Hot off the presses! May 14 Nature

The May 14 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Politics proves its worth
  - Nature 459(7244):139 (2009)
  The European Parliament has reaffirmed its legislative value by reversing the potentially disruptive restrictions in the draft directive for protecting laboratory animals.
• Bracing for the unknown
  - Nature 459(7244):139-140 (2009)
  Last year's earthquake in China is a salutary reminder about preparing for risk in the face of uncertainty.
• A measure of marine life
  - Nature 459(7244):140 (2009)
  The extraordinary emerging images of ocean microbiology need the fourth dimension of time.
• Migration: The long bask
  - Nature 459(7244):142 (2009)
  
• Ecology: Bouillabaisse
  - Nature 459(7244):142 (2009)
  
• Astronomy: Strange star
  - Nature 459(7244):142 (2009)
  
• Quantum physics: Atomic painting
  - Nature 459(7244):142 (2009)
  
• Geosciences: The forever landscape
  - Nature 459(7244):142 (2009)
  
• Imaging: Seeing beyond skin deep
  - Nature 459(7244):142-143 (2009)
  
• Materials: Everlasting memory
  - Nature 459(7244):143 (2009)
  
• Polymer chemistry: Doughnut machine
  - Nature 459(7244):143 (2009)
  
• Microbiology: On the surface
  - Nature 459(7244):143 (2009)
  
• Conservation: Amphibian additions
  - Nature 459(7244):143 (2009)
  
• Journal club
  - Nature 459(7244):143 (2009)
  
• Vaccine decisions loom for new flu strain
  - Nature 459(7244):144 (2009)
  
• Stem-cell therapy faces more scrutiny in China
  - Nature 459(7244):146-147 (2009)
  
• Exome sequencing takes centre stage in cancer profiling
  - Nature 459(7244):146 (2009)
  
• Deep concerns
  - Nature 459(7244):148-149 (2009)
  
• Austria quits CERN after 50 years
  - Nature 459(7244):151 (2009)
  
• Social scientists join synthetic-biology centre
  - Nature 459(7244):152 (2009)
  
• South Africa's cabinet a mixed bag for science
  - Nature 459(7244):152 (2009)
  
• University fined after safety-failure lab death
  - Nature 459(7244):152 (2009)
  
• Human space-flight review in US budget proposals
  - Nature 459(7244):152 (2009)
  
• Japan to pay firms to relieve postdoc glut
  - Nature 459(7244):152 (2009)
  
• Quiet Sun enters new sunspot cycle
  - Nature 459(7244):152 (2009)
  
• Seismology: The sleeping dragon
  - Nature 459(7244):153-157 (2009)
  
• Microbiology: Tinker, bacteria, eukaryote, spy
  - Nature 459(7244):159-161 (2009)
  
• Leading the tributes to editor John Maddox
  - Nature 459(7244):163 (2009)
  In April 1974, some months after I had taken over from John Maddox as editor of Nature, I was driving home from the printers with a colleague at four in the morning, having just put the latest issue to bed. News came in over the radio of a coup in Portugal.
• Water: conflicts set to arise within as well as between states
  - Nature 459(7244):163 (2009)
  In her Essay 'Do nations go to war over water?' (Nature 458, 282–283; 2009
• Water: resistance on the route towards a fair share for all
  - Nature 459(7244):163 (2009)
  Wendy Barnaby's Essay 'Do nations go to war over water?' (Nature 458, 282–283; 2009
• Is free will an illusion?
  - Nature 459(7244):164-165 (2009)
  Scientists and philosophers are using new discoveries in neuroscience to question the idea of free will. They are misguided, says Martin Heisenberg. Examining animal behaviour shows how our actions can be free.
• The otherness of the oceans
  - Nature 459(7244):166-167 (2009)
  As scientists discover more about the genomes of marine microorganisms, new views of their physiology and ecosystem networks are opening up, explain Alexandra Z. Worden and Darcy McRose.
• Ecology lost and found
  - Nature 459(7244):167-168 (2009)
  
