Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes occur both within the hormone (...) and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

Current models of insulin binding to the insulin receptor (IR) propose (i) that there are two binding sites on the surface of insulin which engage with two binding sites on the receptor and (ii) that ligand binding involves structural changes in both the ligand and the receptor. Many of the features of insulin binding to its receptor, namely B‐chain helix interactions with the leucine‐rich repeat domain and A‐chain residue interactions with peptide loops from another part of the receptor, are also (...) seen in models of relaxin and insulin‐like peptide 3 binding to their receptors. We show that these principles can likely be extended to the group of mimetic peptides described by Schäffer and coworkers, which are reported to have no sequence identity with insulin. This review summarizes our current understanding of ligand‐induced activation of the IR and highlights the key issues that remain to be addressed. (shrink)

The aim of this paper is to explore the conditions under which generalisation from single case studies, in the sense of making inferences concerning a wider class of phenomena beyond a case, is reasonable. Two sets of conditions, in particular, provide the basis for our consideration of this issue. The first is an exploration of the impressive amount of empirical knowledge that is contained within the theories that are used to make observations, to classify phenomena, and to understand and interpret (...) cases. The second is recognition of the role of a pattern of inference known as abduction, or inference to the best explanation, in drawing conclusions from case studies. It is argued that these two conditions, when applied to the procedures for conducting case studies, can be used to defend, as reasonable, the making of certain provisional generalisations from single cases. An epistemological procedure for testing and further justifying these generalisations, with a particular emphasis on dealing with the problem of confirmation bias, is then discussed and recommended. (shrink)

The aim of this paper is to explore the conditions under which generalisation from single case studies, in the sense of making inferences concerning a wider class of phenomena beyond a case, is reasonable. Two sets of conditions, in particular, provide the basis for our consideration of this issue. The first is an exploration of the impressive amount of empirical knowledge that is contained within the theories that are used to make observations, to classify phenomena, and to understand and interpret (...) cases. The second is recognition of the role of a pattern of inference known as abduction, or inference to the best explanation, in drawing conclusions from case studies. It is argued that these two conditions, when applied to the procedures for conducting case studies, can be used to defend, as reasonable, the making of certain provisional generalisations from single cases. An epistemological procedure for testing and further justifying these generalisations, with a particular emphasis on dealing with the problem of confirmation bias, is then discussed and recommended. (shrink)

This paper considers the prospects for objectivity in reasoning strategies in response to empirical studies that apparently show systematic culture‐based differences in patterns of reasoning. I argue that there is at least one modest class of exceptions to the claim that there are alternative, equally warranted standards of good reasoning: the class that entails the solution of certain well‐structured problems which, suitably chosen, are common, or touchstone, to the sorts of culturally different viewpoints discussed. There is evidence that some cognitive (...) tasks are seen in much the same way across cultures, not least by virtue of the common run of experiences with the world of material objects in early childhood by creatures with similar cognitive endowments. These tasks thus present as similarly structured sets of claims that have similar priority: what is framed, and what is bracketed, or held constant in the background, is shown to be naturally common across cultures. As a consequence, a normative view of reasoning and, by implication, critical thinking can be defended. While this might be a modest sense of objectivity, the high level of intercultural articulation that is able to occur among people of different backgrounds suggests that it provides cognitive scaffolding for a lot of other reasoning tasks as well. (shrink)

This paper considers the prospects for objectivity in reasoning strategies in response to empirical studies that apparently show systematic culture‐based differences in patterns of reasoning. I argue that there is at least one modest class of exceptions to the claim that there are alternative, equally warranted standards of good reasoning: the class that entails the solution of certain well‐structured problems which, suitably chosen, are common, or touchstone, to the sorts of culturally different viewpoints discussed. There is evidence that some cognitive (...) tasks are seen in much the same way across cultures, not least by virtue of the common run of experiences with the world of material objects in early childhood by creatures with similar cognitive endowments. These tasks thus present as similarly structured sets of claims that have similar priority: what is framed, and what is bracketed, or held constant in the background, is shown to be naturally common across cultures. As a consequence, a normative view of reasoning and, by implication, critical thinking can be defended. While this might be a modest sense of objectivity, the high level of intercultural articulation that is able to occur among people of different backgrounds suggests that it provides cognitive scaffolding for a lot of other reasoning tasks as well. (shrink)

