Depression and the Problem of Absent Desires

I argue that consideration of certain cases of severe depression reveals a problem for desire-based theories of welfare. I first show that depression can result in a person losing her desires and then identify a case wherein it seems right to think that, as a result of very severe depression, the individuals described no longer have any desires whatsoever. I argue that the state these people are in is a state of profound ill-being: their lives are going very poorly for them. Yet desire theories get this case wrong. Because no desires are being frustrated, the desire theorist has no grounds for ascribing ill-being; indeed, because the individuals described seem utterly without desire, the desire theorist has no grounds for treating these people as subjects of welfare ascription at all. I argue that these results are unacceptable; therefore, we should reject desire-based theories of well-being and ill-being

Parsing the Blues: What Depression Reveals About the Life Well-Lived

This dissertation explores the way depression illuminates –and is illuminated by – certain aspects of moral philosophy. I begin by defending, in chapter one, a cognitive theory of one important subtype of depression. The subsequent chapters then investigate what depression can teach us about the nature of well- (and ill-) being, and about the nature of moral virtue. In chapter two I ask ‘what makes depression bad for us?’ and go on to argue that reflection upon this question shows that desire-based theories of welfare are false. Then, in the next chapter, I provide a (partial) answer to that question, arguing that a central harm of depression is its undermining of the values or cares that constitute the core of a person’s self. This, in turn, vitiates effective agency and saps a person’s life of subjective meaningfulness. Given the results from the previous three chapters, I then ask, in chapter 4, whether it is ever permissible to allow those suffering from depression to choose physician-assisted suicide, and answer in the affirmative. Finally, in chapter five I take up the relationship between depression and virtue. Though the virtuous should never seek to become clinically depressed, I contend that morally virtuous people ought to preferentially attend to what it is fitting to feel negative attitudes towards, and thus, that they should be unhappy

On Greene’s Neuroscientific Challenge To Deontological Ethics

In this paper, I respond to the case against deontological moral theory that Joshua Greene develops in \u22The Secret Joke of Kant\u27s Soul\u22 and elsewhere. Using empirical data he and colleagues collected on peoples\u27 judgments in various moral dilemmas, Greene attempts to show that deontology rests on unsound foundations. In brief, he contends that the intuitions used to support deontological theory are undermined because they are responses to a morally irrelevant feature he calls \u22personalness.\u22 I argue that deontologists can respond to Greene\u27s arguments by drawing a distinction between \u22practical\u22 and \u22theoretical\u22 intuitions. I contend that it is only the former sort of intuitions that are undermined by Greene\u27s evidence, and that deontological theory can be supported purely on the basis of theoretical intuitions

Exploring the link between CHD2 mutations and double strand break repair in developing neurons

Introduction: Heterozygous mutations CHD2 cause intellectual disability and refractory epilepsy. Functional studies demonstrate a deficit in DNA double strand break (DSB) repair via nonhomologous end joining (NHEJ) in CHD2 deficient cells. This project aims to investigate the impact of CHD2 mutations on the outcomes of DSB repair in developing neurons. Methods: A doxycycline inducible CRISPR-Cas9 (iCas9) construct was integrated into the AAVS1 safe harbour. A pipeline for high-throughput analysis of CRISPR experiments was designed and implemented based on nanopore sequencing. This pipeline was used to create a CHD2- deficient human induced pluripotent stem cell (hIPSC) line, which was used to investigate the effects of CHD2 on neurodifferentiation and DSB repair. The pipeline was then adapted to monitor repair outcomes of targeted DSBs in differentiating cells. Spontaneously occurring DSBs were examined using a novel next-generation sequencing technique, INDUCE-Seq, in which unrepaired DSBs are captured from permeabilised cells in-situ and sequenced in order to provide a snapshot of DSBs existing at the time of extraction in differentiating cells. Results: Cas9 induction of DSBs demonstrated changes in the repair, with an increased rate of large deletions in the CHD2-deficient cell line. No reproducible change in the pattern of smaller indels was identified. There was a significant increase of the number of DSBs captured by INDUCE-seq at D19 of differentiation in WT cells, which was not present until D40 in CHD2-deficient cells. Differences in the enrichment of DSBs at various histone markers, gene bodies and transcription start sites (TSS) were identified between CHD2-deficient cells and WT cells. Conclusions: This study demonstrates an impact on the occurrence and repair of DSBs in CHD2- deficient cell lines. Integration of RNA-Seq data and analysis of the pattern of spontaneous breakage suggests that altered DSB repair physiology could contribute towards the phenotype exhibited by patients with CHD2 mutations

Benzene tricarboxamide derivatives with lipid and ethylene glycol chains self-assemble into distinct nanostructures driven by molecular packing

The self-assembly in aqueous solution of benzene-1,3,5-tricarboxamide (BTA) bearing one alkyl chain and two PEG (polyethylene glycol) chains or two alkyl chains and one PEG chain yields completely distinct nanostructures. Two series of derivatives were synthesized and extensively characterized and electron microscopy and small-angle X-ray scattering (SAXS) reveal micelle structures for derivatives with one alkyl and two PEG chains, but nanotapes and nanoribbons for the series with two alkyl and one PEG chain

High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease

Background & Aims The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution. Methods To investigate the spatial influence of liver architecture on viral replication we measured HCV RNA and ISG mRNA from each of the 8 Couinaud segments of the liver from 21 patients undergoing liver transplant. Results HCV RNA and ISG mRNA levels were comparable across all sites from an individual liver but showed up to 500-fold difference between patients. Importantly, there was no association between ISG and HCV RNA expression across all sites in the liver or plasma. Deep sequencing of HCV RNA isolated from the 8 hepatic sites from two subjects showed a similar distribution of viral quasispecies across the liver and uniform sequence diversity. Single genome amplification of HCV E1E2-envelope clones from 6 selected patients at 2 hepatic sites supported these data and showed no evidence for HCV compartmentalization. Conclusions We found no differences between the hepatic and plasma viral quasispecies in all patients sampled. We conclude that in end-stage liver disease HCV RNA levels and the genetic pool of HCV envelope sequences are indistinguishable between distant sites in the liver and plasma, arguing against viral compartmentalization