Finding human genetic variation in whole genome expression data with applications for “missing” heritability: The GWCoGAPS algorithm, the PatternMarkers statistic, and the ProjectoR package

Starting from a single fertilized egg, the compendium of human cells is generated via stochastic perturbations of earlier generations. Concurrently, canalization of developmental pathways limits the type and degree of variation to ensure viability; thus, it is unsurprising that deviations early in life have been linked to late manifesting diseases. Human pluripotent stem cells (hPSCs) are a highly robust and uniquely human experimental system in which to model the sources and consequences of this variability. Further, variation in hPSCs’ transcriptomes has been directly linked to both genomic background and biases in differentiation efficiency. Taking advantage of this link between genomic background and developmental phenotypes, we developed Genome-Wide CoGAPS Analysis in Parallel Sets (GWCoGAPS), the first robust whole genome Bayesian non-negative matrix factorization (NMF), to find conserved transcriptional signatures representative of the functional effect of human genetic variation. Time course RNA-seq data obtained from three human embryonic stem cells (ESC) and three human induced pluripotent stem cells (IPSC) in three different experimental conditions was analyzed. GWCoGAPS distinguished shared developmental trajectories from unique transcriptional signatures of each of the cell lines. Further analysis of these “identity” signatures found they were predictive of lineage biases during neuronal differentiation. Additionally, lineage biases were consistent with early differences in morphogenetic phenotypes within monolayer culture, thus, linking transcriptional genomic signatures to stable quantifiable cellular features. To test whether the cell line signatures were genome specific, we next developed the projectoR algorithm to assess a given signatures robustness in independent data sets. By using the identity signatures as inputs to projectoR, we were able to identify samples from the same donor genome in datasets from multiple tissues and across technical platforms, including RNA-seq results from post-mortem brain, micro arrayed embryoid bodies, and publicly available datasets. The identification of signatures that define the functional rather than physical background of an individual’s genome has the potential to profoundly influence our view of human variation and disease

Flexible provisioning of Web service workflows

Web services promise to revolutionise the way computational resources and business processes are offered and invoked in open, distributed systems, such as the Internet. These services are described using machine-readable meta-data, which enables consumer applications to automatically discover and provision suitable services for their workflows at run-time. However, current approaches have typically assumed service descriptions are accurate and deterministic, and so have neglected to account for the fact that services in these open systems are inherently unreliable and uncertain. Specifically, network failures, software bugs and competition for services may regularly lead to execution delays or even service failures. To address this problem, the process of provisioning services needs to be performed in a more flexible manner than has so far been considered, in order to proactively deal with failures and to recover workflows that have partially failed. To this end, we devise and present a heuristic strategy that varies the provisioning of services according to their predicted performance. Using simulation, we then benchmark our algorithm and show that it leads to a 700% improvement in average utility, while successfully completing up to eight times as many workflows as approaches that do not consider service failures

‘Keep Calm and Carry on’: EU legal developments in 2016

This is an accepted manuscript of an article published by Wiley in Journal of Common Market Studies on 06/06/2017, available online: https://doi.org/10.1111/jcms.12580 The accepted version of the publication may differ from the final published version.For reasons not requiring much exposition, 2016 was an annus horribilis for the EU. A review of the EU judiciary’s 2016 activity reveals that the constituent courts of the Court of Justice of the EU (CJEU), the Court of Justice and the General Court, do not have the luxury of existing above the tumult in splendid isolation. In a year in which old and new problems for the EU dominated the headlines, these challenges found shape in justiciable controversies. In total, the Court of Justice and the General Court delivered 844 judgments in 2016, with the Grand Chamber, the Court of Justice’s upper tier, responsible for 42 judgments, representing a reduction in the number of judgments compared to previous years.1 The growth in the CJEU’s personnel continued, with an 11th Advocate-General, Evgeni Tanchev (a Bulgarian), taking his place on the Court of Justice, and 22 General Court Judges appointed throughout the year, bringing the total number at the General Court to 44.2 2016 also saw the abolition of the Civil Service Tribunal, a specialized court that had adjudicated disputes between the EU and its civil servants: its competences have been returned to the General Court.3 This contribution seeks to analyze the year’s most significant judgments in terms of their impact on European integration, with a particular focus on the approaches adopted by the EU judiciary in response to challenges facing the EU. In accordance with convention, this contribution concentrates on the work of the Grand Chamber. In order to ensure continuity with previous years, this contribution confines itself to three subject areas. Section I provides a brief overview of the Grand Chamber’s activity in the area of eurozone crisis management, before providing a more in-depth analysis of its judgment in Ledra Advertising.4 Section II examines developments in EU data protection law, particularly the ruling in Tele2 Sverige.5 Section III discusses the Court’s development of EU citizenship rights in 2016

Development of a biomimetic collagen-hydroxyapatite scaffold for bone tissue engineering using a SBF immersion technique.

