Invasive meningococcal disease and a need to understand host genetic susceptibility.
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Genetic Predisposition to Disease↗
Biomedical subjects
Michael F Murray
Publications and source records attributed to Michael F Murray.
Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr).
Aldolase (E.C. 4.1.2.13), a homotetrameric protein encoded by the ALDOA gene, converts fructose-1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. Three isozymes are encoded by distinct genes. The sole aldolase present in red blood cells and skeletal muscle is the A isozyme. We report here the case of a girl of Sicilian descent with aldolase A deficiency. Clinical manifestations included transfusion-dependent anemia until splenectomy at age 3 and increasing muscle weakness, with death at age 4 associated with rhabdomyolysis and hyperkalemia. Sequence analysis of the ALDOA coding regions revealed 2 novel heterozygous ALDOA mutations in conserved regions of the protein. The paternal allele encoded a nonsense mutation, Arg303X, in the enzyme-active site. The maternal allele encoded a missense mutation, Cys338Tyr, predicted to cause enzyme instability. This is the most severely affected patient reported to date and only the second with both rhabdomyolysis and hemolysis.
Amino Acid Sequence↗
Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus.
Coinfection with Mycobacterium tuberculosis and human immunodeficiency virus (HIV) is responsible for one-third of all deaths due to acquired immunodeficiency syndrome. More than 99% of cases of HIV-M. tuberculosis coinfection occur in the developing world, where limited resources add urgency to the search for effective and affordable therapies. Although antimicrobial agents against each of these infections are available, single agents that have activity against both M. tuberculosis and HIV are uncommon. The activity of nicotinamide has been evaluated in 2 different eras: in anti-M. tuberculosis studies performed during 1945-1961 and in anti-HIV studies performed from 1991 to the present. This review brings together these 2 bodies of inquiry and raises the possibility that, with more study, this small molecule could emerge at the beginning of the 21st century either as a therapeutic agent in itself or as the lead compound for a new class of agents with activity against both M. tuberculosis and HIV.
Anti-Bacterial Agents↗
Tryptophan depletion and HIV infection: a metabolic link to pathogenesis.
HIV-1-infected patients have low circulating tryptophan concentrations despite evidence of adequate dietary intake of this essential amino acid. A chronic increase in inducible tryptophan oxidation is the basis of HIV-1-associated tryptophan depletion. This metabolic process results in the irretrievable loss of tryptophan molecules from the available pool. Such sustained disruption of normal tryptophan metabolism over time disturbs the many metabolic processes involving this amino acid, and has been implicated in some features of AIDS pathogenesis. Normal T-cell function is adversely affected by tryptophan depletion, but the extent of the effect in HIV-1-infected patients is still unclear. Attempting to directly supplement tryptophan is not advised given the potential increase in circulating concentrations of neurotoxic intermediates. Although only preliminary data are available, evidence suggests that antiretroviral and nicotinamide treatments can boost plasma tryptophan concentrations in HIV-1-infected patients and impact the secondary effects of tryptophan depletion. Additional study of this metabolism could lead to improved treatment strategies for patients with HIV infection. In this review I focus on the potential links between disturbed tryptophan metabolism and pathogenesis.
Anti-HIV Agents↗
Embryonic stem cell-specific MicroRNAs.
We have identified microRNAs (miRNAs) in undifferentiated and differentiated mouse embryonic stem (ES) cells. Some of these appear to be ES cell specific, have related sequences, and are encoded by genomic loci clustered within 2.2 kb of each other. Their expression is repressed as ES cells differentiate into embryoid bodies and is undetectable in adult mouse organs. In contrast, the levels of many previously described miRNAs remain constant or increase upon differentiation. Our results suggest that miRNAs may have a role in the maintenance of the pluripotent cell state and in the regulation of early mammalian development.
Animals↗
siRNA-directed inhibition of HIV-1 infection.
RNA interference silences gene expression through short interfering 21 23-mer double-strand RNA segments that guide mRNA degradation in a sequence-specific fashion. Here we report that siRNAs inhibit virus production by targeting the mRNAs for either the HIV-1 cellular receptor CD4, the viral structural Gag protein or green fluorescence protein substituted for the Nef regulatory protein. siRNAs effectively inhibit pre- and/or post-integration infection events in the HIV-1 life cycle. Thus, siRNAs may have potential for therapeutic intervention in HIV-1 and other viral infections.
Base Sequence↗