Impact of Pre-Existing Immunity on the Selection of Rare Adenovirus Vector Candidates: Implications for HIV Vaccine Development

Background: Adenovirus serotype 5 (Ad5) phase IIb vaccine trial (STEP) was prematurely stopped due to a lack of efficacy and two-fold higher incidence of HIV infection among Ad5 seropositive vaccine recipients. We have recently demonstrated that Ad5 immune complexes (Ad5 ICs)-mediated activation of the dendritic cell (DC)-T cell axis was associated with the enhancement of HIV infection in vitro. Although the direct role of Ad5 neutralizing antibodies (NAbs) in the increase of HIV susceptibility during the STEP trial is still under debate, vector-specific NAbs remain a major hurdle for vector-based gene therapies or vaccine strategies. To surmount this obstacle, vectors based on ''rare'' Ad serotypes including Ad6, Ad26, Ad36 and Ad41 were engineered.Methods: The present study aimed to determine whether Ad ICmediated DC maturation could be circumvented using these Advector candidates.Results: We found that all Ad vectors tested forming ICs with plasma containing serotype-specific NAbs had the capacity to 1) mature human DCs as monitored by the up-regulation of costimulatory molecules and the release of pro-inflammatory cytokines (TNF-a), via the stabilization of Ad capsid at endosomal but not lysosomal pH rendering Ad DNA/TLR9 interactions possible and 2) potentiate Ad-specific CD4 and CD8 T cell responses.Conclusion: In conclusion, despite a conserved DC maturation potential, the low prevalence of serotype-specific NAbs renders rare Ad vectors attractive for vaccine strategies.

Increased frequency of regulatory T cells and selection of highly potent CD62L+ cells during treatment of human lung transplant recipients with rapamycin.

The currently available immunosuppressive agents applied in human transplantation medicine are highly potent in the protection from acute allograft rejection. However, long-term allograft survival is still poor as these drugs fail to sufficiently prevent chronic allograft rejection. Naturally occurring regulatory T cells have been postulated as the key players to establish long-lasting transplantation tolerance. Thus, the development of immunosuppressive regimens which shift the pathological balance of cytopathic versus regulatory T cells of human allograft recipients towards a protective T-cell composition is a promising approach to overcome limitations of current transplantation medicine. Thirty-three patients that received rapamycin (RPM) or calcineurin inhibitor treatment following lung transplantation were included and their T-cell compartments analysed. Twelve healthy volunteers without history of lung disease served as controls. In this article, we show that treatment of human lung transplant recipients with RPM is associated with an increased frequency of regulatory T cells, as compared with treatment with calcineurin inhibitors or to healthy controls. Moreover, regulatory T cells during treatment with RPM were CD62Lhigh, a phenotype that displayed an enhanced immunosuppressive capacity ex vivo. Our data support the use of RPM in human lung transplant recipients and undertaking of further prospective studies evaluating its impact on allograft and patient survival.

A genetic algorithm to ensemble feature selection

We are going to implement the "GA-SEFS" by Tsymbal and analyse experimentally its performance depending on the classifier algorithms used in the fitness function (NB, MNge, SMO). We are also going to study the effect of adding to the fitness function a measure to control complexity of the base classifiers.

gcodeml: A Grid-enabled Tool for Detecting Positive Selection in Biological Evolution

One of the important questions in biological evolution is to know if certain changes along protein coding genes have contributed to the adaptation of species. This problem is known to be biologically complex and computationally very expensive. It, therefore, requires efficient Grid or cluster solutions to overcome the computational challenge. We have developed a Grid-enabled tool (gcodeml) that relies on the PAML (codeml) package to help analyse large phylogenetic datasets on both Grids and computational clusters. Although we report on results for gcodeml, our approach is applicable and customisable to related problems in biology or other scientific domains.

Fishery-induced selection on an Alpine whitefish: quantifying genetic and environmental effects on individual growth rate

Size-selective fishing, environmental changes and reproductive strategies are expected to affect life-history traits such as the individual growth rate. The relative contribution of these factors is not clear, particularly whether size-selective fishing can have a substantial impact on the genetics and hence on the evolution of individual growth rates in wild populations. We analysed a 25-year monitoring survey of an isolated population of the Alpine whitefish Coregonus palaea. We determined the selection differentials on growth rate, the actual change of growth rate over time and indicators of reproductive strategies that may potentially change over time. The selection differential can be reliably estimated in our study population because almost all the fish are harvested within their first years of life, i.e. few fish escape fishing mortality. We found a marked decline in average adult growth rate over the 25 years and a significant selection differential for adult growth, but no evidence for any linear change in reproductive strategies over time. Assuming that the heritability of growth in this whitefish corresponds to what was found in other salmonids, about a third of the observed decline in growth rate would be linked to fishery-induced evolution. Size-selective fishing seems to affect substantially the genetics of individual growth in our study population.

Stick insect genomes reveal natural selection's role in parallel speciation.

Natural selection can drive the repeated evolution of reproductive isolation, but the genomic basis of parallel speciation remains poorly understood. We analyzed whole-genome divergence between replicate pairs of stick insect populations that are adapted to different host plants and undergoing parallel speciation. We found thousands of modest-sized genomic regions of accentuated divergence between populations, most of which are unique to individual population pairs. We also detected parallel genomic divergence across population pairs involving an excess of coding genes with specific molecular functions. Regions of parallel genomic divergence in nature exhibited exceptional allele frequency changes between hosts in a field transplant experiment. The results advance understanding of biological diversification by providing convergent observational and experimental evidence for selection's role in driving repeatable genomic divergence.

