PNAS | March 18, 2008 | vol. 105 | no. 11 | 4075-4076
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THIS WEEK IN PNAS
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BIOPHYSICS
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Paragliders vs. storks and falcons
Glider pilots rely on the "MacCready formula" to maximize cross-country speed. The formula states that the faster a glider travels, the faster it sinks, and time must be spent rising in warm air pockets known as thermals. The formula is well exercised, but whether wild birds follow its precepts unconsciously, or whether they have a better strategy, has been unknown. To compare flight performance between humans and animals, Zsuzsa Ákos et al. analyzed data obtained from GPS devices strapped to human gliding racers, storks, and peregrine falcons. The authors looked into how the three candidates circled as they rose in thermals. In storks and falcons, the mean circling radius was proportional to the ratio of bird weight-to-wing area. However, human paragliders circled at a larger radius than would be expected from the bird rule. From the GPS data of cross-country travel, the authors compared bird and paraglider performance with the optimum flight strategy predicted from the MacCready formula. Storks, falcons, and paragliders behaved similarly, although all deviated somewhat from the theoretical curves, traveling sometimes slower and sometimes faster. These deviations may have happened as the gliders encountered wind conditions not accounted for in the equation, the authors say. They conclude that birds and humans have likely evolved similar flight strategy. — K.M.
"Comparing bird and human soaring strategies" by Zsuzsa Ákos, Máté Nagy, and Tamás Vicsek (see pages 4139–4143)
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DEVELOPMENTAL BIOLOGY
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Putting a finger on digit development
Although clumsy people may be referred to as "all thumbs," chemical signals during development make sure that is not literally true. Takayuki Suzuki et al. examined the molecular factors that help specify each of the digits of the developing chick foot, or autopod. The autopod consists of two alternating types of tissue: digital rays, the tissue that will become the "finger bones" or phalanges; and autopod interdigits, tissue thought to produce chemical signals that act on the adjacent digital rays to determine digit identity. The authors found that the digital ray contains a specialized region, which they termed the phalanx-forming region (PFR), containing molecularly distinct cells that give rise to the phalanges of that digit. In molecular profiling studies, they determined that the PFRs for each digit have unique levels of SMAD1/5/8 activity during each stage of development; digit 3 (measured from the left side) requires the highest levels, whereas digit 1, the equivalent of a human thumb, the lowest. Although the signal coming from the interdigits remains unknown, the results offer a molecular profile for the PFR and suggest a model for the development of digit identity. — M.M.
"Unique SMAD1/5/8 activity at the phalanx-forming region determines digit identity" by Takayuki Suzuki, Sean M. Hasso, and John F. Fallon (see pages 4185–4189)
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MEDICAL SCIENCES
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Genetic evolution of cancer's spread
Colon cancer progresses through a number of well-defined stages linked to mutations in specific sets of genes. Mutations in one set of genes (APC/β-catenin) initiate cancer formation, whereas later stages—from benign tumor formation, to advanced cancer development, and, finally, to metastasis—are linked to mutations in other pathways (e.g., KRAS/BRAF, TGF-β, and p53). But how long does it take for colorectal cancer cells to acquire the mutations responsible for disease progression? Siân Jones et al. report that a timeline can be determined by analyzing mutations that are shared by cancer lesions in the various stages. The investigators compared previously identified colorectal cancer mutations with mutations found in other cancerous lesions from the same patients. Using this "comparative lesion sequencing" technique, they estimated that it takes 
17 years for a large, benign tumor to evolve into an advanced cancer but <2 years for that cancer to acquire the ability to metastasize. These timeframes are in agreement with clinical observations. The authors' findings advance the understanding of human tumor progression, and particularly metastasis—the least well understood stage of disease that is responsible for the majority of cancer-related deaths. — M.M.
