Eternity, Boredom, and One’s Part-Whole-Reality Conception

Bernard Williams famously argued that eternal life is undesirable for a human because it would inevitably grow intolerably boring. I will argue against Williams and those who share his view. To make my case, I will provide an account of what staves off boredom in our current, earthly-mortal lives, and then I will draw on this account while advancing reasons for thinking that eternal life is desirable, given certain conditions. Though my response to Williams will partly overlap with some prior responses to Williams, especially the one offered by J. M. Fischer, my response will also be distinctive in some important ways. For instance, it will be distinctive in that it will discuss the role that one’s part-whole-reality conception plays in fending off boredom, where by “one’s part-whole-reality conception” I mean “one’s conception of his or her place in the whole of reality.

Current recommendations on the selection of measures for well-being

Measures of well-being have proliferated over the past decades. Very little guidance has been available as to which measures to use in what contexts. This paper provides a series of recommendations, based on the present state of knowledge and the existing measures available, of what measures might be preferred in which contexts. The recommendations came out of an interdisciplinary workshop on the measurement of well-being. The recommendations are shaped around the number of items that can be included in a survey, and also based on the differing potential contexts and purposes of data collection such as, for example, government surveys, or multi-use cohort studies, or studies specifically about psychological well-being. The recommendations are not intended to be definitive, but to stimulate discussion and refinement, and to provide guidance to those relatively new to the study of well-being

Human well -being: The no priority theory

Desire-fulfillment (DF) theories and objective list (OL) theories are the two dominant types of theories of human well-being. I argue that DF theories fail to capture the good part of ‘good for’, and that OL theories fail to capture the for part of ‘good for’. Then, with the aim of capturing both of these parts of ‘good for’, I advance a theory that places both a value constraint and a desire constraint on human well-being. The most important objection to my theory comes from OL theorists. My theory implies that, if one lacks the desire for accomplishment, or friendship, or health, etc., then this non-desired good isn’t part of one’s welfare. OL theorists find this implication of my theory unacceptable. However, I argue that there is no genuine worry for my theory here, because (1) the vast majority of humans just do desire accomplishment, friendship, health, etc., and stably so, and because (2) in those very rare cases where the desires for these goods are missing, we don’t have sufficient reasons for thinking that the relevant non-desired goods really are part of the welfare of the agents in question

Hedgehog proteins create a dynamic cholesterol interface.

During formation of the Hedgehog (Hh) signaling proteins, cooperative activities of the Hedgehog INTein (Hint) fold and Sterol Recognition Region (SRR) couple autoproteolysis to cholesterol ligation. The cholesteroylated Hh morphogens play essential roles in embryogenesis, tissue regeneration, and tumorigenesis. Despite the centrality of cholesterol in Hh function, the full structure of the Hint-SRR ("Hog") domain that attaches cholesterol to the last residue of the active Hh morphogen remains enigmatic. In this work, we combine molecular dynamics simulations, photoaffinity crosslinking, and mutagenesis assays to model cholesterolysis intermediates in the human Sonic Hedgehog (hSHH) protein. Our results provide evidence for a hydrophobic Hint-SRR interface that forms a dynamic, non-covalent cholesterol-Hog complex. Using these models, we suggest a unified mechanism by which Hh proteins can recruit, sequester, and orient cholesterol, and offer a molecular basis for the effects of disease-causing hSHH mutations

Hedgehog proteins create a dynamic cholesterol interface

During formation of the Hedgehog (Hh) signaling proteins, cooperative activities of the Hedgehog INTein (Hint) fold and Sterol Recognition Region (SRR) couple autoproteolysis to cholesterol ligation. The cholesteroylated Hh morphogens play essential roles in embryogenesis, tissue regeneration, and tumorigenesis. Despite the centrality of cholesterol in Hh function, the full structure of the Hint-SRR (“Hog”) domain that attaches cholesterol to the last residue of the active Hh morphogen remains enigmatic. In this work, we combine molecular dynamics simulations, photoaffinity crosslinking, and mutagenesis assays to model cholesterolysis intermediates in the human Sonic Hedgehog (hSHH) protein. Our results provide evidence for a hydrophobic Hint-SRR interface that forms a dynamic, non-covalent cholesterol-Hog complex. Using these models, we suggest a unified mechanism by which Hh proteins can recruit, sequester, and orient cholesterol, and offer a molecular basis for the effects of disease-causing hSHH mutations