This month in Science Roundup:
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Inside the Nucleus
Special Online Collection
The animal cell nucleus not only houses and protects an organism’s genetic material, but also undergoes dramatic physical transformations during each cell cycle -- breaking down completely during mitosis and reforming afresh in each daughter cell after cell division. In the 30 November issue, Science and its online companion Signal Transduction Knowledge Environment (STKE) explored some of the complexities of this dynamic organelle. In the magazine, a News story discussed renewed efforts to define the spindle matrix -- a hypothetical structure implicated in helping a dividing cell move its chromosome -- and three Review articles described the impact of new proteomics and imaging technologies on our understanding of nuclear dynamics, how the nuclear envelope influences events within the nucleus and throughout the cell, and the regulation of protein and nucleic acid transport through nuclear pores. In STKE, two Perspectives highlighted how nuclear localization of the growth hormone receptor might influence gene expression and the role of p53 poly(ADP-ribosyl)ation in maintaining genomic integrity.
Induced Pluripotent Cells
In addition to the capacity for self-renewal, embryonic stem (ES) cells have the remarkable ability to develop into any cell type in the body, and as such, hold great therapeutic promise. However, the requirement for human eggs or embryos to derive these cells has elicited intense controversy over their use and has invigorated scientists to find alternative means of generating so-called pluripotent cells. Now, in a Report published online on Science Express on 22 Nov, Yu et al. describe such an achievement. The team reports that insertion of just four genes into fetal skin cells is sufficient to reprogram them into pluripotent stem cells that look and act like ES cells. The reprogrammed cells express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all three primary germ layers. Although important technical obstacles remain -- the induced cells carry multiple copies of the retroviruses used to insert the genes, which could cause mutations and lead to tumor formation -- a related News story by G. Vogel and C. Holden notes that human cell reprogramming could eventually help solve some of the long-standing political and ethical fights about stem cells and cloning. Dr. Yu, lead author on the study, discussed the work in a related podcast interview.
G protein-coupled receptors (GPCRs) are transmembrane proteins that respond to diverse stimuli from outside of the cell -- including photons, cations, and peptides -- to trigger an array of responses within the cell. These receptors are associated with a multitude of diseases, and as such are important pharmacological targets. However, drug design has been hampered because structural information has been available only for rhodopsin -- an atypical member of the GPCR family in that it is highly abundant and tightly locked into an inactive state by its covalently bound ligand (retinal), whereas most other GPCRs are activated by diffusible molecules, are expressed at low levels, and can assume multiple conformational states. Two Research Articles in the 23 Nov 2007 Science (both published online 25 Oct) now provide structural insights into a canonical GPCR -- the human beta 2-adrenergic receptor, which resides in smooth muscle throughout the body. To overcome the structural flexibility of the receptor and to facilitate its crystallization, Rosenbaum et al. engineered a beta 2-adrenergic receptor fusion protein and then analyzed mutatgenesis data for insights into ligand binding. Cherezov et al. described the high-resolution crystal structure of the engineered receptor, and discussed key similarities and differences between this human GPCR and rhodopsin. An accompanying Perspective by R. Ranganathan highlighted the studies.
Gestational Diabetes Culprit
During pregnancy, maternal pancreatic islet beta cells expand to accommodate the increased physiological demands placed on the mother by the growing fetus. In about 4% of pregnancies, however, mothers are unable to make and use sufficient insulin to meet these metabolic needs, and develop what is called gestational diabetes. In a Report in the 2 Nov 2007 Science, Karnik et al. offered insight into the molecular mechanisms that regulate islet growth during pregnancy. Specifically, the team showed that menin, a protein previously characterized as an endocrine tumor suppressor and transcriptional regulator, controls islet growth in pregnant mice. Transgenic expression of menin in maternal beta cells prevented islet expansion and caused the mice to develop hallmark features of human gestational diabetes, including hyperglycemia and impaired glucose tolerance. Moreover, the team found that prolactin -- a hormonal regulator of pregnancy -- repressed islet menin levels and stimulated the proliferation of islet beta cells. As noted in an accompanying News story by J. Couzin, the new findings suggests that manipulating regulators and targets of menin might be a therapeutic strategy for stimulating beta cell growth in diabetes patients.
