http://barf.jcowboy.org Nature recent publications en-us http://barf.jcowboy.org/pubmed.gif http://barf.jcowboy.org http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698508 Publication Date: 2013 May 22 PMID: 23698508<br/>Authors: Owens, B.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698508&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698507 Publication Date: 2013 May 22 PMID: 23698507<br/>Authors: Dolgin, E.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698507&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698506 Publication Date: 2013 May 22 PMID: 23698506<br/>Authors: Smith, K.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698506&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698505 Publication Date: 2013 May 22 PMID: 23698505<br/>Authors: Peplow, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698505&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698504 Publication Date: 2013 May 22 PMID: 23698504<br/>Authors: Costandi, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698504&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698503 Publication Date: 2013 May 22 PMID: 23698503<br/>Authors: Crow, J. M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698503&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698502 Publication Date: 2013 May 22 PMID: 23698502<br/>Authors: Deweerdt, S.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698502&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698501 Publication Date: 2013 May 22 PMID: 23698501<br/>Authors: Czeisler, C. A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698501&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698500 Publication Date: 2013 May 22 PMID: 23698500<br/>Authors: Eisenstein, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698500&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698499 Publication Date: 2013 May 22 PMID: 23698499<br/>Authors: Scully, T.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698499&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698449 Publication Date: 2013 May 22 PMID: 23698449<br/>Authors: Haynes, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698449&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698448 Publication Date: 2013 May 22 PMID: 23698448<br/>Authors: Kawatani, Y. - Hamilton, K.<br/>Journal: Nature<br/><br/>The zonal wind in the tropical stratosphere switches between prevailing easterlies and westerlies with a period of about 28 months. In the lowermost stratosphere, the vertical structure of this quasibiennial oscillation (QBO) is linked to the mean upwelling, which itself is a key factor in determining stratospheric composition. Evidence for changes in the QBO have until now been equivocal, raising questions as to the extent of stratospheric circulation changes in a global warming context. Here we report an analysis of near-equatorial radiosonde observations for 1953-2012, and reveal a long-term trend of weakening amplitude in the zonal wind QBO in the tropical lower stratosphere. The trend is particularly notable at the 70-hectopascal pressure level (an altitude of about 19 kilometres), where the QBO amplitudes dropped by roughly one-third over the period. This trend is also apparent in the global warming simulations of the four models in the Coupled Model Intercomparison Project Phase 5 (CMIP5) that realistically simulate the QBO. The weakening is most reasonably explained as resulting from a trend of increased mean tropical upwelling in the lower stratosphere. Almost all comprehensive climate models have projected an intensifying tropical upwelling in global warming scenarios, but attempts to estimate changes in the upwelling by using observational data have yielded ambiguous, inconclusive or contradictory results. Our discovery of a weakening trend in the lower-stratosphere QBO amplitude provides strong support for the existence of a long-term trend of enhanced upwelling near the tropical tropopause.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698448&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698447 Publication Date: 2013 May 22 PMID: 23698447<br/>Authors: Patterson, D. - Schnell, M. - Doyle, J. M.<br/>Journal: Nature<br/><br/>Chirality plays a fundamental part in the activity of biological molecules and broad classes of chemical reactions, but detecting and quantifying it remains challenging. The spectroscopic methods of choice are usually circular dichroism and vibrational circular dichroism, methods that are forbidden in the electric dipole approximation. The resultant weak effects produce weak signals, and thus require high sample densities. In contrast, nonlinear techniques probing electric-dipole-allowed effects have been used for sensitive chiral analyses of liquid samples. Here we extend this class of approaches by carrying out nonlinear resonant phase-sensitive microwave spectroscopy of gas phase samples in the presence of an adiabatically switched non-resonant orthogonal electric field; we use this technique to map the enantiomer-dependent sign of an electric dipole Rabi frequency onto the phase of emitted microwave radiation. We outline theoretically how this results in a sensitive and species-selective method for determining the chirality of cold gas-phase molecules, and implement it experimentally to distinguish between the S and R enantiomers of 1,2-propanediol and their racemic mixture. This technique produces a large and definitive signature of chirality, and has the potential to determine the chirality of multiple species in a mixture.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698447&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698446 Publication Date: 2013 May 22 PMID: 23698446<br/>Authors: Xu, T. - Agrawal, A. - Abashin, M. - Chau, K. J. - Lezec, H. J.<br/>Journal: Nature<br/><br/>Decades ago, Veselago predicted that a material with simultaneously negative electric and magnetic polarization responses would yield a 'left-handed' medium in which light propagates with opposite phase and energy velocities-a condition described by a negative refractive index. He proposed that a flat slab of left-handed material possessing an isotropic refractive index of -1 could act like an imaging lens in free space. Left-handed materials do not occur naturally, and it has only recently become possible to achieve a left-handed response using metamaterials, that is, electromagnetic structures engineered on subwavelength scales to elicit tailored polarization responses. So far, left-handed responses have typically been implemented using resonant metamaterials composed of periodic arrays of unit cells containing inductive-capacitive resonators and conductive wires. Negative refractive indices that are isotropic in two or three dimensions at microwave frequencies have been achieved in resonant metamaterials with centimetre-scale features. Scaling the left-handed response to higher frequencies, such as infrared or visible, has been done by shrinking critical dimensions to submicrometre scales by means of top-down nanofabrication. This miniaturization has, however, so far been achieved at the cost of reduced unit-cell symmetry, yielding a refractive index that is negative along only one axis. Moreover, lithographic scaling limits have so far precluded the fabrication of resonant metamaterials with left-handed responses at frequencies beyond the visible. Here we report the experimental implementation of a bulk metamaterial with a left-handed response to ultraviolet light. The structure, based on stacked plasmonic waveguides, yields an omnidirectional left-handed response for transverse magnetic polarization characterized by a negative refractive index. By engineering the structure to have a refractive index close to -1 over a broad angular range, we achieve Veselago flat lensing, in free space, of arbitrarily shaped, two-dimensional objects beyond the near field. We further demonstrate active, all-optical modulation of the image transferred by the flat lens.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698446&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698445 Publication Date: 2013 May 22 PMID: 23698445<br/>Authors: Eyink, G. - Vishniac, E. - Lalescu, C. - Aluie, H. - Kanov, K. - Burger, K. - Burns, R. - Meneveau, C. - Szalay, A.<br/>Journal: Nature<br/><br/>The idea of 'frozen-in' magnetic field lines for ideal plasmas is useful to explain diverse astrophysical phenomena, for example the shedding of excess angular momentum from protostars by twisting of field lines frozen into the interstellar medium. Frozen-in field lines, however, preclude the rapid changes in magnetic topology observed at high conductivities, as in solar flares. Microphysical plasma processes are a proposed explanation of the observed high rates, but it is an open question whether such processes can rapidly reconnect astrophysical flux structures much greater in extent than several thousand ion gyroradii. An alternative explanation is that turbulent Richardson advection brings field lines implosively together from distances far apart to separations of the order of gyroradii. Here we report an analysis of a simulation of magnetohydrodynamic turbulence at high conductivity that exhibits Richardson dispersion. This effect of advection in rough velocity fields, which appear non-differentiable in space, leads to line motions that are completely indeterministic or 'spontaneously stochastic', as predicted in analytical studies. The turbulent breakdown of standard flux freezing at scales greater than the ion gyroradius can explain fast reconnection of very large-scale flux structures, both observed (solar flares and coronal mass ejections) and predicted (the inner heliosheath, accretion disks, gamma-ray bursts and so on). For laminar plasma flows with smooth velocity fields or for low turbulence intensity, stochastic flux freezing reduces to the usual frozen-in condition.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698445&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698444 Publication Date: 2013 May 22 PMID: 23698444<br/>Authors: Tobias, S. M. - Cattaneo, F.<br/>Journal: Nature<br/><br/>Astrophysical magnetic fields often display remarkable organization, despite being generated by dynamo action driven by turbulent flows at high conductivity. An example is the eleven-year solar cycle, which shows spatial coherence over the entire solar surface. The difficulty in understanding the emergence of this large-scale organization is that whereas at low conductivity (measured by the magnetic Reynolds number, Rm) dynamo fields are well organized, at high Rm their structure is dominated by rapidly varying small-scale fluctuations. This arises because the smallest scales have the highest rate of strain, and can amplify magnetic field most efficiently. Therefore most of the effort to find flows whose large-scale dynamo properties persist at high Rm has been frustrated. Here we report high-resolution simulations of a dynamo that can generate organized fields at high Rm; indeed, the generation mechanism, which involves the interaction between helical flows and shear, only becomes effective at large Rm. The shear does not enhance generation at large scales, as is commonly thought; instead it reduces generation at small scales. The solution consists of propagating dynamo waves, whose existence was postulated more than 60 years ago and which have since been used to model the solar cycle.