Natural selection on individual variation in tolerance of gastrointestinal nematode infection

This is the final version of the article. Available from the publisher via the DOI in this record.Hosts may mitigate the impact of parasites by two broad strategies: resistance, which limits parasite burden, and tolerance, which limits the fitness or health cost of increasing parasite burden. The degree and causes of variation in both resistance and tolerance are expected to influence host-parasite evolutionary and epidemiological dynamics and inform disease management, yet very little empirical work has addressed tolerance in wild vertebrates. Here, we applied random regression models to longitudinal data from an unmanaged population of Soay sheep to estimate individual tolerance, defined as the rate of decline in body weight with increasing burden of highly prevalent gastrointestinal nematode parasites. On average, individuals lost weight as parasite burden increased, but whereas some lost weight slowly as burden increased (exhibiting high tolerance), other individuals lost weight significantly more rapidly (exhibiting low tolerance). We then investigated associations between tolerance and fitness using selection gradients that accounted for selection on correlated traits, including body weight. We found evidence for positive phenotypic selection on tolerance: on average, individuals who lost weight more slowly with increasing parasite burden had higher lifetime breeding success. This variation did not have an additive genetic basis. These results reveal that selection on tolerance operates under natural conditions. They also support theoretical predictions for the erosion of additive genetic variance of traits under strong directional selection and fixation of genes conferring tolerance. Our findings provide the first evidence of selection on individual tolerance of infection in animals and suggest practical applications in animal and human disease management in the face of highly prevalent parasites.This study was funded by Natural Environment Research Council (http://www.nerc.ac.uk/) Standard Grant no. NE/G004854/1 and European Research Council (http://erc.europa.eu/) Large Grant no. 250098 to JMP. ADH is supported by European Research Council grant no. R/120448-11-1 to V. Lummaa; DHN is supported by Biotechnology and Biological Sciences Research Council (http://www.bbsrc.ac.uk/) David Phillips Fellowship no. BB/H021686/1; AJW is supported by BBSRC David Phillips Fellowship no. BB/G022976/1; ALG is supported by Princeton University and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Early reproductive investment, senescence and lifetime reproductive success in female Asian elephants

The evolutionary theory of senescence posits that as the probability of extrinsic mortality increases with age, selection should favour early-life over late-life reproduction. Studies on natural vertebrate populations show early reproduction may impair later-life performance, but the consequences for lifetime fitness have rarely been determined, and little is known of whether similar patterns apply to mammals which typically live for several decades. We used a longitudinal dataset on Asian elephants (Elephas maximus) to investigate associations between early-life reproduction and female age-specific survival, fecundity and offspring survival to independence, as well as lifetime breeding success (lifetime number of calves produced). Females showed low fecundity following sexual maturity, followed by a rapid increase to a peak at age 19 and a subsequent decline. High early life reproductive output (before the peak of performance) was positively associated with subsequent age-specific fecundity and offspring survival, but significantly impaired a female's own later-life survival. Despite the negative effects of early reproduction on late-life survival, early reproduction is under positive selection through a positive association with lifetime breeding success. Our results suggest a trade-off between early reproduction and later survival which is maintained by strong selection for high early fecundity, and thus support the prediction from life history theory that high investment in reproductive success in early life is favoured by selection through lifetime fitness despite costs to later-life survival. That maternal survival in elephants depends on previous reproductive investment also has implications for the success of (semi-)captive breeding programmes of this endangered species. © 2014 The Authors. Journal of Evolutionary Biology published by John Wiley & Sons Ltd on behalf of European Society for Evolutionary Biology

Maternally derived anti-helminth antibodies predict offspring survival in a wild mammal

The transfer of antibodies from mother to offspring provides crucial protection against infection to offspring during early life in humans and domestic and laboratory animals. However, few studies have tested the consequences of variation in maternal antibody transfer for offspring fitness in the wild. Further, separating the immunoprotective effects of antibodies from their association with nutritional resources provided by mothers is difficult. Here, we measured plasma levels of total and parasite-specific antibodies in neonatal (less than 10 days old) wild Soay sheep over 25 years to quantify variation in maternal antibody transfer and test its association with offspring survival. Maternal antibody transfer was predicted by maternal age and previous antibody responses, and was consistent within mothers across years. Neonatal total IgG antibody levels were positively related to early growth, suggesting they reflected nutritional transfer. Neonatal parasite-specific IgG levels positively predicted first-year survival, independent of lamb weight, total IgG levels and subsequent lamb parasite-specific antibody levels. This relationship was partly mediated via an indirect negative association with parasite burden. We show that among-female variation in maternal antibody transfer can have long-term effects on offspring growth, parasite burden and fitness in the wild, and is likely to impact naturally occurring host–parasite dynamics

Improving the use of research evidence in guideline development: 14. Reporting guidelines

BACKGROUND: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 14(th )of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. OBJECTIVES: We reviewed the literature on reporting guidelines and recommendations. METHODS: We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. KEY QUESTIONS AND ANSWERS: There is little empirical evidence that addresses these questions. Our answers are based on logical arguments and standards put forward by other groups. What standard types of recommendations or reports should WHO use? • WHO should develop standard formats for reporting recommendations to facilitate recognition and use by decision makers for whom the recommendations are intended, and to ensure that all the information needed to judge the quality of a guideline, determine its applicability and, if needed, adapt it, is reported. • WHO should develop standard formats for full systematically developed guidelines that are sponsored by WHO, rapid assessments, and guidelines that are endorsed by WHO. • All three formats should include the same information as full guidelines, indicating explicitly what the group preparing the guideline did not do, as well as the methods that were used. • These formats should be used across clinical, public health and health systems recommendations. How should recommendations be formulated and reported? • Reports should be structured, using headings that correspond to those suggested by the Conference on Guideline Standardization or similar headings. • The quality of evidence and strength of recommendations should be reported explicitly using a standard approach. • The way in which recommendations are formulated should be adapted to the specific characteristics of a specific guideline. • Urgent attention should be given to developing a template that provides decision makers with the relevant global evidence that is needed to inform a decision and offers practical methods for incorporating the context specific evidence and judgements that are needed

