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Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public.

Making the paper: Daniel Stark Tracking the swirl of gases in a far-off galaxy's rotation. Abstractions First authorThe Tibetan Plateau, sometimes called the 'roof of the world', is thought to be the largest and highest flat area ever to exist on Earth. We know how it formed ? through a massive collision between the Indian and Asian continental plates ? From the blogosphere What happens if proposed stem-cell-based therapies actually work? Monya Baker, editor of Nature Reports Stem Cells, ponders this question for stem-cell researchers in a post at 'The Niche' blog (http://tinyurl.com/4qrybk).In discussions at several large conferences, as reported on The Niche, scientists are Malaria's watershed Malaria's moment has come, but success in control, let alone eradication, demands a renewed commitment to basic research. The Red List still matters And the IUCN has more to offer than just data on the nearly extinct. Beta blockers? Proprietary data formats may be legally defensible but open standards can be a better spur for innovation. Human biology: Bird's eye view Biol. Psychiatry doi: 10.1016/j.biopsych.2008.06.012 (2008)People with autism have incredibly keen eyesight, seeing almost as acutely as birds of prey.The surprise finding from Emma Ashwin and her colleagues at the University of Cambridge, UK, shows that the unusually keen senses that have Cosmology: Dark limit J. Phys. A41, 412002 (2008) doi:10.1088/1751-8113/41/41/412002Dark matter is a hypothetical class of particles that interact mainly through the force of gravity. How much dark stuff might be lurking around Earth is the subject of some debate, but Stephen Adler at the Institute Biomechanics: Fungal ballistics PLoS ONE3, e3237 (2008) doi:10.1371/journal.pone.0003237Some dung-feeding fungi squirt their spores at speeds of up to 25 metres per second. The spores need to travel several metres for herbivores to eat them ? because most animals won't graze near their droppings ? and Zoology: Boomerang bluefins Science doi:10.1126/science.1161473 (2008) Isotopic analysis of the ear bones of Atlantic bluefin tuna (Thunnus thynnus) has shown, for the first time, that an ocean-roaming fish returns to where it was born before spawning.Jay Rooker of Texas A&M University in Galveston and Physics: Light squeezing Phys. Rev. Lett.101, 123601 (2008) doi:10.1103/PhysRevLett.101.123601Physicists at the Pierre and Marie Curie University in Paris have proposed 'squeezing' light in order to measure the distance between objects in space more precisely.The classic method, called the Einstein protocol, bounces pulses of light Organic chemistry: State benefits Angew. Chem. Int. Edn doi:10.1002/anie.200803648 (2008)A new explosive that is among the most powerful known has the added benefits of being a solid at room temperature but having a low melting point of about 85 °C. This means it should make for a Geosciences: The melting ocean Nature Geosci. doi:10.1038/ngeo316 (2008)After 1997, a glacier that drains 7% of Greenland's ice sheet switched from thickening slowly to thinning quickly, causing the glacier's velocity to double. Several theories have been put forward to explain the change, including increased lubrication of the bedrock Phylogeography: Viking mice Proc. R. Soc. Bdoi:10.1098/rspb.2008.0958; 10.1098/rspb.2008.0959; (2008)Mus musculus, the house mouse, has been colonizing new lands for several thousand years by hitchhiking with the humans whose crumbs it has come to rely on. Jeremy Searle of the University of York, UK, Microbiology: Half life Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0807707105 (2008)The exceedingly abundant phytoplankton, Emiliania huxleyi, has unusual population dynamics. It can evade viral infection in its haploid form, when it has only one copy of each of its chromosomes, but it is susceptible to the Zoology: Dik dik trick Behav. Ecol. doi:10.1093/beheco/arn064 (2008) Of the animals that understand other species' vocalizations, almost all are social creatures with complex calls of their own. But ecologists have identified an eavesdropper that is neither social nor particularly vocal: the dik-dik.Daniel Blumstein and his colleagues at Journal club A plant scientist finds beauty in floral arrangements.On the face of it, flower arranging is a fiddly affair, and its underlying rules are not immediately obvious to the beholder. But a plant's flowers are always arranged in one of three basic architectures, or 'inflorescences'. Science lobbying in Canada needs stepping up SirYour Editorial 'The other North American election' (Nature455, 263; 2008) draws attention to an apparent lack of urgency towards general