The Social Contract Theory in the Face of Empirical Morality: Integration and Its Consequences

The following study experimentally investigated moral attitudes, both intuitive and reasoned, to assess the validity of the social contract theories of four prominent thinkers: Thomas Hobbes, John Locke, Jean-Jacques Rousseau, and John Rawls. These social contract thinkers, though different in their proposals, all attempt to provide an answer to one long-withstanding question: which governmental structure is best? Their theories also interweave moral cognition with the governmental structure recommended. Thus, this research endeavored to contribute to the contemporary discussion of the social contract theory, encourage empirical investigation of the social contract theory, and provide a framework for future research of a similar kind in order to answer such a question. The research was conducted in survey format with two modules and the data collected was analyzed through evaluation of each section. Module 1, moral consistency, is the quantitative portion of the experimental design which assessed whether or not there was a consistency amongst respondents’ intuitions. Module 2, moral compatibility, is the qualitative portion of the experimental design which considered whether respondents’ moral intuitions and moral reasoning align or not and assigned each respondent’s moral reasoning responses to a thinker based on their method of reasoning. The data was then considered within the framework of the social contract theories presented in order to determine which theory the data best supported. The hypothesis put forth was that, given previous and distinct scholarship on the issues of the social contract theory and moral cognition, that Rawls would represent the majority in both modules of the experiment. However, the empirical results supported Lockeian theory most favorably in both modules, and the weight of such a conclusion considered in the context of practical politics. A discussion is then had on the complications such results pose for moral and political theory, and further experimentation encouraged

Genetic and functional analyses point to FAN1 as the source of multiple Huntington Disease modifier effects

A recent genome-wide association study of Huntington’s disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene FAN1. Here, we have carried out detailed genetic, molecular and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hastening modifier signals. We also identified a third onset-hastening modifier signal whose mechanism of action remains uncertain but does not involve an amino acid change in FAN1. We present additional evidence that a frequent onset-delaying modifier signal does not alter FAN1 coding sequence but is associated with increased FAN1 mRNA expression in the cerebral cortex. Consistent with these findings and other cellular overexpression/suppression studies, knock out of FAN1 increased CAG repeat expansion in HD induced pluripotent stem cells. Together, these studies support the process of somatic CAG repeat expansion as a therapeutic target in HD, and clearly indicate that multiple genetic variations act by different means through FAN1 to influence HD onset in a manner that is largely additive, except in the rare circumstance that two onset-hastening alleles are present. Thus, an individual’s particular combination of FAN1 haplotypes may influence their suitability for HD clinical trials, particularly if the therapeutic agent aims to reduce CAG repeat instability

Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington’s disease

Many Mendelian disorders, such as Huntington’s disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD. Strikingly, FAN1 , previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse FAN1 haplotypes independently modify HD, with rare genetic variants diminishing DNA binding or nuclease activity of the FAN1 protein, hastening HD onset. However, the mechanism behind the frequent and the most significant onset-delaying FAN1 haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3′-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant FAN1 expression quantitative trait loci signal and allelic imbalance in FAN1 messenger ribonucleic acid (mRNA), accounting for the most significant and frequent onset-delaying modifier haplotype in HD. Specifically, miR-124-3p selectively targets the reference allele at rs3512, diminishing the stability of FAN1 mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3′-UTR reporter vectors with swapped alleles, confirmed the specificity of miR-124-3p at rs3512. Together, these findings indicate that the alternative allele at rs3512 renders the FAN1 mRNA less susceptible to miR-124-3p-mediated posttranscriptional regulation, resulting in increased FAN1 levels and a subsequent delay in HD onset by mitigating CAG repeat instability

Clinical endpoints in peripheral endovascular revascularization trials: a case for standardized definitions

BACKGROUND: Endovascular therapy is a rapidly expanding option for the treatment of patients with peripheral arterial disease (PAD), leading to a myriad of published studies reporting on various revascularization strategies. However, these reports are often difficult to interpret and compare because they do not utilize uniform clinical endpoint definitions. Moreover, few of these studies describe clinical outcomes from a patients' perspective. METHODS AND RESULTS: The DEFINE Group is a collaborative effort of an ad-hoc multidisciplinary team from various specialties involved in peripheral arterial disease therapy in Europe and the United States. DEFINE's goal was to arrive at a broad based consensus for baseline and endpoint definitions in peripheral endovascular revascularization trials for chronic lower limb ischemia. In this project, which started in 2006, the individual team members reviewed the existing pertinent literature. Following this, a series of telephone conferences and face-to-face meetings were held to agree upon definitions. Input was also obtained from regulatory (United States Food and Drug Administration) and industry (device manufacturers with an interest in peripheral endovascular revascularization) stakeholders, respectively. The efforts resulted in the current document containing proposed baseline and endpoint definitions in chronic lower limb PAD. Although the consensus has inevitably included certain arbitrary choices and compromises, adherence to these proposed standard definitions would provide consistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of various endovascular revascularization techniques. CONCLUSION: This current document is based on a broad based consensus involving relevant stakeholders from the medical community, industry and regulatory bodies. It is proposed that the consensus document may have value for study design of future clinical trials in chronic lower limb ischemia as well as for regulatory purposes

New developments in the diagnosis and management of cardiac allograft vasculopathy.

The major cause of late death in cardiac transplant recipients is cardiac allograft vasculopathy, also referred to as cardiac transplant atherosclerosis, which occurs in as many as 45% of transplant recipients who survive longer than 1 year. It differs from typical atherosclerosis in that intimal hyperplasia is concentric and diffuse, the internal elastic lamina remains intact, calcification is rare, and the disease tends to develop rapidly. Intravascular ultrasound and coronary angioscopy are more sensitive diagnostic measures of cardiac allograft vasculopathy than is coronary angiography. Although retransplantation at present seems to be the only definitive therapy for cardiac allograft vasculopathy, it has shown only fair results. Recent studies have suggested that calcium entry blockers and angiotensin-converting enzyme inhibitors may play a beneficial role in delaying the progression of cardiac allograft vasculopathy