|
ScienceWeek
SCIENCEWEEK
September 1, 2007
Vol. 11 - Number 33
--------------------------------
The simplest schoolboy is now familiar with truths for which Archimedes would have sacrificed his life.
-- Ernest Renan (1823-1892)
--------------------------------
Contents (full text below):
1. Geophysics: Mapping the Earth's Engine
2. Molecular Biology: miRNAs in Neurodegeneration
3. Structural Biology: Getting DNA to Unwind
4. Behavioral Neurobiology: Pheromones and Female Behavior
5. Theoretical Physics: A Black Hole Full of Answers
6. Molecular Biology: Damage Control
7. Planets: The First Movement
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
1.
Science 31 August 2007: Vol. 317. no. 5842, pp. 1177 - 1178 DOI: 10.1126/science.1144405
Geophysics: Mapping the Earth's Engine
William F. McDonough
Particle physicists and geophysicists rarely meet to compare notes, but earlier this year researchers from these two disciplines gathered to discuss antineutrinos (the antiparticle of the neutrino) (1). These fundamental particles are a by-product of reactions occurring in nuclear reactors and pass easily through Earth, but they are also generated deep inside Earth by the natural radioactive decay of uranium, thorium, and potassium (in which case they are called geoneutrinos). Particle physicists have recently shown that it is possible to detect geoneutrinos and thus establish limits on the amount of radioactive energy produced in the interior of our planet (2). This year's joint meeting was aimed at enhancing communication between the two disciplines in order to better constrain the distribution of Earth's radioactive elements.
Researchers from the Kamioka Liquid scintillator Anti-Neutrino Detector (KamLAND) in Japan reported results that are consistent with the power output produced from the decay of thorium and uranium (16 TW), and the abundances of these elements in Earth, as estimated by geoscientists (3). (Potassium geoneutrinos cannot be detected at present due to the high background in this region of the spectrum.) The initial measurement is also broadly consistent with the Th/U ratio for Earth being equal to that of chondritic meteorites, which is a fundamental assumption used by geochemists to model planetary compositions. However, the upper power limit determined by the experiment (60 TW at the 3sigma limit) exceeds Earth's surface heat flow by a factor of 1.5 and is thus not very useful as a constraint for the models.
Nevertheless, there is great excitement within the two communities, as advances in antineutrino detection are anticipated. The KamLAND detector was intentionally sited near nuclear reactors in order to characterize antineutrino oscillation parameters (the reactor produces so-called electron antineutrinos, and antineutrinos can oscillate between the three different "flavors"--the electron, muon, and tau antineutrinos)--and sense fluctuations in reactor power output. Consequently, the reactor signal overwhelmed the geoneutrino signal. New detectors are being developed, deployed, and positioned in locations that have substantially smaller contributions from nuclear reactors, and thus will provide more precise measurements of neutrinos and antineutrinos to both the Earth science and astrophysical communities.
In addition to detecting geoneutrinos, these facilities are designed to detect neutrinos from supernovae and determine their oscillation properties (like antineutrinos, neutrinos can oscillate among their three different states). As particle physicists continue to count geoneutrinos, the signal-to-noise ratio will improve and, with more counts, the uncertainty in the radioactive energy budget of Earth will shrink and the measured Th/U ratio of the planet will be determined to a greater precision. Measurement uncertainties of 10% or better are possible with the new detectors, and are achievable with only 4 years of counting.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
2.
Science 31 August 2007: Vol. 317. no. 5842, pp. 1179 - 1180 DOI: 10.1126/science.1148530
Molecular Biology: miRNAs in Neurodegeneration
Sébastien S. Hébert and Bart De Strooper
The human genome sequencing effort has taught us that it takes relatively few genes to build a human being. Complexity arises from the combination of these building blocks into genetic programs that are finely tuned in space and time during cell and tissue differentiation. A major part of this regulation is performed by microRNAs (miRNAs), small RNA molecules encoded by the genome that are not translated into proteins; rather, they control the expression of genes. Deregulation of miRNA function has been implicated in human diseases including cancer and heart disease (1, 2). On page 1220 of this issue, Kim et al. (3) suggest that miRNAs are essential for maintaining dopaminergic neurons in the brain, and thus could play a role in the pathogenesis of Parkinson's disease.