science issues in the Canadian election campaign. This must surely reflect public opinion and therefore inadequate advocacy efforts by the Playing the system puts self-citation's impact under review SirIn reply to Tomá? Opatrný's Correspondence 'Playing the system to give low-impact journals more clout' (Nature455, 167; 2008), we would like to point out that the practice of journal self-citation is not new. Thomson Reuters is aware that some journals Austria: investigation likely to have serious consequences SirIn the Editorial 'Scandalous behaviour' (Nature454, 917?918; 2008), you unjustifiably implicate the whole Austrian nation in your comments about a scientific institution. In fact, the dismissal of the rector of the Medical University of Innsbruck had nothing to do with As someone wise or funny and probably famous once said ... SirThere comes a time when quotations should be laid to rest. Adam Rutherford, in his Book Review 'The future ain't what it used to be' (Nature454, 1051; 2008), cites baseball legend 'Yogi' Berra as declaring that it's tough to make A network solution With the right plan, systems biology can empower drug discovery, say Adriano Henney and Giulio Superti-Furga. Field leaders have contributed and now the authors want to hear from you. The many faces of carbon An enticing new book ties together the vital roles this element has in life, the Universe and climate change, explains John Meurig Thomas. Burning down the house Eschatology, the study of how and when the world will end, has always grabbed attention, but perhaps never more so than now. Disaster movies play out our fear of our own extinction following a massive comet impact or cataclysmic volcanic super-eruption. The market for books Crisis reading Books on natural cataclysm, often climate-induced, are in vogue. Two books, Bruce Johansen's The Global Warming Combat Manual (Praeger, 2008) and Bill McGuire's Seven Years to Save the Planet (Weidenfeld & Nicolson, 2008), seek to make readers more environmentally aware. McGuire explains how Painting by night Van Gogh and the Colors of the Night, an exquisite exhibition now on show at the Museum of Modern Art in New York, explores this artist's fascination with portraying the night. Unlike earlier artists who painted night scenes by day from memory, Vincent van Science at the movies When scientists appear on the big screen, if at all, they tend to be going mad or else paying for their hubris ? think Dr. Strangelove, Jurassic Park and A Beautiful Mind. This month, two new film festivals ? the Imagine Science Neutrinos: wonderful or crass? John Updike's 1960 poem vents frustration at the detached and elusive quantum particles that have no consideration for our earthly perceptions, says Martin Kemp. Hidden treasures: Turin's anatomy museum Some controversial nineteenth-century theories about brain shape and human nature are revealed by an extensive collection of neuroscience memorabilia, reports Alison Abbott Meetings that changed the world: Madrid 1995: Diagnosing climate change John Houghton chaired the tense IPCC meeting without which there would be no Kyoto Protocol. Here he recalls how science won the day. Gerontology: Healthy old age Do longer lives mean that growing numbers of us will spend more time in a state of high-cost dependency? Evidence from one elderly cohort suggests that excessive levels of disability are far from inevitable. Molecular biology: DNA endgames If it is not repaired efficiently, damage to DNA double strands can have dire consequences for both the cell and the organism. Given the gravity of this situation, cells use two pathways to start the process. Solid-state physics: Recipe for spin currents Generating currents that rely on the spins of electrons to make electronic devices requiring less power is both desirable and daunting. A neat way of creating such currents eases that task. Neuroscience: Brain's defence against cocaine Long-term exposure to cocaine changes the organization of synaptic connections within the addiction circuitry of the brain. This process might protect against the development and persistence of addiction. Materials science: Solar cells go round the bend With high oil prices sparking a surge of interest in alternative energy sources, solar cells have become the subject of intense research. Much of this effort focuses on finding new designs that open up fresh applications. John Rogers and colleagues now report just such a Immunology: Helpful T cells are sticky Prolonged physical interaction between helper T cells and antibody-producing B cells is crucial for efficient immune responses. Mutations in a protein that underlies this process cause human disease. 