The objective of this study was to develop a biomimetic, highly porous collagen-hydroxyapatite (HA) composite scaffold for bone tissue engineering (TE), combining the biological performance and the high porosity of a collagen scaffold with the high mechanical stiffness of a HA scaffold. Pure collagen scaffolds were produced using a lyophilization process and immersed in simulated body fluid (SBF) to provide a biomimetic coating. Pure collagen scaffolds served as a control. The mechanical, material, and structural properties of the scaffolds were analyzed and the biological performance of the scaffolds was evaluated by monitoring the cellular metabolic activity and cell number at 1, 2, and 7 days post seeding. The SBF-treated scaffolds exhibited a significantly increased stiffness compared to the pure collagen group (4-fold increase), while a highly interconnected structure (95%) was retained. FTIR indicated that the SBF coating exhibited similar characteristics to pure HA. Micro-CT showed a homogeneous distribution of HA. Scanning electron microscopy also indicated a mineralization of the collagen combined with a precipitation of HA onto the collagen. The excellent biological performance of the collagen scaffolds was maintained in the collagen-HA scaffolds as demonstrated from cellular metabolic activity and total cell number. This investigation has successfully developed a biomimetic collagen-HA composite scaffold. An increase in the mechanical properties combined with an excellent biological performance in vitro was observed, indicating the high potential of the scaffold for bone TE

White dwarf envelopes: further results of a non-local model of convection

We present results of a fully non-local model of convection for white dwarf envelopes. We show that this model is able to reproduce the results of numerical simulations for convective efficiencies ranging from very inefficient to moderately efficient; this agreement is made more impressive given that no closure parameters have been adjusted in going from the previously reported case of A-stars to the present case of white dwarfs; for comparison, in order to match the peak convective flux found in numerical simulations for both the white dwarf envelopes discussed in this paper and the A-star envelopes discussed in our previous work requires changing the mixing length parameter of commonly used local models by a factor of 4. We also examine in detail the overshooting at the base of the convection zone, both in terms of the convective flux and in terms of the velocity field: we find that the flux overshoots by approximately 1.25 H_P and the velocity by approximately 2.5 H_P. Due to the large amount of overshooting found at the base of the convection zone the new model predicts the mixed region of white dwarf envelopes to contain at least 10 times more mass than local mixing length theory (MLT) models having similar photospheric temperature structures. This result is consistent with the upper limit given by numerical simulations which predict an even larger amount of mass to be mixed by convective overshooting. Finally, we attempt to parametrise some of our results in terms of local MLT-based models, insofar as is possible given the limitations of MLTComment: Accepted for publication in MNRAS; 11 pages, 5 figures, 3 table

ParameciumDB in 2011: new tools and new data for functional and comparative genomics of the model ciliate Paramecium tetraurelia

ParameciumDB is a community model organism database built with the GMOD toolkit to integrate the genome and biology of the ciliate Paramecium tetraurelia. Over the last four years, post-genomic data from proteome and transcriptome studies has been incorporated along with predicted orthologs in 33 species, annotations from the community and publications from the scientific literature. Available tools include BioMart for complex queries, GBrowse2 for genome browsing, the Apollo genome editor for expert curation of gene models, a Blast server, a motif finder, and a wiki for protocols, nomenclature guidelines and other documentation. In-house tools have been developed for ontology browsing and evaluation of off-target RNAi matches. Now ready for next-generation deep sequencing data and the genomes of other Paramecium species, this open-access resource is available at http://paramecium.cgm.cnrs-gif.fr

Polarizing a stored proton beam by spin flip?