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698444&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698443 Publication Date: 2013 May 22 PMID: 23698443<br/>Authors: Houtkooper, R. H. - Mouchiroud, L. - Ryu, D. - Moullan, N. - Katsyuba, E. - Knott, G. - Williams, R. W. - Auwerx, J.<br/>Journal: Nature<br/><br/>Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698443&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698442 Publication Date: 2013 May 22 PMID: 23698442<br/>Authors: Ren, W. - Cheng, H. M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698442&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698441 Publication Date: 2013 May 22 PMID: 23698441<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698441&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698440 Publication Date: 2013 May 22 PMID: 23698440<br/>Authors: Nafie, L. A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698440&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698439 Publication Date: 2013 May 22 PMID: 23698439<br/>Authors: Rey, F. A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698439&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698438 Publication Date: 2013 May 22 PMID: 23698438<br/>Authors: Wolff, S. - Dillin, A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698438&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698437 Publication Date: 2013 May 22 PMID: 23698437<br/>Authors: Morange, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698437&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698436 Publication Date: 2013 May 22 PMID: 23698436<br/>Authors: Maojo, V. - Pazos, J. - Kulikowski, C. A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698436&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698435 Publication Date: 2013 May 22 PMID: 23698435<br/>Authors: Holbrook, J. B. - Barr, K. R. - Brown, K. W.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698435&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698434 Publication Date: 2013 May 22 PMID: 23698434<br/>Authors: Arnaout, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698434&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698433 Publication Date: 2013 May 22 PMID: 23698433<br/>Authors: Cory, S.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698433&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698432 Publication Date: 2013 May 22 PMID: 23698432<br/>Authors: King, A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698432&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698431 Publication Date: 2013 May 22 PMID: 23698431<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698431&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698430 Publication Date: 2013 May 22 PMID: 23698430<br/>Authors: Naeem, S.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698430&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698429 Publication Date: 2013 May 22 PMID: 23698429<br/>Authors: Jay, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698429&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698428 Publication Date: 2013 May 22 PMID: 23698428<br/>Authors: Begley, C. G.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698428&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698427 Publication Date: 2013 May 22 PMID: 23698427<br/>Authors: Eicken, H.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698427&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698426 Publication Date: 2013 May 22 PMID: 23698426<br/>Authors: Hughes, V.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698426&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698425 Publication Date: 2013 May 22 PMID: 23698425<br/>Authors: Witze, A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698425&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698424 Publication Date: 2013 May 22 PMID: 23698424<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698424&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698423 Publication Date: 2013 May 22 PMID: 23698423<br/>Authors: Samuel Reich, E.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698423&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698422 Publication Date: 2013 May 22 PMID: 23698422<br/>Authors: Witze, A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698422&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698421 Publication Date: 2013 May 22 PMID: 23698421<br/>Authors: Schiermeier, Q.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698421&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698420 Publication Date: 2013 May 21 PMID: 23698420<br/>Authors: Witze, A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698420&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698419 Publication Date: 2013 May 21 PMID: 23698419<br/>Authors: Morello, L.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698419&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698418 Publication Date: 2013 May 21 PMID: 23698418<br/>Authors: Cowen, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698418&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698417 Publication Date: 2013 May 22 PMID: 23698417<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698417&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698416 Publication Date: 2013 May 22 PMID: 23698416<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698416&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698415 Publication Date: 2013 May 22 PMID: 23698415<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698415&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698414 Publication Date: 2013 May 22 PMID: 23698414<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698414&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698413 Publication Date: 2013 May 22 PMID: 23698413<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698413&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698412 Publication Date: 2013 May 22 PMID: 23698412<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698412&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698411 Publication Date: 2013 May 22 PMID: 23698411<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698411&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698410 Publication Date: 2013 May 22 PMID: 23698410<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698410&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698409 Publication Date: 2013 May 22 PMID: 23698409<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698409&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698408 Publication Date: 2013 May 22 PMID: 23698408<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698408&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698407 Publication Date: 2013 May 22 PMID: 23698407<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698407&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698406 Publication Date: 2013 May 22 PMID: 23698406<br/>Authors: Sarewitz, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698406&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698372 Publication Date: 2013 May 22 PMID: 23698372<br/>Authors: Baker, N. M. - Der, C. J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698372&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698371 Publication Date: 2013 May 22 PMID: 23698371<br/>Authors: Hepworth, M. R. - Monticelli, L. A. - Fung, T. C. - Ziegler, C. G. - Grunberg, S. - Sinha, R. - Mantegazza, A. R. - Ma, H. L. - Crawford, A. - Angelosanto, J. M. - Wherry, E. J. - Koni, P. A. - Bushman, F. D. - Elson, C. O. - Eberl, G. - Artis, D. - Sonnenberg, G. F.<br/>Journal: Nature<br/><br/>Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4+ T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-gammat-positive (RORgammat+) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORgammat+ ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4+ T-cell responses. Consistent with this, selective deletion of MHCII in murine RORgammat+ ILCs resulted in dysregulated commensal bacteria-dependent CD4+ T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4+ T cells that limit pathological adaptive immune cell responses to commensal bacteria.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698371&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698370 Publication Date: 2013 May 22 PMID: 23698370<br/>Authors: Austin, C. - Smith, T. M. - Bradman, A. - Hinde, K. - Joannes-Boyau, R. - Bishop, D. - Hare, D. J. - Doble, P. - Eskenazi, B. - Arora, M.<br/>Journal: Nature<br/><br/>Early-life dietary transitions reflect fundamental aspects of primate evolution and are important determinants of health in contemporary human populations. Weaning is critical to developmental and reproductive rates; early weaning can have detrimental health effects but enables shorter inter-birth intervals, which influences population growth. Uncovering early-life dietary history in fossils is hampered by the absence of prospectively validated biomarkers that are not modified during fossilization. Here we show that large dietary shifts in early life manifest as compositional variations in dental tissues. Teeth from human children and captive macaques, with prospectively recorded diet histories, demonstrate that barium (Ba) distributions accurately reflect dietary transitions from the introduction of mother's milk through the weaning process. We also document dietary transitions in a Middle Palaeolithic juvenile Neanderthal, which shows a pattern of exclusive breastfeeding for seven months, followed by seven months of supplementation. After this point, Ba levels in enamel returned to baseline prenatal levels, indicating an abrupt cessation of breastfeeding at 1.2 years of age. Integration of Ba spatial distributions and histological mapping of tooth formation enables novel studies of the evolution of human life history, dietary ontogeny in wild primates, and human health investigations through accurate reconstructions of breastfeeding history.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698370&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698369 Publication Date: 2013 May 22 PMID: 23698369<br/>Authors: Dykhuizen, E. C. - Hargreaves, D. C. - Miller, E. L. - Cui, K. - Korshunov, A. - Kool, M. - Pfister, S. - Cho, Y. J. - Zhao, K. - Crabtree, G. R.<br/>Journal: Nature<br/><br/>Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies, but the mechanisms involved in tumour suppression are unclear. BAF chromatin-remodelling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb repressive complex 2 (PRC2) across the genome. Several proteins dedicated to this multisubunit complex, including BRG1 (also known as SMARCA4) and BAF250a (also known as ARID1A), are mutated at frequencies similar to those of recognized tumour suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastomas and more than 15% of Burkitt's lymphomas. Here we show a previously unknown function of BAF complexes in decatenating newly replicated sister chromatids, a requirement for proper chromosome segregation during mitosis. We find that deletion of Brg1 in mouse cells, as well as the expression of BRG1 point mutants identified in human tumours, leads to anaphase bridge formation (in which sister chromatids are linked by catenated strands of DNA) and a G2/M-phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes interact directly with endogenous topoisomerase IIalpha (TOP2A) through BAF250a and are required for the binding of TOP2A to approximately 12,000 sites across the genome. Our results demonstrate that TOP2A chromatin binding is dependent on the ATPase activity of BRG1, which is compromised in oncogenic BRG1 mutants. These studies indicate that the ability of TOP2A to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumour suppressors.