• The dangers of denying HIV
  - Nature 459(7244):168 (2009)
  
• Q&A: Origami unfolded
  - Nature 459(7244):169 (2009)
  In her documentary Between the Folds, film director Vanessa Gould explores the expression of mathematics through origami. She tells Nature how she became captivated by the art and science of transforming sheets of paper into three-dimensional geometric shapes — and exposed a hidden subculture.
• Art tied up
  - Nature 459(7244):169 (2009)
  
• Origins of life: Systems chemistry on early Earth
  - Nature 459(7244):171-172 (2009)
  Understanding how life emerged on Earth is one of the greatest challenges facing modern chemistry. A new way of looking at the synthesis of RNA sidesteps a thorny problem in the field.
• Molecular microbiology: A key event in survival
  - Nature 459(7244):172-173 (2009)
  The parasitic microorganism Trypanosoma brucei evades recognition by its host's immune system by repeatedly changing its surface coat. The switch in coat follows a risky route, though: DNA break and repair.
• Astrophysics: Cosmic crystals caught in the act
  - Nature 459(7244):173-176 (2009)
  The outburst of a Sun-like star offers a rare opportunity to witness the making of silicate crystals in the star's planet-forming disk, providing key information about the formation of comets and the Solar System.
• Microbiology: Signals for change
  - Nature 459(7244):175 (2009)
  The strategy that the protozoan parasite Trypanosoma brucei — which causes fatal disease in humans and cattle — uses to evade its host's immune defences is the subject of a News & Views article on page 172. Elsewhere in this issue, Dean et al.
• Archaeology: Origins of the female image
  - Nature 459(7244):176-177 (2009)
  Discovery of the sexually explicit figurine of a woman, dating to 35,000 years ago, provides striking evidence of the symbolic explosion that occurred in the earliest populations of Homo sapiens in Europe.
• 50 & 100 years ago
  - Nature 459(7244):177 (2009)
  A recent issue of the Australian Museum Magazine is devoted almost entirely to New Guinea ... The physical geography is described by D. F.
• Microbial oceanography
  - Nature 459(7244):180-184 (2009)
  Plankton use solar energy to drive the nutrient cycles that make the planet habitable for larger organisms. We can now explore the diversity and functions of plankton using genomics, revealing the gene repertoires associated with survival in the oceans. Such studies will help us to appreciate the sensitivity of ocean systems and of the ocean's response to climate change, improving the predictive power of climate models.
• Microbial oceanography in a sea of opportunity
  - Nature 459(7244):180-184 (2009)
  Plankton use solar energy to drive the nutrient cycles that make the planet habitable for larger organisms. We can now explore the diversity and functions of plankton using genomics, revealing the gene repertoires associated with survival in the oceans. Such studies will help us to appreciate the sensitivity of ocean systems and of the ocean's response to climate change, improving the predictive power of climate models.
• The life of diatoms in the world's oceans
  - Nature 459(7244):185-192 (2009)
  Marine diatoms rose to prominence about 100 million years ago and today generate most of the organic matter that serves as food for life in the sea. They exist in a dilute world where compounds essential for growth are recycled and shared, and they greatly influence global climate, atmospheric carbon dioxide concentration and marine ecosystem function. How these essential organisms will respond to the rapidly changing conditions in today's oceans is critical for the health of the environment and is being uncovered by studies of their genomes.
• Microbial community structure and its functional implications
  - Nature 459(7244):193-199 (2009)
  Marine microbial communities are engines of globally important processes, such as the marine carbon, nitrogen and sulphur cycles. Recent data on the structures of these communities show that they adhere to universal biological rules. Co-occurrence patterns can help define species identities, and systems-biology tools are revealing networks of interacting microorganisms. Some microbial systems are found to change predictably, helping us to anticipate how microbial communities and their activities will shift in a changing world.
• The microbial ocean from genomes to biomes
  - Nature 459(7244):200-206 (2009)
  Numerically, microbial species dominate the oceans, yet their population dynamics, metabolic complexity and synergistic interactions remain largely uncharted. A full understanding of life in the ocean requires more than knowledge of marine microbial taxa and their genome sequences. The latest experimental techniques and analytical approaches can provide a fresh perspective on the biological interactions within marine ecosystems, aiding in the construction of predictive models that can interrelate microbial dynamics with the biogeochemical matter and energy fluxes that make up the ocean ecosystem.
