HLA-B⁎27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope

Background & Aims: HLA-B⁄27 is associated with spontaneous HCV genotype 1 clearance. HLA-B⁄27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B⁄27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B⁄27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope. Methods: Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B⁄27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B⁄27:02 and 05. Results: The NS5B2820 epitope is only restricted by the HLA-B⁄27 subtype HLA-B⁄27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B⁄27 subtype B⁄27:05. Indeed, the epitope is very dominant in HLA-B⁄27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B⁄27:02+ chronically infected patients. Conclusions: The NS5B2820 epitope is immunodominant in the context of HLA-B⁄27:02, but is not restricted by other HLA-B⁄27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines.

An application of combinatorial optimization in the printing industry

Offset printing is a common method to produce large amounts of printed matter. We consider a real-world offset printing process that is used to imprint customer-specific designs on napkin pouches. The print- ing technology used yields a number of specific constraints. The planning problem consists of allocating designs to printing-plate slots such that the given customer demand for each design is fulfilled, all technologi- cal and organizational constraints are met and the total overproduction and setup costs are minimized. We formulate this planning problem as a mixed-binary linear program, and we develop a multi-pass matching-based savings heuristic. We report computational results for a set of problem instances devised from real-world data.

Specimen specific parameter identification of ovine lumbar intervertebral discs: On the influence of fibre-matrix and fibre-fibre shear interactions.

Numerical models of the intervertebral disc, which address mechanical questions commonly make use of the difference in water content between annulus and nucleus, and thus fluid and solid parts are separated. Despite this simplification, models remain complex due to the anisotropy and nonlinearity of the annulus and regional variations of the collagen fibre density. Additionally, it has been shown that cross-links make a large contribution to the stiffness of the annulus. Because of this complex composite structure, it is difficult to reproduce several sets of experimental data with one single set of material parameters. This study addresses the question to which extent the ultrastructure of the intervertebral disc should be modelled so that its moment-angle behaviour can be adequately described. Therefore, a hyperelastic constitutive law, based on continuum mechanical principles was derived, which does not only consider the anisotropy from the collagen fibres, but also interactions among the fibres and between the fibres and the ground substance. Eight ovine lumbar intervertebral discs were tested on a custom made spinal loading simulator in flexion/extension, lateral bending and axial rotation. Specimen-specific geometrical models were generated using CT images and T2 maps to distinguish between annulus fibrosus and nucleus pulposus. For the identification of the material parameters the annulus fibrosus was described with two scenarios: with and without fibre-matrix and fibre-fibre interactions. Both scenarios showed a similar behaviour on a load displacement level. Comparing model predictions to the experimental data, the mean RMS of all specimens and all load cases was 0.54±0.15° without the interaction and 0.54±0.19° when the fibre-matrix and fibre-fibre interactions were included. However, due to the increased stiffness when cross-links effects were included, this scenario showed more physiological stress-strain relations in uniaxial and biaxial stress states. Thus, the present study suggests that fibre-matrix and fibre-fibre interactions should be considered in the constitutive law when the model addresses questions concerning the stress field of the annulus fibrosus.

Fast parallel kriging-based stepwise uncertainty reduction with application to the identification of an excursion set

Stepwise uncertainty reduction (SUR) strategies aim at constructing a sequence of points for evaluating a function  f in such a way that the residual uncertainty about a quantity of interest progressively decreases to zero. Using such strategies in the framework of Gaussian process modeling has been shown to be efficient for estimating the volume of excursion of f above a fixed threshold. However, SUR strategies remain cumbersome to use in practice because of their high computational complexity, and the fact that they deliver a single point at each iteration. In this article we introduce several multipoint sampling criteria, allowing the selection of batches of points at which f can be evaluated in parallel. Such criteria are of particular interest when f is costly to evaluate and several CPUs are simultaneously available. We also manage to drastically reduce the computational cost of these strategies through the use of closed form formulas. We illustrate their performances in various numerical experiments, including a nuclear safety test case. Basic notions about kriging, auxiliary problems, complexity calculations, R code, and data are available online as supplementary materials.