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698369&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698368 Publication Date: 2013 May 22 PMID: 23698368<br/>Authors: Hondele, M. - Stuwe, T. - Hassler, M. - Halbach, F. - Bowman, A. - Zhang, E. T. - Nijmeijer, B. - Kotthoff, C. - Rybin, V. - Amlacher, S. - Hurt, E. - Ladurner, A. G.<br/>Journal: Nature<br/><br/>Facilitates chromatin transcription (FACT) is a conserved histone chaperone that reorganizes nucleosomes and ensures chromatin integrity during DNA transcription, replication and repair. Key to the broad functions of FACT is its recognition of histones H2A-H2B (ref. 2). However, the structural basis for how histones H2A-H2B are recognized and how this integrates with the other functions of FACT, including the recognition of histones H3-H4 and other nuclear factors, is unknown. Here we reveal the crystal structure of the evolutionarily conserved FACT chaperone domain Spt16M from Chaetomium thermophilum, in complex with the H2A-H2B heterodimer. A novel 'U-turn' motif scaffolded onto a Rtt106-like module embraces the alpha1 helix of H2B. Biochemical and in vivo assays validate the structure and dissect the contribution of histone tails and H3-H4 towards Spt16M binding. Furthermore, we report the structure of the FACT heterodimerization domain that connects FACT to replicative polymerases. Our results show that Spt16M makes several interactions with histones, which we suggest allow the module to invade the nucleosome gradually and block the strongest interaction of H2B with DNA. FACT would thus enhance 'nucleosome breathing' by re-organizing the first 30 base pairs of nucleosomal histone-DNA contacts. Our snapshot of the engagement of the chaperone with H2A-H2B and the structures of all globular FACT domains enable the high-resolution analysis of the vital chaperoning functions of FACT, shedding light on how the complex promotes the activity of enzymes that require nucleosome reorganization.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698368&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698367 Publication Date: 2013 May 22 PMID: 23698367<br/>Authors: Kanekiyo, M. - Wei, C. J. - Yassine, H. M. - McTamney, P. M. - Boyington, J. C. - Whittle, J. R. - Rao, S. S. - Kong, W. P. - Wang, L. - Nabel, G. J.<br/>Journal: Nature<br/><br/>Influenza viruses pose a significant threat to the public and are a burden on global health systems. Each year, influenza vaccines must be rapidly produced to match circulating viruses, a process constrained by dated technology and vulnerable to unexpected strains emerging from humans and animal reservoirs. Here we use knowledge of protein structure to design self-assembling nanoparticles that elicit broader and more potent immunity than traditional influenza vaccines. The viral haemagglutinin was genetically fused to ferritin, a protein that naturally forms nanoparticles composed of 24 identical polypeptides. Haemagglutinin was inserted at the interface of adjacent subunits so that it spontaneously assembled and generated eight trimeric viral spikes on its surface. Immunization with this influenza nanoparticle vaccine elicited haemagglutination inhibition antibody titres more than tenfold higher than those from the licensed inactivated vaccine. Furthermore, it elicited neutralizing antibodies to two highly conserved vulnerable haemagglutinin structures that are targets of universal vaccines: the stem and the receptor binding site on the head. Antibodies elicited by a 1999 haemagglutinin-nanoparticle vaccine neutralized H1N1 viruses from 1934 to 2007 and protected ferrets from an unmatched 2007 H1N1 virus challenge. This structure-based, self-assembling synthetic nanoparticle vaccine improves the potency and breadth of influenza virus immunity, and it provides a foundation for building broader vaccine protection against emerging influenza viruses and other pathogens.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698367&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698366 Publication Date: 2013 May 22 PMID: 23698366<br/>Authors: Findley, K. - Oh, J. - Yang, J. - Conlan, S. - Deming, C. - Meyer, J. A. - Schoenfeld, D. - Nomicos, E. - Park, M. - Becker, J. - Benjamin, B. - Blakesley, R. - Bouffard, G. - Brooks, S. - Coleman, H. - Dekhtyar, M. - Gregory, M. - Guan, X. - Gupta, J. - Han, J. - Hargrove, A. - Ho, S. L. - Johnson, T. - Legaspi, R. - Lovett, S. - Maduro, Q. - Masiello, C. - Maskeri, B. - McDowell, J. - Montemayor, C. - Mullikin, J. - Park, M. - Riebow, N. - Schandler, K. - Schmidt, B. - Sison, C. - Stantripop, M. - Thomas, J. - Thomas, P. - Vemulapalli, M. - Young, A. - Kong, H. H. - Segre, J. A.<br/>Journal: Nature<br/><br/>Traditional culture-based methods have incompletely defined the microbial landscape of common recalcitrant human fungal skin diseases, including athlete's foot and toenail infections. Skin protects humans from invasion by pathogenic microorganisms and provides a home for diverse commensal microbiota. Bacterial genomic sequence data have generated novel hypotheses about species and community structures underlying human disorders. However, microbial diversity is not limited to bacteria; microorganisms such as fungi also have major roles in microbial community stability, human health and disease. Genomic methodologies to identify fungal species and communities have been limited compared with those that are available for bacteria. Fungal evolution can be reconstructed with phylogenetic markers, including ribosomal RNA gene regions and other highly conserved genes. Here we sequenced and analysed fungal communities of 14 skin sites in 10 healthy adults. Eleven core-body and arm sites were dominated by fungi of the genus Malassezia, with only species-level classifications revealing fungal-community composition differences between sites. By contrast, three foot sites-plantar heel, toenail and toe web-showed high fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that physiologic attributes and topography of skin differentially shape these two microbial communities. These results provide a framework for future investigation of the contribution of interactions between pathogenic and commensal fungal and bacterial communities to the maintainenace of human health and to disease pathogenesis.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698366&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698365 Publication Date: 2013 May 22 PMID: 23698365<br/>Authors: Dasso, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698365&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698364 Publication Date: 2013 May 22 PMID: 23698364<br/>Authors: Sederoff, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698364&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698363 Publication Date: 2013 May 22 PMID: 23698363<br/>Authors: Fu, H. - Cooray, A. - Feruglio, C. - Ivison, R. J. - Riechers, D. A. - Gurwell, M. - Bussmann, R. S. - Harris, A. I. - Altieri, B. - Aussel, H. - Baker, A. J. - Bock, J. - Boylan-Kolchin, M. - Bridge, C. - Calanog, J. A. - Casey, C. M. - Cava, A. - Chapman, S. C. - Clements, D. L. - Conley, A. - Cox, P. - Farrah, D. - Frayer, D. - Hopwood, R. - Jia, J. - Magdis, G. - Marsden, G. - Martinez-Navajas, P. - Negrello, M. - Neri, R. - Oliver, S. J. - Omont, A. - Page, M. J. - Perez-Fournon, I. - Schulz, B. - Scott, D. - Smith, A. - Vaccari, M. - Valtchanov, I. - Vieira, J. D. - Viero, M. - Wang, L. - Wardlow, J. L. - Zemcov, M.<br/>Journal: Nature<br/><br/>Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 x 1010 solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 x 1011 solar masses at z approximately 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 x 1011 solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z approximately 1.5.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698363&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698362 Publication Date: 2013 May 22 PMID: 23698362<br/>Authors: Hunt, K. A. - Mistry, V. - Bockett, N. A. - Ahmad, T. - Ban, M. - Barker, J. N. - Barrett, J. C. - Blackburn, H. - Brand, O. - Burren, O. - Capon, F. - Compston, A. - Gough, S. C. - Jostins, L. - Kong, Y. - Lee, J. C. - Lek, M. - Macarthur, D. G. - Mansfield, J. C. - Mathew, C. G. - Mein, C. A. - Mirza, M. - Nutland, S. - Onengut-Gumuscu, S. - Papouli, E. - Parkes, M. - Rich, S. S. - Sawcer, S. - Satsangi, J. - Simmonds, M. J. - Trembath, R. C. - Walker, N. M. - Wozniak, E. - Todd, J. A. - Simpson, M. A. - Plagnol, V. - van Heel, D. A.<br/>Journal: Nature<br/><br/>Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698362&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698361 Publication Date: 2013 May 22 PMID: 23698361<br/>Authors: Zimmermann, G. - Papke, B. - Ismail, S. - Vartak, N. - Chandra, A. - Hoffmann, M. - Hahn, S. A. - Triola, G. - Wittinghofer, A. - Bastiaens, P. I. - Waldmann, H.<br/>Journal: Nature<br/><br/>The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEdelta, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEdelta to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEdelta interaction that selectively bind to the prenyl-binding pocket of PDEdelta with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698361&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23698360 Publication Date: 2013 May 22 PMID: 23698360<br/>Authors: Nystedt, B. - Street, N. R. - Wetterbom, A. - Zuccolo, A. - Lin, Y. C. - Scofield, D. G. - Vezzi, F. - Delhomme, N. - Giacomello, S. - Alexeyenko, A. - Vicedomini, R. - Sahlin, K. - Sherwood, E. - Elfstrand, M. - Gramzow, L. - Holmberg, K. - Hallman, J. - Keech, O. - Klasson, L. - Koriabine, M. - Kucukoglu, M. - Kaller, M. - Luthman, J. - Lysholm, F. - Niittyla, T. - Olson, A. - Rilakovic, N. - Ritland, C. - Rossello, J. A. - Sena, J. - Svensson, T. - Talavera-Lopez, C. - Theissen, G. - Tuominen, H. - Vanneste, K. - Wu, Z. Q. - Zhang, B. - Zerbe, P. - Arvestad, L. - Bhalerao, R. - Bohlmann, J. - Bousquet, J. - Garcia Gil, R. - Hvidsten, T. R. - de Jong, P. - Mackay, J. - Morgante, M. - Ritland, K. - Sundberg, B. - Lee Thompson, S. - Van de Peer, Y. - Andersson, B. - Nilsson, O. - Ingvarsson, P. K. - Lundeberg, J. - Jansson, S.<br/>Journal: Nature<br/><br/>Conifers have dominated forests for more than 200 million years and are of huge ecological and economic importance. Here we present the draft assembly of the 20-gigabase genome of Norway spruce (Picea abies), the first available for any gymnosperm. The number of well-supported genes (28,354) is similar to the >100 times smaller genome of Arabidopsis thaliana, and there is no evidence of a recent whole-genome duplication in the gymnosperm lineage. Instead, the large genome size seems to result from the slow and steady accumulation of a diverse set of long-terminal repeat transposable elements, possibly owing to the lack of an efficient elimination mechanism. Comparative sequencing of Pinus sylvestris, Abies sibirica, Juniperus communis, Taxus baccata and Gnetum gnemon reveals that the transposable element diversity is shared among extant conifers. Expression of 24-nucleotide small RNAs, previously implicated in transposable element silencing, is tissue-specific and much lower than in other plants. We further identify numerous long (>10,000 base pairs) introns, gene-like fragments, uncharacterized long non-coding RNAs and short RNAs. This opens up new genomic avenues for conifer forestry and breeding.