• Viruses manipulate the marine environment
  - Nature 459(7244):207-212 (2009)
  Marine viruses affect Bacteria, Archaea and eukaryotic organisms and are major components of the marine food web. Most studies have focused on their role as predators and parasites, but many of the interactions between marine viruses and their hosts are much more complicated. A series of recent studies has shown that viruses have the ability to manipulate the life histories and evolution of their hosts in remarkable ways, challenging our understanding of this almost invisible world.
• A surface transporter family conveys the trypanosome differentiation signal
  - Nature 459(7244):213-217 (2009)
  Microbial pathogens use environmental cues to trigger the developmental events needed to infect mammalian hosts or transmit to disease vectors. The parasites causing African sleeping sickness respond to citrate or cis-aconitate (CCA) to initiate life-cycle development when transmitted to their tsetse fly vector. This requires hypersensitization of the parasites to CCA by exposure to low temperature, conditions encountered after tsetse fly feeding at dusk or dawn. Here we identify a carboxylate-transporter family, PAD (proteins associated with differentiation), required for perception of this differentiation signal. Consistent with predictions for the response of trypanosomes to CCA, PAD proteins are expressed on the surface of the transmission-competent 'stumpy-form' parasites in the bloodstream, and at least one member is thermoregulated, showing elevated expression and surface access at low temperature. Moreover, RNA-interference-mediated ablation of PAD expression d! iminishes CCA-induced differentiation and eliminates CCA hypersensitivity under cold-shock conditions. As well as being molecular transducers of the differentiation signal in these parasites, PAD proteins provide the first example of a surface marker able to discriminate the transmission stage of trypanosomes in their mammalian host.
• Select Drosophila glomeruli mediate innate olfactory attraction and aversion
  - Nature 459(7244):218-223 (2009)
  Fruitflies show robust attraction to food odours, which usually excite several glomeruli. To understand how the representation of such odours leads to behaviour, we used genetic tools to dissect the contribution of each activated glomerulus. Apple cider vinegar triggers robust innate attraction at a relatively low concentration, which activates six glomeruli. By silencing individual glomeruli, here we show that the absence of activity in two glomeruli, DM1 and VA2, markedly reduces attraction. Conversely, when each of these two glomeruli was selectively activated, flies showed as robust an attraction to vinegar as wild-type flies. Notably, a higher concentration of vinegar excites an additional glomerulus and is less attractive to flies. We show that activation of the extra glomerulus is necessary and sufficient to mediate the behavioural switch. Together, these results indicate that individual glomeruli, rather than the entire pattern of active glomeruli, mediate inna! te behavioural output.
• Episodic formation of cometary material in the outburst of a young Sun-like star
  - Nature 459(7244):224-226 (2009)
  The Solar System originated in a cloud of interstellar gas and dust. The dust is in the form of amorphous silicate particles1, 2 and carbonaceous dust. The composition of cometary material, however, shows that a significant fraction of the amorphous silicate dust was transformed into crystalline form during the early evolution of the protosolar nebula3. How and when this transformation happened has been a question of debate, with the main options being heating by the young Sun4, 5 and shock heating6. Here we report mid-infrared features in the outburst spectrum of the young Sun-like star EX Lupi that were not present in quiescence. We attribute them to crystalline forsterite. We conclude that the crystals were produced through thermal annealing in the surface layer of the inner disk by heat from the outburst, a process that has hitherto not been considered. The observed lack of cold crystals excludes shock heating at larger radii.
• Radiation-pressure mixing of large dust grains in protoplanetary disks
  - Nature 459(7244):227-229 (2009)
