ScienceWeek

SCIENCEWEEK

March 16, 2007

Vol. 11 - Number 11

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Man's destiny is to know, if only because societies with knowledge culturally dominate societies that lack it. Luddites and anti-intellectuals do not master the differential equations of thermodynamics or the biochemical cures of illness. They stay in thatched huts and die young.

-- Edward O. Wilson

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Contents (full text below):

1. Climate Change: Rethinking Ice Sheet Time Scales

2. AIDS/HIV: Finding Footprints Among the Trees

3. Evolution: Hybrid speciation

4. Physical chemistry: The peripatetic proton

5. Neuroscience: The impact of structural biology on neurobiology

6. Neuroscience: Small worlds inside big brains

7. Evolution: Germ cells carry the epigenetic benefits of grandmother's diet

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1. Science 16 March 2007: Vol. 315. no. 5818, pp. 1508 - 1510 DOI: 10.1126/science.1140469

Climate Change: Rethinking Ice Sheet Time Scales

Martin Truffer and Mark Fahnestock

According to glaciology textbooks, glaciers respond to climate change on time scales that vary from a decade or more for nonpolar glaciers to millennia for polar ice sheets. These numbers have lured the scientific community into thinking that while small glaciers undergo rapid changes, the big ice sheets adjust at a leisurely pace.

Lately, the ice sheets have been teaching us differently. Recent reports documented rapidly increasing discharge of Greenland's outlet glaciers (1-3). These glaciers are responsible for most of the ice sheet's mass loss, acting as "bathtub drains" to the vast interior ice mass (see the figure). On page 1559 of this issue, Howat et al. (4) report that ice discharge can also decrease at a high rate: Two of the major outlet glaciers in southeastern Greenland--Helheim and Kangerdlugssuaq--doubled their discharge of ice into the ocean within 1 year in 2004. Two years later, the discharge quickly dropped back close to its former rate.

Near the other pole, Fricker et al. [page 1544 (5)] report changes in ice surface elevation from data recorded by NASA's Ice, Cloud, and land Elevation Satellite (ICESat). These observations are interpreted as a sign of moving subglacial water under a large ice stream. At one ice stream location, the surface drop can be explained by the drainage of 2 km3 of subglacial water. Elsewhere, the ice surface rose sufficiently to account for the storage of this water. Earlier studies had shown the existence of such elevation changes (6, 7), but Fricker et al.'s analysis reveals a surprisingly active system of subglacial hydrology in a part of the world where little or no surface melting occurs.

Today, we can monitor ice sheets with unprecedented spatial and temporal resolution, thanks to an array of Earth-observing satellites and many ground-based studies. The resulting news has consistently had an element of surprise with regard to time scales. Invariably, processes are happening more rapidly than previously thought possible (2-4, 8, 9). The discovery of moving water pockets underneath the West Antarctic ice streams by Fricker et al. and the rapidly oscillating fluxes at two of Greenland's outlet glaciers reported by Howat et al. further illustrate how rapidly ice sheets can change.

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2. Science 16 March 2007: Vol. 315. no. 5818, pp. 1505 - 1507 DOI: 10.1126/science.1140768

AIDS/HIV: Finding Footprints Among the Trees

Paul Klenerman and Andrew McMichael

To establish a long-term persistent infection, HIV has evolved many strategies. One of these is to mutate at the sites in virus proteins that stimulate immune responses. This gives rise to variant viruses that evade recognition by host immune cells (T cells) and antibodies. An earlier analysis of virus sequences in HIV-infected populations indicated that such "immune escape" plays a major role in the evolution of the virus (1). But on page 1583 in this issue, Bhattacharya et al. (2) take another look at HIV sequence data in infected populations and find that viral lineage (or genetic relatedness) is a confounding factor in the analysis of HIV sequence evolution. This means that the effect of immune escape may not be as strong as suspected. Virus variability may not be as predictable as first thought, making it harder to cover the variation of HIV by vaccines.

The targets of T cell immune responses are very diverse and are determined by the host human leukocyte antigen (HLA) or tissue type. HLA class I molecules are expressed on most cells and, when the cell is infected, HLA molecules "present" peptides derived from virus proteins to T cells of the CD8+ subtype. HLA proteins are highly polymorphic so that in different individuals, CD8+ T cells respond to different viral peptides, depending on the individual's HLA type. A virus can escape a host's T cell response by mutating one or more of these presented viral peptides such that they no longer bind to HLA molecules, fail to interact with the T cell's receptors, or are not processed correctly within the cell. The T cell response then becomes ineffective.