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23698360&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23685455 Publication Date: 2013 May 19 PMID: 23685455<br/>Authors: Kaplon, J. - Zheng, L. - Meissl, K. - Chaneton, B. - Selivanov, V. A. - Mackay, G. - van der Burg, S. H. - Verdegaal, E. M. - Cascante, M. - Shlomi, T. - Gottlieb, E. - Peeper, D. S.<br/>Journal: Nature<br/><br/>In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells, and senescent cells are thought to remain metabolically active, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAFV600E, an oncogene commonly mutated in melanoma and other cancers. BRAFV600E-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAFV600E-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23685455&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23685454 Publication Date: 2013 May 19 PMID: 23685454<br/>Authors: Shalek, A. K. - Satija, R. - Adiconis, X. - Gertner, R. S. - Gaublomme, J. T. - Raychowdhury, R. - Schwartz, S. - Yosef, N. - Malboeuf, C. - Lu, D. - Trombetta, J. T. - Gennert, D. - Gnirke, A. - Goren, A. - Hacohen, N. - Levin, J. Z. - Park, H. - Regev, A.<br/>Journal: Nature<br/><br/>Recent molecular studies have shown that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels and phenotypic output, with important functional consequences. Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs or proteins simultaneously, because genomic profiling methods could not be applied to single cells until very recently. Here we use single-cell RNA sequencing to investigate heterogeneity in the response of mouse bone-marrow-derived dendritic cells (BMDCs) to lipopolysaccharide. We find extensive, and previously unobserved, bimodal variation in messenger RNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23685454&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23685453 Publication Date: 2013 May 19 PMID: 23685453<br/>Authors: Waight, A. B. - Pedersen, B. P. - Schlessinger, A. - Bonomi, M. - Chau, B. H. - Roe-Zurz, Z. - Risenmay, A. J. - Sali, A. - Stroud, R. M.<br/>Journal: Nature<br/><br/>Eukaryotic Ca2+ regulation involves sequestration into intracellular organelles, and expeditious Ca2+ release into the cytosol is a hallmark of key signalling transduction pathways. Bulk removal of Ca2+ after such signalling events is accomplished by members of the Ca2+:cation (CaCA) superfamily. The CaCA superfamily includes the Na+/Ca2+ (NCX) and Ca2+/H+ (CAX) antiporters, and in mammals the NCX and related proteins constitute families SLC8 and SLC24, and are responsible for the re-establishment of Ca2+ resting potential in muscle cells, neuronal signalling and Ca2+ reabsorption in the kidney. The CAX family members maintain cytosolic Ca2+ homeostasis in plants and fungi during steep rises in intracellular Ca2+ due to environmental changes, or following signal transduction caused by events such as hyperosmotic shock, hormone response and response to mating pheromones. The cytosol-facing conformations within the CaCA superfamily are unknown, and the transport mechanism remains speculative. Here we determine a crystal structure of the Saccharomyces cerevisiae vacuolar Ca2+/H+ exchanger (Vcx1) at 2.3 A resolution in a cytosol-facing, substrate-bound conformation. Vcx1 is the first structure, to our knowledge, within the CAX family, and it describes the key cytosol-facing conformation of the CaCA superfamily, providing the structural basis for a novel alternating access mechanism by which the CaCA superfamily performs high-throughput Ca2+ transport across membranes.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23685453&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23685452 Publication Date: 2013 May 19 PMID: 23685452<br/>Authors: Rigotti, M. - Barak, O. - Warden, M. R. - Wang, X. J. - Daw, N. D. - Miller, E. K. - Fusi, S.<br/>Journal: Nature<br/><br/>Single-neuron activity in the prefrontal cortex (PFC) is tuned to mixtures of multiple task-related aspects. Such mixed selectivity is highly heterogeneous, seemingly disordered and therefore difficult to interpret. We analysed the neural activity recorded in monkeys during an object sequence memory task to identify a role of mixed selectivity in subserving the cognitive functions ascribed to the PFC. We show that mixed selectivity neurons encode distributed information about all task-relevant aspects. Each aspect can be decoded from the population of neurons even when single-cell selectivity to that aspect is eliminated. Moreover, mixed selectivity offers a significant computational advantage over specialized responses in terms of the repertoire of input-output functions implementable by readout neurons. This advantage originates from the highly diverse nonlinear selectivity to mixtures of task-relevant variables, a signature of high-dimensional neural representations. Crucially, this dimensionality is predictive of animal behaviour as it collapses in error trials. Our findings recommend a shift of focus for future studies from neurons that have easily interpretable response tuning to the widely observed, but rarely analysed, mixed selectivity neurons.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23685452&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23682399 Publication Date: 2013 May 16 PMID: 23682399<br/>Authors: Deming, L.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23682399&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23682398 Publication Date: 2013 May 16 PMID: 23682398<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23682398&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23682397 Publication Date: 2013 May 16 PMID: 23682397<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23682397&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23682396 Publication Date: 2013 May 16 PMID: 23682396<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23682396&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23682395 Publication Date: 2013 May 16 PMID: 23682395<br/>Authors: Schiermeier, Q.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23682395&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676755 Publication Date: 2013 May 16 PMID: 23676755<br/>Authors: Moosmann, J. - Ershov, A. - Altapova, V. - Baumbach, T. - Prasad, M. S. - LaBonne, C. - Xiao, X. - Kashef, J. - Hofmann, R.<br/>Journal: Nature<br/><br/>An ambitious goal in biology is to understand the behaviour of cells during development by imaging-in vivo and with subcellular resolution-changes of the embryonic structure. Important morphogenetic movements occur throughout embryogenesis, but in particular during gastrulation when a series of dramatic, coordinated cell movements drives the reorganization of a simple ball or sheet of cells into a complex multi-layered organism. In Xenopus laevis, the South African clawed frog and also in zebrafish, cell and tissue movements have been studied in explants, in fixed embryos, in vivo using fluorescence microscopy or microscopic magnetic resonance imaging. None of these methods allows cell behaviours to be observed with micrometre-scale resolution throughout the optically opaque, living embryo over developmental time. Here we use non-invasive in vivo, time-lapse X-ray microtomography, based on single-distance phase contrast and combined with motion analysis, to examine the course of embryonic development. We demonstrate that this powerful four-dimensional imaging technique provides high-resolution views of gastrulation processes in wild-type X. laevis embryos, including vegetal endoderm rotation, archenteron formation, changes in the volumes of cavities within the porous interstitial tissue between archenteron and blastocoel, migration/confrontation of mesendoderm and closure of the blastopore. Differential flow analysis separates collective from relative cell motion to assign propulsion mechanisms. Moreover, digitally determined volume balances confirm that early archenteron inflation occurs through the uptake of external water. A transient ectodermal ridge, formed in association with the confrontation of ventral and head mesendoderm on the blastocoel roof, is identified. When combined with perturbation experiments to investigate molecular and biomechanical underpinnings of morphogenesis, our technique should help to advance our understanding of the fundamentals of development.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676755&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676754 Publication Date: 2013 May 16 PMID: 23676754<br/>Authors: Cheung, W. W. - Watson, R. - Pauly, D.<br/>Journal: Nature<br/><br/>Marine fishes and invertebrates respond to ocean warming through distribution shifts, generally to higher latitudes and deeper waters. Consequently, fisheries should be affected by 'tropicalization' of catch (increasing dominance of warm-water species). However, a signature of such climate-change effects on global fisheries catch has so far not been detected. Here we report such an index, the mean temperature of the catch (MTC), that is calculated from the average inferred temperature preference of exploited species weighted by their annual catch. Our results show that, after accounting for the effects of fishing and large-scale oceanographic variability, global MTC increased at a rate of 0.19 degrees Celsius per decade between 1970 and 2006, and non-tropical MTC increased at a rate of 0.23 degrees Celsius per decade. In tropical areas, MTC increased initially because of the reduction in the proportion of subtropical species catches, but subsequently stabilized as scope for further tropicalization of communities became limited. Changes in MTC in 52 large marine ecosystems, covering the majority of the world's coastal and shelf areas, are significantly and positively related to regional changes in sea surface temperature. This study shows that ocean warming has already affected global fisheries in the past four decades, highlighting the immediate need to develop adaptation plans to minimize the effect of such warming on the economy and food security of coastal communities, particularly in tropical regions.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676754&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676753 Publication Date: 2013 May 16 PMID: 23676753<br/>Authors: Holland, G. - Lollar, B. S. - Li, L. - Lacrampe-Couloume, G. - Slater, G. F. - Ballentine, C. J.<br/>Journal: Nature<br/><br/>Fluids trapped as inclusions within minerals can be billions of years old and preserve a record of the fluid chemistry and environment at the time of mineralization. Aqueous fluids that have had a similar residence time at mineral interfaces and in fractures (fracture fluids) have not been previously identified. Expulsion of fracture fluids from basement systems with low connectivity occurs through deformation and fracturing of the brittle crust. The fractal nature of this process must, at some scale, preserve pockets of interconnected fluid from the earliest crustal history. In one such system, 2.8 kilometres below the surface in a South African gold mine, extant chemoautotrophic microbes have been identified in fluids isolated from the photosphere on timescales of tens of millions of years. Deep fracture fluids with similar chemistry have been found in a mine in the Timmins, Ontario, area of the Canadian Precambrian Shield. Here we show that excesses of (124)Xe, (126)Xe and (128)Xe in the Timmins mine fluids can be linked to xenon isotope changes in the ancient atmosphere and used to calculate a minimum mean residence time for this fluid of about 1.5 billion years. Further evidence of an ancient fluid system is found in (129)Xe excesses that, owing to the absence of any identifiable mantle input, are probably sourced in sediments and extracted by fluid migration processes operating during or shortly after mineralization at around 2.64 billion years ago. We also provide closed-system radiogenic noble-gas ((4)He, (21)Ne, (40)Ar, (136)Xe) residence times. Together, the different noble gases show that ancient pockets of water can survive the crustal fracturing process and remain in the crust for billions of years.