  Dusty disks around young stars are formed out of interstellar dust that consists of amorphous, submicrometre grains. Yet the grains found in comets1 and meteorites2, and traced in the spectra of young stars3, include large crystalline grains that must have undergone annealing or condensation at temperatures in excess of 1,000 K, even though they are mixed with surrounding material that never experienced temperatures as high as that4. This prompted theories of large-scale mixing capable of transporting thermally altered grains from the inner, hot part of accretion disks to outer, colder disk regions5, 6, 7, but all have assumptions that may be problematic8, 9, 10, 11, 12. Here I report that infrared radiation arising from the dusty disk can loft grains bigger than one micrometre out of the inner disk, whereupon they are pushed outwards by stellar radiation pressure while gliding above the disk. Grains re-enter the disk at radii where it is too cold to produce sufficient! infrared radiation-pressure support for a given grain size and solid density. Properties of the observed disks suggest that this process might be active in almost all young stellar objects and young brown dwarfs.
• Thermal vestige of the zero-temperature jamming transition
  - Nature 459(7244):230-233 (2009)
  When the packing fraction is increased sufficiently, loose particulates jam to form a rigid solid in which the constituents are no longer free to move. In typical granular materials and foams, the thermal energy is too small to produce structural rearrangements. In this zero-temperature (T = 0) limit, multiple diverging1, 2, 3, 4, 5, 6, 7, 8 and vanishing2, 9, 10 length scales characterize the approach to a sharp jamming transition. However, because thermal motion becomes relevant when the particles are small enough, it is imperative to understand how these length scales evolve as the temperature is increased. Here we used both colloidal experiments and computer simulations to progress beyond the zero-temperature limit to track one of the key parameters—the overlap distance between neighbouring particles—which vanishes at the T = 0 jamming transition. We find that this structural feature retains a vestige of its T = 0 behaviour and evolves in an unusual manner, whi! ch has masked its appearance until now. It is evident as a function of packing fraction at fixed temperature, but not as a function of temperature at fixed packing fraction or pressure. Our results conclusively demonstrate that length scales associated with the T = 0 jamming transition persist in thermal systems, not only in simulations but also in laboratory experiments.
• White organic light-emitting diodes with fluorescent tube efficiency
  - Nature 459(7244):234-238 (2009)
  The development of white organic light-emitting diodes1 (OLEDs) holds great promise for the production of highly efficient large-area light sources. High internal quantum efficiencies for the conversion of electrical energy to light have been realized2, 3, 4. Nevertheless, the overall device power efficiencies are still considerably below the 60–70 lumens per watt of fluorescent tubes, which is the current benchmark for novel light sources. Although some reports about highly power-efficient white OLEDs exist5, 6, details about structure and the measurement conditions of these structures have not been fully disclosed: the highest power efficiency reported in the scientific literature is 44 lm W-1 (ref. 7). Here we report an improved OLED structure which reaches fluorescent tube efficiency. By combining a carefully chosen emitter layer with high-refractive-index substrates8, 9, and using a periodic outcoupling structure, we achieve a device power efficiency of 90 lm W-! 1 at 1,000 candelas per square metre. This efficiency has the potential to be raised to 124 lm W-1 if the light outcoupling can be further improved. Besides approaching internal quantum efficiency values of one, we have also focused on reducing energetic and ohmic losses that occur during electron–photon conversion. We anticipate that our results will be a starting point for further research, leading to white OLEDs having efficiencies beyond 100 lm W-1. This could make white-light OLEDs, with their soft area light and high colour-rendering qualities, the light sources of choice for the future.
• Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions
  - Nature 459(7244):239-242 (2009)
