ScienceWeek July 7, 2007
Dan Agin
July 7, 2007
Vol. 11 - Number 26
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It can never be satisfied, the mind, never.
-- Wallace Stevens (1879-1955)
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Contents (full text below):
1. Neuroscience: Remembering the Subtle Differences
2. Cancer: Sex, Cytokines, and Cancer
3. Chemistry: Light on the Rapidly Evolving Structure of Water
4. Synthetic Biology: Designs for Life
5. Astronomy: A Constant Surprise
6. Neuroscience: Neural Mechanisms of Aggression
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1.
Science 6 July 2007: Vol. 317. no. 5834, pp. 50 - 51 DOI:
10.1126/science.1145811
Neuroscience: Remembering the Subtle Differences
David M. Bannerman and Rolf Sprengel
A good taxi driver in a cosmopolitan city has to find an
arbitrary destination from any starting point, efficiently and
with high precision, relying on recollection of the city's layout
and taking into account changes in traffic or road conditions.
The hippocampus is central to such tasks that rely on memory and
spatial navigation, and the way in which it does this is a key
issue in neuroscience. Over more than a decade, the Tonegawa
laboratory has analyzed the function of neuronal plasticity in
the rodent hippocampus by selectively altering the expression of
genes associated with the function of synapses, the junctions
that facilitate communication between neurons (1, 2). On page 94
of this issue, McHugh, Tonegawa, and colleagues (3) identify an
important role for synaptic plasticity in the dentate gyrus of
the hippocampus for learning. The findings explain how we detect
small changes in our environment, perhaps allowing us to update
and guide our choices.
The principal excitatory neurons of the mammalian hippocampus are
organized into three different cell layers that are linearly
connected. The entorhinal cortex, which provides the major input
of sensorial information to the hippocampus, sends activating
signals to the granule cells of the dentate gyrus (see the
figure). The dentate gyrus, in turn, sends neuronal projections
(axons) to CA3 hippocampal cells. CA3 neurons project to CA1
pyramidal cells, thus establishing a "trisynaptic" pathway in the
hippocampus. To complete the circuit, CA1 cells send output
signals back to the entorhinal cortex. In addition to this major
trisynaptic pathway, there are connections between CA3 cells and
additional entorhinal cortical inputs onto both CA3 and CA1
cells. Synaptic strengths at each node in the trisynaptic pathway
can be modulated, and this is partly dependent on the N-methyl-D-
aspartate (NMDA) receptor, which is activated at synapses by the
neurotransmitter glutamate. Altering the strength of individual
synapses might enable hippocampal neurons to integrate into
ensembles that, when activated, could represent salient features
of the environment. Hippocampal "place" cells have long been
taken as evidence for such internal representations (4).
Place cells are active only when the animal is at a particular
position in space. These neurons could therefore identify the
animal's current spatial location and, in concert with other
neuronal ensembles, track the animal's movement. But beyond
spatial information, hippocampal neuronal activity may provide a
more complete representation of episodes or experiences (5, 6).
Distinct features of hippocampal activity--its so-called neuronal
code--are differentially sensitive to small and large changes in
environmental or contextual features, suggesting that there are
multiple mechanisms by which experiences can be differentiated
(7, 8). Small changes in contextual cues result in a change in
the correlated neuronal activities ("rate remapping") in the
dentate gyrus and CA3, whereas larger changes in contextual
information result in the recruitment of different neurons,
especially in CA3 ("global remapping") (8). McHugh et al.
observed that rate remapping, but not global remapping, was
disrupted in mice genetically engineered to lack NMDA receptors
in the dentate gyrus (lack of a functional receptor prevents
changes in synaptic strength). This phenotype allowed the authors
to assess the role of rate remapping in differentiating between
similar experiences.
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2.
Science 6 July 2007: Vol. 317. no. 5834, pp. 51 - 52 DOI:
10.1126/science.1146052
Cancer: Sex, Cytokines, and Cancer
Toby Lawrence, Thorsten Hagemann, Frances Balkwill
Cancers are not just malignant cells. More than half of the
cancer mass can be made of supporting cells such as fibroblasts,
tissue macrophages, and endothelial cells; cancers cannot
progress into life-threatening metastatic lesions without them.