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676753&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676752 Publication Date: 2013 May 16 PMID: 23676752<br/>Authors: Schneider, C. - Rahimi-Iman, A. - Kim, N. Y. - Fischer, J. - Savenko, I. G. - Amthor, M. - Lermer, M. - Wolf, A. - Worschech, L. - Kulakovskii, V. D. - Shelykh, I. A. - Kamp, M. - Reitzenstein, S. - Forchel, A. - Yamamoto, Y. - Hofling, S.<br/>Journal: Nature<br/><br/>Conventional semiconductor laser emission relies on stimulated emission of photons, which sets stringent requirements on the minimum amount of energy necessary for its operation. In comparison, exciton-polaritons in strongly coupled quantum well microcavities can undergo stimulated scattering that promises more energy-efficient generation of coherent light by 'polariton lasers'. Polariton laser operation has been demonstrated in optically pumped semiconductor microcavities at temperatures up to room temperature, and such lasers can outperform their weak-coupling counterparts in that they have a lower threshold density. Even though polariton diodes have been realized, electrically pumped polariton laser operation, which is essential for practical applications, has not been achieved until now. Here we present an electrically pumped polariton laser based on a microcavity containing multiple quantum wells. To prove polariton laser emission unambiguously, we apply a magnetic field and probe the hybrid light-matter nature of the polaritons. Our results represent an important step towards the practical implementation of polaritonic light sources and electrically injected condensates, and can be extended to room-temperature operation using wide-bandgap materials.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676752&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676751 Publication Date: 2013 May 16 PMID: 23676751<br/>Authors: Kaspi, Y. - Showman, A. P. - Hubbard, W. B. - Aharonson, O. - Helled, R.<br/>Journal: Nature<br/><br/>The observed cloud-level atmospheric circulation on the outer planets of the Solar System is dominated by strong east-west jet streams. The depth of these winds is a crucial unknown in constraining their overall dynamics, energetics and internal structures. There are two approaches to explaining the existence of these strong winds. The first suggests that the jets are driven by shallow atmospheric processes near the surface, whereas the second suggests that the atmospheric dynamics extend deeply into the planetary interiors. Here we report that on Uranus and Neptune the depth of the atmospheric dynamics can be revealed by the planets' respective gravity fields. We show that the measured fourth-order gravity harmonic, J4, constrains the dynamics to the outermost 0.15 per cent of the total mass of Uranus and the outermost 0.2 per cent of the total mass of Neptune. This provides a stronger limit to the depth of the dynamical atmosphere than previously suggested, and shows that the dynamics are confined to a thin weather layer no more than about 1,000 kilometres deep on both planets.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676751&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676750 Publication Date: 2013 May 16 PMID: 23676750<br/>Authors: Read, P.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676750&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676749 Publication Date: 2013 May 16 PMID: 23676749<br/>Authors: Payne, M. R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676749&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676748 Publication Date: 2013 May 16 PMID: 23676748<br/>Authors: Gosden, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676748&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676747 Publication Date: 2013 May 16 PMID: 23676747<br/>Authors: Sagar, A. D. - Smith, K. R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676747&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676746 Publication Date: 2013 May 16 PMID: 23676746<br/>Authors: Milligan, I.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676746&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676745 Publication Date: 2013 May 16 PMID: 23676745<br/>Authors: Fernandez, A. - Arbelo, M. - Martin, V.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676745&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676744 Publication Date: 2013 May 16 PMID: 23676744<br/>Authors: McGlade, J. - Quist, D. - Gee, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676744&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676743 Publication Date: 2013 May 16 PMID: 23676743<br/>Authors: Hayashi, M. - Iguchi, S.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676743&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676742 Publication Date: 2013 May 16 PMID: 23676742<br/>Authors: Mehrotra, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676742&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676738 Publication Date: 2013 May 16 PMID: 23676738<br/>Authors: Schneider, W. H.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676738&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676737 Publication Date: 2013 May 16 PMID: 23676737<br/>Authors: Livio, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676737&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676736 Publication Date: 2013 May 16 PMID: 23676736<br/>Authors: Nicholls, H.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676736&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676735 Publication Date: 2013 May 16 PMID: 23676735<br/>Authors: Appenzeller, T.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676735&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676733 Publication Date: 2013 May 16 PMID: 23676733<br/>Authors: Van Noorden, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676733&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676732 Publication Date: 2013 May 16 PMID: 23676732<br/>Authors: Cressey, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676732&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676731 Publication Date: 2013 May 16 PMID: 23676731<br/>Authors: Yong, E.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676731&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676730 Publication Date: 2013 May 16 PMID: 23676730<br/>Authors: Reich, E. S.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676730&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676729 Publication Date: 2013 May 16 PMID: 23676729<br/>Authors: Cyranoski, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676729&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676717 Publication Date: 2013 May 16 PMID: 23676717<br/>Authors: Macilwain, C.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676717&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676681 Publication Date: 2013 May 15 PMID: 23676681<br/>Authors: Daniel, R. - Rubens, J. R. - Sarpeshkar, R. - Lu, T. K.<br/>Journal: Nature<br/><br/>A central goal of synthetic biology is to achieve multi-signal integration and processing in living cells for diagnostic, therapeutic and biotechnology applications. Digital logic has been used to build small-scale circuits, but other frameworks may be needed for efficient computation in the resource-limited environments of cells. Here we demonstrate that synthetic analog gene circuits can be engineered to execute sophisticated computational functions in living cells using just three transcription factors. Such synthetic analog gene circuits exploit feedback to implement logarithmically linear sensing, addition, ratiometric and power-law computations. The circuits exhibit Weber's law behaviour as in natural biological systems, operate over a wide dynamic range of up to four orders of magnitude and can be designed to have tunable transfer functions. Our circuits can be composed to implement higher-order functions that are well described by both intricate biochemical models and simple mathematical functions. By exploiting analog building-block functions that are already naturally present in cells, this approach efficiently implements arithmetic operations and complex functions in the logarithmic domain. Such circuits may lead to new applications for synthetic biology and biotechnology that require complex computations with limited parts, need wide-dynamic-range biosensing or would benefit from the fine control of gene expression.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676681&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676680 Publication Date: 2013 May 15 PMID: 23676680<br/>Authors: Stevens, N. J. - Seiffert, E. R. - O'Connor, P. M. - Roberts, E. M. - Schmitz, M. D. - Krause, C. - Gorscak, E. - Ngasala, S. - Hieronymus, T. L. - Temu, J.<br/>Journal: Nature<br/><br/>Apes and Old World monkeys are prominent components of modern African and Asian ecosystems, yet the earliest phases of their evolutionary history have remained largely undocumented. The absence of crown catarrhine fossils older than approximately 20 million years (Myr) has stood in stark contrast to molecular divergence estimates of approximately 25-30 Myr for the split between Cercopithecoidea (Old World monkeys) and Hominoidea (apes), implying long ghost lineages for both clades. Here we describe the oldest known fossil 'ape', represented by a partial mandible preserving dental features that place it with 'nyanzapithecine' stem hominoids. Additionally, we report the oldest stem member of the Old World monkey clade, represented by a lower third molar. Both specimens were recovered from a precisely dated 25.2-Myr-old stratum in the Rukwa Rift, a segment of the western branch of the East African Rift in Tanzania. These finds extend the fossil record of apes and Old World monkeys well into the Oligocene epoch of Africa, suggesting a possible link between diversification of crown catarrhines and changes in the African landscape brought about by previously unrecognized tectonic activity in the East African rift system.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676680&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676679 Publication Date: 2013 May 15 PMID: 23676679<br/>Authors: Sidorenkov, L. A. - Tey, M. K. - Grimm, R. - Hou, Y. H. - Pitaevskii, L. - Stringari, S.