Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed µCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass

On staying grounded and avoiding Quixotic dead ends

The 15 articles in this special issue on The Representation of Concepts illustrate the rich variety of theoretical positions and supporting research that characterize the area. Although much agreement exists among contributors, much disagreement exists as well, especially about the roles of grounding and abstraction in conceptual processing. I first review theoretical approaches raised in these articles that I believe are Quixotic dead ends, namely, approaches that are principled and inspired but likely to fail. In the process, I review various theories of amodal symbols, their distortions of grounded theories, and fallacies in the evidence used to support them. Incorporating further contributions across articles, I then sketch a theoretical approach that I believe is likely to be successful, which includes grounding, abstraction, flexibility, explaining classic conceptual phenomena, and making contact with real-world situations. This account further proposes that (1) a key element of grounding is neural reuse, (2) abstraction takes the forms of multimodal compression, distilled abstraction, and distributed linguistic representation (but not amodal symbols), and (3) flexible context-dependent representations are a hallmark of conceptual processing

Ontology-based end-user visual query formulation: Why, what, who, how, and which?

Value creation in an organisation is a time-sensitive and data-intensive process, yet it is often delayed and bounded by the reliance on IT experts extracting data for domain experts. Hence, there is a need for providing people who are not professional developers with the flexibility to pose relatively complex and ad hoc queries in an easy and intuitive way. In this respect, visual methods for query formulation undertake the challenge of making querying independent of users’ technical skills and the knowledge of the underlying textual query language and the structure of data. An ontology is more promising than the logical schema of the underlying data for guiding users in formulating queries, since it provides a richer vocabulary closer to the users’ understanding. However, on the one hand, today the most of world’s enterprise data reside in relational databases rather than triple stores, and on the other, visual query formulation has become more compelling due to ever-increasing data size and complexity—known as Big Data. This article presents and argues for ontology-based visual query formulation for end-users; discusses its feasibility in terms of ontology-based data access, which virtualises legacy relational databases as RDF, and the dimensions of Big Data; presents key conceptual aspects and dimensions, challenges, and requirements; and reviews, categorises, and discusses notable approaches and systems

Classification and function of small open reading frames

Small open reading frames (smORFs) of 100 codons or fewer are usually - if arbitrarily - excluded from proteome annotations. Despite this, the genomes of many metazoans, including humans, contain millions of smORFs, some of which fulfil key physiological functions. Recently, the transcriptome of Drosophila melanogaster was shown to contain thousands of smORFs of different classes that actively undergo translation, which produces peptides of mostly unknown function. Here, we present a comprehensive analysis of smORFs in flies, mice and humans. We propose the existence of several functional classes of smORFs, ranging from inert DNA sequences to transcribed and translated cis-regulators of translation and peptides with a propensity to function as regulators of membrane-associated proteins, or as components of ancient protein complexes in the cytoplasm. We suggest that the different smORF classes could represent steps in gene, peptide and protein evolution. Our analysis introduces a distinction between different peptide-coding classes of smORFs in animal genomes, and highlights the role of model organisms for the study of small peptide biology in the context of development, physiology and human disease

Single-cell analysis tools for drug discovery and development

The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed

Search for Dark Matter and Supersymmetry with a Compressed Mass Spectrum in the Vector Boson Fusion Topology in Proton-Proton Collisions at root s=8 TeV

Peer reviewe

Identifier mapping performance for integrating transcriptomics and proteomics experimental results

Background\ud Studies integrating transcriptomic data with proteomic data can illuminate the proteome more clearly than either separately. Integromic studies can deepen understanding of the dynamic complex regulatory relationship between the transcriptome and the proteome. Integrating these data dictates a reliable mapping between the identifier nomenclature resultant from the two high-throughput platforms. However, this kind of analysis is well known to be hampered by lack of standardization of identifier nomenclature among proteins, genes, and microarray probe sets. Therefore data integration may also play a role in critiquing the fallible gene identifications that both platforms emit.\ud \ud Results\ud We compared three freely available internet-based identifier mapping resources for mapping UniProt accessions (ACCs) to Affymetrix probesets identifications (IDs): DAVID, EnVision, and NetAffx. Liquid chromatography-tandem mass spectrometry analyses of 91 endometrial cancer and 7 noncancer samples generated 11,879 distinct ACCs. For each ACC, we compared the retrieval sets of probeset IDs from each mapping resource. We confirmed a high level of discrepancy among the mapping resources. On the same samples, mRNA expression was available. Therefore, to evaluate the quality of each ACC-to-probeset match, we calculated proteome-transcriptome correlations, and compared the resources presuming that better mapping of identifiers should generate a higher proportion of mapped pairs with strong inter-platform correlations. A mixture model for the correlations fitted well and supported regression analysis, providing a window into the performance of the mapping resources. The resources have added and dropped matches over two years, but their overall performance has not changed.\ud \ud Conclusions\ud The methods presented here serve to achieve concrete context-specific insight, to support well-informed decisions in choosing an ID mapping strategy for "omic" data merging

Disability in young adults following major trauma: 5 year follow up of survivors

BACKGROUND: Injuries are a major cause of mortality and morbidity in young people. Despite this, the long-term consequences for young survivors of severe injury are relatively unexplored. METHODS: Population based cohort study involving 5 year post injury structured interview of all cases of major trauma (Injury Severity Score > 15) identified retrospectively for 12 month period (1988 to 1989) within former Yorkshire Health Authority area of the United Kingdom. RESULTS: 125 individuals aged 11–24 years at time of injury were identified. Of these, 109 (87%) were interviewed. Only 20% (95% CI 14–29%) of those interviewed reported no disability. Mean Office of Population Census and Surveys (OPCS) disability score of the remainder was 7.5 (median 5.8, range 0.5 to 19.4). The most commonly encountered areas of disability were behaviour (54%, 95% CI 45–63%), intellectual functioning (39%, 95% CI 31–49%) and locomotion (29%, 95% CI 22–39%). Many respondents reported that their daily lives were adversely affected by their health problems for example, causing problems with work, 54% (95% CI 45–63%), or looking after the home, 28% (95% CI 21–38%). Higher OPCS scores were usually but not always associated with greater impact on daily activities. The burden of caring responsibilities fell largely on informal carers. 51% (95% CI 42–61%) of those interviewed would have liked additional help to cope with their injury and disability. CONCLUSION: The study has revealed significant disability amongst a cohort of young people 5 years post severe injury. Whilst many of these young people were coping well with the consequences of their injuries, others reported continuing problems with the activities of daily life. The factors underpinning the young people's differing experiences and social outcome should be explored