Similar to classical genes, regions of the genome that encode miRNAs are transcribed in the cell nucleus. Nascent miRNA transcripts are initially processed into long (up to several kilobases in length) precursor miRNAs that are then sequentially cleaved by two enzymes, Drosha and Dicer, into small functional RNAs (~22 nucleotides). These miRNAs are subsequently incorporated into an RNA-induced silencing complex (RISC), which suppresses the translation and/or promotes the degradation of target messenger RNAs (mRNAs)--RNA molecules that encode proteins--by binding to their 3?-untranslated regions (3?-UTRs) (4). miRNAs are abundant in the brain and are essential for efficient brain function. In this regard, expression of a brain-specific miRNA (miR-124a) in nonneuronal cells converts the overall gene-expression pattern to a neuronal one (5, 6). Another brain-specific miRNA, miR-134, modulates the development of dendritic spines--neuronal protrusions that connect with other neurons--and therefore probably controls neuronal transmission and plasticity (7).
Recent evidence suggests that miRNAs and transcription factors work in close concert. For instance, the RE1 silencing transcription factor can inhibit transcription of miR-124a, thereby suppressing cell differentiation into neurons (8). Kim et al. observe a similar relationship between miR-133b and the transcription factor Pitx3. The pair forms a negative-feedback loop that regulates dopaminergic neuron differentiation (see the figure). Pitx3 transcribes miR-133b, which in turn suppresses Pitx3 expression.
Although Kim et al. provide insights into current concepts in the miRNA field and in neuronal differentiation, the implication that miRNA dysfunction could underlie certain cases of sporadic Parkinson's disease is profound given that after Alzheimer's disease, Parkinson's disease is the second most prevalent age-associated neurodegenerative disorder. The gradual loss of dopaminergic (and eventually other) neurons results in severe mobility problems and occasionally evolves into full-blown dementia. As with Alzheimer's disease, gene mutations can result in inherited forms of Parkinson's disease (9). Although the study of these rare familial forms has helped enormously in understanding their molecular pathogenesis, the real challenge for future research in the field is the vast number of nonfamilial cases.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
3.
Science 31 August 2007: Vol. 317. no. 5842, pp. 1181 - 1182 DOI: 10.1126/science.1147795
Structural Biology: Getting DNA to Unwind
Roxana E. Georgescu and Mike O'Donnell
The initial step in duplicating a cellular genome is the unwinding of a limited region of double-stranded DNA to form a small single-stranded DNA bubble (see the figure) (1). In bacteria, archaea, and lower eukaryotes, the unwinding process begins at a sequence called the replication origin, which contains several conserved binding sites for a protein called the initiator. Binding of the initiator results in a nucleoprotein complex that "melts" DNA, forming the DNA bubble into which the replication machinery assembles. The architecture of the initiator-origin DNA nucleoprotein complex is largely unknown, but reports by Gaudier et al. on page 1213 (2) and by Dueber et al. on page 1210 (3) of this issue solve high-resolution structures of archaean initiator protein-origin DNA complexes that reveal several unexpected and novel features of initiator protein function.
Initiator proteins in all three domains of life share homology in a region that binds adenosine triphosphate (ATP), placing them in the AAA+ family of adenosine triphosphatases (4). AAA+ proteins are associated with diverse cellular activities and typically function as oligomers that remodel other macromolecules. Once bound to sites within a replication origin, initiator proteins oligomerize and use ATP to separate DNA strands in a nearby region (called the duplex unwinding element) that is enriched with adenine (A) and thymine (T) nucleotides. ATP binding and hydrolysis occurs at the interface between adjacent initiator proteins, which may underlie communication and cooperative action among subunits of an AAA+ protein oligomer.
DnaA, the replication initiator in the bacterium Escherichia coli, is monomeric in solution and oligomerizes upon binding to multiple initiator sites at a replication origin (5). By contrast, the eukaryotic initiator ORC (origin recognition complex) is a tightly associated heterohexamer both in solution and when bound to DNA; five ORC subunits are thought to be AAA+ proteins (6-8). Moreover, the replication origins of higher eukaryotes lack defined initiator binding sites (9). But like those of bacteria, the replication origins of archaea contain several conserved initiator binding sites positioned near an A and T-rich unwinding element (10).
Archaea usually contain a few different but homologous AAA+ initiators known as Orc proteins. Like bacterial DnaA, archaean Orc proteins contain an AAA+ region connected to a DNA binding domain and form an oligomer upon binding the replication origin. The archaean Orc DNA binding domain has a winged helix motif. Many winged helix proteins bind as dimers to near-palindromic sites, and because archaean initiator binding sites contain a conserved symmetric dyad, it has been presumed that two Orc proteins bind to each initiator site.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
4.
Nature 448, 999-1000 (30 August 2007) | doi:10.1038/nature05892; Published online 29 August 2007
Behavioral Neurobiology: Pheromones and Female Behavior
Nirao M. Shah1 & S. Marc Breedlove
Is the preference to mate as a male or a female irreversibly set during development? Apparently not: a study in mice shows that pheromone perception determines how an adult female behaves sexually.