We discuss polarizing a proton beam in a storage ring, either by selective removal or by spin flip of the stored ions. Prompted by recent, conflicting calculations, we have carried out a measurement of the spin flip cross section in low-energy electron-proton scattering. The experiment uses the cooling electron beam at COSY as an electron target. The measured cross sections are too small for making spin flip a viable tool in polarizing a stored beam. This invalidates a recent proposal to use co-moving polarized positrons to polarize a stored antiproton beam.Comment: 18 pages, 6 figure

Molecular response with blinatumomab in relapsed/refractory B-cell precursor acute lymphoblastic leukemia

Minimal residual disease (MRD), where leukemic cell levels are lower than the morphologic detection threshold, is the most important prognostic factor for acute lymphoblastic leukemia (ALL) relapse during first-line chemotherapy treatment and is standard of care in treatment monitoring and decision making. Limited data are available on the prognostic value of MRD response after relapse. We evaluated the relationship between MRD response and outcomes in blinatumomab-treated adults with relapsed/refractory (R/R) B-cell precursor ALL. Of 90 patients with complete remission (CR) or CR with partial hematologic recovery (CRh), 64 (71.1%) achieved a complete MRD response (no detectable individual rearrangements of immunoglobulin/T-cell receptor genes by polymerase chain reaction [PCR] at a minimum sensitivity level of 10-4). Eleven patients had MRD <10-4. Therefore, overall, 75 (83.3%) experienced an MRD response (no detectable MRD or detectable MRD) measured by PCR within the first 2 treatment cycles. Overall survival (OS) and relapse-free survival (RFS) were significantly longer in patients who achieved CR/CRh and MRD response (median, 20.6 and 9.0 months, respectively) compared with CR/CRh patients without MRD response (median, 12.5 and 2.3 months, respectively). In conclusion, longer durations of OS and RFS associated with MRD response support the value of achieving MRD response and its use as a prognostic factor for blinatumomab treatment in R/R ALL. This trial was registered at www.clinicaltrials.gov as #NCT01466179

Modelling native and alien vascular plant species richness: at which scales is geodiversity most relevant?

Aim: To explore the scale-dependency of relationships between novel geodiversity measures and 26 both native and alien vascular plant species richness. Location: Great Britain Time period: Data collected 1995-2015 Major taxa: Vascular plants Methods: We calculated terrestrial native and alien vascular plant species richness (6,932 species in total) across the island of Great Britain at 1km2 (N=219,964) and 100km2 (N=2,121) grain sizes and regional extents 25-250 km in diameter, centred around each 100km2 cell. We compiled geodiversity data on landforms, soils, hydrological and geological features using existing national datasets, and used a newly developed geomorphometric method to extract landform coverage data (e.g. hollows, ridges, valleys, peaks). We used these as predictors of species richness, alongside climate, commonly used topographic metrics, land-cover variety and human population. We analysed species richness across scales using boosted regression tree (BRT) modelling and compared models with and without geodiversity data. Results: Geodiversity significantly improved models over and above widely used topographic metrics, particularly at smaller extents and the finer grain size, and slightly more so for native species richness. For each increase in extent, the contribution of climatic variables increased and that of geodiversity decreased. Of the geodiversity variables, automatically extracted landform data added the most explanatory power, but hydrology (rivers, lakes) and materials (soil, superficial deposits, geology) were also important. Main conclusions Geodiversity improves our understanding of, and ability to model, the relationship between species richness and abiotic heterogeneity at multiple spatial scales by allowing us to get closer to the real-world physical processes that affect patterns of life. Greatest benefit comes from measuring the constituent parts of geodiversity separately, rather than one combined variable (as for most of the few studies to date). Automatically extracted landform data, the use of which is novel in ecology and biogeography, proved particularly valuable in our study

WormBase 2007

WormBase (www.wormbase.org) is the major publicly available database of information about Caenorhabditis elegans, an important system for basic biological and biomedical research. Derived from the initial ACeDB database of C. elegans genetic and sequence information, WormBase now includes the genomic, anatomical and functional information about C. elegans, other Caenorhabditis species and other nematodes. As such, it is a crucial resource not only for C. elegans biologists but the larger biomedical and bioinformatics communities. Coverage of core areas of C. elegans biology will allow the biomedical community to make full use of the results of intensive molecular genetic analysis and functional genomic studies of this organism. Improved search and display tools, wider cross-species comparisons and extended ontologies are some of the features that will help scientists extend their research and take advantage of other nematode species genome sequences