<br/>Journal: Nature<br/><br/>Superfluidity is a macroscopic quantum phenomenon occurring in systems as diverse as liquid helium and neutron stars. It occurs below a critical temperature and leads to peculiar behaviour such as frictionless flow, the formation of quantized vortices and quenching of the moment of inertia. Ultracold atomic gases offer control of interactions and external confinement, providing unique opportunities to explore superfluid phenomena. Many such (finite-temperature) phenomena can be explained in terms of a two-fluid mixture comprising a normal component, which behaves like an ordinary fluid, and a superfluid component with zero viscosity and zero entropy. The two-component nature of a superfluid is manifest in 'second sound', an entropy wave in which the superfluid and the non-superfluid components oscillate with opposite phases (as opposed to ordinary 'first sound', where they oscillate in phase). Here we report the observation of second sound in an ultracold Fermi gas with resonant interactions. The speed of second sound depends explicitly on the value of the superfluid fraction, a quantity that is sensitive to the spectrum of elementary excitations. Our measurements allow us to extract the temperature dependence of the superfluid fraction, a previously inaccessible quantity that will provide a benchmark for theories of strongly interacting quantum gases.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676679&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676678 Publication Date: 2013 May 15 PMID: 23676678<br/>Authors: Ponomarenko, L. A. - Gorbachev, R. V. - Yu, G. L. - Elias, D. C. - Jalil, R. - Patel, A. A. - Mishchenko, A. - Mayorov, A. S. - Woods, C. R. - Wallbank, J. R. - Mucha-Kruczynski, M. - Piot, B. A. - Potemski, M. - Grigorieva, I. V. - Novoselov, K. S. - Guinea, F. - Fal'ko, V. I. - Geim, A. K.<br/>Journal: Nature<br/><br/>Superlattices have attracted great interest because their use may make it possible to modify the spectra of two-dimensional electron systems and, ultimately, create materials with tailored electronic properties. In previous studies (see, for example, refs 1, 2, 3, 4, 5, 6, 7, 8), it proved difficult to realize superlattices with short periodicities and weak disorder, and most of their observed features could be explained in terms of cyclotron orbits commensurate with the superlattice. Evidence for the formation of superlattice minibands (forming a fractal spectrum known as Hofstadter's butterfly) has been limited to the observation of new low-field oscillations and an internal structure within Landau levels. Here we report transport properties of graphene placed on a boron nitride substrate and accurately aligned along its crystallographic directions. The substrate's moire potential acts as a superlattice and leads to profound changes in the graphene's electronic spectrum. Second-generation Dirac points appear as pronounced peaks in resistivity, accompanied by reversal of the Hall effect. The latter indicates that the effective sign of the charge carriers changes within graphene's conduction and valence bands. Strong magnetic fields lead to Zak-type cloning of the third generation of Dirac points, which are observed as numerous neutrality points in fields where a unit fraction of the flux quantum pierces the superlattice unit cell. Graphene superlattices such as this one provide a way of studying the rich physics expected in incommensurable quantum systems and illustrate the possibility of controllably modifying the electronic spectra of two-dimensional atomic crystals by varying their crystallographic alignment within van der Waals heterostuctures.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676678&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676677 Publication Date: 2013 May 15 PMID: 23676677<br/>Authors: Li, D. - Lyons, J. A. - Pye, V. E. - Vogeley, L. - Aragao, D. - Kenyon, C. P. - Shah, S. T. - Doherty, C. - Aherne, M. - Caffrey, M.<br/>Journal: Nature<br/><br/>Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue kinase has served as a model for investigating membrane protein enzymology, folding, assembly and stability. Here we present crystal structures for three functional forms of this unique and paradigmatic kinase, one of which is wild type. These reveal a homo-trimeric enzyme with three transmembrane helices and an amino-terminal amphiphilic helix per monomer. Bound lipid substrate and docked ATP identify the putative active site that is of the composite, shared site type. The crystal structures rationalize extensive biochemical and biophysical data on the enzyme. They are, however, at variance with a published solution NMR model in that domain swapping, a key feature of the solution form, is not observed in the crystal structures.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676677&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676676 Publication Date: 2013 May 15 PMID: 23676676<br/>Authors: Gordon, D. M.<br/>Journal: Nature<br/><br/>Collective behaviour, arising from local interactions, allows groups to respond to changing conditions. Long-term studies have shown that the traits of individual mammals and birds are associated with their reproductive success, but little is known about the evolutionary ecology of collective behaviour in natural populations. An ant colony operates without central control, regulating its activity through a network of local interactions. This work shows that variation among harvester ant (Pogonomyrmex barbatus) colonies in collective response to changing conditions is related to variation in colony lifetime reproductive success in the production of offspring colonies. Desiccation costs are high for harvester ants foraging in the desert. More successful colonies tend to forage less when conditions are dry, and show relatively stable foraging activity when conditions are more humid. Restraint from foraging does not compromise a colony's long-term survival; colonies that fail to forage at all on many days survive as long, over the colony's 20-30-year lifespan, as those that forage more regularly. Sensitivity to conditions in which to reduce foraging activity may be transmissible from parent to offspring colony. These results indicate that natural selection is shaping the collective behaviour that regulates foraging activity, and that the selection pressure, related to climate, may grow stronger if the current drought in their habitat persists.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676676&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676675 Publication Date: 2013 May 15 PMID: 23676675<br/>Authors: Sauro, H. M. - Kim, K.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676675&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676674 Publication Date: 2013 May 15 PMID: 23676674<br/>Authors: Wu, L. - Candille, S. I. - Choi, Y. - Xie, D. - Jiang, L. - Li-Pook-Than, J. - Tang, H. - Snyder, M.<br/>Journal: Nature<br/><br/>Gene expression differs among individuals and populations and is thought to be a major determinant of phenotypic variation. Although variation and genetic loci responsible for RNA expression levels have been analysed extensively in human populations, our knowledge is limited regarding the differences in human protein abundance and the genetic basis for this difference. Variation in messenger RNA expression is not a perfect surrogate for protein expression because the latter is influenced by an array of post-transcriptional regulatory mechanisms, and, empirically, the correlation between protein and mRNA levels is generally modest. Here we used isobaric tag-based quantitative mass spectrometry to determine relative protein levels of 5,953 genes in lymphoblastoid cell lines from 95 diverse individuals genotyped in the HapMap Project. We found that protein levels are heritable molecular phenotypes that exhibit considerable variation between individuals, populations and sexes. Levels of specific sets of proteins involved in the same biological process covary among individuals, indicating that these processes are tightly regulated at the protein level. We identified cis-pQTLs (protein quantitative trait loci), including variants not detected by previous transcriptome studies. This study demonstrates the feasibility of high-throughput human proteome quantification that, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676674&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676673 Publication Date: 2013 May 15 PMID: 23676673<br/>Authors: Dean, C. R. - Wang, L. - Maher, P. - Forsythe, C. - Ghahari, F. - Gao, Y. - Katoch, J. - Ishigami, M. - Moon, P. - Koshino, M. - Taniguchi, T. - Watanabe, K. - Shepard, K. L. - Hone, J. - Kim, P.<br/>Journal: Nature<br/><br/>Electrons moving through a spatially periodic lattice potential develop a quantized energy spectrum consisting of discrete Bloch bands. In two dimensions, electrons moving through a magnetic field also develop a quantized energy spectrum, consisting of highly degenerate Landau energy levels. When subject to both a magnetic field and a periodic electrostatic potential, two-dimensional systems of electrons exhibit a self-similar recursive energy spectrum. Known as Hofstadter's butterfly, this complex spectrum results from an interplay between the characteristic lengths associated with the two quantizing fields, and is one of the first quantum fractals discovered in physics. In the decades since its prediction, experimental attempts to study this effect have been limited by difficulties in reconciling the two length scales. Typical atomic lattices (with periodicities of less than one nanometre) require unfeasibly large magnetic fields to reach the commensurability condition, and in artificially engineered structures (with periodicities greater than about 100 nanometres) the corresponding fields are too small to overcome disorder completely. Here we demonstrate that moire superlattices arising in bilayer graphene coupled to hexagonal boron nitride provide a periodic modulation with ideal length scales of the order of ten nanometres, enabling unprecedented experimental access to the fractal spectrum. We confirm that quantum Hall features associated with the fractal gaps are described by two integer topological quantum numbers, and report evidence of their recursive structure. Observation of a Hofstadter spectrum in bilayer graphene means that it is possible to investigate emergent behaviour within a fractal energy landscape in a system with tunable internal degrees of freedom.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676673&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676672 Publication Date: 2013 May 15 PMID: 23676672<br/>Authors: Zheng, J. - Jia, Z.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676672&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676671 Publication Date: 2013 May 15 PMID: 23676671<br/>Authors: Landgraf, B. J. - Booker, S. J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676671&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676670 Publication Date: 2013 May 15 PMID: 23676670<br/>Authors: Kim, J. - Xiao, H. - Bonanno, J. B. - Kalyanaraman, C. - Brown, S. - Tang, X. - Al-Obaidi, N. F. - Patskovsky, Y. - Babbitt, P. C. - Jacobson, M. P. - Lee, Y. S. - Almo, S. C.<br/>Journal: Nature<br/><br/>The identification of novel metabolites and the characterization of their biological functions are major challenges in biology. X-ray crystallography can reveal unanticipated ligands that persist through purification and crystallization. These adventitious protein-ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand consistent with Cx-SAM in the catalytic site. Mechanistic analyses showed an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine into 5-oxyacetyl uridine at the wobble position of multiple tRNAs in Gram-negative bacteria, resulting in expanded codon-recognition properties. CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676670&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23676669 Publication Date: 2013 May 15 PMID: 23676669<br/>Authors: Sistla, S. A. - Moore, J. C. - Simpson, R. T. - Gough, L. - Shaver, G. R. - Schimel, J. P.