Isolated and dynamical horizons and their applications

Over the past three decades, black holes have played an important role in quantum gravity, mathematical physics, numerical relativity and gravitational wave phenomenology. However, conceptual settings and mathematical models used to discuss them have varied considerably from one area to another. Over the last five years a new, quasi-local framework was introduced to analyze diverse facets of black holes in a unified manner. In this framework, evolving black holes are modeled by dynamical horizons and black holes in equilibrium by isolated horizons. We review basic properties of these horizons and summarize applications to mathematical physics, numerical relativity and quantum gravity. This paradigm has led to significant generalizations of several results in black hole physics. Specifically, it has introduced a more physical setting for black hole thermodynamics and for black hole entropy calculations in quantum gravity; suggested a phenomenological model for hairy black holes; provided novel techniques to extract physics from numerical simulations; and led to new laws governing the dynamics of black holes in exact general relativity.Comment: 77 pages, 12 figures. Typos and references correcte

Increased Mortality Exposure within the Family Rather than Individual Mortality Experiences Triggers Faster Life-History Strategies in Historic Human Populations

Life History Theory predicts that extrinsic mortality risk is one of the most important factors shaping (human) life histories. Evidence from contemporary populations suggests that individuals confronted with high mortality environments show characteristic traits of fast life-history strategies: they marry and reproduce earlier, have shorter birth intervals and invest less in their offspring. However, little is known of the impact of mortality experiences on the speed of life histories in historical human populations with generally higher mortality risk, and on male life histories in particular. Furthermore, it remains unknown whether individual-level mortality experiences within the family have a greater effect on life-history decisions or family membership explains life-history variation. In a comparative approach using event history analyses, we study the impact of family versus individual-level effects of mortality exposure on two central life-history parameters, ages at first marriage and first birth, in three historical human populations (Germany, Finland, Canada). Mortality experience is measured as the confrontation with sibling deaths within the natal family up to an individual's age of 15. Results show that the speed of life histories is not adjusted according to individual-level mortality experiences but is due to family-level effects. The general finding of lower ages at marriage/reproduction after exposure to higher mortality in the family holds for both females and males. This study provides evidence for the importance of the family environment for reproductive timing while individual-level mortality experiences seem to play only a minor role in reproductive life history decisions in humans

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Constitutional patriotism

Constitutional patriotism is a political theory that seeks to provide an explanation for the sense of ownership that most individuals have towards their national constitutional system. Specifically, constitutional patriotism assumes that free-thinking individuals involved in a discussion over the common good will reach an agreement that is perceived, at least by those involved in the debate, as having normative value. The awareness that such a deliberative process has historically been a part of the constitutional system also induces a sense of ownership of past historical accommodations of constitutional principles. The shared perception of being part of historically grounded institutions within a deliberative democracy is sometimes called the ‘normative surplus effect’ or ‘normative spill-over effect’ of the deliberative process. The theory, in its current form, was proposed by Jürgen Habermas and Jean-Werner Müller. Debates over the common good might take place informally or within the state’s institutions. Pell-mell informal debates, with few exceptions, have a limited effect on amending constitutional norms. Yet, the prerogative to openly discuss laws and policies legitimised by constitutional norms is normally sufficient to develop an inner sense of belonging to a constitutional system. Deliberative debates within public institutions (e.g. parliaments and courts) are more likely to change the functioning of a constitutional system, but they are, by way of comparison to informal political discussions, normally constrained by the system of rules that regulate representative democracy and the administration of justice. Thus, the theory of constitutional patriotism provides an explanatory model for the historical development of a democratic constitutional system. As one of the most persuasive explanatory theories of modern pluralist democracy, constitutional patriotism has attracted a series of well-articulated critiques. It has been suggested, for instance, that constitutional patriotism might not provide a plausible model of social integration for international organisations such as the European Union (EU). In this essay, I will provide an overview of the theory and a selection of its critiques

The Mechanism of Ubiquitination in the Cullin-RING E3 Ligase Machinery: Conformational Control of Substrate Orientation

In cullin-RING E3 ubiquitin ligases, substrate binding proteins, such as VHL-box, SOCS-box or the F-box proteins, recruit substrates for ubiquitination, accurately positioning and orienting the substrates for ubiquitin transfer. Yet, how the E3 machinery precisely positions the substrate is unknown. Here, we simulated nine substrate binding proteins: Skp2, Fbw7, β-TrCP1, Cdc4, Fbs1, TIR1, pVHL, SOCS2, and SOCS4, in the unbound form and bound to Skp1, ASK1 or Elongin C. All nine proteins have two domains: one binds to the substrate; the other to E3 ligase modules Skp1/ASK1/Elongin C. We discovered that in all cases the flexible inter-domain linker serves as a hinge, rotating the substrate binding domain, optimally and accurately positioning it for ubiquitin transfer. We observed a conserved proline in the linker of all nine proteins. In all cases, the prolines pucker substantially and the pucker is associated with the backbone rotation toward the E2/ubiquitin. We further observed that the linker flexibility could be regulated allosterically by binding events associated with either domain. We conclude that the flexible linker in the substrate binding proteins orients the substrate for the ubiquitin transfer. Our findings provide a mechanism for ubiquitination and polyubiquitination, illustrating that these processes are under conformational control