We perceive gender as a core characteristic, generally unwavering in almost any social context. So we regard gender differences in behaviour as reflecting irrevocable, pervasive differences in the adult brain of the two sexes1, rather than the flip of a switch between male or female behavioural repertoires. But on page 1009 of this issue, Kimchi et al.2 suggest that, in adult female mice, two crucial components of gender — partner preference and mating behaviour — are controlled by pheromone sensing*. Startlingly, genetic or surgical disabling of pheromone perception seems to switch on full-blown male mating behaviours in females. Together with a previous study3, these experiments indicate that neural pathways responsible for male-typical sexual behaviour are present in the brains of females but lie dormant, and that it is the gender-specific processing of sensory information that determines the masculine or feminine nature of behaviour.
Pheromones are olfactory cues that aid communication of the social and reproductive status of members of a species. In vertebrates, pheromones are recognized by neurons located in two sensory tissues in the nasal cavity, the main olfactory epithelium (MOE) and the vomeronasal organ (VNO)4. The MOE is essential for chemoinvestigation (such as anogenital sniffing), mating and aggressive behaviour5, 6, whereas the VNO is required for aggressive behaviour and for identifying the sex of conspecifics7, 8 — members of the same species.
Previous work7, 8 had shown that deletion of the gene encoding TRPC2, a cation channel expressed only in VNO neurons, profoundly diminishes pheromone-evoked activity in these neurons. Therefore, mutant mice lacking this gene offer a highly specific means of probing the behavioural effects of diminished pheromone sensation. Male mice lacking the Trpc2 gene do not distinguish between males and females, mating with animals of either sex7, 8. Moreover, in contrast to normal males, these mutant male mice do not fight with intruder males7, 8. Such findings had suggested that the VNO recognizes one or more male pheromones that enable gender discrimination and elicit the appropriate behavioural response. Earlier work7 had also shown that, unlike normal females, female mice lacking Trpc2 do not display maternal aggression, failing to attack intruder males when nursing a litter.
Now, Kimchi et al.2 find that Trpc2-deficient females also fail to distinguish between males and females among their conspecifics in terms of mating preference. Unexpectedly, however, they found that mutant females behave like Trpc2-deficient males, sniffing, pursuing and mounting mice of either sex. These behavioural responses do not result from a rewiring of neural circuits during development2, because the authors found that normal females show similar indiscriminate, male-typical sexual behaviour when the VNO is surgically removed in adulthood. These findings suggest that the VNO detects pheromones that normally prevent female mice from displaying male-typical sexual behaviour (Fig. 1).
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
5.
Nature 448, 1000-1001 (30 August 2007) | doi:10.1038/4481000a; Published online 29 August 2007
Theoretical Physics: A Black Hole Full of Answers
Jan Zaanen
A facet of string theory, the currently favoured route to a 'theory of everything', might help to explain some properties of exotic matter phases — such as some peculiarities of high-temperature superconductors.
How are heat and charge transported within a high-temperature superconductor? And what happens when heavy nuclei are torn apart to make the soup of elementary particles known as a quark–gluon plasma? In a paper published on the arXiv preprint server, Hartnoll et al.1 show convincingly that the easiest insight into the superconductor problem, just as into the quark–gluon plasma2, 3, is to be had by looking at a black hole. Not any old black hole, of course, but a black hole in a negatively curved space-time with an extra dimension (Fig. 1).
What might sound like a theoretical physicist's idea of a bad joke could, in fact, be history in the making. The context is a highlight of string theory known as the anti-de-Sitter space/conformal field theory correspondence4 — AdS/CFT for short — which demonstrates an intimate connection between Einstein's general theory of relativity and quantum physics. That it might also find use in such far-flung fields as superconductivity and the quark–gluon plasma is the stuff of physicists' dreams — the unifying power of physical laws as formulated in the language of mathematics.
Viewed as a whole, string theory amounts to a head-on attack on the incompatibility of general relativity and quantum theory, the two greatest accomplishments of twentieth-century physics. According to general relativity, space and time are dynamic entities, linked to matter and energy. By contrast, quantum physics tells us how matter and energy behave, but can only be formulated in a frozen space-time.
String theory is a collection of mathematical discoveries that might just offer a solution to this puzzle. But it has had a bad press of late. This is in part because its 40-year history is littered with claims that, if only we would stick to its true path of enlightenment, the answers to the big questions of physics would be just around the corner. Its failure to deliver on those promises and produce, so far, anything of consequence to experiment has become rather an embarrassment.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
6.
Nature 448, 1001-1002 (30 August 2007) | doi:10.1038/4481001a; Published online 29 August 2007
Molecular Biology: Damage Control
Claus M. Azzalin & Joachim Lingner
The chemical composition of normal DNA at the end of chromosomes does not differ from that of damaged and broken DNA within chromosomes. New findings hint at how the DNA-repair machinery distinguishes the two.