It has been known since 1991 that HIV can mutate and escape from T cell immune responses (3), but in 2002, Moore et al. proposed that T cell escape mutants were much more frequent and predictable than previously thought (1). The authors sequenced the virus gene encoding the HIV Pol protein in a large cohort of HIV-infected patients in Perth, Western Australia. In many cases, they were able to correlate variation at specific sites in the pol gene with the HLA type of the host. In other words, the HLA type of the patient imposed a characteristic change (through T cell selection), or "footprint," on the virus sequence in that patient. This indicated that analysis of viral sequences in the context of HLA type could help identify viral sequences that stimulate T cell responses (4)......

The findings of Bhattacharya et al. have implications for the study of other viruses, notably hepatitis C virus (HCV). Several groups who have taken phylogeny into account have identified "footprints" of T cells on HCV, including a large single-source outbreak among Irish women (15, 16). A clear footprint on HCV was also observed in an epitope restricted by HLA-B27, an allele that is protective in both HCV and HIV (17). Because the sequence diversity of HCV is even greater than that of HIV, taking into account the viral phylogeny when studying HCV-related immunology will likely be of even greater consequence than for HIV.

What does this mean for HIV or HCV vaccine design? It might be possible to design vaccines that anticipate the frequently selected escape mutations by using more than one viral amino acid sequence in the vaccine (18), though this would require very complex vaccines. An alternative would be to use vaccines to redirect the immune response to the most conserved regions of the virus, which may be invariant because of functional or structural constraints. However, the extraordinary power of viruses like HIV and HCV to escape almost any means of host attack remains a daunting hurdle to overcome. The phylogenetic trees may have eliminated some T cell footprints, but they reveal the enormous complexity of the viral epidemic both within individuals and within populations.

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3. Nature 446, 279-283 (15 March 2007) | doi:10.1038/nature05706

Evolution: Hybrid speciation

James Mallet

Botanists have long believed that hybrid speciation is important, especially after chromosomal doubling (allopolyploidy). Until recently, hybridization was not thought to play a very constructive part in animal evolution. Now, new genetic evidence suggests that hybrid speciation, even without polyploidy, is more common in plants and also animals than we thought.

Linnaeus stated in Systema Naturae that species have remained unchanged since the dawn of time, but he later experimented with hybrids and convinced himself that hybridization provided a means of species modification. One hundred and eighty years later, Lotsy1 still argued that species were invariant genetic types, and that novel lineages could evolve only by means of hybridization. These peculiar ideas were overturned when the concept emerged of species as reproductively isolated populations2, 3, 4. In zoology, this concept discouraged the view that hybridization and gene flow (introgression) between species could be important evolutionary forces2, 5, 6, even while botanists continued to argue for their significance4, 7, 8. Today, armed with new and abundant molecular marker data, biologists increasingly find new examples where hybridization seems to facilitate speciation and adaptive radiation in animals, as well as plants.

What is hybrid speciation?

'Hybrid speciation' implies that hybridization has had a principal role in the origin of a new species. The definition applies cleanly to hybrid species that have doubled their chromosome number (allopolyploidy): derived species initially contain exactly one genome from each parent, a 50% contribution from each, although, in older polyploids, recombination and gene conversion may eventually lead to unequal contributions. Furthermore, allopolyploids are largely reproductively isolated by ploidy. Recombinational hybrid speciation, in which the genome remains diploid (homoploid hybrid speciation), is harder to define. The fraction from each parent will rarely be 50% if backcrossing is involved. Homoploid hybrid species may be only weakly reproductively isolated, and are hard to distinguish from species that gain alleles by hybridization and introgression, or from persistent ancestral polymorphisms. Although hybrid speciation is sometimes inferred if any marker alleles originate from different parents, I here restrict the term to cases where hybrid allelic combinations contribute to the spread and maintenance of stabilized hybrid lineages generally recognized as species.

This raises the question of what exactly we mean by 'species'. Hybrid speciation is only possible if reproductive isolation is weak; if hybrids are intermediate, hybrid species will be even more weakly isolated. In practice, we must recognize species as multi-locus 'genotypic clusters' (Box 1)6, 13. A hybrid species will then be a third cluster of genotypes, a hybrid form that has become stabilized and remains distinct when in contact with either parent......

That hybrid species exist at all reveals something perhaps unexpected about adaptive landscapes. If hybrid 'hopeful monsters', with all their problems, are ever to survive in competition with their parents, they must be able to hit (and for polyploid species, hit almost exactly) new adaptive combinations of genes (Fig. 1). This implies both that many adaptive peaks are scattered about in the adaptive landscape, and also that many are unoccupied. Liberal adaptive landscapes are further supported by the successes of many introduced species, and by fossil evidence: for insects, angiosperms and many other groups, diversity seems to have been increasing more or less continuously over geological time40.

