Large-scale validation of methods for cytotoxic T-lymphocyte epitope prediction

<p>Abstract</p> <p>Background</p> <p>Reliable predictions of Cytotoxic T lymphocyte (CTL) epitopes are essential for rational vaccine design. Most importantly, they can minimize the experimental effort needed to identify epitopes. NetCTL is a web-based tool designed for predicting human CTL epitopes in any given protein. It does so by integrating predictions of proteasomal cleavage, TAP transport efficiency, and MHC class I affinity. At least four other methods have been developed recently that likewise attempt to predict CTL epitopes: EpiJen, MAPPP, MHC-pathway, and WAPP. In order to compare the performance of prediction methods, objective benchmarks and standardized performance measures are needed. Here, we develop such large-scale benchmark and corresponding performance measures and report the performance of an updated version 1.2 of NetCTL in comparison with the four other methods.</p> <p>Results</p> <p>We define a number of performance measures that can handle the different types of output data from the five methods. We use two evaluation datasets consisting of known HIV CTL epitopes and their source proteins. The source proteins are split into all possible 9 mers and except for annotated epitopes; all other 9 mers are considered non-epitopes. In the RANK measure, we compare two methods at a time and count how often each of the methods rank the epitope highest. In another measure, we find the specificity of the methods at three predefined sensitivity values. Lastly, for each method, we calculate the percentage of known epitopes that rank within the 5% peptides with the highest predicted score.</p> <p>Conclusion</p> <p>NetCTL-1.2 is demonstrated to have a higher predictive performance than EpiJen, MAPPP, MHC-pathway, and WAPP on all performance measures. The higher performance of NetCTL-1.2 as compared to EpiJen and MHC-pathway is, however, not statistically significant on all measures. In the large-scale benchmark calculation consisting of 216 known HIV epitopes covering all 12 recognized HLA supertypes, the NetCTL-1.2 method was shown to have a sensitivity among the 5% top-scoring peptides above 0.72. On this dataset, the best of the other methods achieved a sensitivity of 0.64. The NetCTL-1.2 method is available at <url>http://www.cbs.dtu.dk/services/NetCTL</url>.</p> <p>All used datasets are available at <url>http://www.cbs.dtu.dk/suppl/immunology/CTL-1.2.php</url>.</p

The impact of language barriers on trust formation in multinational teams

This study systematically investigates how language barriers influence trust formation in multinational teams (MNTs). Based on 90 interviews with team members, team leaders, and senior managers in 15 MNTs in three German automotive corporations, we show how MNT members’ cognitive and emotional reactions to language barriers influence their perceived trustworthiness and intention to trust, which in turn affect trust formation. We contribute to diversity research by distinguishing the exclusively negative language effects from the more ambivalent effects of other diversity dimensions. Our findings also illustrate how surface-level language diversity may create perceptions of deep-level diversity. Furthermore, our study advances MNT research by revealing the specific influences of language barriers on team trust, an important mediator between team inputs and performance outcomes. It thereby encourages the examination of other team processes through a language lens. Finally, our study suggests that multilingual settings necessitate a reexamination and modification of the seminal trust theories by Mayer, Davis and Schoorman (1995) and McAllister (1995). In terms of practical implications, we outline how MNT leaders can manage their subordinates’ problematic reactions to language barriers and how MNT members can enhance their perceived trustworthiness in multilingual settings

Language in international business: a review and agenda for future research

A fast growing number of studies demonstrates that language diversity influences almost all management decisions in modern multinational corporations. Whereas no doubt remains about the practical importance of language, the empirical investigation and theoretical conceptualization of its complex and multifaceted effects still presents a substantial challenge. To summarize and evaluate the current state of the literature in a coherent picture informing future research, we systematically review 264 articles on language in international business. We scrutinize the geographic distributions of data, evaluate the field’s achievements to date in terms of theories and methodologies, and summarize core findings by individual, group, firm, and country levels of analysis. For each of these dimensions, we then put forward a future research agenda. We encourage scholars to transcend disciplinary boundaries and to draw on, integrate, and test a variety of theories from disciplines such as psychology, linguistics, and neuroscience to gain a more profound understanding of language in international business. We advocate more multi-level studies and cross-national research collaborations and suggest greater attention to potential new data sources and means of analysis

