A., Iglesias, C. A., & Garijo, M. (2014). Beast methodology: an agile testing methodology for multi-agent systems based on behaviour driven development. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9438-5 .Criado, N., Such, J. M., & Botti, V. (2014). Norm reasoning services. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9444-7 .Del Val, E., Rebollo, M., & Botti, V. (2014). Enhancing decentralized service discovery in open service-oriented multi-agent systems. Journal of Autonomous Agents and Multi-Agent Systems, 28(1), 1–30.Denti, E., Omicini, A., & Ricci, A. (2002). Coordination tools for MAS development and deployment. Applied Artificial Intelligence, 16(9–10), 721–752.Dignum, V., & Dignum, F. (2012). A logic of agent organizations. Logic Journal of IGPL, 20(1), 283–316.Ferber, J., & Gutknecht, O. (1998). A meta-model for the analysis and design of organizations in multi-agent systems. In Multi agent systems. Proceedings. International Conference on (pp. 128–135). 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A survey of security issue in multi-agent systems. Artificial Intelligence Review, 37(3), 239–260.Kota, R., Gibbins, N., & Jennings, N. R. (2012). Decentralized approaches for self-adaptation in agent organizations. ACM Transactions on Autonomous and Adaptive Systems (TAAS), 7(1), 1.Kraus, S. (1997). Negotiation and cooperation in multi-agent environments. Artificial Intelligence, 94(1), 79–97.Lin, Y. I., Chou, Y. W., Shiau, J. Y., & Chu, C. H. (2013). Multi-agent negotiation based on price schedules algorithm for distributed collaborative design. Journal of Intelligent Manufacturing, 24(3), 545–557.Luck, M., & McBurney, P. (2008). Computing as interaction: agent and agreement technologies.Luck, M., McBurney, P., Shehory, O., & Willmott, S. (2005). Agent technology: Computing as interaction (A roadmap for agent based computing). AgentLink.Ossowski, S., & Menezes, R. (2006). On coordination and its significance to distributed and multiagent systems. 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Erratum: JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) and TF flexible models (TFFMs) for TFs across multiple species in six taxonomic groups. In the 2018 release of JASPAR, the CORE collection has been expanded with 322 new PFMs (60 for vertebrates and 262 for plants) and 33 PFMs were updated (24 for vertebrates, 8 for plants and 1 for insects). These new profiles represent a 30% expansion compared to the 2016 release. In addition, we have introduced 316 TFFMs (95 for vertebrates, 218 for plants and 3 for insects). This release incorporates clusters of similar PFMs in each taxon and each TF class per taxon. The JASPAR 2018 CORE vertebrate collection of PFMs was used to predict TF-binding sites in the human genome. The predictions are made available to the scientific community through a UCSC Genome Browser track data hub. Finally, this update comes with a new web framework with an interactive and responsive user-interface, along with new features. All the underlying data can be retrieved programmatically using a RESTful API and through the JASPAR 2018 R/Bioconductor package

An Open Source Simulation Model for Soil and Sediment Bioturbation

Bioturbation is one of the most widespread forms of ecological engineering and has significant implications for the structure and functioning of ecosystems, yet our understanding of the processes involved in biotic mixing remains incomplete. One reason is that, despite their value and utility, most mathematical models currently applied to bioturbation data tend to neglect aspects of the natural complexity of bioturbation in favour of mathematical simplicity. At the same time, the abstract nature of these approaches limits the application of such models to a limited range of users. Here, we contend that a movement towards process-based modelling can improve both the representation of the mechanistic basis of bioturbation and the intuitiveness of modelling approaches. In support of this initiative, we present an open source modelling framework that explicitly simulates particle displacement and a worked example to facilitate application and further development. The framework combines the advantages of rule-based lattice models with the application of parameterisable probability density functions to generate mixing on the lattice. Model parameters can be fitted by experimental data and describe particle displacement at the spatial and temporal scales at which bioturbation data is routinely collected. By using the same model structure across species, but generating species-specific parameters, a generic understanding of species-specific bioturbation behaviour can be achieved. An application to a case study and comparison with a commonly used model attest the predictive power of the approach

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

sharma et al. define a new primary atopic disorder caused by heterozygous gain-of-function variants in STAT6. this results in severe, early-onset allergies, and is seen in 16 patients from 10 families. Anti-IL-4R & alpha; antibody and JAK inhibitor treatment were highly effective.STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. we have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. the cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). all patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and T(H)2 skewing. Precision treatment with the anti-IL-4R & alpha; antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. this study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder