Adaptive torsion-angle quasi-statics: a general simulation method with applications to protein structure analysis and design

MOTIVATION: The cost of molecular quasi-statics or dynamics simulations increases with the size of the simulated systems, which is a problem when studying biological phenomena that involve large molecules over long time scales. To address this problem, one has often to either increase the processing power (which might be expensive), or make arbitrary simplifications to the system (which might bias the study). RESULTS: We introduce adaptive torsion-angle quasi-statics, a general simulation method able to rigorously and automatically predict the most mobile regions in a simulated system, under user-defined precision or time constraints. By predicting and simulating only these most important regions, the adaptive method provides the user with complete control on the balance between precision and computational cost, without requiring him or her to perform a priori, arbitrary simplifications. We build on our previous research on adaptive articulated-body simulation and show how, by taking advantage of the partial rigidification of a molecule, we are able to propose novel data structures and algorithms for adaptive update of molecular forces and energies. This results in a globally adaptive molecular quasi-statics simulation method. We demonstrate our approach on several examples and show how adaptive quasi-statics allows a user to interactively design, modify and study potentially complex protein structures.     

Darwinian functions and Freudian motivations

Badcock, and Nesse and Lloyd, have argued that there are important points of agreement between Freud's theory of the mind and a theory of mind suggested by adaptive reasoning. Buller, on the other hand, draws attention to the need to avoid confusing an adaptive rationale with an unconscious motivation. The present paper attempts to indicate what role adaptive reasoning might have to play in justifying psychoanalytic claims. First, it is argued that psychoanalytic claims cannot be justified by the clinical experience of psychoanalysts alone. It is urged that, to avoid interpretative proliferation, it is necessary to base interpretation on some theory which is external to psychoanalysis. Next, Buller's reservations about using adaptive reasoning to justify claims about a personal unconscious, are summarized. Then an argument for the existence of a personal unconscious, is offered, based on experimental evidence from Gur and Sackeim. Then it is argued that adaptive reasoning, though it cannot itself provide evidence for the existence of any psychological mechanism, can valuably guide the search for such evidence. It is argued that such an approach has borne fruit, both in biology generally and specifically in psychology. Finally, it is argued that psychoanalysis is important enough to justify such a research project.     

What Controls the Acute Viral Infection Following Yellow Fever Vaccination?

Does target cell depletion, innate immunity, or adaptive immunity play the dominant role in controlling primary acute viral infections? Why do some individuals have higher peak virus titers than others? Answering these questions is a basic problem in immunology and can be particularly difficult in humans due to limited data, heterogeneity in responses in different individuals, and limited ability for experimental manipulation. We address these questions for infections following vaccination with the live attenuated yellow fever virus (YFV-17D) by analyzing viral load data from 80 volunteers. Using a mixed effects modeling approach, we find that target cell depletion models do not fit the data as well as innate or adaptive immunity models. Examination of the fits of the innate and adaptive immunity models to the data allows us to select a minimal model that gives improved fits by widely used model selection criteria (AICc and BIC) and explains why it is hard to distinguish between the innate and adaptive immunity models. We then ask why some individuals have over 1000-fold higher virus titers than others and find that most of the variation arises from differences in the initial/maximum growth rate of the virus in different individuals.     

Cutting edge: a new approach to modeling early lung immunity in murine tuberculosis

In this study, we report a new approach that allows dissection of distinct pathways regulating induction of early adaptive immunity in response to Mycobacterium tuberculosis (Mtb). We used traceable murine dendritic cells (DCs) and macrophage populations to chart their migratory pattern in response to Mtb, and found that only DCs receiving inflammatory stimuli from Mtb up-regulated their expression of CCR7 and migrated specifically to the draining lymph nodes (LNs). Furthermore, these Mtb-modulated DCs initiated a Th1 response only in the draining LNs. Taken together, these results demonstrate that Mtb-induced modulation of DCs is critical for their migration to regional LNs and ensuing T cell priming.     

Connecting behavioural biologists and psychologists: Clarifying distinctions and suggestions for further work

This article is a reply to the commentaries on our target article, which relates our group's work on simple heuristics to biological research on rules of thumb. Several commentators contrasted both these approaches with behaviour analysis, in which the patterns of behaviour investigated in the laboratory are claimed to be near-universal attributes, rather than specific to particular appropriate environments. We question this universality. For instance, learning phenomena such Pavlovian or operant conditioning have mostly been studied only in a few generalist species that learn easily; in many natural situations the environment hinders learning as an adaptive strategy. Other supposedly general phenomena such as impulsiveness and matching are outcome models, which several different models of simple cognitive processes might explain. We clarify some confusions about optimisation, optima and optimality modelling. Lastly, we say a little more about how heuristics might be selected, learnt and tuned to suit the current environment.     

