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This week’s Science sampling

October 17, 2009

Education:

Questions, Questions

Melissa McCartney

Figure 1
CREDIT: JUPITERIMAGES

Question-asking is a fundamental element of practicing science; however, the teaching of question-asking skills is often overlooked in science education. Practicing scientists appreciate the value of asking questions, but do students in science classes? Keeling et al. asked undergraduate students in a senior-level cell biology class to review background material, detailed protocols, types of data to be recorded, and guidelines for analysis, before their laboratory session. After reflecting on the scientific process behind upcoming experiments, students were asked to write at least three questions about the science to be studied. As might be hoped, students’ questioning ability, as assessed by the quality and relevance of questions generated, improved over time. Although repeated practice at writing questions did lead to improvement, “learning by doing” may not be enough, and specifically teaching question-asking skills could usefully be paired with explicit guidance and discussion.

Life Sci. Edu. 8 131 (2009).

Molecular Biology:

Resolving DNA Repair

Barbara R. Jasny

Figure 1
DNA with bound repair proteins.CREDIT: BOAL ET AL., PROC. NATL. ACAD. SCI. U.S.A. 106, 15237 (2009)

Base excision repair (BER) enzymes involved in fixing damaged DNA have low specificity for their targets and occur in low numbers in cells. So how are DNA damage sites located on chromosomes with any efficiency? Boal et al. suggest that the key lies in DNA charge transport chemistry, so that repair proteins can signal to each other rapidly over long distances. The ordered stacking that occurs in DNA makes it an excellent medium for electron transport, and the process is very sensitive to the presence of mismatched bases. When a BER enzyme containing an [4Fe4S] cluster binds DNA it becomes oxidized. In the absence of damage, when a second protein binds, electron transfer will occur and the reduced member of the protein pair will diffuse away. However, if there is damage, both proteins remain bound and, fairly rapidly, repair proteins will redistribute to the damaged region. Boal et al. used atomic force microscopy to establish that redistribution did take place in complexes of the BER enzyme EndoIII with DNA duplexes containing a single mismatch. As predicted, cooperation was observed between different BER enzymes, the bacterial EndoIII and MutY. These enzymes have human homologs linked to cancer predisposition, although the medical implications of the conservation of these iron-sulfur clusters remain unclear.

Proc. Natl. Acad. Sci. U.S.A. 106, 15237 (2009).

Chemistry:

A Charge from Sulfur

Jake Yeston

A zwitterion is essentially a pair of oppositely charged ions connected by a covalent bridge. A common example is the structure of an amino acid dissolved in water near neutral pH—the amino group strips a proton from the carboxylic acid group, leading to a positive ammonium and a negative carboxylate. In general, these highly polarized structures tend to form in solvents that can stabilize the separated charges. Heldebrant et al. have observed a rare instance in which a pure molecular liquid adopts zwitterionic character. The viscous yellow substance forms at room temperature on exposure of an amino alcohol, dibutylundecanolamine, to sulfur dioxide. Formally, the sulfur bonds to the terminal oxygen of the alcohol, forming a negatively charged sulfite group, while the proton formerly on that oxygen shifts to the opposite sinterminus, forming a positively charged ammonium center. The authors characterized the unusual liquid spectroscopically and discovered that the SO2 addition is reversible. Raising the temperature under reduced pressure leads to release of the gas and recovery of the amino alcohol precursor. Because the precursor does not react with CO2, the SO2 binding and release cycle might be applicable to selective removal and recovery of sulfur from combustion exhaust streams.

Energy Environ. Sci. 2, 10.1039/b916550a (2009).