A new model construction by making a detour via intuitionistic theories I: Operational set theory without choice is Π1-equivalent to KP

We introduce a version of operational set theory, OST−, without a choice operation, which has a machinery for Δ0Δ0 separation based on truth functions and the separation operator, and a new kind of applicative set theory, so-called weak explicit set theory WEST, based on Gödel operations. We show that both the theories and Kripke–Platek set theory KPKP with infinity are pairwise Π1Π1 equivalent. We also show analogous assertions for subtheories with ∈-induction restricted in various ways and for supertheories extended by powerset, beta, limit and Mahlo operations. Whereas the upper bound is given by a refinement of inductive definition in KPKP, the lower bound is by a combination, in a specific way, of realisability, (intuitionistic) forcing and negative interpretations. Thus, despite interpretability between classical theories, we make “a detour via intuitionistic theories”. The combined interpretation, seen as a model construction in the sense of Visser's miniature model theory, is a new way of construction for classical theories and could be said the third kind of model construction ever used which is non-trivial on the logical connective level, after generic extension à la Cohen and Krivine's classical realisability model.

The Moldable Debugger: A Framework for Developing Domain-Specific Debuggers

Debuggers are crucial tools for developing object-oriented software systems as they give developers direct access to the running systems. Nevertheless, traditional debuggers rely on generic mechanisms to explore and exhibit the execution stack and system state, while developers reason about and formulate domain-specific questions using concepts and abstractions from their application domains. This creates an abstraction gap between the debugging needs and the debugging support leading to an inefficient and error-prone debugging effort. To reduce this gap, we propose a framework for developing domain-specific debuggers called the Moldable Debugger. The Moldable Debugger is adapted to a domain by creating and combining domain-specific debugging operations with domain-specific debugging views, and adapts itself to a domain by selecting, at run time, appropriate debugging operations and views. We motivate the need for domain-specific debugging, identify a set of key requirements and show how our approach improves debugging by adapting the debugger to several domains.

Controlling for culture-specific response bias using ipsatization and response style indicators: Family orientation in seventeen cultures and two generations

Within-subject standardization (ipsatization) has been advocated as a possible means to control for culture-specific responding (e.g., Fisher, 2004). However, the consequences of different kinds of ipsatization procedures for the interpretation of mean differences remain unclear. The current study compared several ipsatization procedures with ANCOVA-style procedures using response style indicators for the construct of family orientation with data from 14 cultures and two generations from the Value-of-Children-(VOC)-Study (4135 dyads). Results showed that within-subject centering/standardizing across all Likert-scale items of the comprehensive VOC-questionnaire removed most of the original cross-cultural variation in family orientation and lead to a non-interpretable pattern of means in both generations. Within-subject centering/standardizing using a subset of 19 unrelated items lead to a decrease to about half of the original effect size and produced a theoretically meaningful pattern of means. A similar effect size and similar mean differences were obtained when using a measure of acquiescent responding based on the same set of items in an ANCOVA-style analysis. Additional models controlling for extremity and modesty performed worse, and combinations did not differ from the acquiescence-only model. The usefulness of different approaches to control for uniform response styles (scalar equivalence not given) in cross- cultural comparisons is discussed.

Practical domain-specific debuggers using the Moldable Debugger framework

Understanding the run-time behavior of software systems can be a challenging activity. Debuggers are an essential category of tools used for this purpose as they give developers direct access to the running systems. Nevertheless, traditional debuggers rely on generic mechanisms to introspect and interact with the running systems, while developers reason about and formulate domain-specific questions using concepts and abstractions from their application domains. This mismatch creates an abstraction gap between the debugging needs and the debugging support leading to an inefficient and error-prone debugging effort, as developers need to recover concrete domain concepts using generic mechanisms. To reduce this gap, and increase the efficiency of the debugging process, we propose a framework for developing domain-specific debuggers, called the Moldable Debugger, that enables debugging at the level of the application domain. The Moldable Debugger is adapted to a domain by creating and combining domain-specific debugging operations with domain-specific debugging views, and adapts itself to a domain by selecting, at run time, appropriate debugging operations and views. To ensure the proposed model has practical applicability (i.e., can be used in practice to build real debuggers), we discuss, from both a performance and usability point of view, three implementation strategies. We further motivate the need for domain-specific debugging, identify a set of key requirements and show how our approach improves debugging by adapting the debugger to several domains.