ScienceWeek

SCIENCEWEEK

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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