50 & 100 years ago 50 years agoSo far as men of science are concerned, the Lambeth Conference report follows much the same pattern as its immediate predecessor. The bulk of the report is concerned with topics which are not the immediate concern of scientists, as such, though they Developmental biology: Teeth in double trouble Almost all vertebrates have teeth of some sort. But where, in developmental terms, do teeth come from? Results drawn from experimental embryology provide an illuminating perspective on this contentious question. Geomorphology: How Tibet might keep its edge The stability of the margins of the Himalayan?Tibetan mountain belt constitutes a puzzle. Repeated damming of major Tibetan rivers by glaciers, so controlling river erosion, is a possible explanation. Malaria research in the post-genomic era For many pathogens the availability of genome sequence, permitting genome-dependent methods of research, can partially substitute for powerful forward genetic methods (genome-independent) that have advanced model organism research for decades. In 2002 the genome sequence of Plasmodium falciparum, the parasite causing the most severe type of human malaria, was completed, eliminating many of the barriers to performing state-of-the-art molecular biological research on malaria parasites. Although new, licensed therapies may not yet have resulted from genome-dependent experiments, they have produced a wealth of new observations about the basic biology of malaria parasites, and it is likely that these will eventually lead to new therapeutic approaches. This review will focus on the basic research discoveries that have depended, in part, on the availability of the Plasmodium genome sequences. Comparative genomics of the neglected human malaria parasite Plasmodium vivax The human malaria parasite Plasmodium vivax is responsible for 25?40% of the ?515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance SAP-controlled T?B cell interactions underlie germinal centre formation Generation of long-term antibody-mediated immunity depends on the germinal centre reaction, which requires cooperation between antigen-specific T and B lymphocytes. In human X-linked lymphoproliferative disease and its gene-targeted mouse model, loss-of-function mutations in signalling lymphocyte activation molecule-associated protein (SAP, encoded by SH2D1a) cause a Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing DNA ends exposed after introduction of double-strand breaks (DSBs) undergo 5??3? nucleolytic degradation to generate single-stranded DNA, the substrate for binding by the Rad51 protein to initiate homologous recombination. This process is poorly understood in eukaryotes, but several factors have been implicated, including the Mre11 The formation and assembly of a typical star-forming galaxy at redshift z???3 Recent studies of galaxies ?2?3?Gyr after the Big Bang have revealed large, rotating disks, similar to those of galaxies today. The existence of well-ordered rotation in galaxies during this peak epoch of cosmic star formation indicates that gas accretion is likely to be the dominant mode by which galaxies grow, because major mergers of galaxies would completely disrupt the observed velocity fields. But poor spatial resolution and sensitivity have hampered this interpretation; such studies have been limited to the largest and most luminous galaxies, which may have fundamentally different modes of assembly from those of more typical galaxies (which are thought to grow into the spheroidal components at the centres of galaxies similar to the Milky Way). Here we report observations of a typical star-forming galaxy at z = 3.07, with a linear resolution of ?100?parsecs. We find a well-ordered compact source in which molecular gas is being converted efficiently into stars, likely to be assembling a spheroidal bulge similar to those seen in spiral galaxies at the present day. The presence of undisrupted rotation may indicate that galaxies such as the Milky Way gain much of their mass by accretion rather than major mergers. Observation of the spin Seebeck effect The generation of electric voltage by placing a conductor in a temperature gradient is called the Seebeck effect. Its efficiency is represented by the Seebeck coefficient, S, which is defined as the ratio of the generated electric voltage to the temperature difference, and is determined by the scattering rate and the density of the conduction electrons. The effect can be exploited, for example, in thermal electric-power generators and for temperature sensing, by connecting two conductors with different Seebeck coefficients, a device called a thermocouple. Here we report the observation of the thermal generation of driving power, or voltage, for electron spin: the spin Seebeck effect. Using a recently developed