Tackling self-selection into treatment and self-selection into the sample biases in VAA research

Self‐selection into treatment and self‐selection into the sample are major concerns of VAA research and need to be controlled for if the aim is to deduce causal effects from VAA use in observational data. This paper focuses on the methodological aspects of VAA research and outlines omnipresent endogeneity issues, partly imposed through unobserved factors that affect both whether individuals chose to use VAAs and their electoral behavior. We promote using Heckman selection models and apply various versions of the model to data from the Swiss electorate and smartvote users in order to see to what extent selection biases interfere with the estimated effects of interest.

The evolution of XY recombination: sexually antagonistic selection versus deleterious mutation load.

Recombination arrest between X and Y chromosomes, driven by sexually antagonistic genes, is expected to induce their progressive differentiation. However, in contrast to birds and mammals (which display the predicted pattern), most cold-blooded vertebrates have homomorphic sex chromosomes. Two main hypotheses have been proposed to account for this, namely high turnover rates of sex-determining systems and occasional XY recombination. Using individual-based simulations, we formalize the evolution of XY recombination (here mediated by sex reversal; the "fountain-of-youth" model) under the contrasting forces of sexually antagonistic selection and deleterious mutations. The shift between the domains of elimination and accumulation occurs at much lower selection coefficients for the Y than for the X. In the absence of dosage compensation, mildly deleterious mutations accumulating on the Y depress male fitness, thereby providing incentives for XY recombination. Under our settings, this occurs via "demasculinization" of the Y, allowing recombination in XY (sex-reversed) females. As we also show, this generates a conflict with the X, which coevolves to oppose sex reversal. The resulting rare events of XY sex reversal are enough to purge the Y from its load of deleterious mutations. Our results support the "fountain of youth" as a plausible mechanism to account for the maintenance of sex-chromosome homomorphy.

A Structural Analysis of the Health Expenditures and Portfolio Choices of Retired Agents

Richer and healthier agents tend to hold riskier portfolios and spend proportionally less on health expenditures. Potential explanations include health and wealth effects on preferences, expected longevity or disposable total wealth. Using HRS data, we perform a structural estimation of a dynamic model of consumption, portfolio and health expenditure choices with recursive utility, as well as health-dependent income and mortality risk. Our estimates of the deep parameters highlight the importance of health capital, mortality risk control, convex health and mortality adjustment costs and binding liquidity constraints to rationalize the stylized facts. They also provide new perspectives on expected longevity and on the values of life and health.

Inter-rater agreement and reliability of the COSMIN (COnsensus-based Standards for the selection of health status Measurement Instruments) Checklist

Background: The COSMIN checklist is a tool for evaluating the methodological quality of studies on measurement properties of health-related patient-reported outcomes. The aim of this study is to determine the inter-rater agreement and reliability of each item score of the COSMIN checklist (n = 114). Methods: 75 articles evaluating measurement properties were randomly selected from the bibliographic database compiled by the Patient-Reported Outcome Measurement Group, Oxford, UK. Raters were asked to assess the methodological quality of three articles, using the COSMIN checklist. In a one-way design, percentage agreement and intraclass kappa coefficients or quadratic-weighted kappa coefficients were calculated for each item. Results: 88 raters participated. Of the 75 selected articles, 26 articles were rated by four to six participants, and 49 by two or three participants. Overall, percentage agreement was appropriate (68% was above 80% agreement), and the kappa coefficients for the COSMIN items were low (61% was below 0.40, 6% was above 0.75). Reasons for low inter-rater agreement were need for subjective judgement, and accustom to different standards, terminology and definitions.Conclusions: Results indicated that raters often choose the same response option, but that it is difficult on item level to distinguish between articles. When using the COSMIN checklist in a systematic review, we recommend getting some training and experience, completing it by two independent raters, and reaching consensus on one final rating. Instructions for using the checklist are improved.

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Background: Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment andinnate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Results:Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection arefrequent on genes that are known to be at bifurcation points, and that are identified as beingin key position by a network-level analysis such as MGAT3 and GCS1.Conclusions: These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

Signatures of selection in the human olfactory receptor OR5I1 gene

The human olfactory receptor repertoire is reduced in comparison to other mammalsand to other non-human primates. Nonetheless, this olfactory decline opens an opportunity forevolutionary innovation and improvement. In the present study, we focus on an olfactoryreceptor gene, OR5I1, which had previously been shown to present an excess of amino acidreplacement substitutions between humans and chimpanzees. We analyze the geneticvariation in OR5I1 in a large worldwide human panel and find an excess of derived allelessegregating at relatively high frequencies in all populations. Additional evidence for selectionincludes departures from neutrality in allele frequency spectra tests but no unusually extendedhaplotype structure. Moreover, molecular structural inference suggests that one of thenonsynonymous polymorphisms defining the presumably adaptive protein form of OR5I1may alter the functional binding properties of the olfactory receptor. These results arecompatible with positive selection having modeled the pattern of variation found in the OR5I1gene and with a relatively ancient, mild selective sweep predating the “Out of Africa”expansion of modern humans.