Location of the CD8 T Cell Epitope within the Antigenic Precursor Determines Immunogenicity and Protection against the Toxoplasma gondii Parasite

CD8 T cells protect the host from disease caused by intracellular pathogens, such as the Toxoplasma gondii (T. gondii) protozoan parasite. Despite the complexity of the T. gondii proteome, CD8 T cell responses are restricted to only a small number of peptide epitopes derived from a limited set of antigenic precursors. This phenomenon is known as immunodominance and is key to effective vaccine design. However, the mechanisms that determine the immunogenicity and immunodominance hierarchy of parasite antigens are not well understood.Here, using genetically modified parasites, we show that parasite burden is controlled by the immunodominant GRA6-specific CD8 T cell response but not by responses to the subdominant GRA4- and ROP7-derived epitopes. Remarkably, optimal processing and immunodominance were determined by the location of the peptide epitope at the C-terminus of the GRA6 antigenic precursor. In contrast, immunodominance could not be explained by the peptide affinity for the MHC I molecule or the frequency of T cell precursors in the naive animals. Our results reveal the molecular requirements for optimal presentation of an intracellular parasite antigen and for eliciting protective CD8 T cells. © 2013 Feliu et al

Accelerating root system phenotyping of seedlings through a computer-assisted processing pipeline

Background: There are numerous systems and techniques to measure the growth of plant roots. However, phenotyping large numbers of plant roots for breeding and genetic analyses remains challenging. One major difficulty is to achieve high throughput and resolution at a reasonable cost per plant sample. Here we describe a cost-effective root phenotyping pipeline, on which we perform time and accuracy benchmarking to identify bottlenecks in such pipelines and strategies for their acceleration. Results: Our root phenotyping pipeline was assembled with custom software and low cost material and equipment. Results show that sample preparation and handling of samples during screening are the most time consuming task in root phenotyping. Algorithms can be used to speed up the extraction of root traits from image data, but when applied to large numbers of images, there is a trade-off between time of processing the data and errors contained in the database. Conclusions: Scaling-up root phenotyping to large numbers of genotypes will require not only automation of sample preparation and sample handling, but also efficient algorithms for error detection for more reliable replacement of manual interventions

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Extracting phylogenetic signal and accounting for bias in whole-genome data sets supports the Ctenophora as sister to remaining Metazoa

BACKGROUND: Understanding the phylogenetic relationships among major lineages of multicellular animals (the Metazoa) is a prerequisite for studying the evolution of complex traits such as nervous systems, muscle tissue, or sensory organs. Transcriptome-based phylogenies have dramatically improved our understanding of metazoan relationships in recent years, although several important questions remain. The branching order near the base of the tree, in particular the placement of the poriferan (sponges, phylum Porifera) and ctenophore (comb jellies, phylum Ctenophora) lineages is one outstanding issue. Recent analyses have suggested that the comb jellies are sister to all remaining metazoan phyla including sponges. This finding is surprising because it suggests that neurons and other complex traits, present in ctenophores and eumetazoans but absent in sponges or placozoans, either evolved twice in Metazoa or were independently, secondarily lost in the lineages leading to sponges and placozoans. RESULTS: To address the question of basal metazoan relationships we assembled a novel dataset comprised of 1080 orthologous loci derived from 36 publicly available genomes representing major lineages of animals. From this large dataset we procured an optimized set of partitions with high phylogenetic signal for resolving metazoan relationships. This optimized data set is amenable to the most appropriate and computationally intensive analyses using site-heterogeneous models of sequence evolution. We also employed several strategies to examine the potential for long-branch attraction to bias our inferences. Our analyses strongly support the Ctenophora as the sister lineage to other Metazoa. We find no support for the traditional view uniting the ctenophores and Cnidaria. Our findings are supported by Bayesian comparisons of topological hypotheses and we find no evidence that they are biased by long-branch attraction. CONCLUSIONS: Our study further clarifies relationships among early branching metazoan lineages. Our phylogeny supports the still-controversial position of ctenophores as sister group to all other metazoans. This study also provides a workflow and computational tools for minimizing systematic bias in genome-based phylogenetic analyses. Future studies of metazoan phylogeny will benefit from ongoing efforts to sequence the genomes of additional invertebrate taxa that will continue to inform our view of the relationships among the major lineages of animals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2146-4) contains supplementary material, which is available to authorized users

Characterization of a new Leishmania major strain for use in a controlled human infection model

Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development. Here, the authors describe the isolation, characterization, and GMP manufacture of a clinical Leishmania major strain to be used as a resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis

A systematic review of the implementation and impact of asthma protocols

BACKGROUND: Asthma is one of the most common childhood illnesses. Guideline-driven clinical care positively affects patient outcomes for care. There are several asthma guidelines and reminder methods for implementation to help integrate them into clinical workflow. Our goal is to determine the most prevalent method of guideline implementation; establish which methods significantly improved clinical care; and identify the factors most commonly associated with a successful and sustainable implementation. METHODS: PUBMED (MEDLINE), OVID CINAHL, ISI Web of Science, and EMBASE. Study Selection: Studies were included if they evaluated an asthma protocol or prompt, evaluated an intervention, a clinical trial of a protocol implementation, and qualitative studies as part of a protocol intervention. Studies were excluded if they had non-human subjects, were studies on efficacy and effectiveness of drugs, did not include an evaluation component, studied an educational intervention only, or were a case report, survey, editorial, letter to the editor. RESULTS: From 14,478 abstracts, we included 101 full-text articles in the analysis. The most frequent study design was pre-post, followed by prospective, population based case series or consecutive case series, and randomized trials. Paper-based reminders were the most frequent with fully computerized, then computer generated, and other modalities. No study reported a decrease in health care practitioner performance or declining patient outcomes. The most common primary outcome measure was compliance with provided or prescribing guidelines, key clinical indicators such as patient outcomes or quality of life, and length of stay. CONCLUSIONS: Paper-based implementations are by far the most popular approach to implement a guideline or protocol. The number of publications on asthma protocol reminder systems is increasing. The number of computerized and computer-generated studies is also increasing. Asthma guidelines generally improved patient care and practitioner performance regardless of the implementation method