<p>Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance since mice expressing the VH and VL of 2F5 have an arrested B-cell development characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that mitigate effective humoral responses. I hypothesize that discreet human antigens are mimicked by the membrane-proximal external region (MPER) of HIV-1 gp41, and that such mimicry is a wide-spread strategy for HIV-1 to evade immune attacks to its vulnerable neutralizing epitopes.</p><p>In the first part of the study, I propose to identify autoantigens mimicked by the 2F5 and 4E10 epitopes. I used immunoprecipitation coupled with mass spectrometry as well as protein arrays to identify the self-antigens recognized by 2F5 and 4E10. The binding of antigens was confirmed using serological assays and targeted mutagenesis was used to map the binding epitope. We identified human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes a conformational epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but retain all SF3B3 4E10 epitopes. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant.</p><p>Our identification of structural motif shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1. In the second part of the project, I propose to study the mechanisms of immune tolerance to B cells expressing the 2F5 antibodies. To determine the B cell repertoire before and after tolerance checkpoints, I used the Nojima-Kitamura single B-cell culture that supports differentiation into IgG-secreting plasma cells, even autoreactive cells that are normally subject to tolerization in vivo. I found that the pre-tolerance compartment (small pre-B) from 2F5 KI mice are cells that express the 2F5 V(D)J rearrangements and bind HIV-1 gp41, KYNU, and cardiolipin. Mature, post-tolerance B cells from 2F5 KI mice, however, are purged of gp41- and KYNU-reactivity, but retain cardiolipin-binding, and sequence analysis revealed extensive light-chain editing. The anergic B cells in the post-tolerance compartment are enriched with self-reactivity to KYNU and maintain binding to HIV-1 gp41. Our results demonstrate that tolerance of the 2F5 epitope is driven by specific reactivity to KYNU, but not general cross-reactivity to cardiolipin. In addition, that the peripheral anergic B cells retain self-reactivity and binding to HIV-1 gp41 suggests a potential target for activation by immunizations.</p><p>Lastly, we sought to determine whether the host mimicry by 4E10 and 2F5 epitopes is also present in other HIV-1 epitopes, including additional conserved neutralizing epitopes and more importantly, non-neutralizing epitopes. We used protein microarrays to assess autoreactivity of HIV-1 broadly neutralizing antibodies (bnAbs) and non-neutralizing antibodies (nnAbs) and found that as a class, bnAbs are more polyreactive and autoreactive than nnAbs. The poly- and autoreactive property is therefore not a result of chronic inflammation, but rather uniquely associated with neutralization, consistent with the role of heteroligation for HIV-1 neutralizing activity. In addition, mutation frequencies of bNAbs and nnAbs per se do not correlate with poly- and autoreactivity. Our results demonstrate that HIV-1 bnAbs are significantly more polyreactive and self-reactive than non-neutralizers, which may subject them to immunological tolerance control in vivo. Infrequent poly- or autoreactivity among nnAbs implies that their dominance in humoral responses is due to the absence of negative control by immune tolerance.</p><p>The results of this study indicate that mimicry of host antigens by HIV-1 is an effective mechanism to camouflage vulnerable neutralizing epitopes of HIV-1 and evade host immune responses. As a result, protective HIV-1 bnAbs are rare and often poly- or autoreactive, constituting a major hurdle that must be overcome to effectively elicit protective responses by an HIV-1 vaccine.</p> / Dissertation

The homodimeric Ocr protein of bacteriophage T7 is a molecular mimic of a bent double-stranded DNA molecule ~24 bp in length. As such, Ocr is a highly effective competitive inhibitor of the bacterial Type I restriction modification (R/M) system. Thus, Ocr facilitates phage infection of the bacterial cell to proceed unhindered by the action of the R/M defense system. The main aim of this work was to understand the basis of the DNA mimicry displayed by Ocr. The surface of the protein is replete with acidic residues, most or all of which mimic the phosphate backbone of DNA. Aspartate and glutamate residues on the surface of Ocr were either mutated or chemically modified in order to investigate their contribution to the tight binding between Ocr and the EcoKI Type I R/M enzyme. Single or double mutations of Ocr had no discernable effect on binding to EcoKI or its methyltransferase component (M.EcoKI). Chemical modification was then used to specifically modify the carboxyl moieties of Ocr, thereby neutralizing the negative charges on the protein surface. Ocr samples modified to varying degrees were analysed to establish the extent of derivatisation prior to extensive biophysical characterisation to assess the impact of these changes in terms of binding to the EcoKI R/M system. The results of this analysis revealed that the electrostatic mimicry of Ocr increases the binding affinity for its target enzyme by at least ~800-fold. In addition, based on the known 3-D structure of the protein, a set of multiple mutations were introduced into Ocr aimed at eliminating patches of negative charge from the protein surface. Specifically, between 5 and 17 acidic residues were targeted for mutation (Asp and Glu to Asn and Gln, respectively). Analysis of the in vivo activity of the mutant Ocr along with biophysical characterisation of the purified proteins was then performed. Results from these studies identified regions of the Ocr protein that were critical in forming a tight association with the EcoKI R/M system. Furthermore by comparing the relative contribution of different groups of acidic residues to the free energy of binding, the actual mechanism by which Ocr mimics the charge distribution of DNA has been delineated.

