In endotherms, regulation of the degree of mitochondrial coupling affects cell metabolic efficiency. Thus it may be a key contributor to minimizing metabolic rate during long periods of fasting. The aim of the present study was to investigate whether variation in mitochondrial avian uncoupling proteins (avUCP), as putative regulators of mitochondrial oxidative phosphorylation, may contribute to the ability of king penguins (Aptenodytes patagonicus) to withstand fasting for several weeks. After 20 days of fasting, king penguins showed a reduced rate of whole animal oxygen consumption (Vo2; -33%) at rest, together with a reduced abundance of avUCP and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1-alpha) mRNA in pectoralis muscle (-54%, -36%, respectively). These parameters were restored after the birds had been refed for 3 days. Furthermore, in recently fed, but not in fasted penguins, isolated muscle mitochondria showed a guanosine diphosphate-inhibited, fatty acid plus superoxide-activated respiration, indicating the presence of a functional UCP. It was calculated that variation in mitochondrial UCP-dependent respiration in vitro may contribute to nearly 20% of the difference in resting Vo2 between fed or refed penguins and fasted penguins measured in vivo. These results suggest that the lowering of avUCP activity during periods of long-term energetic restriction may contribute to the reduction in metabolic rate and hence the ability of king penguins to face prolonged periods of fasting.
We assessed the efficacy and safety of a seven-day course of artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in 55 non-immune patients living in Bangui, Central African Republic. The parasitologic cure rates were 100%, 95%, and 85% on days 14, 28, and 42, respectively. There were no significant differences in parasitemia density, 50% inhibitory concentration of dihydroartemisinin, and frequency of mutant P. falciparum multidrug resistance 1 codon 86 between patients who were cured and those who displayed recrudescence. However, the 90% inhibitory concentration for dihydroartemisinin and the number of genotypes isolated were both higher in the recrudescent patients (five- and two-fold, respectively). We found an association between recrudescence and decreased sensitivity. This suggests that the use of artemisinin compounds alone will select resistant strains. We conclude that artesunate should not be used in monotherapy even in seven-day courses, but only in combination with other anti-malarials to prevent the emergence of resistant P. falciparum.
The LIM homeodomain transcription factor 1b (Lmx1b) is a key factor in the specification of the serotonergic neurotransmitter phenotype. Here, we explored the capacity of Lmx1b to direct differentiation of mouse embryonic stem (mES) cells into serotonergic neurons. mES cells stably expressing human Lmx1b were generated by lentiviral vector infection. Clones expressing Lmx1b at a low level showed increased neurogenesis and elevated production of neurons expressing serotonin, serotonin transporter, tryptophan hydroxylase 2, and transcription factor Pet1, the landmarks of serotonergic differentiation. To explore the role of Lmx1b in the specification of the serotonin neurotransmission phenotype further, a conditional system making use of a floxed inducible vector targeted into the ROSA26 locus and a hormone-dependent Cre recombinase was engineered. This novel strategy was tested with the reporter gene encoding human placental alkaline phosphatase, and demonstrated its capacity to drive transgene expression in nestin þ neural progenitors (NPs) and in Tuj1 þ neurons. When it was applied to inducible expression of human Lmx1b, it resulted in elevated expression of serotonergic markers. Treatment of neural precursors with the floor plate signal Sonic hedgehog further enhanced differentiation of Lmx1b-overexpressing NPs into neurons expressing 5-HT, serotonin transporter, tryptophan hydroxylase 2, and Pet1, when compared with Lmx1b-nonexpressing progenitors. Together, our results demonstrate the capacity of Lmx1b to specify a serotonin neurotransmitter phenotype when overexpressed in mES cell-derived NPs.
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