Optimization models have often been useful in attempting to understand the adaptive significance of behavioral traits. Originally such models were applied to isolated aspects of behavior, such as foraging, mating, or parental behavior. In reality, organisms live in complex, ever-changing environments, and are simultaneously concerned with many behavioral choices and their consequences. This target article describes a dynamic modeling technique that can be used to analyze behavior in a unified way. The technique has been widely used in behavioral studies of (...) insects, fish, birds, mammals, and other organisms. The models use biologically meaningful parameters and variables, and lead to testable predictions. Limitations arise because nature's complexity always exceeds our modeling capacity. (shrink)

This chapter contains sections titled: Introduction Reviewing the Arguments Problems, Solutions and Objectivity Conclusion References.

The purpose of this paper is to outline some new developments in a mature research program that sees administrative theory as cohering with natural science and uses a coherence theory of epistemic justification to shape the content and structure of administrative theory. Three main developments are discussed. First, the paper shows how to deal with the evaluation of theories where there is a demand that a theory needs to be context relevant, but also comprehensive. The solution is to allow context (...) to determine the scope of comprehensiveness. Second, the paper develops an argument structure employing a coherentist epistemology for how ethical claims can be incorporated into administrative theories. Finally, the paper, drawing on research in neuroscience, argues for the relevance of emotion in rational decision-making. Contrary to the belief that emotion compromises rationality, the paper argues that it is essential for rationality. (shrink)

One conclusion that unites nearly all recent study of Luke-Acts is that Conzelmann's classic formulation of the purpose of the Lukan writings, put forward in The Theology of St. Luke, was incorrect.

The basic form of experiencing process as such, then, lies in the apprehension of an object changing through an ordered sequence of states towards an end state. The sequence is grasped in the light of the final state of things which stands in close relation to the central noema of "changing object" in terms of which the phases of the sequence are recognized and related. The central noema is itself an emergent property of the identification of the sequence of states (...) as "pertaining to the same something." This complex, not to say convoluted, constitution is iteratively established through polythetic acts in which change itself is grasped and sequence evidenced through the positing of possible sequences in the light of the intuition of succession. Eventually the whole sequence may be grasped monothetically and the process experienced as such as a whole. This prototype of process itself provides a basic form by which the events of intentional life may be ordered. The core experience, that objects do change in an ordered manner towards a defined and defining end may provide a way of meaningfully structuring experience. Thus for example, the succession Sii to Siii may be experienced as such. That succession may lead to a question like "towards what end does this succession tend?" More germane to the present argument, a particular state of things may lead to the question "by what process has this state of things come about?" In both these cases, the prototype of process leads to the attempt to interpret the succession or the state of things in terms of orderly change through time and in this way the intuition of process, in its own right, may provide a structure in which the phenomena of consciousness may be experienced and meaningfully related. (shrink)

The great object of Augustus in celebrating Ludi saeculares in 17 b.c. was to encourage the belief in himself and the consequent active loyalty to himself, as the restorer of the pax deorum,—the good relation between the divine and human inhabitants of Rome. So far he had tried to attain this end by the ancient usual and proper means, i.e. by carrying out the various regulations of the ius diuinum, so many of which had long been neglected. But in that (...) year he determined to undertake a special celebration, with the design of more effectually stamping the impression already made on the minds of the people; and it so happens that we have more detailed knowledge of this celebration than of any other Roman rite of any period. This is fortunate, for it stands on the margin between an old and a new régime, like the Aeneid of Virgil, who had died two years earlier: that great religious poem was just becoming known, and there is an allusion to it in the hymn of which I am going to speak. The Ludi were the outward or ritualistic expression of the idea immortalized by the poet, that a regeneration is at hand of Rome and Italy, in religion, morals, agriculture, government: old things are now to be put away, a new and glorious era is to open. Henceforward the Roman was to look ahead of him in hope and confidence, trusting in Augustus, the Aeneas of the actual State. (shrink)

Recent debate has arisen in the neuroethics literature on the extent to which deep brain stimulation (DBS) may cause changes to core personal traits. This has prompted calls for more empirical data...