In eukaryotic organisms, the maternal and paternal copies (alleles) of most genes are thought to be simultaneously expressed at comparable levels, though there are several known exceptions. Imprinted genes -- which are marked by DNA methylation -- have either the maternal or the paternal allele inactivated, and in X-inactivation, one of the two X chromosomes is silenced. In addition, a small group of genes are known to be subject to so-called random monoalleleic expression including genes encoding immunoglobulins, T cell receptors, and interleukins. In the 16 Nov 2007 Science, Gimelbrant et al. report that the mammalian genome employs random monoalleleic expression much more extensively than previously thought. In a study of about 4000 human genes, the researchers found that 300 were expressed from only one allele. Interestingly, most of these genes were found to be biallelically expressed in some cell populations. Thus, different cell populations can display vast heterogeneity in patterns of mono- and biallelic gene expression, providing numerous combinatorial patterns of gene expression that can generate diverse cellular and physiological outcomes. As noted in an accompanying Perspective by R. Ohlsson, "[t]he interplay among genotype, epigenotype, and gene inactivation will now become more important for understanding developmental mechanisms, penetrance of diseases, and responses to medical treatments in an individual."
Tracking Live Neural Stem Cells
The adult mammalian brain can generate new neurons from neural stem and progenitor cells (NPCs) that reside in the hippocampus and subventricular zone. Although the functions of these new cells are not entirely clear, the ability of NPCs to produce neurons raises the prospect of harnessing them to repair nerve tissue damaged or lost to neurological disease or trauma. In a Report in the 9 Nov 2007 Science, Manganas et al. described a noninvasive way to find and track NPCs in living humans that could have important implications for diagnostic and therapeutic applications. Using a technique called proton nuclear magnetic resonance spectroscopy, the team identified a specific biomarker -- likely a fatty acid mixture -- and developed a sensitive signal-processing algorithm that together allowed the detection and quantification of NPCs both in the rodent and human brain in vivo. By imaging people of varying ages, they also showed that neurogenesis in the hippocampus decreases with age. The findings open the possibility of investigating the role of NPCs and neurogenesis in both normal human physiology and disease pathologies. An accompanying News story by G. Miller highlighted the Report.
Melatonin and Memory
Long-term memory formation is known to depend on circadian rhythms, but the mechanisms are unknown. In a study reported in the 16 Nov 2007 Science, Rawashdeh et al. used zebrafish to investigate whether the circadian system plays a regulatory role in learning and memory formation in a diurnal vertebrate. The fish were placed in a tank with two compartments and trained to associate one compartment having a light signal as with safety, and a dark compartment associated with mild electric shocks with hazard. The team found that fish trained and tested during the day learned the task much faster, and with better retention than fish trained at night. The researchers hypothesized that melatonin -- a hormone whose synthesis and release in the brain are stimulated by darkness and suppressed by light -- was responsible for inhibiting memory formation during the night. In support of that theory, they found that melatonin treatment during the day mimicked the nighttime suppression of memory formation and that training the fish in constant light improved nighttime memory formation while reducing endogenous melatonin concentrations. In addition, treating the fish with a melatonin receptor antagonist at night dramatically improved their memory. Further research into melatonin signaling, and how to block it, could lead to therapeutic treatments for improving mental performance.
