The That

This chapter discusses what I call the ‘Existentialist Fallacy,’ that the process of our normative self-constitution is something to be undertaken ex nihilo, right now, from a standing start. I argue that this is indeed a fallacy. It isn’t like that, and it can’t be. The project of making our normative world is a collective enterprise, one we inherit and pass on. It should not be understood in an individualistic spirit. This is a point that might seem to weigh against understandings of the normative that are deflationary and Humean in spirit, but I argue that that too is an error and there is no tension between these things

Ethics and perception : two kinds of quasi-realism

Michael Huemer think the realist about ethical intuition is no worse off than the realist about sense perception when it comes to addressing the challenge of skepticism and so if we reject scepticism about the external, empirical world we should also reject scepticism about ethics. But we do not face in either domain a stark choice between realism and skepticism. There is a range of intermediate options and these options seem much more credible in the ethical case than the perceptual

Cholesterol sensing by CD81 is important for hepatitis C virus entry

CD81 plays a role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus. Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81-cholesterol association, but had disparate effects on HCV, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified an allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol unbound) or closed (cholesterol bound) conformation. The open mutant of CD81 exhibited reduced receptor activity whereas the closed mutant was enhanced. These data are consistent with cholesterol switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81-partner networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry and CD81’s function as a molecular scaffold; these insights are relevant to CD81’s varied roles in health and disease

Hedonism and the experience machine

Money isn’t everything, so what is? Many government leaders, social policy theorists, and members of the general public have a ready answer: happiness. This paper examines an opposing view due to Robert Nozick, which centres on his experience-machine thought experiment. Despite the example's influence among philosophers, the argument behind it is riddled with difficulties. Dropping the example allows us to re-version Nozick's argument in a way that makes it far more forceful - and less dependent on people's often divergent intutions about the experience machine