The ability of hybrid species to invade hitherto unoccupied niches also means that hybridization can contribute to adaptive radiations such as African cichlid fish and Darwin's finches7, 9, 12. This principle is well demonstrated by the 'domestication niche'. Humans have unwittingly created many allopolyploid and other hybrid crops and domestic animals while selecting for transgressively high yields4, 7. Even our own species may have a hybrid genomic ancestry41, 42, although this is contested43. Whichever way the debate about humans is resolved, it would be hardly surprising if hybridization was one trigger for the origin of Homo sapiens, the most invasive mammal on the planet.

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4. Nature 446, 270-273 (15 March 2007) | doi:10.1038/446270a; Published online 14 March 2007

Physical chemistry: The peripatetic proton

James T. Hynes

The way in which protons are transferred between acids and bases has been known in general terms for decades. But the details of the process are complex, and only now is the full proton itinerary becoming clear.

Proton transfer is a headline player in many arenas of chemistry and biology. To name just a few, the process lies at the heart of the chemistry of acids and bases in solution, the workings of enzymes, and transport mechanisms in biological membranes and photosystems1, 2. A broad-brush picture of how protons are transferred between acids and bases in aqueous solution was painted in the 1950s and 1960s, in classic work by Eigen3 and Weller4. Writing in Angewandte Chemie International Edition, Mohammed et al.5 enlarge that picture and add more detail. They build on earlier, related experiments of their own and those of others to show how modern, ultra-rapid techniques can illuminate the myriad, sometimes indirect, molecular pathways between acid and base that a proton can follow.

An acid is a substance that likes to donate protons; a base is a substance that is inclined to accept them. Mohammed et al. used laser excitation to 'trigger' the departure of a proton from the light-sensitive acidic molecule pyranine. This acid can be written ROH, where R is an organic group and OH a hydroxyl group. As a proton is simply a hydrogen atom stripped of its electron, its progress can be tracked by identifying, through spectroscopy, where the 'H' appears in the chemical products of the subsequent reactions.

Using ultra-fast infrared vibrational spectroscopy as a structural probe, the authors could in their experiments reconstruct the dynamics of the proton's entire voyage — from its departure from ROH, leaving behind the base RO-, to its ultimate destination, a negatively charged base molecule, denoted B-. This base molecule is actually a trichloroacetate anion, -OOCCCl3, to which the proton attaches itself to produce a carboxylic acid, or BH in our notation. Different concentrations of the base, from 1 to 3 mol l-1, helped the authors to unravel the exact proton-transfer dynamics.

The authors' first significant finding5 is that infrared bands characteristic of absorption by RO- are observed on a timescale of less than 150 femtoseconds (1 femtosecond is 10-15 s) after the initial laser excitation. These are not, however, immediately accompanied by the appearance of any absorption band corresponding to BH. Indeed, at a B- concentration of 2 mol l-1, protonation to form BH is incomplete even after 700 picoseconds — more than 1,000 times longer than it takes for ROH to be deprotonated.

So where is the proton in the meantime? Making intermediate stops at water molecules, say Mohammed and colleagues. They observe a signal indicating the presence of hydronium ions, H3O+, on the same short timescale as the RO- absorption band. They argue that this signal arises almost exclusively when a single water molecule, H2O, intervenes in a loose complex of ROH and B-. This intervention allows it to gain a proton from ROH, thus generating a 'loose' hydrogen-bonded complex, RO-...H3O+...B-.

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5. PNAS | January 9, 2007 | vol. 104 | no. 2 | 399-400

Neuroscience: The impact of structural biology on neurobiology

Ronald E. Viola

Department of Chemistry, University of Toledo, Toledo, OH 43606

Canavan disease is a fatal neurodegenerative disorder whose symptoms, including loss of motor skills and muscle control, appear in early infancy and typically progress very rapidly, with death usually occurring within the first decade of life. Unlike the case with many neurological disorders where the underlying genetic defects remain to be elucidated, Canavan disease is caused by defects in a single gene, the acy2 gene that encodes for the enzyme aspartoacylase. Recent biochemical studies have begun to characterize the mechanistic properties (1) and structural properties (2) of aspartoacylase, but progress in our understanding of this disease has been slowed by the absence of high-resolution structures of this critical metabolic enzyme. This gap has now been filled by the determination of the structures of both the rat and human forms of aspartoacylase reported by Bitto et al. (3) in this issue of PNAS.

