This thesis will survey several prominent approaches to analysing causation, discuss their differences and similarities, and look at a number of problems which are common to all of them. I will be arguing for the following claims about how we should approach the process of analysing causation. Firstly, I will be arguing that a reductive analysis is desirable, since if we can reductively analyse causation in terms of something empirically accessible, we can explain how it is possible to know anything about causation. I will argue that to reductively analyse causation is to find out what kind of facts ground causal facts. Secondly, I will argue, following Hall and Strevens, that there are two kinds of causation, causal difference making and causal influence. This two-tiered approach explains the cases where we are tempted to ascribe conflicting characteristics to our concept of causation. Thirdly, I will argue that causal influence grounds causal difference making and that it does so necessarily. That the grounding relation holds necessarily is important for defending the two-tiered approach against the objection that it would yield a disjunctive account.

1 / Fatma Aboulnasr

Philosophical analyses of causation take many forms but one major difficulty they all aim to address is that of the spatiotemporal continuity between causes and their effects. Bertrand Russell in 1913 brought the problem to its most transparent form and made it a case against the notion of causation in physics. The issue highlighted in Russell's argument is that of temporal contiguity between cause and effect. This tension arises from the imposition of a spectrum of discrete events occupying spacetime points upon a background of spacetime continuum. An immediate and natural solution is to superpose instead spatiotemporally continuous entities, or processes, on the spacetime continuum. This is indeed the process view of physical causation advocated by Wesley Salmon and Phil Dowe. This view takes the continuous trajectories of physical objects (worldlines) as the causal connection whereby causal influences in the form of conserved quantities are transported amongst events. Because of their reliance on spatiotemporal continuity, these theories have difficulty when confronted with the discontinuous processes in the quantum domain. This thesis is concerned with process theories. It has two parts. The first part introduces and criticizes these theories, which leads to my proposal of the History Conserved Quantity Theory with Transmission. The second part considers the extension of the idea of causal processes to quantum physics. I show how a probability distribution generated by the Schrodinger wavefunction can be regarded as a conserved quantity that makes the spacetime evolution of the wavefunction a quantum causal process. However, there are conceptual problems in the interpretation of the wavefunction, chiefly to do, as I shall argue, with the difference in the behaviours of probabilistic potentials between quantum and classical physics. I propose in the final chapter, the Feynman Path Integral formulation of quantum mechanics (with the Feynman histories) as an alternative approach to incorporating the probabilistic potentials in quantum physics. This account of how to introduce causal processes in quantum mechanics fares better, I claim, than the previous one in dealing with the situational aspect of quantum phenomena that requires the consideration of events at more than one time.

Hepatitis C virus (HCV), a positive-sense RNA virus that chronically infects between 2.7 and 3.9 million Americans, is highly mutational, making the HCV infection difficult to treat. Thus, it is of high interest to search for highly conserved therapeutic targets within the HCV genome. Two such sequences are located within the 5' untranslated region (UTR) of HCV, being complementary for the microRNA miR-122, a liver microRNA essential for the production of the infectious virus. The use of peptide nucleic acids (PNAs) as therapeutic agents has become a promising area of study in recent years. In this study, we characterized the interactions between miR-122 and the HCV 5'UTR and designed PNAs to disrupt these interactions and thus, inhibit RNA replication and translation. Our results show that the PNAs effectively disrupt the interactions involving miR-122 and the 5'UTR, thereby increasing the possibility of a new therapeutic option against HCV. / Bayer School of Natural and Environmental Sciences / Chemistry and Biochemistry / MS / Thesis

The epistemic theory of causality maintains that causality is an epistemic relation, so that causality is taken to be a feature of the way an agent represents the world rather than an agent-independent or non-epistemological feature of the world. The objective of this essay is to cause problems for the epistemic theory of causality. This is not because I think that the epistemic theory is incorrect. In fact, I spend some time arguing in favour of the epistemic theory of causality. Instead, this essay should be regarded as something like an exercise in stress testing. The hope is that by causing problems for a particular version of the epistemic theory, the result will be a more robust version of that theory. My gripe is with a particular version of the epistemic theory of causality, a version that is articulated with the help of objective Bayesianism. At first sight, objective Bayesianism looks like a plausible theory of rational belief. However, I argue that it is committed to a certain theory of evidence, a theory of evidence that recent work in epistemology has shown to be incorrect. In particular, objective Bayesianism maintains that evidence is perfectly accessible in a certain sense. But evidence just is not so perfectly accessible, according to recent developments in epistemology. However, this is not the end of the line for the epistemic theory of causality. Instead, I propose an epistemic theory of causality that dispenses with the assumption that evidence is perfectly accessible in the relevant sense.

