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No description available.

Tay-Sachs and Sandhoff diseases are autosomal recessive disorders of GM2 ganglioside catabolism resulting from deficient activity of lysosomal beta-hexosaminidase A (Hex A) or Hex A and Hex B, respectively. This leads to a massive and fatal accumulation of GM2 ganglioside in the neurons of affected patients. Mouse models of Tay-Sachs and Sandhoff diseases, created via targeted disruption of the Hexa and Hexb genes, revealed that while Hexb -/- mice suffer a profound, fatal neurodegenerative disease as expected, Hexa -/- mice escape disease to about one year. This protection is conferred by an ability to degrade GM2 ganglioside by means of a lysosomal sialidase mediated metabolic bypass. To determine if such a bypass could be made to function in humans, a series of experiments were performed to examine and compare the activity of mouse and human lysosomal sialidases in their ability to promote GM2 catabolism. The results suggest that human lysosomal sialidase, though sluggish, can indeed degrade GM2 when induced sufficiently.

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GM$ sb2$ ganglioside hydrolysis requires the formation of a ternary complex consisting of substrate, enzyme ($ beta$-N-acetylhexosaminidase A = Hex A), and the GM$ sb2$ activator protein. In order to study the interaction between Hex A and GM$ sb2$ activator, the human GM$ sb2$ activator cDNA was cloned into the p-FLAG vector. The fusion protein (FLAG-AP) was expressed in E. coli, and purified to homogeneity using immunoaffinity chromatography. / A retardation assay was designed using the immunoaffinity column to detect transient interactions between FLAG-AP and Hex A. Hex A and Hex S are retarded by the column, but not Hex B or unrelated proteins. Hex A retardation is absolutely dependent upon the presence of immobilized FLAG-AP, but does not require the presence of GM$ sb2$ ganglioside. Interaction of GM$ sb2$ activator and Hex A does not involve the enzyme's active site, but does appear to depend upon hydrophobic interactions between the two proteins.

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The purpose of this dissertation is a study of Korean evidentiality on the basis of presuppositional analysis. My claim is that Korean evidentiality can be accounted for under the binding theory of presupposition (Asher & Lascarides 1998; 2003; Asher 2000). The proposal I motivate in this dissertation is that interpretations of Korean evidentials can be handled using the same mechanism which resolves anaphoric expressions.Dynamic Semantics such as DRT and SDRT give a contribution to account for phenomena like anaphora bridging, presupposition, and accomodation bythe update procedure of the discourse structure. I investigate Korean evidentials by examining their distributions and functions in Korean grammar and specifying the types of information source in Korean evidential system. In particular,there are three evidential types in Korean: Direct te, Reportative tay, Inference ci. I propose that the Korean evidential system corresponds to B-1 system in Aikhenvald (2004). I also give an analysis of the intonation phrase of utterances featuring Korean evidentials with the autosegmental-metrical model of intonational phonology. Moreover, I argue that Korean evidentials are presupposition triggers. To verify my claim, I provide various tests such as negation, challengeability and the interrogative flip. All the tests support for classifying Korean evidentials as one category. I also review and compare three different theoretical frameworks: modal, illocutionary and presuppositional analysis. I reject a modal analysis and an illocutionary analysis and employ a presuppositional analysis for Korean evidentiality.I propose that Korean evidentiality can be explained in terms of SDRT(Asher & Lascarides 1998; 2003). Asher & Lascarides (1998) regard presupposition resolution as an integrated part of the task of building discourse relations. I also show that the speaker-dependency of evidentiality is explicitly associated with characteristics of indexicals. Just as in the line of work stemming from Hunter & Asher (2005), I demonstrated that Korean evidentials are anaphorically resolved by the extra-linguistic context as well as by the linguistic context. / text

This thesis describes a search for DNA polymorphisms at the HEXA locus as well as the characterization of three Tay-Sachs disease (TSD) mutations in the Chinese population. / No polymorphisms were detected in the HEXA gene by three different methods: (1) Southern blotting; (2) PCR amplification and restriction enzyme digestion of intronic sequences; (3) single strand conformational polymorphism (SSCP) analysis of introns. The apparent deficiency of accessible polymorphisms is a handicap in studying the origin, distribution, and frequency of mutant HEXA alleles in human populations. / I have characterized five of six infantile TSD alleles segregating in three unrelated Chinese families in which there is no known consanguinity. Two of the mutations described are novel, the third is a transition previously reported in an Italian patient (Nakano et al, 1988). / The two novel mutations occur in homozygous form in the affected individuals investigated. They are: (1) an insertion of an A at nucleotide 547 (Family 1) and (2) a T1453C transition (Family 2). (Abstract shortened by UMI.)

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