Nature

Making the paperYuichiro Ueno

2006-03-22

Gas bubbles in rocks offer evidence for life on Earth 3.5 billion years ago.

Abstractions

2006-03-22

First authorGlacial ice can shed light on the climate and atmospheric composition found on early Earth. But until recently, only one glacial period — up to 420,000 years ago — was covered by sufficient data. That is now changing thanks to a new core,

QuantifiedNature top ten

2006-03-22

A numerical perspective on Nature authors.Like many online service providers, Nature keeps a watchful eye on the web traffic at its site. Every month, the articles that have been downloaded most often as PDF files are listed in the Nature Top

Steering the future of computing

2006-03-22

Computational power is surging thanks to insatiable consumers. Natural scientists should seize opportunities to stimulate computer science, to help everybody cope with huge volumes of data.

A scramble for Africa

2006-03-22

Large dams benefit contractors and corrupt governments more than they aid the African people.

A colourful past

2006-03-22

The production of dyes in the nineteenth century marked a turning point in the appliance of science.

Research highlights

2006-03-22

Evolution: Under the spotlightScience311, 1617–1621 (2006)The molecular components of the lizard's third, or parietal, eye — a light-sensitive spot thought to sense changing light conditions — reveals something about how light detection evolved in the two familiar vertebrate eyes.Working with

London's disastrous drug trial has serious side effects for research

Meredith Wadman — 2006-03-22

Observers call for rules to be tightened.

Graphic detailAre adverts revealing nuclear secrets?

Geoff Brumfiel — 2006-03-22

Indian newspaper clippings request special parts.

Sidelines

2006-03-22

On the record“I'm sorry if I'm making people a little frightened, but I feel it's my role.“Virologist Robert Webster warns that bird flu could kill half the world's population.“On shuttle missions we often see mosquitoes...They seem very confused and die very quickly.”

Trauma trials leave ethicists uneasy

Rex Dalton — 2006-03-22

Issue of ‘no consent’ raises fundamental questions.

Chemists shrug off unseemly spotlight

Emma Marris — 2006-03-22

Efforts to selectively break carbon-hydrogen bonds continue apace.

Tide of censure for African dams

Jim Giles — 2006-03-22

A wave of Chinese-built dams in Africa, particularly the Merowe project in Sudan, could have devastating consequences for local communities. Jim Giles reports.

Microwave data refine picture of Universe

Jenny Hogan — 2006-03-22

Deeper analysis of probe data released.

News in brief

2006-03-22

Board of Canadian journal sides with sacked editorsThe editorial board of the Canadian Medical Association Journal jumped ship last week. Of its 19 members, 15 resigned, saying they do not trust the leadership of the Canadian Medical Association (CMA).The journal's top two editors

2020 computingChamping at the bits

Philip Ball — 2006-03-22

Despite some remaining hurdles, the mind-bending and frankly weird world of quantum computers is surprisingly close. Philip Ball finds out how these unusual machines will earn their keep.

2020 computingMilestones in scientific computing

Jacqueline Ruttimann — 2006-03-22

View an interactive version of the timelineView an interactive version of the timelinePRE 1960s: PROTOTYPES1946 ENIAC, widely thought of as the first electronic digital computer, is formally unveiled. Designed to compute ballistics during the Second World War, it performs calculations in a

2020 computingEverything, everywhere

Declan Butler — 2006-03-22

Tiny computers that constantly monitor ecosystems, buildings and even human bodies could turn science on its head. Declan Butler investigates.

Drive for drugs leads to baby clinical trials

2006-03-22

US regulators are moving sharply to ease the early stages of drug development, despite safety concerns. Meredith Wadman reports.

In brief

2006-03-22

Unlucky dipShares in Human Genome Sciences, the Maryland biotechnology company founded by William Haseltine, tumbled after it announced mixed results from trials of its most promising drug candidate, the hepatitis C treatment Albuferon. The company said that the drug's performance exceeded that of the

Market watch

Colin Macilwain — 2006-03-22

January 2006 featured an unexpected endorsement of clean energy by the president of the United States.But although shares in clean-energy companies reached their highest level since 2001 around the time of George W. Bush's State of the Union address, they then fell back somewhat.