This study examined the role of attention and trait empathy within the production of neural facial mimicry responses that have been previously found to be associated with the experience of empathy. More specifically, do people who have high trait empathy levels require less attention to emotional information in order to still exhibit these physiological responses than people who have lower trait empathy levels? It has previously been demonstrated that responses in the zygomaticus and corrugator muscles have been associated with the experience of empathy. College aged participants were shown series of happy, angry, and neutral faces with the amount of attention allocated to the emotional information of the faces manipulated. It was predicted that the level of attention directed at the emotional faces would affect the level of these physiological empathetic responses. Attention directed at the emotional content of the photos was shown to elicit higher activations of these physiological responses than when participants’ attention was directed at another characteristic of the stimuli, gender, but trait empathy was not shown to significantly moderate the relationship between these physiological responses and the level of attention directed at the emotional information.

In this thesis, I study a radiation of brood-parasitic finch species, the indigobirds and whydahs (genus Vidua), that occur across Africa. Host colonisation is tightly linked to speciation in Vidua because of their remarkable capacity to imprint on their hosts, with mating traits and host preferences being influenced by the parasite's early environment. The challenge of explaining why the radiation has diversified to the extent it has therefore simplifies to understanding why only certain potential host species have been successfully colonised. Following on from the introduction (Chapter 1), I begin by critically examining the logic with which mimicry in the natural world can be conceptually organized (Chapter 2). This creates a “mimicry landscape” in which to situate the mimetic adaptations of hosts exhibited by Vidua. The framework can be used to contrast and draw parallels between these and other mimetic adaptations present in the natural world. In Chapter 3, I review the literature on begging call mimicry and development across all avian brood parasite species. I outline the conditions under which we expect begging call mimicry to evolve, and when we expect it to develop primarily through genetic or environmental cues. This provides clear predictions for what we expect to occur in Vidua finches, which are tested in Chapters 4 and 5. In Chapter 4, I quantify the mimicry of host nestlings by Vidua in detail. I provide the first quantitative evidence that Vidua nestlings mimic the begging calls and show for the first time that Vidua are imperfect mimics of their hosts. In Chapter 5, I simulate the colonisation of a new host by transferring Vidua eggs into the nest of a new host species. I monitor Vidua survival in the foreign host environment and test several hypotheses about what explains differences in chick survival. I find that Vidua survive poorly in the new nest environment and that they do not show adaptive plasticity in begging calls or head movements. This poor survival occurs despite there being minimal differences in the diets each host species feeds their young. Finally, in Chapter 6, I carry out a comparative analysis on the evolution of estrildid mouth markings. Estrildid finches are the hosts of Vidua and so provide the landscape of potential ecological niches that Vidua may colonise and adapt to. I demonstrate that the host family shows strong phylogenetic signal in mouth marking traits, and find no evidence that ecological factors such as light environment or predation pressure has shaped estrildid mouth marking evolution. The work in this thesis highlights how difficult successfully colonising new hosts is for Vidua finches. Vidua must mimic hosts in multiple traits (mouth markings, begging calls, head movements) to obtain sufficient amounts of food from host parents. Overall, habitat filters, the complex and diverse begging displays of estrildid nestlings, the discriminatory behaviour of estrildid parents against mismatching chicks and the lack of adaptive plasticity in begging displays by Vidua together help explain why the Vidua radiation consists of only 19 species rather than many more or fewer.