The substrate for aspartoacylase, N-acetyl-L-aspartate (NAA) is one of the most abundant amino acids in our brain (4), and the pathway for its production and utilization is quite straightforward (Fig. 1). NAA is produced by an as-yet-uncharacterized acetyltransferase using a CoA-activated acetate group to couple to L-aspartic acid. The NAA synthesized in neuronal cells is transported by a membrane-bound sodium/dicarboxylate symporter (NaC3) that moves three sodium ions across the cell membrane for each NAA transported (5) and is coexpressed in cell types that also express aspartoacylase (6). In the brain, these aspartoacylase-containing cells called oligodendrocytes (7) are responsible for the synthesis of myelin (8), and the increase in aspartoacylase activity parallels the occurrence of myelination in the central nervous system (9)

DNA taken from infants with Canavan disease has identified numerous mutations that result in a loss of aspartoacylase activity (10); however, there have been no systematic studies of how and why these alterations affect catalytic activity and little detailed characterization of aspartoacylase itself. The absence of a properly functioning enzyme in these patients leads to abnormally high levels of the substrate NAA (11), but there have been no definitive studies that show whether the symptoms of the disease are caused by the accumulation and subsequent misprocessing of NAA or whether the failure to form the products L-aspartate and acetate leads to these symptoms. Because acetate is the precursor for fatty acid biosynthesis, it is likely that the loss of aspartoacylase activity is the cause for the decreased myelin lipid production. Analysis of lipid levels in a mouse knockout model confirms a correlation between diminished aspartoacylase activity and a decline in lipid synthesis (12). These studies provide a link between the decline in acetate levels in oligodendrocytes (Fig. 1) and the demyelination that is observed in the brains of Canavan disease patients. However, there have been a number of other reasonable hypotheses advanced to explain the symptoms of Canavan disease, each of which must still be critically evaluated.

The value of this new structure of human brain aspartoacylase is the framework that it provides for researchers in this field to test hypotheses regarding the catalytic mechanism and the possible modes of regulation of this enzyme. These authors have, for the first time, been able to map the known clinical mutants of aspartoacylase onto a three-dimensional structure and correlate these point mutations with proposed functional roles for many of these amino acids (3). This new structure shows the proximity of the zinc binding site to the likely substrate binding site, thereby confirming the previously proposed carboxypeptidase-type mechanism of aspartoacylase (2). This study also demonstrates a critical difference in active site accessibility that allows this enzyme to hydrolyze its physiological substrate NAA with high specificity but is altered compared with other members of the carboxypeptidase family through the addition of a carboxy-terminal domain, thereby preventing access by peptide-like substrates.

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6. PNAS | December 19, 2006 | vol. 103 | no. 51 | 19219-19220

Neuroscience: Small worlds inside big brains

Olaf Sporns and Christopher J. Honey

Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405

Neuroscientists face the challenge of explaining how functional brain states emerge from the interactions of dozens, perhaps hundreds, of brain regions, each containing millions of neurons. Much evidence supports the view that highly evolved nervous systems are capable of rapid, real-time integration of information across segregated sensory channels and brain regions. This integration happens without the need for a central controller or executive: It is the functional outcome of dynamic interactions within and between the complex structural networks of the brain. In this issue of PNAS, the study by Bassett et al. (1) reveals the existence of large-scale functional networks in magnetoencephalographic (MEG) recordings with attributes that are preserved across multiple frequency bands and that flexibly adapt to task demands. These networks exhibit "small-world" structure, i.e., high levels of clustering and short path lengths. The authors' analysis reveals that the small-world topology of brain functional networks is largely preserved across multiple frequency bands and behavioral tasks.

The structure of networks has been analyzed extensively in the social sciences (2) and in physics and information technology (3). In the life sciences, network approaches already have provided quantitative insights into cellular metabolism and transcriptional regulation (4). In neuroscience, researchers have examined the structure of axonal networks connecting individual neurons (5, 6) and whole-brain networks of interregional pathways (7–9). Across these systems and disciplines, network analysis is founded on the graph-theoretic characterization of a network in terms of nodes and connections (vertices and edges). A landmark study by Watts and Strogatz (10) revealed that a disparate set of natural and artificial networks shared small-world attributes. The canonical small-world network is one in which the majority of edges are recruited to form small, densely connected clusters, whereas the remainder are involved in maintaining connections between these clusters. The conjunction of local clustering and global interaction provides a structural substrate for the coexistence of functional segregation and integration in the brain (11), a hallmark of brain network complexity (12).