  At some stage in the origin of life, an informational polymer must have arisen by purely chemical means. According to one version of the 'RNA world' hypothesis1, 2, 3 this polymer was RNA, but attempts to provide experimental support for this have failed4, 5. In particular, although there has been some success demonstrating that 'activated' ribonucleotides can polymerize to form RNA6, 7, it is far from obvious how such ribonucleotides could have formed from their constituent parts (ribose and nucleobases). Ribose is difficult to form selectively8, 9, and the addition of nucleobases to ribose is inefficient in the case of purines10 and does not occur at all in the case of the canonical pyrimidines11. Here we show that activated pyrimidine ribonucleotides can be formed in a short sequence that bypasses free ribose and the nucleobases, and instead proceeds through arabinose amino-oxazoline and anhydronucleoside intermediates. The starting materials for the synthesis—cya! namide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphate—are plausible prebiotic feedstock molecules12, 13, 14, 15, and the conditions of the synthesis are consistent with potential early-Earth geochemical models. Although inorganic phosphate is only incorporated into the nucleotides at a late stage of the sequence, its presence from the start is essential as it controls three reactions in the earlier stages by acting as a general acid/base catalyst, a nucleophilic catalyst, a pH buffer and a chemical buffer. For prebiotic reaction sequences, our results highlight the importance of working with mixed chemical systems in which reactants for a particular reaction step can also control other steps.
• Interior pathways of the North Atlantic meridional overturning circulation
  - Nature 459(7244):243-247 (2009)
  To understand how our global climate will change in response to natural and anthropogenic forcing, it is essential to determine how quickly and by what pathways climate change signals are transported throughout the global ocean, a vast reservoir for heat and carbon dioxide. Labrador Sea Water (LSW), formed by open ocean convection in the subpolar North Atlantic, is a particularly sensitive indicator of climate change on interannual to decadal timescales1, 2, 3. Hydrographic observations made anywhere along the western boundary of the North Atlantic reveal a core of LSW at intermediate depths advected southward within the Deep Western Boundary Current (DWBC)4, 5, 6, 7, 8, 9. These observations have led to the widely held view that the DWBC is the dominant pathway for the export of LSW from its formation site in the northern North Atlantic towards the Equator10, 11. Here we show that most of the recently ventilated LSW entering the subtropics follows interior, not DWBC, ! pathways. The interior pathways are revealed by trajectories of subsurface RAFOS floats released during the period 2003–2005 that recorded once-daily temperature, pressure and acoustically determined position for two years, and by model-simulated 'e-floats' released in the subpolar DWBC. The evidence points to a few specific locations around the Grand Banks where LSW is most often injected into the interior. These results have implications for deep ocean ventilation and suggest that the interior subtropical gyre should not be ignored when considering the Atlantic meridional overturning circulation.
• A female figurine from the basal Aurignacian of Hohle Fels Cave in southwestern Germany
  - Nature 459(7244):248-252 (2009)
  Despite well over 100 years of research and debate, the origins of art remain contentious1, 2, 3. In recent years, abstract depictions have been documented at southern African sites dating to approx75 kyr before present (bp)4, 5, and the earliest figurative art, which is often seen as an important proxy for advanced symbolic communication, has been documented in Europe as dating to between 30 and 40 kyr bp 2. Here I report the discovery of a female mammoth-ivory figurine in the basal Aurignacian deposit at Hohle Fels Cave in the Swabian Jura of southwestern Germany during excavations in 2008. This figurine was produced at least 35,000 calendar years ago, making it one of the oldest known examples of figurative art. This discovery predates the well-known Venuses from the Gravettian culture by at least 5,000 years and radically changes our views of the context and meaning of the earliest Palaeolithic art.
• Snowdrift game dynamics and facultative cheating in yeast
  - Nature 459(7244):253-256 (2009)
  The origin of cooperation is a central challenge to our understanding of evolution1, 2, 3. The fact that microbial interactions can be manipulated in ways that animal interactions cannot has led to a growing interest in microbial models of cooperation4, 5, 6, 7, 8, 9, 10 and competition11, 12. For the budding yeast Saccharomyces cerevisiae to grow on sucrose, the disaccharide must first be hydrolysed by the enzyme invertase13, 14. This hydrolysis reaction is performed outside the cytoplasm in the periplasmic space between the plasma membrane and the cell wall. Here we demonstrate that the vast majority (approx99 per cent) of the monosaccharides created by sucrose hydrolysis diffuse away before they can be imported into the cell, serving to make invertase production and secretion a cooperative