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 2014
RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice.
The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. ⋯ Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.
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Proc. Natl. Acad. Sci. U.S.A. · May 2014
Soloist evaluations of six Old Italian and six new violins.
Many researchers have sought explanations for the purported tonal superiority of Old Italian violins by investigating varnish and wood properties, plate tuning systems, and the spectral balance of the radiated sound. Nevertheless, the fundamental premise of tonal superiority has been investigated scientifically only once very recently, and results showed a general preference for new violins and that players were unable to reliably distinguish new violins from old. The study was, however, relatively small in terms of the number of violins tested (six), the time allotted to each player (an hour), and the size of the test space (a hotel room). ⋯ On average, soloists rated their favorite new violins more highly than their favorite old for playability, articulation, and projection, and at least equal to old in terms of timbre. Soloists failed to distinguish new from old at better than chance levels. These results confirm and extend those of the earlier study and present a striking challenge to near-canonical beliefs about Old Italian violins.
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Proc. Natl. Acad. Sci. U.S.A. · May 2014
Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex.
Pathogen recognition by nucleotide-binding oligomerization domain-like receptor (NLR) results in the formation of a macromolecular protein complex (inflammasome) that drives protective inflammatory responses in the host. It is thought that the number of inflammasome complexes forming in a cell is determined by the number of NLRs being activated, with each NLR initiating its own inflammasome assembly independent of one another; however, we show here that the important foodborne pathogen Salmonella enterica serovar Typhimurium (S. ⋯ Superresolution imaging of Salmonella-infected macrophages revealed a macromolecular complex with an outer ring of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain and an inner ring of NLRs, with active caspase effectors containing the pro-IL-1β substrate localized internal to the ring structure. Our data reveal the spatial localization of different components of the inflammasome and how different members of the NLR family cooperate to drive robust IL-1β processing during Salmonella infection.
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Proc. Natl. Acad. Sci. U.S.A. · May 2014
Cattle ranching intensification in Brazil can reduce global greenhouse gas emissions by sparing land from deforestation.
This study examines whether policies to encourage cattle ranching intensification in Brazil can abate global greenhouse gas (GHG) emissions by sparing land from deforestation. We use an economic model of global land use to investigate, from 2010 to 2030, the global agricultural outcomes, land use changes, and GHG abatement resulting from two potential Brazilian policies: a tax on cattle from conventional pasture and a subsidy for cattle from semi-intensive pasture. We find that under either policy, Brazil could achieve considerable sparing of forests and abatement of GHGs, in line with its national policy targets. ⋯ Complementary policies to directly limit deforestation could help limit these effects. GHG abatement from either the tax or subsidy appears inexpensive but, over time, the tax would become cheaper than the subsidy. A revenue-neutral combination of the policies could be an element of a sustainable development strategy for Brazil and other emerging economies seeking to balance agricultural development and forest protection.
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Proc. Natl. Acad. Sci. U.S.A. · May 2014
Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution.
The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a Severe Acute Respiratory Syndrome-like disease with ∼43% mortality. Given the recent detection of virus in dromedary camels, zoonotic transfer of MERS-CoV to humans is suspected. In addition, little is known about the role of human neutralizing Ab (nAb) pressure as a driving force in MERS-CoV adaptive evolution. ⋯ Importantly, the majority of escape mutations had negative impacts on hDPP4 receptor binding and viral fitness. To our knowledge, these results provide the first report on human nAbs against MERS-CoV that may contribute to MERS-CoV clearance and evolution. Moreover, in the absence of a licensed vaccine or antiviral for MERS, this panel of nAbs offers the possibility of developing human mAb-based immunotherapy, especially for health-care workers.