Antigen-specific T-cell responses to a recombinant fowlpox virus are dependent on MyD88 and interleukin-18 and independent of Toll-like receptor 7 (TLR7)- and TLR9-mediated innate immune recognition

Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live-attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPV(OVA)), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-like receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro, only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPV(OVA) in vivo. The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPV-derived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 receptor signaling, which in turn is essential for the formation of adaptive immunity to FWPV-encoded OVA.     

Stochastic dynamics of immunity in small populations: a general framework

Assessment of immunological status is a powerful tool in the surveillance and control of infectious pathogens in livestock and human populations. The distribution of immunity levels in the population provides information on time and age dependent transmission. A stochastic model is developed for a livestock population which relates the dynamics of the distribution of immunity levels at the population level to those of pathogen transmission. A general model with K immunity level categories is first proposed, taking into account the increase of the immunity level due to an infection or a re-exposure, the decrease of the immunity level with time since infection or exposure, and the effect of immunity level on the susceptibility and the infectivity of individuals. Numerical results are presented in the particular cases with K=2 and K=3 immunity level categories. We demonstrate that for a given distribution of the immunity levels at the population level, the model can be used to identify quantities such as most likely periods of time since introduction of infection. We discuss this approach in relation to analysis of serological data.     

Modularity,and the psychoevolutionary theory of emotion

It is unreasonable to assume that our pre-scientific emotion vocabulary embodies all and only those distinctions required for a scientific psychology of emotion. The psychoevolutionary approach to emotion yields an alternative classification of certain emotion phenomena. The new categories are based on a set of evolved adaptive responses, or affect-programs, which are found in all cultures. The triggering of these responses involves a modular system of stimulus appraisal, whose evoluations may conflict with those of higher-level cognitive processes. Whilst the structure of the adaptive responses is innate, the contents of the system which triggers them are largely learnt. The circuits subserving the adaptive responses are probably located in the limbic system. This theory of emotion is directly applicable only to a small sub-domain of the traditional realm of emotion. It can be used, however, to explain the grouping of various other phenomena under the heading of emotion, and to explain various characteristic failings of the pre-scientific conception of emotion.     

DNA damage: a trigger of innate immunity but a requirement for adaptive immune homeostasis

Chromosome breakage is frequently associated with viral infection and cellular transformation, but it is also required for two processes that are crucial for the development and function of adaptive immunity: V(D)J recombination and class-switch recombination. The cellular responses that result from this type of DNA damage, which are mostly activated by the protein kinase ataxia-telangiectasia mutated (ATM), lead to cell-cycle arrest at several checkpoints and efficient DNA repair. This Review focuses on the important roles of these DNA-damage responses in the activation of innate immunity and the targeting of the innate immune response to infected or transformed cells, as well as in the development and function of adaptive immunity.     

Insight and the no‐self in deep brain stimulation

Ethical analyses of the effects of neural interventions commonly focus on changes to personality and behavior, interpreting these changes in terms of authenticity and identity. These phenomena have led to debate among ethicists about the meaning of these terms for ethical analysis of such interventions. While these theoretical approaches have different criteria for ethical significance, they agree that patients’ reports are concerning because a sense of self is valuable. In this paper, I question this assumption. I propose that the Buddhist theory of no‐self offers a novel approach to making ethical sense of patients’ claims following deep brain stimulation. This alternative approach is based on the value of insight into patterns of cause and effect among mental states and actions.     

The role of indoleamine 2, 3 dioxygenase in regulating host immunity to leishmania infection

Pathogen persistence in immune-competent hosts represents an immunological paradox. Increasing evidence suggests that some pathogens, such as, Leishmania major (L. major) have evolved strategies and mechanisms that actively suppress host adaptive immunity. If this notion is correct conventional vaccination therapies may be ineffective in enhancing host immunity, unless natural processes that suppress host immunity are also targeted therapeutically. The key problem is that the basis of pathogen persistence in immune-competent individuals is unknown, despite decades of intense research. This fact, coupled with poor health care and a dearth of effective treatments means that these diseases will remain a scourge on humans unless a better understanding of why the immune system tolerates such infections emerges from research. Indoleamine 2,3-dioxygenase (IDO) has been shown to act as a molecular switch regulating host responses, and IDO inhibitor drugs shown to possess potential in enhancing host immunity to established leishmania infections. It is hoped that this review will help stimulate and help generate critical new knowledge pertaining to the IDO mechanism and how to exploit it to suppress T cell mediated immunity, thus offer an innovative approach to studying the basis of chronic leishmania infection in mice.     