behaviour15, 16. A mutant cheater strain that does not produce invertase is able to take advantage of and invade a population of wild-type cooperator cells. However, over a wide r! ange of conditions, the wild-type cooperator can also invade a population of cheater cells. Therefore, we observe steady-state coexistence between the two strains in well-mixed culture resulting from the fact that rare strategies outperform common strategies—the defining features of what game theorists call the snowdrift game17. A model of the cooperative interaction incorporating nonlinear benefits explains the origin of this coexistence. We are able to alter the outcome of the competition by varying either the cost of cooperation or the glucose concentration in the media. Finally, we note that glucose repression of invertase expression in wild-type cells produces a strategy that is optimal for the snowdrift game—wild-type cells cooperate only when competing against cheater cells.
• Two-year-olds with autism orient to non-social contingencies rather than biological motion
  - Nature 459(7244):257-261 (2009)
  Typically developing human infants preferentially attend to biological motion within the first days of life1. This ability is highly conserved across species2, 3 and is believed to be critical for filial attachment and for detection of predators4. The neural underpinnings of biological motion perception are overlapping with brain regions involved in perception of basic social signals such as facial expression and gaze direction5, and preferential attention to biological motion is seen as a precursor to the capacity for attributing intentions to others6. However, in a serendipitous observation7, we recently found that an infant with autism failed to recognize point-light displays of biological motion, but was instead highly sensitive to the presence of a non-social, physical contingency that occurred within the stimuli by chance. This observation raised the possibility that perception of biological motion may be altered in children with autism from a very early age, wit! h cascading consequences for both social development and the lifelong impairments in social interaction that are a hallmark of autism spectrum disorders8. Here we show that two-year-olds with autism fail to orient towards point-light displays of biological motion, and their viewing behaviour when watching these point-light displays can be explained instead as a response to non-social, physical contingencies—physical contingencies that are disregarded by control children. This observation has far-reaching implications for understanding the altered neurodevelopmental trajectory of brain specialization in autism9.
• Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche
  - Nature 459(7244):262-265 (2009)
  The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5+ stem cells at the bottoms of small-intestinal crypts1. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5+ stem cells can also initiate these crypt–villus organoids. Tracing experiments indicate that the Lgr5+ stem-cell hierarchy is maintained in organoids. We conclude that intestinal crypt–villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
• Metatranscriptomics reveals unique microbial small RNAs in the ocean's water column
  - Nature 459(7244):266-269 (2009)
  Microbial gene expression in the environment has recently been assessed via pyrosequencing of total RNA extracted directly from natural microbial assemblages. Several such 'metatranscriptomic' studies1, 2 have reported that many complementary DNA sequences shared no significant homology with known peptide sequences, and so might represent transcripts from uncharacterized proteins. Here we report that a large fraction of cDNA sequences detected in microbial metatranscriptomic data sets are comprised of well-known small RNAs (sRNAs)3, as well as new groups of previously unrecognized putative sRNAs (psRNAs). These psRNAs mapped specifically to intergenic regions of microbial genomes recovered from similar habitats, displayed characteristic conserved secondary structures and were frequently flanked by genes that indicated potential regulatory functions. Depth-dependent variation of psRNAs generally reflected known depth distributions of broad taxonomic groups4, but fine-sc! ale differences in the psRNAs within closely related populations indicated potential roles in niche adaptation. Genome-specific mapping of a subset of psRNAs derived from predominant planktonic species such as Pelagibacter revealed recently discovered as well as potentially new regulatory elements. Our analyses show that metatranscriptomic data sets can reveal new information about the diversity, taxonomic distribution and abundance of sRNAs in naturally occurring microbial communities, and indicate their involvement in environmentally relevant processes including carbon metabolism and nutrient acquisition.