Scientists must be able to report without censorship

Barbara A. Mikulski — 2006-03-22

SirGovernment scientists must be able to research and report their findings to the public without fear of censorship or intimidation. We need honest results from our science agencies that we can count on. And taxpayers have the right to know the facts.But in

Scientists should be heard, but not expect to set policy

William R. Dickinson — 2006-03-22

SirYour Editorial “Science under attack” (Nature439, 891; 200610.1038/439891a) and News story “US scientists fight political meddling” (Nature439, 896–897; 200610.1038/439896a), on friction between scientists and the Bush administration, impart a curious

Fraud: anonymous ‘stars’ would not dazzle reviewers

Henning Bauch — 2006-03-22

SirIn the current discussion about fraud (see Correspondence, Nature439, 782–784; 200610.1038/439782b), the important issue of what actually makes people cheat in the first place has not been addressed. Whether an individual cheats and lies is dependent on

Research skewed by stress on highest-impact journals

Mark Maslin — 2006-03-22

SirEmilio Artacho, in Correspondence (“Reader-appeal should not outweigh merit of research” Nature439, 534; 200610.1038/439534d), raises an important point concerning the growing tension between merit and appeal of research, and alludes to the increasing pressure on young scientists to publish

2020 ComputingExceeding human limits

Stephen H. Muggleton — 2006-03-22

Scientists are turning to automated processes and technologies in a bid to cope with ever higher volumes of data. But automation offers so much more to the future of science than just data handling, says Stephen H. Muggleton.

2020 ComputingThe creativity machine

Vernor Vinge — 2006-03-22

What will emerge from using the Internet as a research tool? The answer, Vernor Vinge argues, will be limited only by our imaginations.

2020 ComputingScience in an exponential world

Alexander Szalay — 2006-03-22

The amount of scientific data is doubling every year. Alexander Szalay and Jim Gray analyse how scientific methods are evolving from paper notebooks to huge online databases.

2020 ComputingCan computers help to explain biology?

Roger Brent — 2006-03-22

The road leading from computer formalisms to explaining biological function will be difficult, but Roger Brent and Jehoshua Bruck suggest three hopeful paths that could take us closer to this goal.

2020 ComputingA two-way street to science's future

Ian Foster — 2006-03-22

To view the relationship between computing and science as a one-way street is mostly untrue today, argues Ian Foster, and will be even less true by 2020.

When computers take over

Paul Davies — 2006-03-22

What if the current exponential increase in information-processing power could continue unabated?

A taste of a rotten past

W. F. Bynum — 2006-03-22

Among the formidable list of modern anxieties, those related to food safety loom large. Mad cow disease, genetically modified crops, factory farming, residual pesticides, additives — we read about them daily and are reminded of them when we shop by labels assuring us that we

Boning up on dinosaurs

Luis M. Chiappe — 2006-03-22

Studies of the microstructure of dinosaur bone began soon after the first scientific reports of these Mesozoic behemoths, but it took nearly 150 years for this discipline to enter the mainstream of dinosaur palaeontology. Nowadays, these studies are used to infer numerous aspects of dinosaur

Summing up physics

Malcolm Longair — 2006-03-22

Perhaps the most common comment I receive after delivering a public lecture is: “I enjoyed the lecture, but I couldn't understand the maths.” This difficulty doesn't just affect the public but is one that students and scientists encounter throughout their careers: how does one connect

Science in culture: Porcelain perception

Colin Martin — 2006-03-22

Not everything is as it seems in the ceramics of Pauline Wiertz.

Molecular biologyRNA lost in translation

David Tollervey — 2006-03-22

In any manufacturing process, quality control is crucial, and gene expression is no exception. A new pathway monitors mRNAs — the intermediaries of gene expression — and destroys faulty molecules.

BiochemistryGas with an ancient history

Don E. Canfield — 2006-03-22

Researchers persist in tackling our ignorance of what life was like way back in Earth's history. Evidence of methane production in ancient microbial ecosystems now emerges from 3.5-billion-year-old rocks.

Membrane biologyPermutations of permeability

William N. Zagotta — 2006-03-22

The first glimpse into the molecular basis of how sodium ions are transported across cell membranes by ion channels shows that cation-selective channels are variations on potassium channels.