Bystander effects, adaptive response and genomic instability induced by prenatal irradiation

The developing human embryo and fetus undergo very radiosensitive stages during the prenatal development. It is likely that the induction of low dose related effects such as bystander effects, the adaptive response, and genomic instability would have profound effects on embryonic and fetal development. In this paper, I review what has been reported on the induction of these three phenomena in exposed embryos and fetuses. All three phenomena have been shown to occur in murine embryonic or fetal cells and structures, although the induction of an adaptive response (and also likely the induction of bystander effects) are limited in terms of when during development they can be induced and the dose or dose-rate used to treat animals in utero. In contrast, genomic instability can be induced throughout development, and the effects of radiation exposure on genome instability can be observed for long times after irradiation including through pre- and postnatal development and into the next generation of mice. There are clearly strain-specific differences in the induction of these phenomena and all three can lead to long-term detrimental effects. This is true for the adaptive response as well. While induction of an adaptive response can make fetuses more resistant to some gross developmental defects induced by a subsequent high dose challenge with ionizing radiation, the long-term effects of this low dose exposure are detrimental. The negative effects of all three phenomena reflect the complexity of fetal development, a process where even small changes in the timing of gene expression or suppression can have dramatic effects on the pattern of biological events and the subsequent development of the mammalian organism.     

ER-mediated phagocytosis: a new membrane for new functions

Genomics and other high-throughput approaches, such as proteomics, are changing the way we study complex biological systems. In the past few years, these approaches have contributed markedly to improving our understanding of phagocytosis. Indeed, the ability to study biological systems by monitoring hundreds of proteins provides a level of resolution that is not attainable by the usual 'one protein at a time' approach. In this article, I discuss how proteomic approaches have revealed surprising findings that enable us to revisit established concepts, such as the origin of the phagosome membrane, and to propose new models of cell organization and the link between innate and adaptive immunity.     

Quantifying Adaptive Evolution in the Drosophila Immune System

It is estimated that a large proportion of amino acid substitutions in Drosophila have been fixed by natural selection, and as organisms are faced with an ever-changing array of pathogens and parasites to which they must adapt, we have investigated the role of parasite-mediated selection as a likely cause. To quantify the effect, and to identify which genes and pathways are most likely to be involved in the host–parasite arms race, we have re-sequenced population samples of 136 immunity and 287 position-matched non-immunity genes in two species of Drosophila. Using these data, and a new extension of the McDonald-Kreitman approach, we estimate that natural selection fixes advantageous amino acid changes in immunity genes at nearly double the rate of other genes. We find the rate of adaptive evolution in immunity genes is also more variable than other genes, with a small subset of immune genes evolving under intense selection. These genes, which are likely to represent hotspots of host–parasite coevolution, tend to share similar functions or belong to the same pathways, such as the antiviral RNAi pathway and the IMD signalling pathway. These patterns appear to be general features of immune system evolution in both species, as rates of adaptive evolution are correlated between the D. melanogaster and D. simulans lineages. In summary, our data provide quantitative estimates of the elevated rate of adaptive evolution in immune system genes relative to the rest of the genome, and they suggest that adaptation to parasites is an important force driving molecular evolution.     

Morphogenetic study of brachiopods

In this work we discuss the results of ontogenetic and morphobiological approaches to phylogenetic reconstructions of articulate brachiopods on the basis of morphogenetic data. These data provide the basis for generalizations concerning phylogeny and system of orders. The ontogenetic approach was the subject of criticism mainly because of arbitrary establishment of the homology of brachiopods. The constraints of the morphobiological approach are associated with the phenomena of morphological evolution without adaptive explanation so far. As an example of these phenomena, homeomorphism of brachiopods can be considered. Prospects for morphogenetic studies of brachiopods can be connected with the study of characteristic elements of their shell structure, such as porosity and mantle channels.     