<br/>Journal: Nature<br/><br/>High latitudes contain nearly half of global soil carbon, prompting interest in understanding how the Arctic terrestrial carbon balance will respond to rising temperatures. Low temperatures suppress the activity of soil biota, retarding decomposition and nitrogen release, which limits plant and microbial growth. Warming initially accelerates decomposition, increasing nitrogen availability, productivity and woody-plant dominance. However, these responses may be transitory, because coupled abiotic-biotic feedback loops that alter soil-temperature dynamics and change the structure and activity of soil communities, can develop. Here we report the results of a two-decade summer warming experiment in an Alaskan tundra ecosystem. Warming increased plant biomass and woody dominance, indirectly increased winter soil temperature, homogenized the soil trophic structure across horizons and suppressed surface-soil-decomposer activity, but did not change total soil carbon or nitrogen stocks, thereby increasing net ecosystem carbon storage. Notably, the strongest effects were in the mineral horizon, where warming increased decomposer activity and carbon stock: a 'biotic awakening' at depth.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23676669&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23665962 Publication Date: 2013 May 12 PMID: 23665962<br/>Authors: Commisso, C. - Davidson, S. M. - Soydaner-Azeloglu, R. G. - Parker, S. J. - Kamphorst, J. J. - Hackett, S. - Grabocka, E. - Nofal, M. - Drebin, J. A. - Thompson, C. B. - Rabinowitz, J. D. - Metallo, C. M. - Vander Heiden, M. G. - Bar-Sagi, D.<br/>Journal: Nature<br/><br/>Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23665962&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23665961 Publication Date: 2013 May 12 PMID: 23665961<br/>Authors: Ibarra-Laclette, E. - Lyons, E. - Hernandez-Guzman, G. - Perez-Torres, C. A. - Carretero-Paulet, L. - Chang, T. H. - Lan, T. - Welch, A. J. - Juarez, M. J. - Simpson, J. - Fernandez-Cortes, A. - Arteaga-Vazquez, M. - Gongora-Castillo, E. - Acevedo-Hernandez, G. - Schuster, S. C. - Himmelbauer, H. - Minoche, A. E. - Xu, S. - Lynch, M. - Oropeza-Aburto, A. - Cervantes-Perez, S. A. - de Jesus Ortega-Estrada, M. - Cervantes-Luevano, J. I. - Michael, T. P. - Mockler, T. - Bryant, D. - Herrera-Estrella, A. - Albert, V. A. - Herrera-Estrella, L.<br/>Journal: Nature<br/><br/>It has been argued that the evolution of plant genome size is principally unidirectional and increasing owing to the varied action of whole-genome duplications (WGDs) and mobile element proliferation. However, extreme genome size reductions have been reported in the angiosperm family tree. Here we report the sequence of the 82-megabase genome of the carnivorous bladderwort plant Utricularia gibba. Despite its tiny size, the U. gibba genome accommodates a typical number of genes for a plant, with the main difference from other plant genomes arising from a drastic reduction in non-genic DNA. Unexpectedly, we identified at least three rounds of WGD in U. gibba since common ancestry with tomato (Solanum) and grape (Vitis). The compressed architecture of the U. gibba genome indicates that a small fraction of intergenic DNA, with few or no active retrotransposons, is sufficient to regulate and integrate all the processes required for the development and reproduction of a complex organism.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23665961&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23665960 Publication Date: 2013 May 12 PMID: 23665960<br/>Authors: Zheng, H. - Wisedchaisri, G. - Gonen, T.<br/>Journal: Nature<br/><br/>Mineral nitrogen in nature is often found in the form of nitrate (NO3-). Numerous microorganisms evolved to assimilate nitrate and use it as a major source of mineral nitrogen uptake. Nitrate, which is central in nitrogen metabolism, is first reduced to nitrite (NO2-) through a two-electron reduction reaction. The accumulation of cellular nitrite can be harmful because nitrite can be reduced to the cytotoxic nitric oxide. Instead, nitrite is rapidly removed from the cell by channels and transporters, or reduced to ammonium or dinitrogen through the action of assimilatory enzymes. Despite decades of effort no structure is currently available for any nitrate transport protein and the mechanism by which nitrate is transported remains largely unknown. Here we report the structure of a bacterial nitrate/nitrite transport protein, NarK, from Escherichia coli, with and without substrate. The structures reveal a positively charged substrate-translocation pathway lacking protonatable residues, suggesting that NarK functions as a nitrate/nitrite exchanger and that protons are unlikely to be co-transported. Conserved arginine residues comprise the substrate-binding pocket, which is formed by association of helices from the two halves of NarK. Key residues that are important for substrate recognition and transport are identified and related to extensive mutagenesis and functional studies. We propose that NarK exchanges nitrate for nitrite by a rocker switch mechanism facilitated by inter-domain hydrogen bond networks.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23665960&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23665959 Publication Date: 2013 May 12 PMID: 23665959<br/>Authors: Zaidi, S. - Choi, M. - Wakimoto, H. - Ma, L. - Jiang, J. - Overton, J. D. - Romano-Adesman, A. - Bjornson, R. D. - Breitbart, R. E. - Brown, K. K. - Carriero, N. J. - Cheung, Y. H. - Deanfield, J. - Depalma, S. - Fakhro, K. A. - Glessner, J. - Hakonarson, H. - Italia, M. J. - Kaltman, J. R. - Kaski, J. - Kim, R. - Kline, J. K. - Lee, T. - Leipzig, J. - Lopez, A. - Mane, S. M. - Mitchell, L. E. - Newburger, J. W. - Parfenov, M. - Pe'er, I. - Porter, G. - Roberts, A. E. - Sachidanandam, R. - Sanders, S. J. - Seiden, H. S. - State, M. W. - Subramanian, S. - Tikhonova, I. R. - Wang, W. - Warburton, D. - White, P. S. - Williams, I. A. - Zhao, H. - Seidman, J. G. - Brueckner, M. - Chung, W. K. - Gelb, B. D. - Goldmuntz, E. - Seidman, C. E. - Lifton, R. P.<br/>Journal: Nature<br/><br/>Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23665959&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657350 Publication Date: 2013 May 9 PMID: 23657350<br/>Authors: Nick, F. M. - Vieli, A. - Andersen, M. L. - Joughin, I. - Payne, A. - Edwards, T. L. - Pattyn, F. - van de Wal, R. S.<br/>Journal: Nature<br/><br/>Over the past decade, ice loss from the Greenland Ice Sheet increased as a result of both increased surface melting and ice discharge to the ocean. The latter is controlled by the acceleration of ice flow and subsequent thinning of fast-flowing marine-terminating outlet glaciers. Quantifying the future dynamic contribution of such glaciers to sea-level rise (SLR) remains a major challenge because outlet glacier dynamics are poorly understood. Here we present a glacier flow model that includes a fully dynamic treatment of marine termini. We use this model to simulate behaviour of four major marine-terminating outlet glaciers, which collectively drain about 22 per cent of the Greenland Ice Sheet. Using atmospheric and oceanic forcing from a mid-range future warming scenario that predicts warming by 2.8 degrees Celsius by 2100, we project a contribution of 19 to 30 millimetres to SLR from these glaciers by 2200. This contribution is largely (80 per cent) dynamic in origin and is caused by several episodic retreats past overdeepenings in outlet glacier troughs. After initial increases, however, dynamic losses from these four outlets remain relatively constant and contribute to SLR individually at rates of about 0.01 to 0.06 millimetres per year. These rates correspond to ice fluxes that are less than twice those of the late 1990s, well below previous upper bounds. For a more extreme future warming scenario (warming by 4.5 degrees Celsius by 2100), the projected losses increase by more than 50 per cent, producing a cumulative SLR of 29 to 49 millimetres by 2200.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657350&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657349 Publication Date: 2013 May 9 PMID: 23657349<br/>Authors: Wolfe, S. A. - Pisano, D. J. - Lockman, F. J. - McGaugh, S. S. - Shaya, E. J.<br/>Journal: Nature<br/><br/>Spiral galaxies must acquire gas to maintain their observed level of star formation beyond the next few billion years. A source of this material may be the gas that resides between galaxies, but our understanding of the state and distribution of this gas is incomplete. Radio observations of the Local Group of galaxies have revealed hydrogen gas extending from the disk of the galaxy M31 at least halfway to M33. This feature has been interpreted to be the neutral component of a condensing intergalactic filament, which would be able to fuel star formation in M31 and M33, but simulations suggest that such a feature could also result from an interaction between both galaxies within the past few billion years (ref. 5). Here we report radio observations showing that about 50 per cent of this gas is composed of clouds, with the rest distributed in an extended, diffuse component. The clouds have velocities comparable to those of M31 and M33, and have properties suggesting that they are unrelated to other Local Group objects. We conclude that the clouds are likely to be transient condensations of gas embedded in an intergalactic filament and are therefore a potential source of fuel for future star formation in M31 and M33.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657349&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657348 Publication Date: 2013 May 9 PMID: 23657348<br/>Authors: Gaffney, L. P. - Butler, P. A. - Scheck, M. - Hayes, A. B. - Wenander, F. - Albers, M. - Bastin, B. - Bauer, C. - Blazhev, A. - Bonig, S. - Bree, N. - Cederkall, J. - Chupp, T. - Cline, D. - Cocolios, T. E. - Davinson, T. - De Witte, H. - Diriken, J. - Grahn, T. - Herzan, A. - Huyse, M. - Jenkins, D. G. - Joss, D. T. - Kesteloot, N. - Konki, J. - Kowalczyk, M. - Kroll, T. - Kwan, E. - Lutter, R. - Moschner, K. - Napiorkowski, P. - Pakarinen, J. - Pfeiffer, M. - Radeck, D. - Reiter, P. - Reynders, K. - Rigby, S. V. - Robledo, L. M. - Rudigier, M. - Sambi, S. - Seidlitz, M. - Siebeck, B. - Stora, T. - Thoele, P. - Van Duppen, P. - Vermeulen, M. J. - von Schmid, M. - Voulot, D. - Warr, N. - Wimmer, K. - Wrzosek-Lipska, K. - Wu, C. Y. - Zielinska, M.<br/>Journal: Nature<br/><br/>There is strong circumstantial evidence that certain heavy, unstable atomic nuclei are 'octupole deformed', that is, distorted into a pear shape. This contrasts with the more prevalent rugby-ball shape of nuclei with reflection-symmetric, quadrupole deformations. The elusive octupole deformed nuclei are of importance for nuclear structure theory, and also in searches for physics beyond the standard model; any measurable electric-dipole moment (a signature of the latter) is expected to be amplified in such nuclei. Here we determine electric octupole transition strengths (a direct measure of octupole correlations) for short-lived isotopes of radon and radium. Coulomb excitation experiments were performed using accelerated beams of heavy, radioactive ions. Our data on (220)Rn and (224)Ra show clear evidence for stronger octupole deformation in the latter. The results enable discrimination between differing theoretical approaches to octupole correlations, and help to constrain suitable candidates for experimental studies of atomic electric-dipole moments that might reveal extensions to the standard model.