"Comparative lesion sequencing provides insights into tumor evolution" by Siân Jones, Wei-dong Chen, Giovanni Parmigiani, Frank Diehl, Niko Beerenwinkel, Tibor Antal, Arne Traulsen, Martin A. Nowak, Christopher Siegel, Victor E. Velculescu, Kenneth W. Kinzler, Bert Vogelstein, Joseph Willis, and Sanford D. Markowitz (see pages 4283–4288)
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MEDICAL SCIENCES
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Gene therapy for muscular dystrophy
In the search for cures for muscular dystrophy, researchers have focused on inhibitors of myostatin, a negative regulator of muscle growth. Preclinical results have been obtained for direct injection of myostatin inhibitors, but drawbacks such as potential immune reaction and the need for multiple injections have prevented clinical use. Amanda Haidet et al. now report that myostatin inhibition by gene therapy increases muscle mass and strength in a mouse model. The authors identified exactly which myostatin inhibitor genes would be most effective when inserted into adeno-associated virus and injected their predicted compound into the animals' hindmuscle. The gene encoding follistatin variant FS-344, a secreted, circulating protein, proved to have the most striking effect. Wild-type mice given a single injection of the FS-344 gene grew the largest muscles and demonstrated the greatest fore- and hind-limb strength. The authors also obtained promising results with mdx mice, a model for Duchenne's muscular dystrophy. This study indicates that not only was muscle mass increased in injected compared with untreated mice, but fibrosis and inflammation were reduced. One-time treatment with the FS-344 gene had a positive effect whether it was administered at 35 or 210 days, suggesting that similar gene therapy could be effective in adult humans, according to the authors. — K.M.
"Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors" by Amanda M. Haidet, Liza Rizo, Chalonda Handy, Priya Umapathi, Amy Eagle, Chris Shilling, Daniel Boue, Paul T. Martin, Zarife Sahenk, Jerry R. Mendell, and Brian K. Kaspar (see pages 4318–4322)
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NEUROSCIENCE
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Dopamine transporter amps up amphetamine response
The dopamine transporter (DAT) controls the availability of the neurotransmitter dopamine and plays a critical role in motivated behaviors such as eating, movement, and reward. DAT malfunction may contribute to conditions such as Parkinson's disease, drug addiction, attention deficit hyperactivity disorder (ADHD), schizophrenia, and depression. Ali Salahpour et al. explored the impact of DAT levels on amphetamine response by genetically modifying mice with four additional copies of the DAT gene. These extra copies boosted DAT protein levels 3-fold and increased DAT activity by 50%. When compared with unmodified animals, the transgenic mice were more susceptible to the physical and psychological effects of amphetamine. These animals became hyperactive, and amphetamine was more rewarding. — B.T.
"Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter" by Ali Salahpour, Amy J. Ramsey, Ivan O. Medvedev, Brian Kile, Tatyana D. Sotnikova, Ericka Holmstrand, Valentina Ghisi, Peter J. Nicholls, Ling Wong, Karen Murphy, Susan R. Sesack, R. Mark Wightman, Raul R. Gainetdinov, and Marc G. Caron (see pages 4405–4410)
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Related articles in PNAS:
- Comparing bird and human soaring strategies
- Zsuzsa Ákos, Máté Nagy, and Tamás Vicsek
PNAS 2008 105: 4139-4143.
[Abstract]
[Full Text]
- Unique SMAD1/5/8 activity at the phalanx-forming region determines digit identity
- Takayuki Suzuki, Sean M. Hasso, and John F. Fallon
PNAS 2008 105: 4185-4190.
[Abstract]
[Full Text]
- Comparative lesion sequencing provides insights into tumor evolution
- Siân Jones, Wei-dong Chen, Giovanni Parmigiani, Frank Diehl, Niko Beerenwinkel, Tibor Antal, Arne Traulsen, Martin A. Nowak, Christopher Siegel, Victor E. Velculescu, Kenneth W. Kinzler, Bert Vogelstein, Joseph Willis, and Sanford D. Markowitz
PNAS 2008 105: 4283-4288.
[Abstract]
[Full Text]
- Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors
- Amanda M. Haidet, Liza Rizo, Chalonda Handy, Priya Umapathi, Amy Eagle, Chris Shilling, Daniel Boue, Paul T. Martin, Zarife Sahenk, Jerry R. Mendell, and Brian K. Kaspar
PNAS 2008 105: 4318-4322.
[Abstract]
[Full Text]
- Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter
- Ali Salahpour, Amy J. Ramsey, Ivan O. Medvedev, Brian Kile, Tatyana D. Sotnikova, Ericka Holmstrand, Valentina Ghisi, Peter J. Nicholls, Ling Wong, Karen Murphy, Susan R. Sesack, R. Mark Wightman, Raul R. Gainetdinov, and Marc G. Caron
PNAS 2008 105: 4405-4410.
[Abstract]
[Full Text]
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