ChemistryPerkin, the mauve maker

Philip Ball — 2006-03-22

One hundred and fifty years ago this week, a teenager experimenting in his makeshift home laboratory made a discovery that in effect launched the modern chemicals industry. William Perkin was an 18-year-old student of August Wilhelm Hofmann at the Royal College of Chemistry in London,

EarthquakesA movement in four parts?

Joanne Bourgeois — 2006-03-22

From time to time, over millennia, northwestern North America has experienced huge earthquakes. These events may be preceded by tell-tale subsidence, but the evidence is devilishly difficult to decipher.

Solid-state physicsLight at the end of the channel

Francisco J. Garcia-Vidal — 2006-03-22

If photonic circuits are ever to compete with their electronic counterparts, strong confinement of light waves coupled with low propagation losses is needed. A new class of waveguides offers both.

Mathematical physicsGoing to ground

Christos N. Likos — 2006-03-22

How can one find the minimum total energy of an infinite number of particles? A proof showing that, for certain interactions, periodic ‘ground states’ exist provides a new perspective on this, one of the oldest questions in physics.

Cell divisionRunning rings around the spindle

Deepa Nath — 2006-03-22

When cells divide, each chromosome is duplicated and one copy is passed to each daughter cell. The details of how these duplicated chromosomes are separated are still being puzzled out, but elsewhere in this issue, Georjana Barnes and colleagues (Nature440, 565–

Avian fluInfluenza virus receptors in the human airway

Kyoko Shinya — 2006-03-22

Avian and human flu viruses seem to target different regions of a patient's respiratory tract.Although more than 100 people have been infected by H5N1 influenza A viruses, human-to-human transmission is rare. What are the molecular barriers limiting human-to-human transmission? Here we demonstrate an anatomical difference in the distribution in the human airway of the different binding molecules preferred by the avian and human influenza viruses. The respective molecules are sialic acid linked to galactose by an α-2,3 linkage (SAα2,3Gal) and by an α-2,6 linkage (SAα2,6Gal). Our findings may provide a rational explanation for why H5N1 viruses at present rarely infect and spread between humans although they can replicate efficiently in the lungs.

EcologyHuman role in Russian wild fires

Danilo Mollicone — 2006-03-22

Anomalies in temperature and precipitation in northern Russia over the past few years have been viewed as manifestations of anthropogenic climate change, prompting suggestions that this may also account for exceptional forest fires in the region. Here we examine the number of forest-fire events across the boreal Russian Federation for the period 2002 to 2005 in ‘intact’ forests, where human influence is limited, and in ‘non-intact’ forests, which have been shaped by human activity. Our results show that there were more fires in years during which the weather was anomalous, but that more than 87% of fires in boreal Russia were started by people.

Retraction

2006-03-22

Cell biology: Non-thermal heat-shock response to microwavesD. de Pomerai, C. Daniells, H. David, J. Allan, I. Duce, M. Mutwakil, D. Thomas, P. Sewell, J. Tattersall, D. Jones, P. CandidoNature405, 417–418 (2000)10.1038/35013144Our claim that weak

Ion channels

Lesley Anson — 2006-03-22

What are ion channels? And why are so many people excited about them at the moment? In a nutshell, ion channels are fundamental to cellular existence. They are present in the membranes of almost all living cells — from simple bacteria to highly specialized neurons

From molecule to malady

Frances M. Ashcroft — 2006-03-22

Ion channels are membrane proteins, found in virtually all cells, that are of crucial physiological importance. In the past decade, an explosion in the number of crystal structures of ion channels has led to a marked increase in our understanding of how ion channels open

Recent advances in Cys-loop receptor structure and function

Steven M. Sine — 2006-03-22

Throughout the nervous system, moment-to-moment communication relies on postsynaptic receptors to detect neurotransmitters and change the membrane potential. For the Cys-loop superfamily of receptors, recent structural data have catalysed a leap in our understanding of the three steps of chemical-to-electrical transduction: neurotransmitter binding, communication between