When interacting, people imitate each other. This tendency is truly ubiquitous and occurs in many different situations and behaviours. But what causes it? Several mechanisms have been proposed to contribute to imitation. In this thesis, I focus on three candidate mechanisms: simulation, temporal adaptation, and the goal to affiliate with others. I start by discussing different imitative behaviours, and reviewing the evidence that imitation might at times emerge spontaneously. I also review the evidence suggesting that the three candidate mechanisms might be involved in such emergent imitation. Then, I present three sets of experiments. In the first set, I investigate the role of simulation in language processing. In three experiments, I test the hypothesis that comprehenders use their language production system to simulate their interlocutor, which in turn facilitates their ability to predict the next word they will see or hear. I manipulate whether participants read the sentences silently or aloud and measure their ability to predict the final word of a sentence. My results demonstrate that prediction is enhanced when people use their production system during reading aloud. This gives some credence to the idea that simulation is routinely engaged in language processing, which in turn opens up a possibility that it may contribute to linguistic imitation. In the second set of experiments, I investigate whether temporal adaptation leads agents to imitate features of their partner’s actions. In three experiments, I test this by manipulating the partner’s response speed and the information about the partner’s actions. I show that agents imitate response speed when they are able to observe the partner. Moreover, they adapt to the specific temporal pattern of their partner’s actions. These findings provide evidence for the engagement of the temporal adaptation mechanism during motor interactions, and for its involvement in imitation. In the third set of experiments, I turn to the hypothesis that people engage in linguistic imitation because they want to harness the social benefits it brings. I investigate a key assumption of this hypothesis: that imitation has positive consequences for the social interaction. In three experiments, I manipulate whether participants’ word choice is imitated or counter-imitated by their conversational partner and measure how it affects the participants’ evaluation of the interaction and the partner, and their willingness to cooperate with the partner. I find evidence that linguistic imitation has positive social consequences. These results are consonant with the claim that imitation is motivated by the goal to affiliate and foster social relations. Taken together, these findings suggest that imitation might occur both in motor actions and language, and that it might have diverse causes. My work on language suggests that the tendency to linguistically imitate others could both result from the simulation mechanism, and be motivated by the goal to affiliate. My work on motor actions shows that automatic temporal adaptation contributes to emergent imitation during interactions. This research is conducive to the greater aim of cross-examining the currently known mechanisms of imitation.

Adaptive radiations provide exceptional opportunities to examine the relationships between natural selection, adaptation, and speciation. Neotropical Adelpha butterflies may represent such a radiation, characterized by extraordinary breadth in host plant use and wing color patterns. In this study, we use genome-wide RAD markers to reconstruct the complex evolutionary history of Adelpha and the closely related temperate genus, Limenitis. Despite the presence of significant missing data, a variety of phylogenetic methods produce similar and highly supported trees. These well-resolved phylogenies allow for the identification of an ecologically important shift to a toxic host plant family, as well as the confirmation of rampant wing pattern mimicry throughout the genus. Taken together, our results support the hypothesis that the colonization of novel host plants represents a key evolutionary innovation that is fueling ongoing adaptive diversification within this large, phenotypically diverse butterfly radiation.

Abstract not available

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 170-185).

This thesis analyzes the westernization of Indians as portrayed through the juxtaposition of the power relations between the Western and Third world cultures, and the power relations between the characters of the novel. Indians had become so Anglicized that some of them took the place of the British rulers after Independence. In the novel the relations between parents and children, elders and youngsters, employers and employees are seen to be quite similar to the power relations that exist between the colonizer and the colonized. In the thesis these relations will be analyzed as the result and mimicry of British colonialism.

Mimicry, an adaptation to deceive, fascinated early naturalist and has been proof of evolution by natural selection since proposed by Henry W. Bates 150 years ago. Yet, despite the abundant theoretical and empirical work that it has inspired, little is known of effects in intra and interspecific communication that might result from resembling phenotypic traits of sympatric species. In this dissertation research I studied sexual behavior and communication in Heliconius, a genus of diverse toxic butterflies with extraordinary convergence in wing coloration, habitat preferences and flight characteristics. Well-known ecological interactions and evolutionary history of Heliconius contrast with a poor understanding of key elements of their sexual behavior and intraspecific communication, which are central for the evolution of mimicry in this genus of butterflies. This thesis starts with an introduction that, expanding on the ideas above, explains the motivation behind studying sexual communication and behavior in Heliconius. In the subsequent four chapters I report on two aspects of sexual behavior that are presumably connected in these butterflies with the occurrence of mimicry: Pupal mating behavior and antiaphrodisiac pheromones. Pupal mating is a mate-searching strategy wherein males find females when still immature and guard them with the goal of mating at female eclosion. This mating behavior might have influenced the evolution of mimicry as males rely less on commonly used species recognition traits that in mimetic Heliconius are shared with coexisting species. I identified cues males use to find and recognize conspecific immatures, which not only come from the animal themselves but also from the host plant where they are located. Chemical and visual cues are involved in the process of finding partners, but only sex-specific pheromones allow males to identify females before their eclosion. The second aspect of sexual behavior studied in Heliconius involved the identification of a pheromone that, after being transferred to females at mating, renders them unattractive to courting males. Variation in the chemical composition of such antiaphrodisiacs across eleven species in this genus showed that, contrary to my expectations, there is no evidence that mimicry has affected the evolution of this signal. Instead, I found that clade-specific mating systems in these butterflies adequately explain the observed patterns of interspecific variation. / text