Integrating ecology,psychology and neurobiology within a food-hoarding paradigm

Many animals regularly hoard food for future use, which appears to be an important adaptation to a seasonally and/or unpredictably changing environment. This food-hoarding paradigm is an excellent example of a natural system that has broadly influenced both theoretical and empirical work in the field of biology. The food-hoarding paradigm has played a major role in the conceptual framework of numerous fields from ecology (e.g. plant–animal interactions) and evolution (e.g. the coevolution of caching, spatial memory and the hippocampus) to psychology (e.g. memory and cognition) and neurobiology (e.g. neurogenesis and the neurobiology of learning and memory). Many food-hoarding animals retrieve caches by using spatial memory. This memory-based behavioural system has the inherent advantage of being tractable for study in both the field and laboratory and has been shaped by natural selection, which produces variation with strong fitness consequences in a variety of taxa. Thus, food hoarding is an excellent model for a highly integrative approach to understanding numerous questions across a variety of disciplines. Recently, there has been a surge of interest in the complexity of animal cognition such as future planning and episodic-like-memory as well as in the relationship between memory, the environment and the brain. In addition, new breakthroughs in neurobiology have enhanced our ability to address the mechanisms underlying these behaviours. Consequently, the field is necessarily becoming more integrative by assessing behavioural questions in the context of natural ecological systems and by addressing mechanisms through neurobiology and psychology, but, importantly, within an evolutionary and ecological framework. In this issue, we aim to bring together a series of papers providing a modern synthesis of ecology, psychology, physiology and neurobiology and identifying new directions and developments in the use of food-hoarding animals as a model system.     

Genetic variation in the cellular response of Daphnia magna (Crustacea: Cladocera) to its bacterial parasite

Linking measures of immune function with infection, and ultimately, host and parasite fitness is a major goal in the field of ecological immunology. In this study, we tested for the presence and timing of a cellular immune response in the crustacean Daphnia magna following exposure to its sterilizing endoparasite Pasteuria ramosa. We found that D. magna possesses two cell types circulating in the haemolymph: a spherical one, which we call a granulocyte and an irregular-shaped amoeboid cell first described by Metchnikoff over 125 years ago. Daphnia magna mounts a strong cellular response (of the amoeboid cells) just a few hours after parasite exposure. We further tested for, and found, considerable genetic variation for the magnitude of this cellular response. These data fostered a heuristic model of resistance in this naturally coevolving host–parasite interaction. Specifically, the strongest cellular responses were found in the most susceptible hosts, indicating resistance is not always borne from a response that destroys invading parasites, but rather stems from mechanisms that prevent their initial entry. Thus, D. magna may have a two-stage defence—a genetically determined barrier to parasite establishment and a cellular response once establishment has begun.     

Spatial and temporal extinction dynamics in a freshwater cetacean

Geographical range contraction is a fundamental ecological characteristic of species population decline, but relatively little investigation has been conducted into general trends in the dynamic properties of range collapse. The Yangtze River dolphin or baiji (Lipotes vexillifer), probably the first large mammal species to have become extinct in over 50 years, was believed to have experienced major range collapse during its decline through progressive large-scale range contraction and fragmentation. This range-collapse model is challenged by a new dataset of 406 baiji last-sighting records collected from across the baiji''s historical range during an interview survey of Yangtze fishing communities. Although baiji regional abundance may have varied across its range, analyses of the extensive new sighting series provide comprehensive evidence that baiji population decline was not associated with any major contraction in geographical range across the middle–lower Yangtze drainage, even in the decade immediately before probable global extinction of the species. Extinction risk in baiji was therefore seemingly not related to evidence of range collapse. Baiji apparently underwent large-scale periodic and seasonal movements across their range, and we propose that range contraction and fragmentation may not be general biogeographic characteristics for declining populations of mobile species in connected landscapes.     

Does probabilistic modelling of linkage disequilibrium evolution improve the accuracy of QTL location in animal pedigree?

Background

Since 2001, the use of more and more dense maps has made researchers aware that combining linkage and linkage disequilibrium enhances the feasibility of fine-mapping genes of interest. So, various method types have been derived to include concepts of population genetics in the analyses. One major drawback of many of these methods is their computational cost, which is very significant when many markers are considered. Recent advances in technology, such as SNP genotyping, have made it possible to deal with huge amount of data. Thus the challenge that remains is to find accurate and efficient methods that are not too time consuming. The study reported here specifically focuses on the half-sib family animal design. Our objective was to determine whether modelling of linkage disequilibrium evolution improved the mapping accuracy of a quantitative trait locus of agricultural interest in these populations. We compared two methods of fine-mapping. The first one was an association analysis. In this method, we did not model linkage disequilibrium evolution. Therefore, the modelling of the evolution of linkage disequilibrium was a deterministic process; it was complete at time 0 and remained complete during the following generations. In the second method, the modelling of the evolution of population allele frequencies was derived from a Wright-Fisher model. We simulated a wide range of scenarios adapted to animal populations and compared these two methods for each scenario.