Glutamate receptors at atomic resolution

Mark L. Mayer — 2006-03-22

At synapses throughout the brain and spinal cord, the amino-acid glutamate is the major excitatory neurotransmitter. During evolution, a family of glutamate-receptor ion channels seems to have been assembled from a kit consisting of discrete ligand-binding, ion-channel, modulatory and cytoplasmic domains. Crystallographic studies that exploit

hERG potassium channels and cardiac arrhythmia

Michael C. Sanguinetti — 2006-03-22

hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly

KATP channels as molecular sensors of cellular metabolism

Colin G. Nichols — 2006-03-22

In responding to cytoplasmic nucleotide levels, ATP-sensitive potassium (KATP) channel activity provides a unique link between cellular energetics and electrical excitability. Over the past ten years, a steady drumbeat of crystallographic and electrophysiological studies has led to detailed structural and kinetic models that

The ABC protein turned chloride channel whose failure causes cystic fibrosis

David C. Gadsby — 2006-03-22

CFTR chloride channels are encoded by the gene mutated in patients with cystic fibrosis. These channels belong to the superfamily of ABC transporter ATPases. ATP-driven conformational changes, which in other ABC proteins fuel uphill substrate transport across cellular membranes, in CFTR open and close a

ClC chloride channels viewed through a transporter lens

Christopher Miller — 2006-03-22

Since its discovery, the ClC family of chloride channels has presented biophysicists with unexpected behaviours and unusual surprises. The latest of these is the realization that not only does the family feature genuine chloride channels, it also includes proton-coupled chloride transporters, which move chloride ions

Southern Ocean sea-ice extent, productivity and iron flux over the past eight glacial cycles

E. W. Wolff

Sea ice and dust flux increased greatly in the Southern Ocean during the last glacial period. Palaeorecords provide contradictory evidence about marine productivity in this region, but beyond one glacial cycle, data were sparse. Here we present continuous chemical proxy data spanning the last eight

Human chromosome 11 DNA sequence and analysis including novel gene identification

Todd D. Taylor

Chromosome 11, although average in size, is one of the most gene- and disease-rich chromosomes in the human genome. Initial gene annotation indicates an average gene density of 11.6 genes per megabase, including 1,524 protein-coding genes, some of which were identified using novel methods, and

Significant primordial star formation at redshifts z ≈ 3–4

Raul Jimenez

Four recent observational results have challenged our understanding of high-redshift galaxies, as they require the presence of far more ultraviolet photons than should be emitted by normal stellar populations. First, there is significant ultraviolet emission from Lyman break galaxies (LBGs) at wavelengths shorter than 912 Å. Second, there is strong Lyman α emission from extended ‘blobs’ with little or no associated apparent ionizing continuum. Third, there is a population of galaxies with unusually strong Lyman α emission lines. And fourth, there is a strong He ii (1,640 Å) emission line in a composite of LBGs. The proposed explanations for the first three observations are internally inconsistent, and the fourth puzzle has remained hitherto unexplained. Here we show that all four problems are resolved simultaneously if 10–30 per cent of the stars in many galaxies at z ≈ 3–4 are mainly primordial—unenriched by elements heavier than helium (‘metals’). Most models of hierarchical galaxy formation assume efficient intragalactic metal mixing, and therefore do not predict metal-free star formation at redshifts significantly below z ≈ 5. Our results imply that micromixing of metals within galaxies is inefficient on an approximately gigayear timescale, a conclusion that can be verified with higher-resolution simulations, and future observations of the He ii emission line.

A non-spherical core in the explosion of supernova SN 2004dj

Douglas C. Leonard

An important and perhaps critical clue to the mechanism driving the explosion of massive stars as supernovae is provided by the accumulating evidence for asymmetry in the explosion. Indirect evidence comes from high pulsar velocities, associations of supernovae with long-soft γ-ray bursts, and asymmetries in late-time emission-line profiles. Spectropolarimetry provides a direct probe of young supernova geometry, with higher polarization generally indicating a greater departure from spherical symmetry. Large polarizations have been measured for ‘stripped-envelope’ (that is, type Ic; ref. 7) supernovae, which confirms their non-spherical morphology; but the explosions of massive stars with intact hydrogen envelopes (type II-P supernovae) have shown only weak polarizations at the early times observed. Here we report multi-epoch spectropolarimetry of a classic type II-P supernova that reveals the abrupt appearance of significant polarization when the inner core is first exposed in the thinning ejecta (∼90 days after explosion). We infer a departure from spherical symmetry of at least 30 per cent for the inner ejecta. Combined with earlier results, this suggests that a strongly non-spherical explosion may be a generic feature of core-collapse supernovae of all types, where the asphericity in type II-P supernovae is cloaked at early times by the massive, opaque, hydrogen envelope.

