Erik C. Madsen

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Copper and iron are transition elements essential for life. These metals are required to maintain the brain's biochemistry such that deficiency or excess of either copper or iron results in central nervous system disease. This review focuses on the inherited disorders in humans that directly affect copper or iron homeostasis in the brain. Elucidation of the(More)
Although the molecular basis of many inherited metabolic diseases has been defined, the availability of effective therapies in such disorders remains problematic. Menkes disease is a fatal neurodegenerative disorder due to loss-of-function mutations in the ATP7A gene encoding a copper-transporting P-type Atpase. To develop therapeutic approaches in affected(More)
Recent studies demonstrate that lysyl oxidase cuproenzymes are critical for zebrafish notochord formation, but the molecular mechanisms of copper-dependent notochord morphogenesis are incompletely understood. We, therefore, conducted a forward genetic screen for zebrafish mutants that exhibit notochord sensitivity to lysyl oxidase inhibition, yielding a(More)
Nutrient availability is an important environmental variable during development that has significant effects on the metabolism, health, and viability of an organism. To understand these interactions for the nutrient copper, we used a chemical genetic screen for zebrafish mutants sensitive to developmental copper deficiency. In this screen, we isolated two(More)
PURPOSE OF REVIEW Reports of the neurologic findings in adults with acquired copper deficiency as well as the development of novel models for Menkes disease have permitted a greater understanding of the role of copper in the central nervous system. A role of mitochondrial copper homeostasis in cellular energy metabolism suggests roles for this metal in(More)
Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu(2+)) transporter ATP7A in Menkes disease, or an inability to absorb copper after gastric surgery. However, many causes of copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental copper conditions.(More)
Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches(More)
The design, synthesis, as well as biochemical and biological evaluation of two novel achiral analogs of duocarmycin SA (DUMSA), 1 and 2, are described. Like CC-1065 and adozelesin, compounds 1 and 2 covalently reacted with adenine-N3 in AT-rich sequences and led to the formation of DNA strand breaks upon heating. The cytotoxicity of compounds 1 and 2(More)
OBJECTIVES Low mannose-binding lectin levels and haplotypes associated with low mannose-binding lectin production have been associated with infection and severe sepsis. We tested the hypothesis that mannose-binding lectin levels would be associated with severe infection in a large cohort of critically ill children. DESIGN Prospective cohort study. (More)
Conjugates of racemic seco-cyclopropaneindoline-2-benzofurancarboxamide (CI-Bf) and four diamides (ImIm 1, ImPy 2, PyIm 3, and PyPy 4, where Py is pyrrole, and Im is imidazole), linked by a gamma-aminobutyrate group were synthesized. In addition to alkylating at adenine-N3 positions within an A(5) sequence, the imidazole-containing compounds 1 and 2 were(More)