Significant associations have been found between specific human leukocyte antigen (HLA) alleles and organ transplant rejection, autoimmune disease development, and the response to infection. Traditional searches for disease associations have conventionally measured risk associated with the presence of individual HLA alleles. However, given the high level of HLA polymorphism, the pattern of amino acid variability, and the fact that most of the HLA variation occurs at functionally important sites, it may be that a combination of variable amino acid sites shared (...) by several alleles (shared epitopes) are better descriptors of the actual causative genetic variants. Here we describe a novel approach to genetic association analysis in which genes/proteins are broken down into smaller sequence features and then variant types defined for each feature, allowing for independent analysis of disease association with each sequence feature variant type. We have used this approach to analyze a cohort of systemic sclerosis patients and show that a sequence feature composed of specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk for systemic sclerosis. (shrink)

We greatfully ackknowledge that research for this projrect was supported by N.E.H. fellowship and by grant from the American Philosophical Society. All Transletions are our own, unless otherwise noted.

My purpose in this paper is to argue that the classical notion of entailment is not suitable for non-bivalent logics, to propose an appropriate alternative and to suggest a generalized entailment notion suitable to bivalent and non-bivalent logics alike. In classical two valued logic, one can not infer a false statement from one that is not false, any more than one can infer from a true statement a statement that is not true. In classical logic in fact preserving truth and (...) preserving non-falsity are one and the same thing. They are not the same in non-bivalent logics however and I will argue that the classical notion of entailment that preserves only truth is not strong enough for such a logic. I will show that if we retain the classical notion of entailment in a logic that has three values, true, false and a third value in between, an inconsistency can be derived that can be resolved only by measures that seriously disable the logic. I will show this for a logic designed to allow for semantic presuppositions, then I will show that we get the same result in any three valued logic with the same value ordering. I will finally suggest how the notion of entailment should be generalized so that this problem may be avoided. The strengthened notion of entailment I am proposing is a conservative extension of the classical notion that preserves not only truth but the order of all values in a logic, so that the value of an entailed statement must alway be at least as great as the value of the sequence of statements entailing it. A notion of entailment this strong or stronger will, I believe, be found to be applicable to non-classical logics generally. In the opinion of Dana Scott, no really workable three valued logic has yet been developed. It is hard to disagree with this. A workable three valued logic however could perhaps be developed however, if we had a notion of entailment suitable to non-bivalent logics. (shrink)

This paper is concerned with the kind of non-linear causation that lies behind the production and comprehension of speech in discourse, where multiple ‘input’ data typically act in concert towards a determinate output. To this end Whitehead's philosophy of Process - in particular his theory of ‘prehensions’ — is applied to the analysis of pragmatic implication and inference in a short literary excerpt, which involves the most complex kind of prehension, the `intuitive judgment'. This leads to a number of conclusions (...) concerning the way in which patterns of linguistic behaviour can be evoked out of mere potentiality by contextually embedded prehensions that constrain and modulate the expression of intended discourse acts. Some of these constraints are attributable to the nature of focal consciousness itself. An extension of the Whiteheadian notion of ‘subjective aim’ (usually understood to preside over a single ‘actual occasion’) will be necessitated, since in discourse this can clearly both be suspended and divided into subordinate sub-aims while the overall aim, still unfulfilled, is inherited from occasion to occasion. (shrink)