Biomedicine:

Great Expectations

Helen Pickersgill

Two genetic mutations that in combination cause cell death, whereas each alone does not, are known as synthetically lethal. Fairly recently, the synthetic lethality notion has been applied to the search for anticancer drugs, to identify lethal combinations of drugs with specific tumorigenic mutations. The first targeted anticancer drugs to emerge from this approach were inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). These drugs exploit the synthetically lethal interaction between PARP and the tumor suppressor genes breast cancer 1 (BRCA1) or BRCA2, which are involved in DNA double-strand break repair by homologous recombination. Mutations in the BRCA genes are associated with an increased risk of breast and ovarian cancer, and PARP inhibitors are currently showing great promise in the clinic. Another tumor suppressor gene, phosphatase and tensin homolog (PTEN), is one of the most frequently mutated genes in human cancers and has been implicated in genome stability. Now, Mendes-Pereira et al. have found a role for PTEN in homologous recombination, and they demonstrate the sensitivity of PTEN mutant tumor cells to PARP inhibitors. PTEN-deficient cells were also highly sensitive to PARP inhibitors. BRCA mutations are relatively infrequent and limited mainly to breast and ovarian cancers. This study suggests that PARP inhibitors may also be useful in a far broader range of cancers that involve PTEN mutations, such as lung and colorectal tumors and glioblastomas.

EMBO Mol. Med. 1, 315 (2009).

Development:

Macho Mice

Pamela J. Hines

Male-specific behaviors in mice include mating, aggression, and territorial marking. Development of male-specific behaviors in mice, as well as in humans, requires the testicular hormone testosterone. The hormone estrogen, better known for its function in females, is also required. In males, which lack ovaries, estrogen is produced when the enzyme aromatase converts testosterone to estrogen. Estrogen produced by aromatase-expressing cells in the brain then signals through receptors to affect behavior. Wu et al. have now analyzed the neurons that express aromatase and their connectivity in mice. Although aromatase-expressing neurons represent only a minority of the neurons in the brain, the locations and patterns of these neurons in the adult mouse brain reflect sexual dimorphism. Sexually dimorphic territorial behaviors are also affected by disruption of estrogen-based signaling. The testosterone surge around the time of birth in mice thus seems to direct masculinization of territorial behaviors through aromatization of testosterone into estrogen in key neurons within the the brain, rather than through androgen receptor signaling.

Cell 139, 61, (2009)

Applied Physics:

What a Whopper

Ian S. Osborne

The basic design of a laser sandwiches a gain medium between two mirrors. As the light bounces between the mirrors, the intensity of the electromagnetic field builds up within the cavity and spills out from one of the mirrors. Laser instrument size can vary greatly, from the tiny semiconductor devices in DVD and CD players, to the tabletop-confined systems used in spectroscopy and other laboratory applications. Then there are the football field–sized instruments used to probe high-energy light/matter interactions in attempts to harness the class of fusion energy released by the Sun. Reaching an even greater size scale, Turitsyn et al. present a fiber laser with a cavity 270 kilometers long. Such an ultralong laser could be used in secure communications. Because the properties of the waves building up within the medium depend on how the light bounces off the mirrors, a given protocol between a sender and receiver for manipulating the mirrors could provide mode selection for securely relaying messages.

Phys. Rev. Lett. 103, 133901 (2009).

Chemistry:

Imaging Top and Bottom

Phil Szuromi

Figure 1
CREDIT: HAN ET AL., ACS NANO 3, 10.1021/NN901030X (2009)

Scanning tunneling microscopy of adsorbed molecules on surfaces usually interrogates the topography of the topmost layer of atoms. For small molecules, this information is often sufficient to answer many structural questions, but for long-chain molecules, the bonding of the molecule to the surface can be obscured, especially at high surface coverages. Han et al. imaged both the topmost layer and the bonding interface of alkane thiols containing up to 10 carbon atoms adsorbed on gold. The application of an ac modulation of the tunneling gap allowed the buried methyl groups at the gold/sulfur interface to be imaged in a derivative mode. In the high coverage regime, the coexisting domains of different packing arrangements varied in their gold/sulfur bonding motifs in a manner consistent with previous x-ray diffraction studies. This technique will also be useful in studying other processes where changes in molecular tilt impact function.

ACS Nano 3, 10.1021/nn901030x (2009).