Results

Our results indicated that the improvement produced by probabilistic modelling of linkage disequilibrium evolution was not significant. Both methods led to similar results concerning the location accuracy of quantitative trait loci which appeared to be mainly improved by using four flanking markers instead of two.

Conclusions

Therefore, in animal half-sib designs, modelling linkage disequilibrium evolution using a Wright-Fisher model does not significantly improve the accuracy of the QTL location when compared to a simpler method assuming complete and constant linkage between the QTL and the marker alleles. Finally, given the high marker density available nowadays, the simpler method should be preferred as it gives accurate results in a reasonable computing time.     

Novel Recombinant Mycobacterium bovis BCG,Ovine Atadenovirus,and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques

Mycobacterium bovis bacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA⁴⁰¹ as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA⁴⁰¹ was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankara-vectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA⁴⁰¹ and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration.Vaccine strategies must balance safety with immunogenicity. Recombinant attenuated subunit vaccines are generally regarded as safe, but not sufficiently immunogenic as stand-alone vaccines (17). Heterologous prime-boost regimens employing diverse attenuated viruses or bacteria as vectors delivering a common, often T cell-based, immunogen have been shown to induce stronger responses than multiple repeated dosings of the same vaccine modalities (19, 22, 39, 54). This is because heterologous regimens allow boosting of pathogen insert-specific responses while avoiding the accumulation of antivector immunity, which can significantly decrease vaccine “take” (1, 41). Results of the STEP study, which used a candidate single-vector human immunodeficiency virus type 1 (HIV-1) vaccine (6, 17, 41), have highlighted the need for novel alternative vaccine vectors and strategies. Such alternatives could complement the limited mainstream vectors and provide additional safety and immunogenicity through increased flexibility, for example, through the availability of personalized vaccination regimens based on preexisting immune status and/or responsiveness to vaccination.Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the world''s most widely used vaccine, with over three billion doses administered since its deployment in 1920s. It is the only licensed vaccine against tuberculosis and is administered at birth as part of the WHO Expanded Programme on Immunization (EPI). Due to its many attractive features, BCG or related mycobacterial vectors have also been explored in the context of vaccines against a number of infectious agents such as Leishmania, Borrelia burgdorferi, Streptococcus pneumoniae, Bordetella pertussis, malaria, cottontail rabbit papillomavirus, measles virus, and indeed human and simian immunodeficiency viruses (34). Many of these vaccines showed immunogenicity and protection in murine models, and some were also immunogenic in nonhuman primates (8, 56, 67, 68). In human adults, recombinant BCG (rBCG) vaccines alone failed to provide consistent protection against Lyme disease (13). In addition to adult applications, we have suggested the use of rBCG expressing an HIV-1-derived immunogen as the priming component of a vaccine platform against mother-to-child transmission of HIV-1 through infected breast milk (32), where it would be critical to elicit a protective HIV-1-specific response as soon as possible after birth.To compare vectors and heterologous prime-boost regimens directly, we have advocated and pioneered the development of a panel of vaccine modalities delivering the same shared immunogen (18). Our first such model immunogen is called HIVA (21). This is a T-cell immunogen comprising HIV-1 consensus clade A Gag and a string of partially overlapping immunodominant CD8 T-cell epitopes originating from Gag, Pol, Nef, and Env, which has already been tested extensively in human volunteers (20). To facilitate iterative preclinical improvements of the HIVA vaccines, epitopes recognized by murine (58) and rhesus macaque (44) CD8 T cells were also incorporated. Furthermore, we have formulated HIVA into various vaccine modalities, including plasmid DNA (21), modified vaccinia virus Ankara (MVA) (21), human adenovirus serotype 5 (HAdV-5) (5), Semliki Forest virus replicons (18, 49), recombinant lysine auxotroph BCG strain Pasteur (32), and baculovirus-expressed and purified, bluetongue virus-derived chimeric NS1 tubules (37); the immunogenicity of these vectors has been compared directly and in heterologous combinations. More recently, we reported on the immunogenicity of a novel and promising vaccine vector derived from ovine atadenovirus type 7 (OAdV) (5); OAdV is the prototype member of the genus Atadenovirus, which is structurally and biologically distinct from Mastadenovirus (e.g., HAdV-5) (2, 50). Importantly, no immunity to OAdV has so far been detected in human sera (26). In mice, OAdV.HIVA induced strong polyfunctional HIVA-specific T cell responses with distinct kinetics from those induced by HAdV5.HIVA and displayed demonstrable single-dose efficacy against a surrogate virus challenge (5). OAdV is approved for use in a phase I human clinical trial (http://clinicaltrials.gov identifier no. {"type":"clinical-trial","attrs":{"text":"NCT00625430","term_id":"NCT00625430"}}NCT00625430). All of the vectors/modalities we explore are perceived to be safe and acceptable for use in humans.Here, as a step toward translating our results into human volunteers, we constructed a novel vaccine designated BCG.HIVA⁴⁰¹ vectored by AERAS-401, a Danish 1331 strain of BCG with improved immunogenicity and safety (57), and demonstrated priming of T cells to the HIVA transgene product in rhesus macaques. These BCG.HIVA⁴⁰¹-primed HIV-1-specific CD4 and CD8 T-cell responses were readily boosted with MVA.HIVA and OAdV.HIVA vaccines to elicit broad and robust HIV-1-specific T cell responses.     