spin-detection technique that involves the spin Hall effect, we measure the spin voltage generated from a temperature gradient in a metallic magnet. This thermally induced spin voltage persists even at distances far from the sample ends, and spins can be extracted from every position on the magnet simply by attaching a metal. The spin Seebeck effect observed here is directly applicable to the production of spin-voltage generators, which are crucial for driving spintronic devices. The spin Seebeck effect allows us to pass a pure spin current, a flow of electron spins without electric currents, over a long distance. These innovative capabilities will invigorate spintronics research. High-temperature interface superconductivity between metallic and insulating copper oxides The realization of high-transition-temperature (high-Tc) superconductivity confined to nanometre-sized interfaces has been a long-standing goal because of potential applications and the opportunity to study quantum phenomena in reduced dimensions. This has been, however, a challenging target: in conventional metals, the high electron density restricts interface effects (such as carrier depletion or accumulation) to a region much narrower than the coherence length, which is the scale necessary for superconductivity to occur. By contrast, in copper oxides the carrier density is low whereas Tc is high and the coherence length very short, which provides an opportunity?but at a price: the interface must be atomically perfect. Here we report superconductivity in bilayers consisting of an insulator (La2CuO4) and a metal (La1.55Sr0.45CuO4), neither of which is superconducting in isolation. In these bilayers, Tc is either ?15?K or ?30?K, depending on the layering sequence. This highly robust phenomenon is confined within 2?3?nm of the interface. If such a bilayer is exposed to ozone, Tc exceeds 50?K, and this enhanced superconductivity is also shown to originate from an interface layer about 1?2 unit cells thick. Enhancement of Tc in bilayer systems was observed previously but the essential role of the interface was not recognized at the time. Tibetan plateau river incision inhibited by glacial stabilization of the Tsangpo gorge A considerable amount of research has focused on how and when the Tibetan plateau formed in the wake of tectonic convergence between India and Asia. Although far less enquiry has addressed the controls on river incision into the plateau itself, widely accepted theory predicts that steep fluvial knick points (river reaches with very steep gradients) in the eastern Himalayan syntaxis at the southeastern plateau margin should erode rapidly, driving a wave of incision back into the plateau. Preservation of the plateau edge thus presents something of a conundrum that may be resolved by invoking either differential rock uplift matching erosional decay, or other mechanisms for retarding bedrock river incision in this region where high stream power excludes the potential for aridity as a simple limit to dissection of the plateau. Here we report morphologic evidence showing that Quaternary depression of the regional equilibrium line altitude, where long-term glacier mass gain equals mass loss, was sufficient to repeatedly form moraine dams on major rivers: such damming substantially impeded river incision into the southeastern edge of the Tibetan plateau through the coupled effects of upstream impoundment and interglacial aggradation. Such glacial stabilization of the resulting highly focused river incision centred on the Tsangpo gorge could further contribute to initiating and accentuating a locus of rapid exhumation, known as tectonic anaeurysm. Central role of detachment faults in accretion of slow-spreading oceanic lithosphere The formation of oceanic detachment faults is well established from inactive, corrugated fault planes exposed on sea floor formed along ridges spreading at less than 80?km?Myr?1 (refs 1?4). These faults can accommodate extension for up to 1?3?Myr (ref. 5), and are associated with one of the two contrasting modes of accretion operating along the northern Mid-Atlantic Ridge. The first mode is asymmetrical accretion involving an active detachment fault along one ridge flank. The second mode is the well-known symmetrical accretion, dominated by magmatic processes with subsidiary high-angle faulting and the formation of abyssal hills on both flanks. Here we present an examination of ?2,500?km of the Mid-Atlantic Ridge between 12.5 and 35°?N, which reveals asymmetrical accretion along almost half of the ridge. Hydrothermal activity identified so far in the study region is closely associated with asymmetrical accretion, which also shows high levels of near-continuous hydroacoustically and teleseismically