The maintenance of genome integrity is crucial for the survival of every organism. So even a single break along a chromosome triggers a molecular signalling cascade that leads to an appropriate DNA-damage response (DDR). This response allows recognition of the damage site and decelerates cell-cycle progression, giving the cell a chance to repair the damage1. Theoretically, the two free ends of each eukaryotic linear chromosome — telomeres — should evoke a similar cellular response. However, as long as they are intact, telomeres activate DDR only transiently, if at all, at defined stages of the cell cycle. In a paper published on page 1068 of this issue, Lazzerini Denchi and de Lange2 provide clues on how this is achieved at a molecular level.
Telomeres consist of serial repeats of nucleotides terminating in a 3' protruding, single-stranded sequence. Telomeric DNA associates with a six-protein complex known as shelterin3, which shelters the DNA from recognition by the DDR pathways as sites of damage. Lazzerini Denchi and de Lange show2 that two of the shelterin proteins, TRF2 and POT1, independently repress the two main DDR pathways, which are normally induced by damage to DNA sequences within chromosomes.
In most cells, telomeres progressively erode as cells go through successive cycles of division; this is because of incomplete replication of DNA ends by classical DNA polymerase enzymes, the trimming of telomere ends by nucleases, and the absence of the telomere-lengthening enzyme, telomerase4. On reaching a critically short length, telomeres induce a permanent arrest in the cell cycle through a process called cellular senescence, which is thought to be a powerful tumour-suppressive mechanism. Cellular senescence is triggered by the same DDR pathways that function during genuine damage5.
Activation of DDR relies on the functioning of one of two protein kinases, ATM and ATR, which regulate the activity of downstream DDR factors by adding phosphate groups to specific amino-acid residues1. To investigate which of these DDR pathways TRF2 provides protection from, Lazzerini Denchi and de Lange deleted the gene encoding this protein in either ATM-deficient or ATR-depleted cells. They found that, in the absence of TRF2, DDR is activated only in cells that have normal levels of ATM, indicating that TRF2 protects telomeres from ATM-mediated DDR.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
7.
Nature 448, 1003 (30 August 2007) | doi:10.1038/4481003a; Published online 29 August 2007
Planets: The First Movement
Jeff Cuzzi
How do large objects form from the dusty gas surrounding a young star? A simulation suggests that several familiar processes, among them gas turbulence and self-gravitation, might work together to get the job done.
Making planets is tricky, and probably takes several stages. First, tiny interstellar grains must accrete into mountain-sized objects massive enough to decouple from their cocoon of nebula gas. These objects probably then combine in collisions, growing ever larger, past asteroid-sized planetesimals and lunar-sized embryos, to full-blown planets. How the first stage of this process, primary accretion, works is a fundamental unsolved problem of planetary science. On page 1022 of this issue, Johansen et al.1 show how a combination of previously studied processes, acting together, might be the answer.
Our understanding of how protoplanetary nebulae evolve is generally based on observations of regions where stars are forming today. But the domain near the midplane of a nebula, where large objects grow, is shrouded from observations at visual and infrared wavelengths by opaque dust at higher altitudes in the nebula. And for longer-wavelength studies, insufficient spatial resolution is a problem.
Fortunately, our Solar System provides us with actual samples of primary planetesimals, in the form of primitive meteorites from asteroids and, recently, a milligram of cometary material returned by NASA's Stardust mission2. These planetesimals consist mainly of millimetre-sized particles — silicate 'chondrules' and higher-temperature oxides — often individually melted by intense thermal pulses in the nebula3. The ages of these sand-sized grains, assessed from a growing body of radioisotope data, indicate that primary accretion was an inefficient process that took between 1 million and 3 million years4.
Over such a long period, according to models, the density, temperature and composition of the nebula would have changed profoundly5. Centimetre-to-metre-sized particles would also have migrated long distances, redistributing the nebula's solid component relative to its gas6. The mineral composition of the particles changed with their environment, and the result was the pot-pourri of meteorite classes with differing ages, structures, chemistry and isotopic content that we see today. Working backwards from today's evidence to infer the environment and physics of the primary accretion process is a fascinating challenge.
Take turbulence, for instance. Tiny dust grains routinely seen floating far above the midplane of million-year-old protoplanetary disks beyond our Solar System, and crystalline silicate grains seen in abundance in cometary nuclei2, can be explained if nebula turbulence transports them around. But just what process can provide the energy needed to maintain turbulent gas motions, which would be quickly damped by the viscosity of the gas, remains controversial.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
|