A Robotic Future
Special Online Collection
What differentiates robots from other technological devices is their ability to combine automation with action and at times a considerable amount of mobility. As explained in a special section of the 16 Nov 2007 Science, robots are becoming more and more humanoid and playing an increasing role in both scientific and everyday life. News articles examined the challenges of creating self-replicating robots and the allure of robots to budding computer science students. Review and Perspective articles looked at biologically inspired robots and artificial muscle technologies, robots as tools for ocean and space exploration, and brain-based devices that can learn from environmental cues. An editorial, additional news stories, and a research paper highlighted other aspects of the robotics scene, and a special all-robotics podcast provided interviews about studying insect behavior using robot cockroaches, the dilemmas of robot ethics, a challenge to develop self-navigating robotic cars, and the use of robots in extreme environments.
The Social Lives of Early Hominins
Sexual dimorphism -- differences in size and morphology between males and females of the same species -- is the only direct skeletal evidence available for reconstructing the evolution of human social behavior. However, partly because of the limitations of small fossil samples, estimates of dimorphism have lead to widely divergent inferences about social dynamics in fossil hominins. Now, in a Report in the 30 Nov 2007 Science, Lockwood et al. have combined fossil analysis with another aspect of life history -- differences between males and females in the timing of maturity -- and used the results to reconstruct the social behavior of the early hominin Paranthropus robustus, which lived about 2 million years ago. The team ranked a large sample of facial bones on the basis of dental wear and found a substantial difference in size and robustness of features between young adult and old adult males. The researchers attribute this difference to the continued, slow growth of males between early skeletal adulthood and full maturity. Combined with estimates of sexual dimorphism -- males’ facial features were on average 17% larger than females’ -- this pattern suggests a harem-like male mating strategy in which one male dominates a group of females and wards off other males, in a manner similar to that of gorillas. An accompanying News story by A. Gibbon highlighted the Report, and the Science Podcast featured an interview with the lead author.
High-Energy Cosmic Ray Origins
Cosmic rays are energetic particles that bombard the Earth from space in all directions. A small fraction of them have enormous energies exceeding tens of exa-electron volts -- orders of magnitude greater that any earthly particle accelerators -- and researchers have been trying to determine their source for decades. As described in a Research Article in the 9 Nov issue, the Pierre Auger Collaboration has now detected about 80 of the highest-energy cosmic rays and located their directions in the sky. The data were collected over a period of 3.7 years at the Pierre Auger Observatory in western Argentina, an array of some 1600 detectors spaced over 3000 square kilometers that can simultaneously detect the showers of particles emitted as the rays hit Earth’s atmosphere and the associated fluorescence. The team found that the highest energy comic rays come from areas of the sky that are populated by active galactic nuclei that lie within about 250 million light-years of Earth. These compact regions at the centers of galaxies host central black holes and are thought to eject vast plasma jets into intergalactic space. Acceleration of the rays by magnetic fields around the black holes might thus explain their extreme energies. An accompanying News story by A. Cho highlighted the findings and corresponding author of the study Dr. Letessier-Selvon detailed the team’s detection and analysis techniques in a related podcast interview.
How Radiation Damages Materials
The effects of radiation on materials can be beneficial, in helping to shape and pattern them, or detrimental, as in the degradation of structural materials in nuclear reactors. However, the microscopic processes that underlie these effects are not well understood. Now, two Reports in the 9 Nov 2007 Science shed light on the dynamic behavior of defects called dislocation loops, which can form after radiation causes an atom or ion to leaves its place in a crystalline lattice, and lodge nearby in the crystal. Using in situ transmission electron microscopy, Arakawa et al. showed that for alpha-iron -- a form of iron with a so-called body-centered cubic crystal structure -- nanometer-sized defect loops can migrate though the metal even under zero-stress conditions. The motion arises through the formation of double kinks, and fluctuations in the number of these kinks drives loop motion. The loop diffusion rate depends on the loop size. Meanwhile, Matsukawa and Zinkle observed that loops in radiation-damaged gold foils undergo thermally induced one-dimensional diffusion, contrary to the indications of prior simulation studies. An accompanying Perspective by B.D. Wirth noted that the results should stimulate additional research to better understand nanometer-sized dislocation loops and to use the their unique diffusion behavior to pattern materials at the nanoscale.