The process by which normal cells are recruited, expanded, and
maintained in cancers is closely related to inflammation and to
the remodeling that occurs in tissues as the damage of acute
inflammation is repaired (1). Two papers in this issue, by
Naugler et al. on page 121 (2) and Rakoff-Nahoum and Medzhitov on
page 124 (3), advance our understanding of the mechanisms of
cancer-related inflammation. They describe an important role for
an intracellular signaling protein called MyD88 in the
development of experimental liver and colon cancers in mice.
MyD88 function has been well characterized in the innate immune
response (4), relaying signals elicited by pathogen-associated
molecules and by the inflammatory cytokine interleukin-1 (IL-1).
Its identification in promoting cancer progression reveals a
molecular pathway that could be targeted for drug development.
Early experiments demonstrated the need for inflammatory
cytokines such as tumor necrosis factor-alpha (5), and
inflammatory cells such as macrophages (6), in the development
and spread of some experimental tumors. More recently, activation
of the transcription factor nuclear factor kappaB (NF-kappaB),
which is critical in cellular responses to TLR ligands and IL-1,
was implicated in the innate immune response promoting murine
hepatocellular and colon carcinoma (7, 8). The conclusion from
Naugler et al. and Nahoum and Medzhitov is that MyD88 may
function upstream of NF-kappaB in cells involved in inflammation-
associated cancer (see the figure).
A key finding of Naugler et al. is that chemically induced liver
damage in mice leads to the MyD88-dependent induction of IL-6
production. In this liver cancer model, IL-6, made by liver
macrophages (Kupffer cells), promotes tumor progression. By
specifically eliminating NF-kappaB activation in macrophages,
this group previously established that during the development of
liver cancers, IL-6 secreted by Kupffer cells requires NF-kappaB
activity. MyD88 is required for both TLR and IL-1 to activate NF-
kappaB in the innate immune response (4). The data of Naugler et
al. suggest that TLR ligands (or IL-1beta released by dead
hepatocytes) could drive NF-kappaB activation in Kupffer cells
through MyD88. However, the selective ablation of MyD88 in
Kupffer cells is required to firmly establish this link. Ablation
of specific TLRs or the IL-1 receptor would also reveal whether
inhibition of these receptors could protect against liver tumor
development.
Although the study by Naugler et al. implies that IL-1 or ligands
for TLRs may trigger MyD88 activity and an innate immune response
in liver cancers, it is likely that activation of MyD88 in
spontaneous colon carcinogenesis, as described by Rakoff-Nahoum
and Medzhitov, is driven by commensal bacteria that encounter
intestinal macrophages. These authors crossed MyD88-deficient
(Myd88-/-) mice with mice that spontaneously develop intestinal
tumors due to a mutation in the adenomatous polyposis coli (APC)
gene (ApcMin/+). Mortality of the resulting mice was reduced by
more than 60%. Although the absence of MyD88 did not affect
initiation of malignancy, microscopic tumors failed to progress,
and production of many inflammatory and tissue-remodeling factors
(including IL-6) decreased. This study did not determine the role
of MyD88 or NF-kappaB signaling in the intestinal macrophages of
the ApcMin/+ mice. However, Greten et al. (7) have shown that
ablation of NF-kappaB activation in macrophage cells protect mice
from chemically induced colon carcinomas.
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3.
Science 6 July 2007: Vol. 317. no. 5834, pp. 54 - 55 DOI:
10.1126/science.1144515
Chemistry: Light on the Rapidly Evolving Structure of Water
Andrei Tokmakoff
The molecular origins of the physical properties of water
continue to puzzle scientists. Each tool provides only a limited
perspective, revealing certain aspects of the hydrogen-bonding
structure or of the ultrafast time scales over which the
structure changes. Now, a new generation of time-resolved
vibrational spectroscopies is providing detailed insights into
how the structure of water evolves. The results raise questions
about the nature of hydrogen bonding.
The structure of liquid water is generally conceived as a
disordered network of molecules connected by hydrogen bonds (1).