The Trypanosoma brucei Life Cycle Switch TbPTP1 Is Structurally Conserved and Dephosphorylates the Nucleolar Protein NOPP44/46

Trypanosoma brucei adapts to changing environments as it cycles through arrested and proliferating stages in the human and tsetse fly hosts. Changes in protein tyrosine phosphorylation of several proteins, including NOPP44/46, accompany T. brucei development. Moreover, inactivation of T. brucei protein-tyrosine phosphatase 1 (TbPTP1) triggers differentiation of bloodstream stumpy forms into tsetse procyclic forms through unknown downstream effects. Here, we link these events by showing that NOPP44/46 is a major substrate of TbPTP1. TbPTP1 substrate-trapping mutants selectively enrich NOPP44/46 from procyclic stage cell lysates, and TbPTP1 efficiently and selectively dephosphorylates NOPP44/46 in vitro. To provide insights into the mechanism of NOPP44/46 recognition, we determined the crystal structure of TbPTP1. The TbPTP1 structure, the first of a kinetoplastid protein-tyrosine phosphatase (PTP), emphasizes the conservation of the PTP fold, extending to one of the most diverged eukaryotes. The structure reveals surfaces that may mediate substrate specificity and affords a template for the design of selective inhibitors to interfere with T. brucei transmission.     

Crystal Structure of the Minor Pilin FctB Reveals Determinants of Group A Streptococcal Pilus Anchoring

Cell surface pili are polymeric protein assemblies that enable bacteria to adhere to surfaces and to specific host tissues. The pili expressed by Gram-positive bacteria constitute a unique paradigm in which sortase-mediated covalent linkages join successive pilin subunits like beads on a string. These pili are formed from two or three distinct types of pilin subunit, typically encoded in small gene clusters, often with their cognate sortases. In Group A streptococci (GAS), a major pilin forms the polymeric backbone, whereas two minor pilins are located at the tip and the base. Here, we report the 1.9-Å resolution crystal structure of the GAS basal pilin FctB, revealing an immunoglobulin (Ig)-like N-terminal domain with an extended proline-rich tail. Unexpected structural homology between the FctB Ig-like domain and the N-terminal domain of the GAS shaft pilin helps explain the use of the same sortase for polymerization of the shaft and its attachment to FctB. It also enabled the identification, from mass spectral data, of the lysine residue involved in the covalent linkage of FctB to the shaft. The proline-rich tail forms a polyproline-II helix that appears to be a common feature of the basal (cell wall-anchoring) pilins. Together, our results indicate distinct structural elements in the pilin proteins that play a role in selecting for the appropriate sortases and thereby help orchestrate the ordered assembly of the pilus.     

Human mortality seasonality in Castile-León, Spain, between 1980 and 1998: the influence of temperature, pressure and humidity

This study was carried out in the region of Castile and Leon, Spain, from 1980 to 1998 and analyzes the relationship between the number of monthly deaths caused by cardiovascular, respiratory and digestive diseases and three meteorological variables: temperature, pressure and humidity. One of the innovations in this study is the application of principal component analysis in a way that differs from its usual application: one single series representing the whole region was constructed for each meteorological variable from the series of eight weather stations. Annual and seasonal mortality trends were also studied. Cardiovascular diseases are the leading cause of death in Castile and Leon. The mortality related to cardiovascular, respiratory and digestive systems shows a statistically significant rising trend across the study period (an annual increase of 6, 16 and 4‰, respectively). The pressure at which mortality is lowest is approximately the same for all causes of death (about 915 hPa), but temperature values vary greatly (16.8–19.7°C for the mean, 10.9–18.1°C for the minimum, and 24.1–27.2°C for the maximum temperature). The most comfortable temperatures for patients with cardiovascular diseases (16.8°C) are apparently lower than those for patients with respiratory diseases (18.1°C), which are, in turn, lower than in the case of diseases of the digestive system (19.7°C). Finally, the optimal humidity for patients with respiratory diseases is the lowest (24%) among the diseases, and the highest (51%) corresponds to diseases of the digestive system, while the optimal relative humidity for the cardiovascular system is 45%.