Channel plasmon subwavelength waveguide components including interferometers and ring resonators

Sergey I. Bozhevolnyi

Photonic components are superior to electronic ones in terms of operational bandwidth, but the diffraction limit of light poses a significant challenge to the miniaturization and high-density integration of optical circuits. The main approach to circumvent this problem is to exploit the hybrid nature of surface plasmon polaritons (SPPs), which are light waves coupled to free electron oscillations in a metal that can be laterally confined below the diffraction limit using subwavelength metal structures. However, the simultaneous realization of strong confinement and a propagation loss sufficiently low for practical applications has long been out of reach. Channel SPP modes—channel plasmon polaritons (CPPs)—are electromagnetic waves that are bound to and propagate along the bottom of V-shaped grooves milled in a metal film. They are expected to exhibit useful subwavelength confinement, relatively low propagation loss, single-mode operation and efficient transmission around sharp bends. Our previous experiments showed that CPPs do exist and that they propagate over tens of micrometres along straight subwavelength grooves. Here we report the design, fabrication and characterization of CPP-based subwavelength waveguide components operating at telecom wavelengths: Y-splitters, Mach–Zehnder interferometers and waveguide–ring resonators. We demonstrate that CPP guides can indeed be used for large-angle bending and splitting of radiation, thereby enabling the realization of ultracompact plasmonic components and paving the way for a new class of integrated optical circuits.

Mechanical twisting of a guest by a photoresponsive host

Takahiro Muraoka

Molecular analogues of a variety of mechanical devices such as shuttles, brakes, unidirectional rotors and tweezers have been created. But these ‘molecular machines’ have not yet been used to mechanically manipulate a second molecule in a controlled and reversible manner. Here we show that light-induced scissor-like conformational changes of one molecule can give rise to mechanical twisting of a non-covalently bound guest molecule. To realize this coupling of molecular motions, we use a previously designed system: a ferrocene moiety with an azobenzene strap, each end of which is attached to one of the two cyclopentadienyl rings of the ferrocene unit, acts as a pivot so that photoisomerization of the strap rotates the ferrocene rings relative to each other and thereby also changes the relative position of two ‘pedal’ moieties attached to the ferrocene rings. We translate this effect into intermolecular coupling of motion by endowing the pedals with binding sites, which allow the host system to form a stable complex with a bidentate rotor molecule. Using circular dichroism spectroscopy, we show that the photoinduced conformational changes of the host are indeed transmitted and induce mechanical twisting of the rotor molecule. This design concept, which significantly extends the successful coupling of motion beyond the intramolecular level seen in synthetic allosteric receptors, might allow for the remote control of molecular events in larger interlocked molecular systems.

Evidence from fluid inclusions for microbial methanogenesis in the early Archaean era

Yuichiro Ueno

Methanogenic microbes may be one of the most primitive organisms, although it is uncertain when methanogens first appeared on Earth. During the Archaean era (before 2.5 Gyr ago), methanogens may have been important in regulating climate, because they could have provided sufficient amounts of the greenhouse gas methane to mitigate a severely frozen condition that could have resulted from lower solar luminosity during these times. Nevertheless, no direct geological evidence has hitherto been available in support of the existence of methanogens in the Archaean period, although circumstantial evidence is available in the form of ∼2.8-Gyr-old carbon-isotope-depleted kerogen. Here we report crushing extraction and carbon isotope analysis of methane-bearing fluid inclusions in ∼3.5-Gyr-old hydrothermal precipitates from Pilbara craton, Australia. Our results indicate that the extracted fluids contain microbial methane with carbon isotopic compositions of less than -56‰ included within original precipitates. This provides the oldest evidence of methanogen (> 3.46 Gyr ago), pre-dating previous geochemical evidence by about 700 million years.