This structure fluctuates and reorganizes on time scales between
10 fs (10-14 s) and 10 ps (10-11 s). This hydrogen-bond dynamics
is at the heart of the unique physical, chemical, and biological
properties of water. Insights into its structural properties have
come from x-ray and neutron-scattering experiments, which lack
dynamical information; insights into its dynamics have been
gained from ultrafast time-resolved experiments, which have
lacked structural detail. The most detailed understanding of
liquid water derives from molecular dynamics simulations, which
commonly treat the liquid as rigid molecules with charges. Such
simulations provide an atom-by-atom perspective on how hydrogen
bonding changes with time, but their dynamics have never been
properly tested against experiment.
Femtosecond infrared spectroscopy bridges the gap between these
methods by providing a structure-sensitive probe of how the
hydrogen-bond network in liquid water evolves. In these studies,
hydrogen bonding is probed by monitoring the frequency of the O-H
bond-stretching vibration, which decreases with increased
strength of the hydrogen bond in which it participates. The
newest method of two-dimensional infrared spectroscopy (2D IR)
uses ultrafast infrared light pulses to track how the frequencies
of different O-H bonds evolve with time.
However, spectroscopy cannot tell you everything. Simulations are
important for providing the structural interpretation of the
experiments, drawing on a theoretical description of how the O-H
frequency is determined by hydrogen-bonding structure (2-4). This
interpretation tool has initiated a feedback process in which the
simulation describes how structural changes appear in the
experiment, and the experiment provides the benchmark for the
computer model.
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4.
Nature 448, 32-33 (5 July 2007) | doi:10.1038/448032a; Published
online 1 July 2007
Synthetic Biology: Designs for Life
Philip Ball1
The genome of one bacterium has been successfully replaced with
that of a different bacterium, transforming one species into
another. This development is a harbinger of whole-genome
engineering for practical ends.
If your computer doesn't do the things you want, give it a new
operating system. As they describe in Science1, Carole Lartigue
and colleagues at the J. Craig Venter Institute in Rockville,
Maryland, have now demonstrated that the same idea will work for
living cells*.
In an innovation that presages the dawn of organisms redesigned
from scratch, the authors report the transplantation of an entire
genome between species. They have moved the genome from one
bacterium, Mycoplasma mycoides, to another, Mycoplasma
capricolum, and have shown that the recipient cells can be
'booted up' with the new genome - in effect, a transplant that
converts one species into another.
This is likely to be a curtain-raiser for the replacement of an
organism's genome with a wholly synthetic one, made by DNA-
synthesis technology. The team at the Venter Institute hopes to
identify the 'minimal' Mycoplasma genome: the smallest subset of
genes that will sustain a viable organism2. The group currently
has a patent application for a minimal bacterial genome of 381
genes identified in Mycoplasma genitalium, the remainder of the
organism's 485 protein-coding genes having been culled as non-
essential.
This stripped-down genome would provide a 'chassis' on which
organisms with new functions might be designed by combining it
with genes from other organisms - for example, those encoding
cellulase and hydrogenase enzymes, for making cells that
respectively break down plant matter and generate hydrogen.
Mycoplasma genitalium is a candidate platform for this kind of
designer-genome synthetic biology because of its exceptionally
small genome2. But it has drawbacks, particularly a relatively
slow growth rate and a requirement for complex growth media: it
is a parasite of the primate genital tract, and is not naturally
'competent' on its own. Moreover, its genetic proof-reading
mechanisms are sloppy, giving it a rapid rate of mutation and
evolution. The goat pathogens M. mycoides and M. capricolum are
somewhat faster-growing, dividing in less than two hours.
Incorporation of foreign DNA into cells happens naturally, for
example when viruses transfer DNA between bacteria. And in
biotechnology, artificial plasmids (circular strands of DNA) a
few kilobases big are routinely transferred into microorganisms
using techniques such as electroporation to get them across cell
walls. In these cases, the plasmids and host-cell chromosomes
coexist and replicate independently. It has remained unclear to
what extent transfected DNA can cause a genuine phenotypic change
in the host cells - that is, a full transformation in a species'
characteristics. Two years ago, Itaya et al.3 transferred almost
an entire genome of the photosynthetic bacterium Synechocystis
PCC6803 into the bacterium Bacillus subtilis. But most of the
added genes were silent and the cells remained phenotypically
unaltered.
