ScienceWeek September 1, 2007
Dan Agin
September 1, 2007
Vol. 11 - Number 33
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The simplest schoolboy is now familiar with truths
for which Archimedes would have sacrificed his life.
-- Ernest Renan (1823-1892)
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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
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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