Modelling conservation in the Amazon basin

Britaldo Silveira Soares-Filho

Expansion of the cattle and soy industries in the Amazon basin has increased deforestation rates and will soon push all-weather highways into the region's core. In the face of this growing pressure, a comprehensive conservation strategy for the Amazon basin should protect its watersheds, the full range of species and ecosystem diversity, and the stability of regional climates. Here we report that protected areas in the Amazon basin—the central feature of prevailing conservation approaches—are an important but insufficient component of this strategy, based on policy-sensitive simulations of future deforestation. By 2050, current trends in agricultural expansion will eliminate a total of 40% of Amazon forests, including at least two-thirds of the forest cover of six major watersheds and 12 ecoregions, releasing 32 ± 8 Pg of carbon to the atmosphere. One-quarter of the 382 mammalian species examined will lose more than 40% of the forest within their Amazon ranges. Although an expanded and enforced network of protected areas could avoid as much as one-third of this projected forest loss, conservation on private lands is also essential. Expanding market pressures for sound land management and prevention of forest clearing on lands unsuitable for agriculture are critical ingredients of a strategy for comprehensive conservation.

The nature of plant species

Loren H. Rieseberg

Many botanists doubt the existence of plant species, viewing them as arbitrary constructs of the human mind, as opposed to discrete, objective entities that represent reproductively independent lineages or ‘units of evolution’. However, the discreteness of plant species and their correspondence with reproductive communities have not been tested quantitatively, allowing zoologists to argue that botanists have been overly influenced by a few ‘botanical horror stories’, such as dandelions, blackberries and oaks. Here we analyse phenetic and/or crossing relationships in over 400 genera of plants and animals. We show that although discrete phenotypic clusters exist in most genera (> 80%), the correspondence of taxonomic species to these clusters is poor (< 60%) and no different between plants and animals. Lack of congruence is caused by polyploidy, asexual reproduction and over-differentiation by taxonomists, but not by contemporary hybridization. Nonetheless, crossability data indicate that 70% of taxonomic species and 75% of phenotypic clusters in plants correspond to reproductively independent lineages (as measured by postmating isolation), and thus represent biologically real entities. Contrary to conventional wisdom, plant species are more likely than animal species to represent reproductively independent lineages.

The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production

Lucia Pastorino

Neuropathological hallmarks of Alzheimer's disease are neurofibrillary tangles composed of tau and neuritic plaques comprising amyloid-β peptides (Aβ) derived from amyloid precursor protein (APP), but their exact relationship remains elusive. Phosphorylation of tau and APP on certain serine or threonine residues preceding proline affects tangle formation and Aβ production in vitro. Phosphorylated Ser/Thr-Pro motifs in peptides can exist in cis or trans conformations, the conversion of which is catalysed by the Pin1 prolyl isomerase. Pin1 has been proposed to regulate protein function by accelerating conformational changes, but such activity has never been visualized and the biological and pathological significance of Pin1 substrate conformations is unknown. Notably, Pin1 is downregulated and/or inhibited by oxidation in Alzheimer's disease neurons, Pin1 knockout causes tauopathy and neurodegeneration, and Pin1 promoter polymorphisms appear to associate with reduced Pin1 levels and increased risk for late-onset Alzheimer's disease. However, the role of Pin1 in APP processing and Aβ production is unknown. Here we show that Pin1 has profound effects on APP processing and Aβ production. We find that Pin1 binds to the phosphorylated Thr 668-Pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between two conformations, as visualized by NMR. Whereas Pin1 overexpression reduces Aβ secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble Aβ42 (a major toxic species) in brains in an age-dependent manner, with Aβ42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology. Thus, Pin1-catalysed prolyl isomerization is a novel mechanism to regulate APP processing and Aβ production, and its deregulation may link both tangle and plaque pathologies. These findings provide new insight into the pathogenesis and treatment of Alzheimer's disease.

A P-type ATPase required for rice blast disease and induction of host resistance

Martin J. Gilbert

To cause diseases in plants, pathogenic microorganisms have evolved mechanisms to deliver proteins directly into plant cells, where they suppress plant defences and facilitate tissue invasion. How plant pathogenic fungi, which cause many of the world's most serious plant diseases, deliver proteins during plant infection is currently unknown. Here we report the characterization of a P-type ATPase-encoding gene, MgAPT2, in the economically important rice blast pathogen Magnaporthe grisea, which is required for exocytosis during plant infection. Targeted gene replacement showed that MgAPT2 is required for both foliar and root infection by the fungus, and for the rapid induction of host defence responses in an incompatible reaction. ΔMgapt2 mutants are impaired in the secretion of a range of extracellular enzymes and accumulate abnormal Golgi-like cisternae. However, the loss of MgAPT2 does not significantly affect hyphal growth or sporulation, indicating that the establishment of rice blast disease involves the use of MgApt2-dependent exocytotic processes that operate during plant infection.

CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs

Lawrence R. Shiow — 2006-03-08

Naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. During immune responses, the egress process can be shut down transiently. When this occurs locally it increases lymphocyte numbers in the responding lymphoid organ; when it occurs systemically it can lead to immunosuppression as a result of the depletion of recirculating lymphocytes. Several mediators of the innate immune system are known to cause shutdown, including interferon α/β (IFN-α/β) and tumour necrosis factor, but the mechanism has been unclear. Here we show that treatment with the IFN-α/β inducer polyinosine polycytidylic acid (hereafter ‘poly(I:C)’) inhibited egress by a mechanism that was partly lymphocyte-intrinsic. The transmembrane C-type lectin CD69 was rapidly induced and CD69-/- cells were poorly retained in lymphoid tissues after treatment with poly(I:C) or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P1), and IFN-α/β was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69-/- cells retained S1P1 function after exposure to IFN-α/β. In coexpression experiments, CD69 inhibited S1P1 chemotactic function and led to downmodulation of S1P1. In a reporter assay, S1P1 crosslinking led to co-crosslinking and activation of a CD69–CD3ζ chimaera. CD69 co-immunoprecipitated with S1P1 but not the related receptor, S1P3. These observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-α/β, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.

An excitable gene regulatory circuit induces transient cellular differentiation

Gürol M. Süel

Certain types of cellular differentiation are probabilistic and transient. In such systems individual cells can switch to an alternative state and, after some time, switch back again. In Bacillus subtilis, competence is an example of such a transiently differentiated state associated with the capability for DNA uptake from the environment. Individual genes and proteins underlying differentiation into the competent state have been identified, but it has been unclear how these genes interact dynamically in individual cells to control both spontaneous entry into competence and return to vegetative growth. Here we show that this behaviour can be understood in terms of excitability in the underlying genetic circuit. Using quantitative fluorescence time-lapse microscopy, we directly observed the activities of multiple circuit components simultaneously in individual cells, and analysed the resulting data in terms of a mathematical model. We find that an excitable core module containing positive and negative feedback loops can explain both entry into, and exit from, the competent state. We further tested this model by analysing initiation in sister cells, and by re-engineering the gene circuit to specifically block exit. Excitable dynamics driven by noise naturally generate stochastic and transient responses, thereby providing an ideal mechanism for competence regulation.

CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70

Shu-Bing Qian

Exposure of cells to various stresses often leads to the induction of a group of proteins called heat shock proteins (HSPs, molecular chaperones). Hsp70 is one of the most highly inducible molecular chaperones, but its expression must be maintained at low levels under physiological conditions to permit constitutive cellular activities to proceed. Heat shock transcription factor 1 (HSF1) is the transcriptional regulator of HSP gene expression, but it remains poorly understood how newly synthesized HSPs return to basal levels when HSF1 activity is attenuated. CHIP (carboxy terminus of Hsp70-binding protein), a dual-function co-chaperone/ubiquitin ligase, targets a broad range of chaperone substrates for proteasomal degradation. Here we show that CHIP not only enhances Hsp70 induction during acute stress but also mediates its turnover during the stress recovery process. Central to this dual-phase regulation is its substrate dependence: CHIP preferentially ubiquitinates chaperone-bound substrates, whereas degradation of Hsp70 by CHIP-dependent targeting to the ubiquitin–proteasome system occurs when misfolded substrates have been depleted. The sequential catalysis of the CHIP-associated chaperone adaptor and its bound substrate provides an elegant mechanism for maintaining homeostasis by tuning chaperone levels appropriately to reflect the status of protein folding within the cytoplasm.