Developmental exposure to bisphenol a modulates innate but not adaptive immune responses to influenza A virus infection

Bisphenol A (BPA) is used in numerous products, such as plastic bottles and food containers, from which it frequently leaches out and is consumed by humans. There is a growing public concern that BPA exposure may pose a significant threat to human health. Moreover, due to the widespread and constant nature of BPA exposure, not only adults but fetuses and neonates are also exposed to BPA. There is mounting evidence that developmental exposures to chemicals from our environment, including BPA, contribute to diseases late in life; yet, studies of how early life exposures specifically alter the immune system are limited. Herein we report an examination of how maternal exposure to a low, environmentally relevant dose of BPA affects the immune response to infection with influenza A virus. We exposed female mice during pregnancy and through lactation to the oral reference dose for BPA listed by the US Environmental Protection Agency, and comprehensively examined immune parameters directly linked to disease outcomes in adult offspring following infection with influenza A virus. We found that developmental exposure to BPA did not compromise disease-specific adaptive immunity against virus infection, or reduce the host's ability to clear the virus from the infected lung. However, maternal exposure to BPA transiently reduced the extent of infection-associated pulmonary inflammation and anti-viral gene expression in lung tissue. From these observations, we conclude that maternal exposure to BPA slightly modulates innate immunity in adult offspring, but does not impair the anti-viral adaptive immune response, which is critical for virus clearance and survival following influenza virus infection.     

Specificity on a knife-edge: the alphabeta T cell receptor

The interaction between the alphabeta T cell receptor (TCR) and the peptide bound to the major histocompatibility complex class I molecule (pMHC-I) constitutes a central interaction in adaptive immunity. How these receptors interact with such low affinity while maintaining exquisite specificity for peptide antigen and host MHC (MHC-I restriction) remains a challenge to be explained by structural immunologists. Moreover, how this extracellular interaction is transmitted as an intracellular signal via the CD3 complex remains unresolved. Nevertheless, several structures of TCRs, non-liganded and ligated to a defined pMHC-I, combined with detailed biophysical analyses, have provided insight of the structural basis of MHC-I restriction. In addition, structures of isolated CD3 components have enabled T cell signalling mechanisms to be postulated. Recent findings in this area, which include seven distinct TCR/pMHC-I complexes, have fundamental implications in adaptive immunity as well as therapeutic applications to modulate the adaptive immune response.     

Biological roles of host defense peptides: lessons from transgenic animals and bioengineered tissues

Host defense peptides (HDPs) have long been recognized as microbicidal agents, but their roles as modulators of innate and adaptive immunity have only more recently been appreciated. The study of transgenic animal and tissue models has provided platforms to improve our understanding of the immune modulatory functions of HDPs. Here, the characterization of transgenic animals or tissue models that over-express and/or are deficient for specific HDPs is reviewed. We also attempt to reconcile this data with evidence from human studies monitoring HDP expression at constitutive levels and/or in conjunction with inflammation, infection models, or disease states. We have excluded activities ascribed to HDPs derived exclusively from in vitro experiments. An appreciation of the way that HDPs promote innate immunity or influence the adaptive immune response is necessary in order to exploit their therapeutic or adjuvant potential and to open new perspectives in understanding the basis of immunity. The potential applications for HDPs are discussed.     

Optimization methods to solve adaptive management problems

Determining the best management actions is challenging when critical information is missing. However, urgency and limited resources require that decisions must be made despite this uncertainty. The best practice method for managing uncertain systems is adaptive management, or learning by doing. Adaptive management problems can be solved optimally using decision-theoretic methods; the challenge for these methods is to represent current and future knowledge using easy-to-optimize representations. Significant methodological advances have been made since the seminal adaptive management work was published in the 1980s, but despite recent advances, guidance for implementing these approaches has been piecemeal and study-specific. There is a need to collate and summarize new work. Here, we classify methods and update the literature with the latest optimal or near-optimal approaches for solving adaptive management problems. We review three mathematical concepts required to solve adaptive management problems: Markov decision processes, sufficient statistics, and Bayes’ theorem. We provide a decision tree to determine whether adaptive management is appropriate and then group adaptive management approaches based on whether they learn only from the past (passive) or anticipate future learning (active). We discuss the assumptions made when using existing models and provide solution algorithms for each approach. Finally, we propose new areas of development that could inspire future research. For a long time, limited by the efficiency of the solution methods, recent techniques to efficiently solve partially observable decision problems now allow us to solve more realistic adaptive management problems such as imperfect detection and non-stationarity in systems.