• Discovery of dual function acridones as a new antimalarial chemotype
  - Nature 459(7244):270-273 (2009)
  Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug–haem interaction as in the case of quinolines and many other drugs1, 2, 3, 4, 5. Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial drugs. Beyond the essential intrinsic characteristics common to deserving candidate antimalarials (high potency in vitro against pan-sensitive and multi-drug-resistant Plasmodium falciparum, efficacy and safety in vivo! after oral administration, inexpensive synthesis and favourable physicochemical properties), our initial lead, T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)-acridone), demonstrates unique synergistic properties. In addition to 'verapamil-like' chemosensitization to chloroquine and amodiaquine against quinoline-resistant parasites, T3.5 also results in an apparently mechanistically distinct synergism with quinine and with piperaquine. This synergy, evident in both quinoline-sensitive and quinoline-resistant parasites, has been demonstrated both in vitro and in vivo. In summary, this innovative acridone design merges intrinsic potency and resistance-counteracting functions in one molecule, and represents a new strategy to expand, enhance and sustain effective antimalarial drug combinations.
• qiRNA is a new type of small interfering RNA induced by DNA damage
  - Nature 459(7244):274-277 (2009)
  RNA interference pathways use small RNAs to mediate gene silencing in eukaryotes. In addition to small interfering RNAs (siRNAs) and microRNAs, several types of endogenously produced small RNAs have important roles in gene regulation, germ cell maintenance and transposon silencing1, 2, 3, 4. The production of some of these RNAs requires the synthesis of aberrant RNAs (aRNAs) or pre-siRNAs, which are specifically recognized by RNA-dependent RNA polymerases to make double-stranded RNA. The mechanism for aRNA synthesis and recognition is largely unknown. Here we show that DNA damage induces the expression of the Argonaute protein QDE-2 and a new class of small RNAs in the filamentous fungus Neurospora crassa. This class of small RNAs, known as qiRNAs because of their interaction with QDE-2, are about 20–21 nucleotides long (several nucleotides shorter than Neurospora siRNAs), with a strong preference for uridine at the 5' end, and originate mostly from the ribosomal DNA! locus. The production of qiRNAs requires the RNA-dependent RNA polymerase QDE-1, the Werner and Bloom RecQ DNA helicase homologue QDE-3 and dicers. qiRNA biogenesis also requires DNA-damage-induced aRNAs as precursors, a process that is dependent on both QDE-1 and QDE-3. Notably, our results suggest that QDE-1 is the DNA-dependent RNA polymerase that produces aRNAs. Furthermore, the Neurospora RNA interference mutants show increased sensitivity to DNA damage, suggesting a role for qiRNAs in the DNA-damage response by inhibiting protein translation.
• A yeast-endonuclease-generated DNA break induces antigenic switching in Trypanosoma brucei
  - Nature 459(7244):278-281 (2009)
  Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of the causes of nagana in cattle. This protozoan parasite evades the host immune system by antigenic variation, a periodic switching of its variant surface glycoprotein (VSG) coat. VSG switching is spontaneous and occurs at a rate of about 10-2–10-3 per population doubling in recent isolates from nature, but at a markedly reduced rate (10-5–10-6) in laboratory-adapted strains1, 2, 3. VSG switching is thought to occur predominantly through gene conversion, a form of homologous recombination initiated by a DNA lesion that is used by other pathogens (for example, Candida albicans, Borrelia sp. and Neisseria gonorrhoeae) to generate surface protein diversity, and by B lymphocytes of the vertebrate immune system to generate antibody diversity. Very little is known about the molecular mechanism of VSG switching in T. brucei. Here we demonstrate that the introduction of a DNA double-! stranded break (DSB) adjacent to the approx70-base-pair (bp) repeats upstream of the transcribed VSG gene increases switching in vitro approx250-fold, producing switched clones with a frequency and features similar to those generated early in an infection. We were also able to detect spontaneous DSBs within the 70-bp repeats upstream of the actively transcribed VSG gene, indicating that a DSB is a natural intermediate of VSG gene conversion and that VSG switching is the result of the resolution of this DSB by break-induced replication.
• The chair
  - Nature 459(7244):290 (2009)
  A Friend for life.