RNA-mediated response to heat shock in mammalian cells

Ilya Shamovsky

The heat-shock transcription factor 1 (HSF1) has an important role in the heat-shock response in vertebrates by inducing the expression of heat-shock proteins (HSPs) and other cytoprotective proteins. HSF1 is present in unstressed cells in an inactive monomeric form and becomes activated by heat and other stress stimuli. HSF1 activation involves trimerization and acquisition of a site-specific DNA-binding activity, which is negatively regulated by interaction with certain HSPs. Here we show that HSF1 activation by heat shock is an active process that is mediated by a ribonucleoprotein complex containing translation elongation factor eEF1A and a previously unknown non-coding RNA that we term HSR1 (heat shock RNA-1). HSR1 is constitutively expressed in human and rodent cells and its homologues are functionally interchangeable. Both HSR1 and eEF1A are required for HSF1 activation in vitro; antisense oligonucleotides or short interfering (si)RNA against HSR1 impair the heat-shock response in vivo, rendering cells thermosensitive. The central role of HSR1 during heat shock implies that targeting this RNA could serve as a new therapeutic model for cancer, inflammation and other conditions associated with HSF1 deregulation.

Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation

Meenakshi K. Doma

A fundamental aspect of the biogenesis and function of eukaryotic messenger RNA is the quality control systems that recognize and degrade non-functional mRNAs. Eukaryotic mRNAs where translation termination occurs too soon (nonsense-mediated decay) or fails to occur (non-stop decay) are rapidly degraded. We show that yeast mRNAs with stalls in translation elongation are recognized and targeted for endonucleolytic cleavage, referred to as ‘no-go decay’. The cleavage triggered by no-go decay is dependent on translation and involves Dom34p and Hbs1p. Dom34p and Hbs1p are similar to the translation termination factors eRF1 and eRF3 (refs 3, 4), indicating that these proteins might function in recognizing the stalled ribosome and triggering endonucleolytic cleavage. No-go decay provides a mechanism for clearing the cell of stalled translation elongation complexes, which could occur as a result of damaged mRNAs or ribosomes, or as a mechanism of post-transcriptional control.

The Dam1 kinetochore ring complex moves processively on depolymerizing microtubule ends

Stefan Westermann — 2006-01-15

Chromosomes interact through their kinetochores with microtubule plus ends and they are segregated to the spindle poles as the kinetochore microtubules shorten during anaphase A of mitosis. The molecular natures and identities of coupling proteins that allow microtubule depolymerization to pull chromosomes to poles during anaphase have long remained elusive. In budding yeast, the ten-protein Dam1 complex is a critical microtubule-binding component of the kinetochore that oligomerizes into a 50-nm ring around a microtubule in vitro. Here we show, with the use of a real-time, two-colour fluorescence microscopy assay, that the ring complex moves processively for several micrometres at the ends of depolymerizing microtubules without detaching from the lattice. Electron microscopic analysis of ‘end-on views’ revealed a 16-fold symmetry of the kinetochore rings. This out-of-register arrangement with respect to the 13-fold microtubule symmetry is consistent with a sliding mechanism based on an electrostatically coupled ring–microtubule interface. The Dam1 ring complex is a molecular device that can translate the force generated by microtubule depolymerization into movement along the lattice to facilitate chromosome segregation.

Atomic structure of a Na+- and K+-conducting channel

Ning Shi — 2006-02-08

Ion selectivity is one of the basic properties that define an ion channel. Most tetrameric cation channels, which include the K+, Ca2+, Na+ and cyclic nucleotide-gated channels, probably share a similar overall architecture in their ion-conduction pore, but the structural details that determine ion selection are different. Although K+ channel selectivity has been well studied from a structural perspective, little is known about the structure of other cation channels. Here we present crystal structures of the NaK channel from Bacillus cereus, a non-selective tetrameric cation channel, in its Na+- and K+-bound states at 2.4 Å and 2.8 Å resolution, respectively. The NaK channel shares high sequence homology and a similar overall structure with the bacterial KcsA K+ channel, but its selectivity filter adopts a different architecture. Unlike a K+ channel selectivity filter, which contains four equivalent K+-binding sites, the selectivity filter of the NaK channel preserves the two cation-binding sites equivalent to sites 3 and 4 of a K+ channel, whereas the region corresponding to sites 1 and 2 of a K+ channel becomes a vestibule in which ions can diffuse but not bind specifically. Functional analysis using an 86Rb flux assay shows that the NaK channel can conduct both Na+ and K+ ions. We conclude that the sequence of the NaK selectivity filter resembles that of a cyclic nucleotide-gated channel and its structure may represent that of a cyclic nucleotide-gated channel pore.

The candidate

Jack McDevitt — 2006-03-22

Washington 2.0