Coherent Terahertz Generators
Electromagnetic radiation in the terahertz (THz) range has a variety of potential uses from medical imaging and molecular recognition to spectroscopy, but finding a way to generate it has been a challenge. That’s because THz frequencies are too high to be produced by semiconductor-based electronics, yet too low to be produced by solid-state lasers. In a Report in the 23 Nov 2007 Science, Ozyuzer et al. reported an important step toward filling this "terahertz gap." Josephson junctions -- which consist of two superconducting electrodes separated by a thin insulating layer -- can generate current oscillations in the THz range when voltage is applied between the electrodes. Unfortunately, the emission from a single junction is too weak to be useful, and synchronizing a large number of junctions at high frequencies has proven difficult. In the new study, the researchers took advantage of the intrinsic Josephson junctions that form naturally between the superconducting copper oxide layers in a high-temperature superconductor and reported the generation of coherent radiation at frequencies up to 0.85 THz. The side surfaces of the superconductor crystal define an electromagnetic cavity that acts to synchronize all of the individual junctions, similar to the way light bouncing between the mirrors of a laser synchronizes all the atoms to emit coherently. An accompanying Perspective by R. Kleiner highlighted the Report.
Predictably Selective Oxidation
Organic synthesis has traditionally relied on activating and protecting groups to steer synthetic reactions to the desired products. But these groups generate waste and require extra synthesis steps to add them and take them away, so efforts are being made to eliminate them and instead use catalysts that can provide the requisite reactivity and selectivity. Finding catalysts that can selectively attack carbon-hydrogen (C-H) bonds -- which are ubiquitous in organic compounds, but are often unreactive -- has been particularly challenging, and even more so when considering complex molecules with multiple functional groups. In a Report in the 2 Nov 2007 Science, Chen and White described a promising breakthrough. The researchers reported an iron-based catalyst that uses hydrogen peroxide -- an environmentally friendly and inexpensive reagent -- to oxidize a broad range of substrates. Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C-H bonds, without the need for directing groups. Although the catalyst is unstable in the presence of the hydrogen peroxide oxidant, the reaction proceeds rapidly enough that practical yields can be obtained by tailoring the successive additions of catalyst and oxidant. An accompanying Perspective by R. H. Crabtree highlighted the study.
In Science’s STKE
Clues to Regeneration
In response to amputation of a limb, the tail, or even part of an eye, animals such as newts and salamanders can create new structures that are indistinguishable from the original. In these organisms, regeneration involves a choreographed process that recapitulates many aspects of normal embryogenesis. Although mammals are not so adept at regeneration, several adult tissues exhibit partial or complete regrowth after injury -- but by mechanisms different from amphibians. In a Perspective in the 27 Nov 2007 issue, Dor and Stanger discussed recent studies of developing and regenerating liver and pancreas, which suggest that mammals use distinct programs to regulate tissue growth during embryogenesis and adulthood. For example, the developing and regenerating liver both express genes involved in proliferation, but important gene expression modules that are active during liver development -- including those involved in chromatin modification and transcription -- are not used during regeneration. And in the case of insulin-producing beta cells, regeneration does not appear to rely at all on embryonic mechanisms. The authors suggest that methods that enhance the proliferative and functional capacity of terminally differentiated cells may offer the greatest promise for creating functional tissues for clinical use.
Also in STKE this month:
--Fan et al. discussed recent insights into the molecular mechanisms by which temperature cycles synchronize circadian rhythms with the environment (20 Nov 2007)
--Sano et al. discussed the multiple mechanisms used by border cells of the Drosophila ovary, which form a channel that allows sperm to enter the egg, to move as a collective unit (13 Nov 2007)
--Dauer highlighted the identification of a new class of neurotrophic factors that may provide new hope for therapeutic approaches to neurodegenerative disorders such as Parkinson’s disease (6 Nov 2007)
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