What happens to the DNA vaccine in fish? A review of current knowledge

The primary function of DNA vaccines, a bacterial plasmid DNA containing a construct for a given protective antigen, is to establish specific and long-lasting protective immunity against diseases where conventional vaccines fail to induce protection. It is acknowledged that less effort has been made to study the fate, in terms of cellular uptake, persistence and degradation, of DNA vaccines after in vivo administration. However, during the last year some papers have given new insights into the fate of DNA vaccines in fish. By comparing the newly acquired information in fish with similar knowledge from studies in mammals, similarities with regard to transport, blood clearance, cellular uptake and degradation of DNA vaccines have been found. But the amount of DNA vaccine redistributed from the administration site after intramuscular administration seems to differ between fish and mammals. This review presents up-to-date and in-depth knowledge concerning the fate of DNA vaccines with emphasis on tissue distribution, cellular uptake and uptake mechanism(s) before finally describing the intracellular hurdles that DNA vaccines need to overcome in order to produce their gene product.     

Proteochemometrics analysis of substrate interactions with dengue virus NS3 proteases

The prime side specificity of dengue protease substrates was investigated by use of proteochemometrics, a technology for drug target interaction analysis. A set of 48 internally quenched peptides were designed using statistical molecular design (SMD) and assayed with proteases of four subtypes of dengue virus (DEN-1-4) for Michaelis (K(m)) and cleavage rate constants (k(cat)). The data were subjected to proteochemometrics modeling, concomitantly modeling all peptides on all the four dengue proteases, which yielded highly predictive models for both activities. Detailed analysis of the models then showed that considerably differing physico-chemical properties of amino acids contribute independently to the K(m) and k(cat) activities. For k(cat), only P1' and P2' prime side residues were important, while for K(m) all four prime side residues, P1'-P4', were important. The models could be used to identify amino acids for each P' substrate position that are favorable for, respectively, high substrate affinity and cleavage rate.     

Novel selective melanocortin 4 receptor antagonist induces food intake after peripheral administration

We synthesized a new series of small cyclic melanocyte-stimulating hormone (MSH) analogues and screened them for binding affinity at the four MSH binding melanocortin (MC) receptors. We identified a novel substance HS131, with about 20-fold higher affinity for the MC4 receptor than the MC3 receptor. This substance proved to be antagonist for all the four MC receptors in a cAMP assay. HS131 is a six amino acid long peptide, has a molecular weight below 1000, and has only two amino acids in common with the natural MSH peptides. HS131 potently and dose dependently increased food intake after i.c.v. administration. Moreover, s.c. administration of HS131 (1.0 mg/kg) increased food intake, suggesting that HS131 may be able to pass the blood brain barrier. This cyclic low molecular weight peptidomimetic will enable studies of the functional role of the MC4 receptors by peripheral administration and it may be used as a template for further development of low molecular weight substances for the MC receptors.     

Exploration or exploitation: life expectancy changes the value of learning in foraging strategies

The acquisition of information is a fundamental part of individual foraging behaviour in heterogeneous and changing environments. We examine how foragers may benefit from utilizing a simple learning rule to update estimates of temporal changes in resource levels. In the model, initial expectation of resource conditions and rate of replacing past information by new experiences are genetically inherited traits. Patch-time allocation differs between learners and foragers that use a fixed patch-leaving threshold throughout the foraging season. It also deviates from foragers that obtain information about the environment at no cost. At the start of a foraging season, learners sample the environment by frequent movements between patches, sacrificing current resource intake for information acquisition. This is done to obtain more precise and accurate estimates of resource levels, resulting in increased intake rates later in season. Risk of mortality may alter the trade-off between exploration and exploitation and thus change patch sampling effort. As lifetime expectancy decreases, learners invest less in information acquisition and show lower foraging performance when resource level changes through time.     

Extra‐pair mating in a passerine bird with highly duplicated major histocompatibility complex class II: Preference for the golden mean

Genes of the major histocompatibility complex (MHC) are essential in vertebrate adaptive immunity, and they are highly diverse and duplicated in many lineages. While it is widely established that pathogen‐mediated selection maintains MHC diversity through balancing selection, the role of mate choice in shaping MHC diversity is debated. Here, we investigate female mating preferences for MHC class II (MHCII) in the bluethroat (Luscinia svecica), a passerine bird with high levels of extra‐pair paternity and extremely duplicated MHCII. We genotyped family samples with mixed brood paternity and categorized their MHCII alleles according to their functional properties in peptide binding. Our results strongly indicate that females select extra‐pair males in a nonrandom, self‐matching manner that provides offspring with an allelic repertoire size closer to the population mean, as compared to offspring sired by the social male. This is consistent with a compatible genes model for extra‐pair mate choice where the optimal allelic diversity is intermediate, not maximal. This golden mean presumably reflects a trade‐off between maximizing pathogen recognition benefits and minimizing autoimmunity costs. Our study exemplifies how mate choice can reduce the population variance in individual MHC diversity and exert strong stabilizing selection on the trait. It also supports the hypothesis that extra‐pair mating is adaptive through altered genetic constitution in offspring.     

Development of a high-resolution NGS-based HLA-typing and analysis pipeline

The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions.     

Trauma and Poor Mental Health in Relation to Economic Status: The Case of Cambodia 35 Years Later

Background

Cambodia is one of the poorest countries in south-east Asia and is still emerging from the events of the Khmer Rouge reign. It has been suggested that the atrocities experienced by the Cambodian population can explain why Cambodia continues to lag behind its neighbours in economic outcomes. The purpose of this study is to investigate whether there is an association between exposure to past trauma and/or current poor mental health and current economic status in Cambodia.

Method

A newly conducted survey performed in two regions (north-west and south-east Cambodia) collected information on trauma exposure, psychiatric symptoms, self-rated health outcomes and socio-economic information for 3200 persons aged 18–60. Economic outcomes were measured as household debt and poverty status and whether the respondent was economically inactive. All models were analysed using logistic regression.

Results

No association was found between high exposure to conflict-related or civilian trauma and any economic outcomes save for a negative association between civilian trauma and poverty in the south-east. Current post-traumatic stress was related solely to poverty status. All other measures of current mental health status, however, were found to be strongly negatively associated with all measures of economic status. Thus, mental health interventions could potentially be utilised in poverty reduction strategies, but greater efficacy is likely to be achieved by targeting current mental health status rather than previous trauma exposure.     

Bioclipse: an open source workbench for chemo- and bioinformatics

Background  

There is a need for software applications that provide users with a complete and extensible toolkit for chemo- and bioinformatics accessible from a single workbench. Commercial packages are expensive and closed source, hence they do not allow end users to modify algorithms and add custom functionality. Existing open source projects are more focused on providing a framework for integrating existing, separately installed bioinformatics packages, rather than providing user-friendly interfaces. No open source chemoinformatics workbench has previously been published, and no sucessful attempts have been made to integrate chemo- and bioinformatics into a single framework.