Seeing the Brain’s One, Two, Three

Figure 1
CREDIT: NED T. SAHIN/UCSD, HARVARD UNIVERSITY

Taking advantage of the rare opportunity to record neuronal activity in the human brain using intracranial electrodes, Sahin et al. (p. 445; see the Perspective by Hagoort and Levelt) document the spatial and temporal pattern of neuronal populations within Broca’s area as patients thought of a single word, changed its tense (for verbs) or number (for nouns), and articulated the word silently. For these three stages, they detected activity at 200, 320, and 450 milliseconds, moving in a caudal to rostral direction. These data fit neatly within the roughly 600 milliseconds required for the onset of speech and map the distinct neural computations within an area of the brain, known for almost a century and a half, as important for the production of language.

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Confined Germanium Thermodynamics

When a material is confined to nanoscale volumes, the very high proportion of surface to bulk can alter its thermodynamic properties. This has been studied using in situ electron microscopy, but in most cases the volume of the material is not constrained. Holmberg et al. (p. 405) studied the thermodynamics of a germanium nanowire attached to a gold seed and coated with a carbon shell to restrict its volume, measuring the reaction temperature, as well as the liquid composition without changes in volume throughout the heating cycle. This enabled monitoring of phase behavior while the germanium was being heated, and tracking solid-state diffusion across the confined interface.

Balancing the Nitrogen Budget

Setting the global budget for elements presents difficult challenges, such as accounting for possibly unknown sources or sinks. An unresolved imbalance in the oceanic nitrogen budget suggests that there may be additional sources of biological nitrogen fixation in the deep sea. Using high-resolution imaging techniques, Dekas et al. (p. 422; see the Perspective by Fulweiler) observed direct assimilation of isotopically labeled N2 by anaerobic methane-oxidizing archaea from deep marine sediment and the subsequent transfer of nitrogen to their sulfate-reducing bacterial symbionts. This slow and energetically costly conversion by archaea is dependent upon methane and requires physical contact with the associated bacterial partner. Such syntrophic consortia represent a potential source of nitrogen in the oceans and may help to balance the global nitrogen budget.

Like Beads on a String

The optimal packing of spheres, and the somewhat lower densities obtained in the compaction of granular materials are well studied problems. What is less clear is what happens when the spheres are connected, as in the case of polymeric materials—often represented by connected sphere models. Zou et al. (p. 408; see the Perspective by Reichhardt and Lopatina) examined the packing of chains of metal beads commonly used for securing bathroom drain plugs or for raising or lowering window blinds. Both the length of the chains, and whether they were linear or looped, influenced the overall packing density. Jamming the chains together captured the key physics of the glass transition of polymeric materials.

Magnetic Monopoles

Magnets come with a north and a south pole. Despite being predicted to exist, searches in astronomy and in high-energy particle physics experiments for magnetic monopoles (either north or south on their own) have defied observation. Theoretical work in condensed-matter systems has predicted that spin-ice structures may harbor such elusive particles (see the Perspective by Gingras). Fennell et al. (p. 415, published online 3 September) and Morris et al. (p. 411, published online 3 September) used polarized neutron scattering to probe the spin structure forming in two spin-ice compounds—Ho2Ti2O7 and Dy2Ti2O7—and present results in support of the presence of magnetic monopoles in both materials.

Haploid Medaka Stem Cells

Although diploid embryonic stem cells have been generated by various means, there would also be value in deriving haploid stem cells. In these cells, recessive mutations in essential genes would show phenotypes that would not be apparent in heterozygous animals. Yi et al. (p. 430) used the medaka fish model system to generate haploid stem cells that show stable growth and pluripotency. In addition, a fertile female medaka fish was produced by haploid embryonic stem cell nuclear transfer into a normal egg. This system has potential for analyzing recessive genes, for example, in disease phenotypes or in various cell lineages in culture.

Diddy Dinosaurs

Figure 1
CREDIT: SERENO ET AL.

