Proceedings of the National Academy of Sciences of the United States of America
-
Proc. Natl. Acad. Sci. U.S.A. · Oct 2005
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. ⋯ Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
-
Proc. Natl. Acad. Sci. U.S.A. · Oct 2005
Comparative StudyDynamics of sleep-wake cyclicity in developing rats.
Adult mammals cycle between periods of sleep and wakefulness. Recent assessments of these cycles in humans and other mammals indicate that sleep bout durations exhibit an exponential distribution, whereas wake bout durations exhibit a power-law distribution. Moreover, it was found that wake bout distributions, but not sleep bout distributions, exhibit scale invariance across mammals of different body sizes. ⋯ Further analyses failed to find substantial evidence either of short- or long-term correlations in the data, thus suggesting that the durations of current sleep and wake bouts evolve through time without memory of the durations of preceding bouts. These findings further support the notion that bouts of sleep and wakefulness are regulated independently. Moreover, in light of recent evidence that developmental changes in sleep and wake bouts can be attributed in part to increasing forebrain influences, these findings suggest the possibility of identifying specific neural circuits that modulate the changing complexity of sleep and wake dynamics during development.
-
Proc. Natl. Acad. Sci. U.S.A. · Oct 2005
Comparative StudyInhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle.
Malonyl-CoA functions as a mediator in the hypothalamic sensing of energy balance and regulates the neural physiology that governs feeding behavior and energy expenditure. The central administration of C75, a potent inhibitor of the fatty acid synthase (FAS), increases malonyl-CoA concentration in the hypothalamus and suppresses food intake while activating fatty acid oxidation in skeletal muscle. Closely correlated with the increase in muscle fatty acid oxidation is the phosphorylation/inactivation of acetyl-CoA carboxylase, which leads to reduced malonyl-CoA concentration. ⋯ Thus, the sympathetic nervous system is implicated in the transmission of the "malonyl-CoA signal" from brain to skeletal muscle. Consistent with the up-regulation of UCP3 and PPARalpha is the concomitant increase in the expression of PGC1alpha, transcriptional coactivator of the UCP3 and PPARalpha-activated genes. These findings clarify the mechanism by which the hypothalamic malonyl-CoA signal is communicated to metabolic systems in skeletal muscle that regulate fatty acid oxidation and energy expenditure.
-
Proc. Natl. Acad. Sci. U.S.A. · Oct 2005
Comparative StudyMechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway.
The radiation-induced bystander effect is defined as "the induction of biological effects in cells that are not directly traversed by a charged particle but are in close proximity to cells that are." Although these bystander effects have been demonstrated with a variety of biological endpoints in both human and rodent cell lines (as well as in 3D tissue samples), the mechanism of the phenomenon is not known. Although gap junction communication and the presence of soluble mediator(s) are both known to play important roles in the bystander response, the precise signaling molecules have yet to be identified. ⋯ Because the critical event of the COX-2 signaling is the activation of the mitogen-activated protein kinase pathways, our finding that inhibition of the extracellular signal-related kinase phosphorylation suppressed bystander response further confirmed the important role of mitogen-activated protein kinase signaling cascade in the bystander process. These results provide evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory response, is the critical signaling link for the bystander phenomenon.
-
Proc. Natl. Acad. Sci. U.S.A. · Oct 2005
Comparative StudyRapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease.
Frequently, mtDNA with pathogenic mutations coexist with wild-type genomes (mtDNA heteroplasmy). Mitochondrial dysfunction and disease ensue only when the proportion of mutated mtDNAs is high, thus a reduction in this proportion should provide an effective therapy for these disorders. We developed a system to decrease specific mtDNA haplotypes by expressing a mitochondrially targeted restriction endonuclease, ApaLI, in cells of heteroplasmic mice. ⋯ We tested the efficacy of this approach in vivo, by using recombinant viral vectors expressing the mitochondrially targeted ApaLI. We observed a significant shift in mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses. This strategy could prevent disease onset or reverse clinical symptoms in patients harboring certain heteroplasmic pathogenic mutations in mtDNA.