Diss. (sammanfattning) Umeå : Univ., 2005. / Härtill 5 uppsatser + appendix.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 91-100).

by Lai Wai Kai. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 70-74). / Acknowledgement --- p.iv / Abstract --- p.v / Figures and Tables --- p.vii / Abbreviations used in this study --- p.ix / Contents / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Biochemistry of cobalamin --- p.2 / Chapter 1.1.1 --- Biological functions of cobalamin --- p.2 / Chapter 1.1.2 --- Causes of cobalamin deficiency --- p.4 / Chapter 1.1.3 --- Significances of cobalamin deficiency --- p.7 / Chapter 1.1.4 --- Assessment of cobalamin deficiency --- p.8 / Chapter 1.2 --- Biochemistry of Methylmalonic acid (MMA) --- p.10 / Chapter 1.2.1 --- Elevation of MMA in biological fluids --- p.11 / Chapter 1.2.2 --- Significances of measurement of MMA --- p.11 / Chapter 1.2.3 --- Methods of measurement of urinary MMA --- p.13 / Chapter 2. --- Objectives of this project --- p.16 / Chapter 3. --- Materials and Methods / Chapter 3.1 --- Study subjects --- p.18 / Chapter 3.2 --- Sample collection --- p.18 / Chapter 3.3 --- Biochemical and haematological analysis --- p.18 / Chapter 3.4 --- Measurement of urinary creatinine concentration --- p.19 / Chapter 3.5 --- Measurement of serum cobalamin concentration --- p.20. / Chapter 3.6 --- GC-MS determination of urinary MMA --- p.21 / Chapter 3.7 --- Statistical analysis --- p.24 / Chapter 4. --- Results / Chapter 4.1 --- Clinical features of subjects --- p.28 / Chapter 4.2 --- General blood analysis --- p.28 / Chapter 4.3 --- Serum cobalamin analysis --- p.30 / Chapter 4.4 --- Urinary MMA analysis --- p.33 / Chapter 4.5 --- Relationship between urinary MMA excretion and age --- p.53 / Chapter 4.6 --- Relationship between urinary MMA excretion and serum cobalamin concentrations --- p.53 / Chapter 5. --- Discussions / Chapter 5.1 --- Serum cobalamin analysis --- p.62 / Chapter 5.2 --- Urinary MMA analysis --- p.62 / Chapter 5.3 --- Relationship between urinary MMA excretion and age --- p.66 / Chapter 5.4 --- Relationship between urinary MMA excretion and serum cobalamin concentration --- p.66 / Chapter 5.5 --- Relationship between urinary MMA excretion and diet --- p.68 / Chapter 6. --- Conclusions --- p.69 / Chapter 7. --- References --- p.70

Maintaining cellular homeostasis is a complex task, which involves monitoring energy states and essential nutrients, regulating metabolic fluxes to accommodate energy and biomass needs, and preventing buildup of potentially toxic metabolic intermediates and byproducts. Measures aimed at maintaining a healthy cellular economy inherently depend on the composition of nutrients available to the organism through its diet. We sought to delineate links between dietary composition, metabolic gene regulation, and physiological responses in the model organism C. elegans. As a soil-dwelling bacterivore, C. elegans encounters diverse bacterial diets. Compared to a diet of E. coli OP50, a diet of Comamonas aquatica accelerates C. elegans developmental rate, alters egg-laying dynamics and shortens lifespan. These physiological responses are accompanied by gene expression changes. Taking advantage of this natural, genetically tractable predator-prey system, we performed genetic screens i) in C. elegans to identify regulators of diet-responsive genes, and ii) in E. coli and Comamonas to determine dietary factors driving transcriptional responses in C. elegans. We identified a C. elegans transcriptional program that regulates metabolic genes in response to vitamin B12 content in the bacterial diet. Interestingly, several B12- repressed metabolic genes of unknown function are highly activated when B12- dependent propionyl-CoA breakdown is impaired, and inactivation of these genes renders animals sensitive to propionate-induced toxicity. We provide genetic and metabolomic evidence in support of the hypothesis that these genes form a parallel, B12-independent, β-oxidation-like propionate breakdown shunt in C. elegans, similar to the pathway utilized by organisms like yeast and plants that do not use vitamin B12.