Myelin Proteomics: Molecular Anatomy of an Insulating Sheath

Fast-transmitting vertebrate axons are electrically insulated with multiple layers of nonconductive plasma membrane of glial cell origin, termed myelin. The myelin membrane is dominated by lipids, and its protein composition has historically been viewed to be of very low complexity. In this review, we discuss an updated reference compendium of 342 proteins associated with central nervous system myelin that represents a valuable resource for analyzing myelin biogenesis and white matter homeostasis. Cataloging the myelin proteome has been made possible by technical advances in the separation and mass spectrometric detection of proteins, also referred to as proteomics. This led to the identification of a large number of novel myelin-associated proteins, many of which represent low abundant components involved in catalytic activities, the cytoskeleton, vesicular trafficking, or cell adhesion. By mass spectrometry-based quantification, proteolipid protein and myelin basic protein constitute 17% and 8% of total myelin protein, respectively, suggesting that their abundance was previously overestimated. As the biochemical profile of myelin-associated proteins is highly reproducible, differential proteome analyses can be applied to material isolated from patients or animal models of myelin-related diseases such as multiple sclerosis and leukodystrophies

Spatial and Spectral Representations of the Geoid-to-Quasigeoid Correction

In geodesy, the geoid and the quasigeoid are used as a reference surface for heights. Despite some similarities between these two concepts, the differences between the geoid and the quasigeoid (i.e. the geoid-to-quasigeoid correction) have to be taken into consideration in some specific applications which require a high accuracy. Over the world’s oceans and marginal seas, the quasigeoid and the geoid are identical. Over the continents, however, the geoid-to-quasigeoid correction could reach up to several metres especially in the mountainous, polar and geologically complex regions. Various methods have been developed and applied to compute this correction regionally in the spatial domain using detailed gravity, terrain and crustal density data. These methods utilize the gravimetric forward modelling of the topographic density structure and the direct/inverse solutions to the boundary-value problems in physical geodesy. In this article, we provide a brief summary of existing theoretical and numerical studies on the geoid-to-quasigeoid correction. We then compare these methods with the newly developed procedure and discuss some numerical and practical aspects of computing this correction. In global applications, the geoid-to-quasigeoid correction can conveniently be computed in the spectral domain.For this purpose, we derive and present also the spectral expressions for computing this correction based on applying methods for a spherical harmonic analysis and synthesis of global gravity, terrain and crustal structure models. We argue that the newly developed procedure for the regional gravity-to-potential conversion, applied for computing the geoid-to-quasigeoid correction in the spatial domain, is numerically more stable than the existing inverse models which utilize the gravity downward continuation. Moreover, compared to existing spectral expressions, our definition in the spectral domain takes not only the terrain geometry but also the mass density heterogeneities within the whole Earth into consideration. In this way, the geoid-to-quasigeoid correction and the respective geoid model could be determined more accurately

Lithospheric stress tensor from gravity and lithospheric structure models

n this study we investigate the lithospheric stresses computed from the gravity and lithospheric structure models. The functional relation between the lithospheric stress tensor and the gravity field parameters is formulated based on solving the boundary-value problem of elasticity in order to determine the propagation of stresses inside the lithosphere, while assuming the horizontal shear stress components (computed at the base of the lithosphere) as lower boundary values for solving this problem. We further suppress the signature of global mantle flow in the stress spectrum by subtracting the long-wavelength harmonics (below the degree of 13). This numerical scheme is applied to compute the normal and shear stress tensor components globally at the Moho interface. The results reveal that most of the lithospheric stresses are accumulated along active convergent tectonic margins of oceanic subductions and along continent-to-continent tectonic plate collisions. These results indicate that, aside from a frictional drag caused by mantle convection, the largest stresses within the lithosphere are induced by subduction slab pull forces on the side of subducted lithosphere, which are coupled by slightly less pronounced stresses (on the side of overriding lithospheric plate) possibly attributed to trench suction. Our results also show the presence of (intra-plate) lithospheric loading stresses along Hawaii islands. The signature of ridge push (along divergent tectonic margins) and basal shear traction resistive forces is not clearly manifested at the investigated stress spectrum (between the degrees from 13 to 180)