BackgroundThe Cell Ontology (CL) is an OBO Foundry candidate ontology covering the domain of canonical, natural biological cell types. Since its inception in 2005, the CL has undergone multiple rounds of revision and expansion, most notably in its representation of hematopoietic cells. For in vivo cells, the CL focuses on vertebrates but provides general classes that can be used for other metazoans, which can be subtyped in species-specific ontologies.Construction and contentRecent work on the CL has focused on extending the representation of various cell types, and developing new modules in the CL itself, and in related ontologies in coordination with the CL. For example, the Kidney and Urinary Pathway Ontology was used as a template to populate the CL with additional cell types. In addition, subtypes of the class ‘cell in vitro’ have received improved definitions and labels to provide for modularity with the representation of cells in the Cell Line Ontology and Reagent Ontology. Recent changes in the ontology development methodology for CL include a switch from OBO to OWL for the primary encoding of the ontology, and an increasing reliance on logical definitions for improved reasoning.Utility and discussionThe CL is now mandated as a metadata standard for large functional genomics and transcriptomics projects, and is used extensively for annotation, querying, and analyses of cell type specific data in sequencing consortia such as FANTOM5 and ENCODE, as well as for the NIAID ImmPort database and the Cell Image Library. The CL is also a vital component used in the modular construction of other biomedical ontologies—for example, the Gene Ontology and the cross-species anatomy ontology, Uberon, use CL to support the consistent representation of cell types across different levels of anatomical granularity, such as tissues and organs.ConclusionsThe ongoing improvements to the CL make it a valuable resource to both the OBO Foundry community and the wider scientific community, and we continue to experience increased interest in the CL both among developers and within the user community.

Summary Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS+ blood Tfh cells in SLE. OX40 signals promoted naïve and memory CD4+ T cells to express multiple Tfh cell molecules, and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.

T cell activation involves a cascade of TCR-mediated signals that are regulated by three distinct intracellular signaling motifs located within the cytoplasmic tails of the CD3 chains. While all the CD3 subunits possess at least one ITAM, CD3 ε subunit also contains a proline-rich sequence (PRS) and a basic-rich stretch (BRS). The CD3 ε BRS complexes selected phosphoinositides, interactions that are required for normal cell surface expression of the TCR. The cytoplasmic domain of CD3 ζ also contains several clusters of arginine and lysine residues. Herein, we report that these basic amino acids enable CD3 ζ to complex the phosphoinositides PtdIns(3)P, PtdIns(4)P, PtdIns(5)P, PtdIns(3,5)P2, and PtdIns(3,4,5)P3 with high affinity. Early TCR signaling pathways were unaffected by the targeted loss of the phosphoinositide-binding functions of CD3 ζ. Instead, the elimination of the phosphoinositide-binding function of CD3 ζ significantly impaired the ability of this invariant chain to stably accumulate at the immunological synapse during T cell-antigen presenting cell interactions. Without its phosphoinositide-binding functions, CD3 ζ was concentrated in intracellular structures following T cell activation. Such findings demonstrate a novel functional role for CD3 ζ BRS-phosphoinositide interactions in supporting T cell activation.

Three experiments were performed in singlepass, flow-through systems to determine the dietary phosphorus requirement of striped bass Morone saxatilis. In Experiment 1, three semi-purified diets were formulated to contain 0.20,0.40, or 0.60% total phosphorus (entirely from animal protein) and were fed to striped bass having an average initial weight of 321 g. After 14 wk of feeding, significant differences in bone and scale mineralization were found among treatment groups. At a level of 0.40% dietary phosphorus there was a significant improvement of serum calcium (Ca) and tissue mineralization. In Experiment 2, five diets were formulated with graded levels of monopotnssium phosphate to yield total phosphorus levels of 0.15 (no P supplementation), 0.35,0.55,0.75, and 0.95% and fed to juvenile striped bass initially weighing an average of 7.9 g. After 6 wk, significant improvement in scale and vertebral mineralization occurred when fish were fed diets containing at least 0.55% phosphorus. Improvements were observed in growth, serum phosphorus, incidence of scoliosis, survival, and feed efficiency when the diet contained at least 035% P. In Experiment 3, the dietary phosphorus levels fed were 0.30, 038, 0.46, 0.54, and 0.62% total phosphorus using graded levels of monopotassium phosphate. Diets were fed to striped bass fingerlings initially weighing an average of 48 g. After 10 wk, significant improvement in scale, vertebral, and dorsal fin mineralization was observed when dietary phosphorus was at least 0.46%. A summary of the broken-line regression analyses of the data from these experiments indicated that the average total dietary phosphorus level required for optimal growth and mineralization of striped bass was 0.58%. Phosphorus (P) is considered to be the most limiting nutrient for plant and algal growth in freshwater estuaries. When algae die, oxygen in the water is reduced due to degradative reactions associated with the resulting dry matter. This often results in severe oxygen depletion of the water. A level of 10-30 hg/L phosphate P has been reported for unpolluted lakes (U.S. EPA 1976). The latter is considerably below values observed in some intensive fish culture systems. The excessive P content of many com-

BackgroundNew technologies are focusing on characterizing cell types to better understand their heterogeneity. With large volumes of cellular data being generated, innovative methods are needed to structure the resulting data analyses. Here, we describe an ‘Ontologically BAsed Molecular Signature’ (OBAMS) method that identifies novel cellular biomarkers and infers biological functions as characteristics of particular cell types. This method finds molecular signatures for immune cell types based on mapping biological samples to the Cell Ontology (CL) and navigating the space of all possible pairwise comparisons between cell types to find genes whose expression is core to a particular cell type’s identity.ResultsWe illustrate this ontological approach by evaluating expression data available from the Immunological Genome project (IGP) to identify unique biomarkers of mature B cell subtypes. We find that using OBAMS, candidate biomarkers can be identified at every strata of cellular identity from broad classifications to very granular. Furthermore, we show that Gene Ontology can be used to cluster cell types by shared biological processes in order to find candidate genes responsible for somatic hypermutation in germinal center B cells. Moreover, through in silico experiments based on this approach, we have identified genes sets that represent genes overexpressed in germinal center B cells and identify genes uniquely expressed in these B cells compared to other B cell types.ConclusionsThis work demonstrates the utility of incorporating structured ontological knowledge into biological data analysis – providing a new method for defining novel biomarkers and providing an opportunity for new biological insights.