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This Week in PNAS
CHEMISTRY
Observing a rotaxane twist and bend
Olaf Larsen et al. present a method for observing a rotaxane as it twists and bends at picosecond time scales. This technique can be used to observe molecular devices operate on an ultra-fast time scale and help understand how nanotechnology devices move and function. Rotations around covalent bonds and the making and breaking of hydrogen bonds are not normally considered at macroscopic scales, but according to the authors, such parameters should be observed to understand the capabilities of nanoscale devices. Larsen et al. used two-dimensional infrared spectroscopy to probe a rotaxane's conformation. Specifically, the authors investigated a [2]rotaxane composed of a benzylic amide macrocycle bound by hydrogen bonds to a succinamide thread. By measuring the coupling between the carbonyl (C═O) stretching modes, the macrocycle-thread configuration of the rotaxane was determined with picosecond time resolution. This type of measurement could make it possible to produce a “movie” showing transitions between different conformations. Two-dimensional infrared spectroscopy may thus be useful in determining the degrees of freedom of a given molecular device. — P.D.
X-ray crystal structure of a rotaxane.
“Probing the structure of a rotaxane with two-dimensional infrared spectroscopy” by Olaf F. A. Larsen, Pavol Bodis, Wybren Jan Buma, Jeffrey S. Hannam, David A. Leigh, and Sander Woutersen (see pages 13378-13382)
DEVELOPMENTAL BIOLOGY
Regulator of fasting response identified
Marc Van Gilst et al. have identified a regulator of the response to food deprivation in Caenorhabditis elegans, which may shed light on how the body adapts to starvation. Many genes for the metabolic pathways that help multicellular organisms survive periods of food deprivation are known, but the mechanisms are not well understood. Because fat metabolism pathways are conserved in C. elegans, Van Glist et al. used quantitative RT-PCR in the worms to identify genes important for the fasting response. Eighteen genes with expression levels significantly altered by fasting were found. Fasting stimulated the expression of genes involved in fat metabolism, as well as genes involved in mono- and polyunsaturated fatty acid synthesis. In contrast, expression of a stearoyl-CoA desaturase was repressed, thereby maintaining the relative abundance of saturated fat in fasted organisms. In an nhr-49 deletion mutant, impaired regulation of seven of the 18 fasting response genes was observed. The results suggest that nhr-49, which is related to the mammalian HNF4 nuclear receptor, regulates part of the nutritional response by stimulating gene expression for the breakdown of fat and conversion to sugar, and by controlling levels of saturated fat. — M.M.
Localization of fat metabolism enzyme in C. elegans body wall muscle (bwm) and intestine (int), upon fasting.
“A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49” by Marc R. Van Gilst, Haralambos Hadjivassiliou, and Keith R. Yamamoto (see pages 13496-13501)
ECOLOGY
Salinity increasing in northeastern U.S. fresh water
Increases in the number of roadways and deicer use are salinizing fresh water across the northeastern United States, report Sujay Kaushal et al. Using municipal records and other long-term data, the authors investigated the baseline concentration of chloride in inland waterways in Baltimore County in Maryland, the Hudson River Valley in New York, and the White Mountains in New Hampshire. Baseline concentrations were shown to be increased over the past 30 years in all three regions, and average chloride concentrations increased in relation to the level of impervious surface coverage. A number of urban and suburban streams already exceeded the chloride limit of 250 mg/liter recommended to protect freshwater biota. During the winter months, extensive deicer usage appeared to elevate chloride levels in some urban waterways to as high as 5 g/liter, or 25% of the concentration of seawater. Furthermore, some rural streams and rivers in areas of low road density were found to contain 100 mg of chloride per liter. Kaushal et al. estimate that, if salinity continues to increase at the present rate, surface waters in the northeastern region of the United States could become unfit for human consumption and toxic to freshwater life within the next century. — N.Z.
Deicer salt accumulation on road-way, Baltimore County, MD.
“Increased salinization of fresh water in the northeastern United States” by Sujay S. Kaushal, Peter M. Groffman, Gene E. Likens, Kenneth T. Belt, William P. Stack, Victoria R. Kelly, Lawrence E. Band, and Gary T. Fisher (see pages 13517-13520)
GENETICS
p53 expression signatures in breast cancer
Lance Miller et al. show that gene expression profiles can distinguish p53 mutant and wild-type breast cancers and that these profiles more accurately predict patient survival compared with using p53 mutation status alone. Although p53 mutations are associated with low survival in various cancer types, the compilation of all the downstream changes associated with a p53 deficiency may be a more accurate indicator of clinical behavior. Miller et al. analyzed global transcript levels of 251 primary invasive human breast tumors for which mutational status of p53 had been determined. The authors found that p53 mutant and wild-type tumors separated into two molecularly distinct clusters, with p53 mutations often correlated with estrogen receptor negativity and high tumor grade. Within the 30,000 genes analyzed, an optimal 32-gene signature distinguished tumors on the basis of p53 sequence status, and this signature was consistently associated with patient outcome. Moreover, the p53 signature identified a subset of aggressive tumors with deficient p53 transcript levels but no sequence mutations in the p53 gene, demonstrating the importance of p53 functional status over sequence status in predicting breast cancer behavior. — N.Z.
Mutant-like class of p53 gene signature.
“An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival” by Lance D. Miller, Johanna Smeds, Joshy George, Vinsensius B. Vega, Liza Vergara, Alexander Ploner, Yudi Pawitan, Per Hall, Sigrid Klaar, Edison T. Liu, and Jonas Bergh (see pages 13550-13555)
MEDICAL SCIENCES
Cancer-killing potential for intravenous vitamin C
Qi Chen et al. provide evidence that high-dose ascorbate (vitamin C) administered intravenously may be effective for treating cancer. Observational studies have suggested that high doses of ascorbate may provide a clinical benefit for cancer, though controlled trials using the same high doses have shown no benefit. However, the original studies used intravenous and oral ascorbate, whereas subsequent studies used only oral administration. Recognizing this methodological difference, Chen et al. reexamined ascorbate therapy in cultured cancer cell lines. Using a range of ascorbate concentrations (0.1-20 mM), the authors found that five of the nine cancer cell lines were sensitive to ascorbate at concentrations obtainable only by intravenous infusion. Normal cells were not affected by ascorbate at any concentration. Additionally, ascorbate acted as an intermediate in the generation of hydrogen peroxide, a chemical that can directly damage cells and induce cell death. Because the mechanism may involve the generation of hydrogen peroxide, ascorbate may have additional potential in treating infections. — M.M.
“Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues” by Qi Chen, Michael Graham Espey, Murali C. Krishna, James B. Mitchell, Christopher P. Corpe, Garry R. Buettner, Emily Shacter, and Mark Levine (see pages 13604-13609)