Tyrannosaurs were the dominant large dinosaur predator during the Late Cretaceous. They have several distinct specialized features, including an oversized skull, huge hindlimbs, and tiny arms, that have been thought to have evolved in concert with their large size and carnivorous diet. Sereno et al. (p. 418, published online 17 September; see the Perspective by Clark) now describe an earlier, diminutive tyrannosaur from China that also has these common specializations. Thus, these features were not a result of size increase but appear to have been required for feeding efficiency at all sizes.

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Coupling Clocks and Metabolism

Circadian clocks in mammals coordinate behavior and physiology with daily light-dark cycles by driving rhythmic transcription of thousands of genes. The master clock in the brain is set by light, but clocks in peripheral tissues, such as the liver, are set by daily feeding. Such coupling should allow tissues to “anticipate” food consumption and optimize the timing of metabolic processes, but how nutritional status is communicated to peripheral clocks is unclear. Studying cell culture models and mice, Lamia et al. (p. 437; see the Perspective by Suter and Schibler) show that the nutrient-responsive signaling molecule AMPK (AMP-activated protein kinase) provides metabolic information to circadian clocks by triggering phosphorylation and subsequent degradation of the clock component cryptochrome-1. Thus—cryptochromes, which originally evolved as blue-light photoreceptors in plants, act as chemical energy sensors in mammals.

The Taming of the Silkworm

Silkworms, Bombyx mori, represent one of the few domesticated insects, having been domesticated over 10,000 years ago. Xia et al. (p. 433, published online 27 August) sequenced 29 domestic and 11 wild silkworm lines and identified genes that were most likely to be selected during domestication. These genes represent those that enhance silk production, reproduction, and growth. Furthermore, silkworms were probably only domesticated once from a large progenitor population, rather than on multiple occasions, as has been observed for other domesticated animals.

Teaching Teacher

High-school science teachers rarely have an opportunity to participate in scientific research. A program from Columbia University studies what happens when these teachers do get laboratory experience. After a summer program spanning 2 years, including professional development programs, as well as laboratory research, Silverstein et al. (p. 440) show that the teachers’ students benefit. Students of teachers who participated in this summer research experience showed greater pass rates on the tough New York State Regents exams than did students of teachers who did not participate in the program.

A Fix to the Heart

Figure 1
CREDIT: DOMIAN ET AL.

Regenerative cardiovascular medicine is a promising avenue for therapeutic application in advanced heart failure. Although clinical trials have suggested some limited benefits in cell transplantation therapy, robust cardiac muscle formation is lacking. Domian et al. (p. 426) examined the developmental processes in normal mature cardiac muscle. A two-color murine reporter system was used to isolate committed ventricular progenitors, which were then used to build functional force-generating cardiac tissue. Such combinations of tissue engineering and stem cell biology may eventually lead to cardiac regenerative therapy.

Gee Fizz

The next time you enjoy a carbonated beverage, you can do so with an enhanced understanding of the molecular mechanism that provides its distinctive flavor sensation. Chandrashekar et al. (p. 443) genetically ablated specific sets of taste cells in mice and found that the sensation of CO2 was lost in animals lacking taste cells that sense sour flavors. A screen for genes specifically expressed in these cells revealed the gene encoding carbonic anhydrase 4, which catalyzes hydration of CO2 to form bicarbonate and free protons. Knockout animals not expressing the carbonic anhydrase 4 gene also showed diminished sensation of CO2. The protons produced by the enzyme appear to be the actual molecules sensed by the sour-sensitive cells. This process, combined with tactile sensations, appears to be the source of the popular fizzy sensation.

Subcortical Network Regulation

Subcortical neuromodulatory centers dominate the motivational and emotional state–dependent control of cortical functions. Control of cortical circuits has been thought to involve a slow, diffuse neuromodulation that affects the excitability of large numbers of neurons relatively indiscriminately. Varga et al. (p. 449) describe a form of subcortical control of cortical information processing whereby strong, spatiotemporally precise excitatory input from midbrain serotonergic neurons produces a robust activation of hippocampal interneurons. This effect is mediated by a synaptic release of both serotonin and glutamate and impacts network activity patterns.

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