recorded seismicity. Increased seismicity is probably generated along detachment faults that accommodate a sizeable proportion of the total plate separation. In contrast, symmetrical segments have lower levels of seismicity, which occurs primarily at segment ends. Basalts erupted along asymmetrical segments have compositions that are consistent with crystallization at higher pressures than basalts from symmetrical segments, and with lower extents of partial melting of the mantle. Both seismic evidence and geochemical evidence indicate that the axial lithosphere is thicker and colder at asymmetrical sections of the ridge, either because associated hydrothermal circulation efficiently penetrates to greater depths or because the rising mantle is cooler. We suggest that much of the variability in sea-floor morphology, seismicity and basalt chemistry found along slow-spreading ridges can be thus attributed to the frequent involvement of detachment faults in oceanic lithospheric accretion. Dual epithelial origin of vertebrate oral teeth The oral cavity of vertebrates is generally thought to arise as an ectodermal invagination. Consistent with this, oral teeth are proposed to arise exclusively from ectoderm, contributing to tooth enamel epithelium, and from neural crest derived mesenchyme, contributing to dentin and pulp. Yet in many vertebrate groups, teeth are not restricted only to the oral cavity, but extend posteriorly as pharyngeal teeth that could be derived either directly from the endodermal epithelium, or from the ectodermal epithelium that reached this location through the mouth or through the pharyngeal slits. However, when the oropharyngeal membrane, which forms a sharp ecto/endodermal border, is broken, the fate of these cells is poorly known. Here, using transgenic axolotls with a combination of fate-mapping approaches, we present reliable evidence of oral teeth derived from both the ectoderm and endoderm and, moreover, demonstrate teeth with a mixed ecto/endodermal origin. Despite the enamel epithelia having a different embryonic source, oral teeth in the axolotl display striking developmental uniformities and are otherwise identical. This suggests a dominant role for the neural crest mesenchyme over epithelia in tooth initiation and, from an evolutionary point of view, that an essential factor in teeth evolution was the odontogenic capacity of neural crest cells, regardless of possible ?outside-in? or ?inside-out? influx of the epithelium. The genome of the simian and human malaria parasite Plasmodium knowlesi Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the ?kra? monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or ?hypnozoite? in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIII? (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIII? markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIII?, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes. ATP drives lamina propria TH17 cell differentiation Interleukin (IL)-17-producing CD4+ T lymphocytes (TH17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders. An intriguing feature of TH17 cells is their selective and constitutive presence in the intestinal lamina propria. Here we show that adenosine 5?-triphosphate (ATP) that can be derived from commensal bacteria activates a unique subset of lamina propria cells, CD70highCD11clow cells, leading to the differentiation of TH17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria TH17 cells, compared to specific-pathogen-free mice. Systemic or rectal administration of ATP into these germ-free mice results in a marked increase in the number of lamina propria TH17 cells. A CD70highCD11clow subset of the lamina propria cells expresses TH17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor-?-activating integrin-?V and -?8, in response to ATP stimulation, and preferentially induces TH17 differentiation of co-cultured naive CD4+ T cells. The critical role of ATP is further underscored by the observation that administration of ATP exacerbates a T-cell-mediated colitis model with enhanced TH17 differentiation. These observations highlight the importance of commensal bacteria and ATP for TH17 differentiation in health and disease, and offer an explanation of why TH17 cells specifically present in the intestinal lamina propria. The deubiquitinylation and localization of PTEN are regulated by a HAUSP?PML network Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear?cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML?RAR? fusion oncoprotein. Remarkably, treatment with drugs that trigger PML?RAR? degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML?DAXX?HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization. Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism DNA methylation of CpG dinucleotides is an important epigenetic modification of mammalian genomes and is essential for the regulation of chromatin structure, of gene expression and of genome stability. Differences in DNA methylation patterns underlie a wide range of biological processes, such as genomic imprinting, inactivation of the X chromosome, embryogenesis, and carcinogenesis. Inheritance of the epigenetic methylation pattern is mediated by the enzyme DNA methyltransferase 1 (Dnmt1), which methylates newly synthesized CpG sequences during DNA replication, depending on the methylation status of the template strands. The protein UHRF1 (also known as Np95 and ICBP90) recognizes hemi-methylation sites via a SET and RING-associated (SRA) domain and directs Dnmt1 to these sites. Here we report the crystal structures of the SRA domain in free and hemi-methylated DNA-bound states. The SRA domain folds into a globular structure with a basic concave surface formed by highly conserved residues. Binding of DNA to the concave surface causes a loop and an amino-terminal tail of the SRA domain to fold into DNA interfaces at the major and minor grooves of the methylation site. In contrast to fully methylated CpG sites recognized by the methyl-CpG-binding domain, the methylcytosine base at the hemi-methylated site is flipped out of the DNA helix in the SRA?DNA complex and fits tightly into a protein pocket on the concave surface. The complex structure suggests that the successive flip out of the pre-existing methylated cytosine and the target cytosine to be methylated is associated with the coordinated transfer of the hemi-methylated CpG site from UHRF1 to Dnmt1. Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1 Epigenetic inheritance in mammals is characterized by high-fidelity replication of CpG methylation patterns during development. UHRF1 (also known as ICBP90 in humans and Np95 in mouse) is an E3 ligase important for the maintenance of global and local DNA methylation in vivo. The preferential affinity of UHRF1 for hemi-methylated DNA over symmetrically methylated DNA by means of its SET and RING-associated (SRA) domain and its association with the maintenance DNA methyltransferase 1 (DNMT1) suggests a role in replication of the epigenetic code. Here we report the 1.7?Å crystal structure of the apo SRA domain of human UHRF1 and a 2.2?Å structure of its complex with hemi-methylated DNA, revealing a previously unknown reading mechanism for methylated CpG sites (mCpG). The SRA?DNA complex has several notable structural features including a binding pocket that accommodates the 5-methylcytosine that is flipped out of the duplex DNA. Two specialized loops reach through the resulting gap in the DNA from both the major and the minor grooves to read the other three bases of the CpG duplex. The major groove loop confers both specificity for the CpG dinucleotide and discrimination against methylation of deoxycytidine of the complementary strand. The structure, along with mutagenesis data, suggests how UHRF1 acts as a key factor for DNMT1 maintenance methylation through recognition of a fundamental unit of epigenetic inheritance, mCpG. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix Maintenance methylation of hemimethylated CpG dinucleotides at DNA replication forks is the key to faithful mitotic inheritance of genomic methylation patterns. UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is required for maintenance methylation by interacting with DNA nucleotide methyltransferase 1 (DNMT1), the maintenance methyltransferase, and with hemimethylated CpG, the substrate for DNMT1 (refs 1 and 2). Here we present the crystal structure of the SET and RING-associated (SRA) domain of mouse UHRF1 in complex with DNA containing a hemimethylated CpG site. The DNA is contacted in both the major and minor grooves by two loops that penetrate into the middle of the DNA helix. The 5-methylcytosine has flipped completely out of the DNA helix and is positioned in a binding pocket with planar stacking contacts, Watson?Crick polar hydrogen bonds and van der Waals interactions specific for 5-methylcytosine. Hence, UHRF1 contains a previously unknown DNA-binding module and is the first example of a non-enzymatic, sequence-specific DNA-binding protein domain to use the base flipping mechanism to interact with DNA. Functional metagenomic profiling of nine biomes Nature452, 629?632 (2008)In this Letter, functional diversity and evenness were calculated using log10, but it has been drawn to our attention that the calculations should have been made with natural logs (Table 2). Recalculation does The picture of Oscar X An image of the future.

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