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5.
Nature 448, 29 (5 July 2007) | doi:10.1038/448029a; Published
online 4 July 2007
Astronomy: A Constant Surprise
John Cowan
Whether ancient or new, in distant galaxies or our own cosmic
back-yard, stars have dramatic similarities that hint at
remarkably robust formative processes.
The Big Bang gave us hydrogen, helium and a fraction of lithium.
All the other elements in nature - the iron in our blood, the
calcium in our bones and the gold in our jewelry - were
synthesized inside stars that lived and died millions or even
billions of years ago. In other words, the nature and extent of
the synthesis of elements over the history of the Universe has
changed with time and stellar evolution. Yet one aspect of stars
has altered very little over billions of years, and of light
years: the relative abundance patterns of certain heavy elements.
These are consistent all the way through, from the Methuselahs of
the star world to infants such as our Sun. AstronomyA constant
surprise
This suggests that the conditions forming these elements within
stars have remained unchanged since the early Universe.
Otherwise, today's stars would be producing a cocktail of
elements different from the ancient stellar recipe. These
striking similarities could help us to explore the nature of
element formation throughout the Universe.
These findings answer a fundamental question of today's large
surveys and detailed observations of the oldest surviving stars
in our Galaxy and beyond. That is, whether the processes and
stars that formed elements in our Galaxy were unique, or part of
a broader pattern spanning large distances and times. Is our
'local neighbourhood' special, or really rather similar to other
parts of the Universe?
Over the past decade, astronomical observations have unveiled
interesting differences, but also pointed to commonalities
throughout the Universe. For example, the oldest stars in our
Galaxy lie in the galactic halo, the spherical 'cloud' of thinly
scattered globular clusters and old stars surrounding it. What we
are seeing is that the abundance pattern of rare heavy elements
in halo stars - such as barium, europium and platinum - mirror
those in our Solar System.
This is quite surprising, given the billions of years that
elapsed between the birth of halo stars and our Sun. It implies
that the formative processes for these elements, including the
types of stars and internal conditions, are remarkably robust.
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6.
Nature Reviews Neuroscience 8, 536-546 (July 2007) |
doi:10.1038/nrn2174
Neuroscience: Neural Mechanisms of Aggression
Randy J. Nelson & Brian C. Trainor
Summary
Dysregulated aggressive behaviour has important negative
consequences for human societies. A complicating factor is that
aggression that is exhibited in different social contexts can be
regulated by different neurobiological mechanisms.
Neurobiological studies have identified a subset of hypothalamic
and limbic brain areas that tend to facilitate aggressive
behaviour in rodents and primates. In contrast, neural activity
in the frontal cortex generally acts to inhibit aggressive
behaviour.
Aggressive behaviours in animal models and humans are known to be
regulated by serotonin neurotransmission. Behaviour can be
modified at several levels, including regulation of serotonin
release, reuptake and sensitivity (via serotonin receptors).
Dopaminergic function appears to be necessary for aggressive
behaviour, possibly by regulating arousal, learning and memory.
Neuronal nitric oxide (nNOS) synthase signalling (via nitric
oxide gas) exerts inhibitory effects on male aggression in
rodents. Several studies suggest that nNOS assists in the
processing of salient social stimuli.
Mutations in the monoamine oxidase A (MAOA) enzyme are associated
with increased aggressive behaviours in humans. MAOA knockout
mice show increased aggression.
Steroid hormones have long been a focus of aggression research,
but the relationship among androgens, oestrogens and behaviour is
complex. These hormones do not function in isolation and their
actions are affected by the environmental context.
Gene-environment interactions have important effects on
aggressive behaviours. Mutations or hormones that increase
aggression in one environment have no effect (or decrease
aggression) in different environments.
Novel pharmacological treatments must target specific subtypes of
aggression to have improved effectiveness. An appreciation of the
contribution of environmental stressors to aggressive phenotypes
is necessary for further advancements in the successful
management of maladaptive aggression.
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