Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · May 2013
Historical ArticleClimate change frames debate over the extinction of megafauna in Sahul (Pleistocene Australia-New Guinea).
Around 88 large vertebrate taxa disappeared from Sahul sometime during the Pleistocene, with the majority of losses (54 taxa) clearly taking place within the last 400,000 years. The largest was the 2.8-ton browsing Diprotodon optatum, whereas the ∼100- to 130-kg marsupial lion, Thylacoleo carnifex, the world's most specialized mammalian carnivore, and Varanus priscus, the largest lizard known, were formidable predators. ⋯ Human involvement in the disappearance of some species remains possible but unproven. Mounting evidence points to the loss of most species before the peopling of Sahul (circa 50-45 ka) and a significant role for climate change in the disappearance of the continent's megafauna.
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Proc. Natl. Acad. Sci. U.S.A. · May 2013
Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site.
The Mycobacterium tuberculosis genome contains an unusually high number of toxin-antitoxin modules, some of which have been suggested to play a role in the establishment and maintenance of latent tuberculosis. Nine of these toxin-antitoxin loci belong to the mazEF family, encoding the intracellular toxin MazF and its antitoxin inhibitor MazE. Nearly every MazF ortholog recognizes a unique three- or five-base RNA sequence and cleaves mRNA. ⋯ To gain further mechanistic insight, we demonstrated that MazF-mt6-mediated cleavage of rRNA can inhibit protein synthesis in the absence of mRNA cleavage. Finally, consistent with the position of 23S rRNA cleavage, MazF-mt6 destabilized 50S-30S ribosomal subunit association. Collectively, these results show that MazF toxins do not universally act as mRNA interferases, because MazF-mt6 inhibits protein synthesis by cleaving 23S rRNA in the ribosome active center.
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Human use of land has transformed ecosystem pattern and process across most of the terrestrial biosphere, a global change often described as historically recent and potentially catastrophic for both humanity and the biosphere. Interdisciplinary paleoecological, archaeological, and historical studies challenge this view, indicating that land use has been extensive and sustained for millennia in some regions and that recent trends may represent as much a recovery as an acceleration. ⋯ Contrasting two spatially explicit global reconstructions of land-use history shows that reconstructions incorporating adaptive changes in land-use systems over time, including land-use intensification, offer a more spatially detailed and plausible assessment of our planet's history, with a biosphere and perhaps even climate long ago affected by humans. Although land-use processes are now shifting rapidly from historical patterns in both type and scale, integrative global land-use models that incorporate dynamic adaptations in human-environment relationships help to advance our understanding of both past and future land-use changes, including their sustainability and potential global effects.
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Proc. Natl. Acad. Sci. U.S.A. · May 2013
Regulator of G protein signaling 4 [corrected] is a crucial modulator of antidepressant drug action in depression and neuropathic pain models.
Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. ⋯ Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.
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Proc. Natl. Acad. Sci. U.S.A. · May 2013
Castor is required for Hedgehog-dependent cell-fate specification and follicle stem cell maintenance in Drosophila oogenesis.
Asymmetric division of stem cells results in both self-renewal and differentiation of daughters. Understanding the molecules and mechanisms that govern differentiation of specific cell types from adult tissue stem cells is a major challenge in developmental biology and regenerative medicine. Drosophila follicle stem cells (FSCs) represent an excellent model system to study adult stem cell behavior; however, the earliest stages of follicle cell differentiation remain largely mysterious. ⋯ Hedgehog signaling is essential to repress Eya to allow Cas expression in polar and stalk cells. Finally, we show that the complementary patterns of Cas and Eya reveal the gradual differentiation of polar and stalk precursor cells at the earliest stages of their development. Our studies provide a marker for cell fates in this model and insight into the molecular and cellular mechanisms by which FSC progeny diverge into distinct fates.