Concept and application of a computational vaccinology workflow

BACKGROUND : The last years have seen a renaissance of the vaccine area, driven by clinical needs in infectious diseases but also chronic diseases such as cancer and autoimmune disorders. Equally important are technological improvements involving nano-scale delivery platforms as well as third generation adjuvants. In parallel immunoinformatics routines have reached essential maturity for supporting central aspects in vaccinology going beyond prediction of antigenic determinants. On this basis computational vaccinology has emerged as a discipline aimed at ab-initio rational vaccine design.Here we present a computational workflow for implementing computational vaccinology covering aspects from vaccine target identification to functional characterization and epitope selection supported by a Systems Biology assessment of central aspects in host-pathogen interaction. We exemplify the procedures for Epstein Barr Virus (EBV), a clinically relevant pathogen causing chronic infection and suspected of triggering malignancies and autoimmune disorders. RESULTS : We introduce pBone/pView as a computational workflow supporting design and execution of immunoinformatics workflow modules, additionally involving aspects of results visualization, knowledge sharing and re-use. Specific elements of the workflow involve identification of vaccine targets in the realm of a Systems Biology assessment of host-pathogen interaction for identifying functionally relevant targets, as well as various methodologies for delineating B- and T-cell epitopes with particular emphasis on broad coverage of viral isolates as well as MHC alleles.Applying the workflow on EBV specifically proposes sequences from the viral proteins LMP2, EBNA2 and BALF4 as vaccine targets holding specific B- and T-cell epitopes promising broad strain and allele coverage. CONCLUSION : Based on advancements in the experimental assessment of genomes, transcriptomes and proteomes for both, pathogen and (human) host, the fundaments for rational design of vaccines have been laid out. In parallel, immunoinformatics modules have been designed and successfully applied for supporting specific aspects in vaccine design. Joining these advancements, further complemented by novel vaccine formulation and delivery aspects, have paved the way for implementing computational vaccinology for rational vaccine design tackling presently unmet vaccine challenges

Analysis domain model for shared virtual environments

The field of shared virtual environments, which also encompasses online games and social 3D environments, has a system landscape consisting of multiple solutions that share great functional overlap. However, there is little system interoperability between the different solutions. A shared virtual environment has an associated problem domain that is highly complex raising difficult challenges to the development process, starting with the architectural design of the underlying system. This paper has two main contributions. The first contribution is a broad domain analysis of shared virtual environments, which enables developers to have a better understanding of the whole rather than the part(s). The second contribution is a reference domain model for discussing and describing solutions - the Analysis Domain Model

Standardization procedure for flow cytometry data harmonization in prospective multicenter studies

One of the most challenging objective for clinical cytometry in prospective multicenter immunomonitoring trials is to compare frequencies, absolute numbers of leukocyte populations and further the mean fluorescence intensities of cell markers, especially when the data are generated from different instruments. Here, we describe an innovative standardization workflow to compare all data to carry out any large-scale, prospective multicentric flow cytometry analysis whatever the duration, the number or type of instruments required for the realization of such project

Deriving feasible deployment alternatives for parallel and distributed simulation systems

Cataloged from PDF version of article.Parallel and distributed simulations (PADS) realize the distributed execution of a simulation system over multiple physical resources. To realize the execution of PADS, different simulation infrastructures such as HLA, DIS and TENA have been defined. Recently, the Distributed Simulation Engineering and Execution Process (DSEEP) that supports the mapping of the simulations on the infrastructures has been defined. An important recommended task in DSEEP is the evaluation of the performance of the simulation systems at the design phase. In general, the performance of a simulation is largely influenced by the allocation of member applications to the resources. Usually, the deployment of the applications to the resources can be done in many different ways. DSEEP does not provide a concrete approach for evaluating the deployment alternatives. Moreover, current approaches that can be used for realizing various DSEEP activities do not yet provide adequate support for this purpose. We provide a concrete approach for deriving feasible deployment alternatives based on the simulation system and the available resources. In the approach, first the simulation components and the resources are designed. The design is used to define alternative execution configurations, and based on the design and the execution configuration; a feasible deployment alternative can be algorithmically derived. Tool support is developed for the simulation design, the execution configuration definition and the automatic generation of feasible deployment alternatives. The approach has been applied within a large-scale industrial case study for simulating Electronic Warfare systems. © 2013 ACM

Agents for educational games and simulations

This book consists mainly of revised papers that were presented at the Agents for Educational Games and Simulation (AEGS) workshop held on May 2, 2011, as part of the Autonomous Agents and MultiAgent Systems (AAMAS) conference in Taipei, Taiwan. The 12 full papers presented were carefully reviewed and selected from various submissions. The papers are organized topical sections on middleware applications, dialogues and learning, adaption and convergence, and agent applications

Generation of hypoimmunogenic induced pluripotent stem cells by CRISPR-Cas9 system and detailed evaluation for clinical application

In order to expand the promise of regenerative medicine using allogeneic induced pluripotent stem cells (iPSCs), precise and efficient genome editing of human leukocyte antigen (HLA) genes would be advantageous to minimize the immune rejection caused by mismatches of HLA type. However, clinical-grade genome editing of multiple HLA genes in human iPSC lines remains unexplored. Here, we optimized the protocol for good manufacturing practice (GMP)-compatible CRISPR-Cas9 genome editing to deplete the three gene locus (HLA-A, HLA-B, and CIITA genes) simultaneously in HLA homozygous iPSCs. The use of HLA homozygous iPSCs has one main advantage over heterozygous iPSCs for inducing biallelic knockout by a single gRNA. RNA-seq and flow cytometry analyses confirmed the successful depletion of HLAs, and lineage-specific differentiation into cardiomyocytes was verified. We also confirmed that the pluripotency of genome-edited iPSCs was successfully maintained by the three germ layers of differentiation. Moreover, whole-genome sequencing, karyotyping, and optical genome mapping analyses revealed no evident genomic abnormalities detected in some clones, whereas unexpected copy number losses, chromosomal translocations, and complex genomic rearrangements were observed in other clones. Our results indicate the importance of multidimensional analyses to ensure the safety and quality of the genome-edited cells. The manufacturing and assessment pipelines presented here will be the basis for clinical-grade genome editing of iPSCs

Evaluation of a cardiac flow phantom for absolute myocardial perfusion SPECT measurements

Absolute myocardial perfusion imaging (MPI) can be beneficial in the diagnosis and prognosis of patients with coronary artery disease. However, validation and standardization of perfusion estimates across centers is needed to ensure safe and adequate integration into clinical routine. MPI phantoms can contribute to this clinical need as these models can provide ground truth evaluation of absolute MPI in a simplified, though controlled setup. This work presents verification of phantom design choices, including the justification for using sorbents in mimicking contrast kinetics (i.e., tracer uptake and retention). Moreover, we compare preliminary phantom results obtained with SPECT-MPI with a patient example. Finally, we applied a general two-tissue compartment model to describe the obtained phantom time activity curve data. These evaluation steps support shaping of a suitable verification and validation strategy for the multimodal myocardial perfusion phantom design and realization.</p