Hepatitis C virus recurrence (which is defined by detection of HCV RNA in serum) in post-transplanted liver is universal but the progression of infection remains unpredictable, varying from case to case. It has been estimated that 75%-80% of the HCV recurrence patients will suffer chronic hepatitis C infection and up to a third of them will progress into the development of fibrosis and cirrhosis within 5 years post-transplantation. Therefore, finding ways to predict early on the progression of fibrosis can contribute to better prognoses. Recent literatures have mentioned that the hepatitis C virus relies on the host microRNA-122 (miR-122) for assistance in replication of the viral genome in hepatocytes. Experimental depletion of miRNA-122 in the cell line Huh 7 has shown up to an 80% decrease in HCV whereas an increase of miRNA-122 has shown an increase of HCV. Since miRNAs are known to have numerous indirect roles by the binding of the target messenger RNAs (mRNAs) and repressing the expression of their proteins, we hypothesized that the elucidation of associations between miRNA-122 and the histological severity in HCV recurrence post-liver transplantation might serve as a biomarker in predicting the outcome of HCV recurrence severity in patients. We also evaluated the expression levels of BCAP31 (a predicted target of miRNA-122), and CD4 (T cell surface molecules involved in immune response) among the HCV recurrence severity groups. RNA samples were isolated from FFPE liver samples from patients with HCV recurrence post-transplantation, and Reverse Transcription and TaqMan Real-Time PCR were carried out for qualitative analysis. We did not see any association between the levels of miRNA-122 expression and severity of HCV recurrence, but we did find a positive correlation between the miRNA-122 expression and the HCV viral load in Group 3 (Severe) at time of HCV recurrence, which supports previous studies of the role of miRNA-122 in HCV replication. We did not find any associations between the expression of BCAP31 and the severity of HCV recurrence but we did discovery an inverse relationship between miRNA-122 and BCAP31 in Group 3 (Severe) at time of HCV recurrence, confirming our assumption of miRNA:mRNA interaction. Also, we did find CD4 expression being statistically significant between Group 1 (Benign) versus Group 3 (Severe), which may support the hypothesis that strong, adequate CD4+ T-cell response is associated with better outcome post-liver transplantation.

This thesis comprises an introduction and six papers on causation, freedom and responsibility. Though mostly self-standing, the papers are unified by two common goals - to recognise and analyse the role of context in the semantics of causal claims and ascriptions of freedom; and to put metaphysical approaches to causation into closer contact with actual causal reasoning in science and the law. Chapter One defends a contextualist semantics of causal language that combines the ancient idea that causes necessitate their effects with Angelika Kratzer's semantics of modality. Chapter Two extends this approach to ascriptions of freedom, by combining Kratzer's account with the principle that an agent acts freely only if she could have acted otherwise. Chapter Three explores a neglected view which combines David Lewis's counterfactual account of causation with his counterpart-theoretic approach to de re modality. Chapter Four proposes an amendment to the interventionist account of causation in response to a worry raised by John Campbell about causation in psychology. Chapter Five motivates the idea that causation is a relation to which multiple events can contribute to different degrees, and defends a novel account of an event's degree of contribution to a causing of an effect. Chapter Six then argues, from a conception of tort law as a system of corrective justice, that a defendant should be held liable for a claimant's losses only to the degree to which the defendant's wrongdoing contributed to the causing of the claimant's harm.

[by] T.P. Cheatham, Jr. / "This report is essentially the same as a doctoral thesis in the Dept. of Electrical Engineering, M.I.T." / Bibliography: p. 86-87. / Army Signal Corps Contract No. W-36-039 sc-32037, Project no. 102B. Dept. of the Army Project No. 3-99-10-022.

by Hedayat Z. Aashtiani and Thomas L. Magnanti. / "This article has appeared in Proceedings, IEEE 192 Large-Scale Systems Symposium"--P.1. / Includes bibliographical references (leaves 11-12). / Supported in part by Dept. of Transportation DOT-TSC-1058. Supported in part by National Science Foundation 79-26225-ECS.

MicroRNAs (miRNAs) are non-coding small RNAs that regulate eukaryotic gene activity at the post-transcriptional level by a process termed miRNA gene suppression. MicroRNA-122 (miR-122) is predominantly expressed in human liver cells and recent studies indicated that miR-122 promotes Hepatitis C Virus (HCV) replication and translation through physical interaction with two tandem binding sites located in the 5 untranslated region (5UTR) of the HCV genome (Jopling, et al., 2006; Jopling, et al., 2008). It has been reported that host genes that are also implicated in the miRNA gene suppression pathway are key regulators of HCV replication (Randall, et al., 2007). Two proteins, Dicer, a key RNaseIII enzyme, and its binding partner TRBP are essential proteins for miRNA activity. They are part of a protein complex called the RNA induced silencing complex (RISC) which also includes Argonaute proteins, and function in miRNA biogenesis loading the miRNA into RISC. As such, they are intriguing targets to study host-viral interplay during HCV replication.<p> In our study, we designed siRNAs to knock down Dicer and TRBP and then observed the effects of gene knockdown on full length J6/JFH-1-RLuc HCV (genotype 2a chimeric genome) replication and translation. The results showed that knocking down Dicer and TRBP reduced wild type (wt) J6/JFH-1-RLuc replication but had almost no effects on HCV translation in human liver cells. However, since knocking down Dicer and TRBP did not significantly alter miR-122 levels in the cell, it appears that the role of Dicer and TRBP was not solely the biogenesis of miR-122. This was confirmed by an experiment in which we observed that knocking down Dicer and TRBP also attenuated replication of a mutant virus in which replication is dependent on a exogenously supplied miRNA instead of endogenous miR-122.<p> Taken together, the results supported the hypotheses that Dicer and TRBP facilitate HCV infection mainly through HCV replication but not translation. The effects of Dicer and TRBP on HCV replication are not solely due to miR-122 biogenesis, and may be due to RISC loading functions in steps of miRNA gene suppression.<p> This study has set some essential groundwork for investigating potential roles of host factors in the RNAi machinery modulating HCV replication/translation and exploring novel antiviral targets.