Bassett et al. (1) provide strong new evidence for the existence in the human brain of functional networks exhibiting small-world attributes. Their approach is based on a novel application of wavelet analysis to MEG recordings obtained from human subjects who were either at rest or engaged in a finger-tapping task. Patterns of functional connectivity across a large number of recording sites were obtained for each of six distinct temporal scales ranging over all classical EEG frequency bands, from low {delta} (1.1–2.2 Hz) to {gamma} (37.5–75 Hz). These correlations between signals in wavelet space express a statistical association between recording sites, a signature of dynamical interactions between brain regions. The authors then transform the continuous symmetric matrix of wavelet correlations obtained for each frequency band to a binary symmetric matrix by applying a threshold. The symmetric binary matrix is interpreted as an undirected graph and is analyzed by using network-analytic tools that measure clustering, path length, centrality, and synchronizability. Bassett et al. (1) find that the global topology of the functional networks at different frequency bands is both highly clustered and highly integrated, forming a small world, in accordance with several earlier reports of small-world brain functional networks obtained from neurophysiological and neuroimaging data sets (13–15).

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7. PNAS | November 14, 2006 | vol. 103 | no. 46 | 17071-17072

Evolution: Germ cells carry the epigenetic benefits of grandmother's diet

Craig A. Cooney

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205

Environmental influences on epigenetics are important for understanding the mechanisms and inheritance of biological variation. Some of the best models for mammalian epigenetics are the yellow alleles of agouti in mice. Alleles such as Avy produce readily distinguished agouti, yellow, and mottled coat-color epigenetic phenotypes. Dietary and genetic variations during development affect the epigenetic phenotypes of offspring (1, 2). Little is known regarding the gestational timing of dietary treatments to affect epigenetics. Although the epigenetic phenotype is partially maternally, and grandmaternally, inherited (1, 3, 4), transgenerational effects of grandmaternal diets have not been reported. In this issue of PNAS, Cropley et al. (5) report the effects of specific timing of maternal dietary methyl supplementation on the coat color of offspring. Surprisingly, they find that maternal supplementation only during midgestation substantially affects offspring coat color. Importantly, they also find that this effect is inherited by the next generation, presumably through germ-line modifications during grandmaternal supplementation.

Mice carrying the Avy or Aiapy agouti allele, combined with a null allele (called a), produce a spectrum of epigenetic variation. This spectrum includes coat color, which varies from entirely yellow mice, through an array of mottled varieties, to fully agouti mice (1, 6). Yellow and mottled mice are obese and are prone to diabetes and cancer, in contrast to fully agouti mice, known as pseudoagoutis, which are lean and nondiabetic (7, 8). There is a high correlation between DNA methylation of the Avy or Aiapy alleles and the proportion of agouti in the coats of these mice (2, 4, 6, 9, 10). This spectrum of epigenetic variation is shifted toward agouti (and away from yellow) by maternal dietary methyl supplementation (1, 9, 10).

In gestation, much of the genomewide demethylation of DNA occurs between fertilization and preimplantation (day 4.5). This stage is followed by a wave of methylation after implantation (11). Recent data suggest that Avy may follow similar timing of demethylation and methylation (12). However, Avy silencing is passed from dam to offspring in a substantial minority of the population (1, 3, 4), indicating that DNA methylation, histone modification(s) (13), or other epigenetic mechanism(s) maintain some Avy silencing throughout gestation.

DNA methylation is established and maintained by DNA methyltransferases (Dnmts). Studies of the oocyte and somatic forms of Dnmt1 suggest that most times of gestation (early and mid-to-late gestation) may be important for Aiapy silencing (2). These previous Avy and Aiapy studies do not address other silencing mechanisms such as histone methylation, which also may be affected by maternal diet.

Because the full mechanism of silencing is not established and because diet studies often supplement throughout pregnancy, the timing of supplementation needed for Avy silencing is undefined. Cropley et al. (5) supplemented pregnant dams between embryonic day 8.5 (E8.5) and E15.5 and compared this with supplementation from 2 weeks before pregnancy until birth. Gestation is normally 21 days in mice. Cropley et al. (5) mated a/a dams with Avy/a sires (P1) and scored offspring (F1) phenotypes (Fig. 1). They found that the proportion of agouti coat was higher in offspring (F1) from supplemented dams than from control diet dams. Their results show that maternal (P1) diet affects Avy silencing in developing fetuses after E8.5 and that supplementation during early embryogenesis is not necessary.

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