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657348&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657346 Publication Date: 2013 May 9 PMID: 23657346<br/>Authors: Smith-Garvin, J. E. - Sigal, L. J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657346&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657345 Publication Date: 2013 May 9 PMID: 23657345<br/>Authors: Braun, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657345&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657344 Publication Date: 2013 May 9 PMID: 23657344<br/>Authors: Lister, C. J. - Butterworth, J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657344&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657343 Publication Date: 2013 May 9 PMID: 23657343<br/>Authors: Shepherd, J. - Abegaz, B. - Long, J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657343&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657341 Publication Date: 2013 May 9 PMID: 23657341<br/>Authors: Decourtye, A. - Henry, M. - Desneux, N.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657341&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657340 Publication Date: 2013 May 9 PMID: 23657340<br/>Authors: Lees, A. C. - Vieira, I. C.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657340&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657339 Publication Date: 2013 May 9 PMID: 23657339<br/>Authors: Harris, H.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657339&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657334 Publication Date: 2013 May 9 PMID: 23657334<br/>Authors: Hublin, J. J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657334&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657333 Publication Date: 2013 May 9 PMID: 23657333<br/>Authors: Burns, L. D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657333&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657332 Publication Date: 2013 May 9 PMID: 23657332<br/>Authors: Solow, A. R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657332&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657331 Publication Date: 2013 May 9 PMID: 23657331<br/>Authors: Kwok, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657331&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657330 Publication Date: 2013 May 9 PMID: 23657330<br/>Authors: Hayden, E. C.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657330&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657329 Publication Date: 2013 May 9 PMID: 23657329<br/>Authors: Reich, E. S.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657329&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657328 Publication Date: 2013 May 9 PMID: 23657328<br/>Authors: Peplow, M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657328&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657327 Publication Date: 2013 May 9 PMID: 23657327<br/>Authors: Schiermeier, Q.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657327&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657326 Publication Date: 2013 May 9 PMID: 23657326<br/>Authors: Tollefson, J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657326&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657314 Publication Date: 2013 May 9 PMID: 23657314<br/>Authors: Wang, Q.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657314&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657313 Publication Date: 2013 May 9 PMID: 23657313<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657313&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657312 Publication Date: 2013 May 9 PMID: 23657312<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657312&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657311 Publication Date: 2013 May 9 PMID: 23657311<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657311&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657261 Publication Date: 2013 May 8 PMID: 23657261<br/>Authors: Paeschke, K. - Bochman, M. L. - Garcia, P. D. - Cejka, P. - Friedman, K. L. - Kowalczykowski, S. C. - Zakian, V. A.<br/>Journal: Nature<br/><br/>The Saccharomyces cerevisiae Pif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteria to humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1 helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolution suppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generated in the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressed in yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657261&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657260 Publication Date: 2013 May 16 PMID: 23657260<br/>Authors: Romling, U.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657260&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657259 Publication Date: 2013 May 16 PMID: 23657259<br/>Authors: Zhao, K. - Tseng, B. S. - Beckerman, B. - Jin, F. - Gibiansky, M. L. - Harrison, J. J. - Luijten, E. - Parsek, M. R. - Wong, G. C.<br/>Journal: Nature<br/><br/>Bacterial biofilms are surface-associated, multicellular, morphologically complex microbial communities. Biofilm-forming bacteria such as the opportunistic pathogen Pseudomonas aeruginosa are phenotypically distinct from their free-swimming, planktonic counterparts. Much work has focused on factors affecting surface adhesion, and it is known that P. aeruginosa secretes the Psl exopolysaccharide, which promotes surface attachment by acting as 'molecular glue'. However, how individual surface-attached bacteria self-organize into microcolonies, the first step in communal biofilm organization, is not well understood. Here we identify a new role for Psl in early biofilm development using a massively parallel cell-tracking algorithm to extract the motility history of every cell on a newly colonized surface. By combining this technique with fluorescent Psl staining and computer simulations, we show that P. aeruginosa deposits a trail of Psl as it moves on a surface, which influences the surface motility of subsequent cells that encounter these trails and thus generates positive feedback. Both experiments and simulations indicate that the web of secreted Psl controls the distribution of surface visit frequencies, which can be approximated by a power law. This Pareto-type behaviour indicates that the bacterial community self-organizes in a manner analogous to a capitalist economic system, a 'rich-get-richer' mechanism of Psl accumulation that results in a small number of 'elite' cells becoming extremely enriched in communally produced Psl. Using engineered strains with inducible Psl production, we show that local Psl concentrations determine post-division cell fates and that high local Psl concentrations ultimately allow elite cells to serve as the founding population for initial microcolony development.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657259&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657258 Publication Date: 2013 May 16 PMID: 23657258<br/>Authors: Salichos, L. - Rokas, A.<br/>Journal: Nature<br/><br/>To tackle incongruence, the topological conflict between different gene trees, phylogenomic studies couple concatenation with practices such as rogue taxon removal or the use of slowly evolving genes. Phylogenomic analysis of 1,070 orthologues from 23 yeast genomes identified 1,070 distinct gene trees, which were all incongruent with the phylogeny inferred from concatenation. Incongruence severity increased for shorter internodes located deeper in the phylogeny. Notably, whereas most practices had little or negative impact on the yeast phylogeny, the use of genes or internodes with high average internode support significantly improved the robustness of inference. We obtained similar results in analyses of vertebrate and metazoan phylogenomic data sets. These results question the exclusive reliance on concatenation and associated practices, and argue that selecting genes with strong phylogenetic signals and demonstrating the absence of significant incongruence are essential for accurately reconstructing ancient divergences.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657258&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657257 Publication Date: 2013 May 8 PMID: 23657257<br/>Authors: Zhu, J. - Peng, T. - Johnston, C. - Phasouk, K. - Kask, A. S. - Klock, A. - Jin, L. - Diem, K. - Koelle, D. M. - Wald, A. - Robins, H. - Corey, L.<br/>Journal: Nature<br/><br/>Most herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown that CD8+ T cells persist in genital skin and mucosa at the dermal-epidermal junction (DEJ)-the portal of neuronal release of reactivating virus-for prolonged time periods after herpes lesions are cleared. The phenotype and function of this persistent CD8+ T-cell population remain unknown. Here, using cell-type-specific laser capture microdissection, transcriptional profiling and T-cell antigen receptor beta-chain (TCRbeta) genotyping on sequential genital skin biopsies, we show that CD8alphaalpha+ T cells are the dominant resident population of DEJ CD8+ T cells that persist at the site of previous HSV-2 reactivation. CD8alphaalpha+ T cells located at the DEJ lack chemokine-receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCR beta-chain repertoire reveals that the DEJ CD8alphaalpha+ T cells are oligoclonal with diverse usage of TCR variable-beta genes, which differ from those commonly described for mucosa-associated invariant T cells and natural killer T cells. Dominant clonotypes are shown to overlap among multiple recurrences over a period of two-and-a-half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8alphaalpha+ T cells. These studies indicate that DEJ CD8alphaalpha+ T cells are tissue-resident cells that seem to have a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8alphaalpha+ T cells may be a critical component for developing effective vaccines against skin and mucosal infections.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657257&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657256 Publication Date: 2013 May 8 PMID: 23657256<br/>Authors: Kim, C. - Schmidt, T. - Cho, E. G. - Ye, F. - Ulmer, T. S. - Ginsberg, M. H.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657256&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657255 Publication Date: 2013 May 8 PMID: 23657255<br/>Authors: Mirkin, S. M.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657255&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657254 Publication Date: 2013 May 16 PMID: 23657254<br/>Authors: Allanore, A. - Yin, L. - Sadoway, D. R.<br/>Journal: Nature<br/><br/>Molten oxide electrolysis (MOE) is an electrometallurgical technique that enables the direct production of metal in the liquid state from oxide feedstock, and compared with traditional methods of extractive metallurgy offers both a substantial simplification of the process and a significant reduction in energy consumption. MOE is also considered a promising route for mitigation of CO2 emissions in steelmaking, production of metals free of carbon, and generation of oxygen for extra-terrestrial exploration. Until now, MOE has been demonstrated using anode materials that are consumable (graphite for use with ferro-alloys and titanium) or unaffordable for terrestrial applications (iridium for use with iron). To enable metal production without process carbon, MOE requires an anode material that resists depletion while sustaining oxygen evolution. The challenges for iron production are threefold. First, the process temperature is in excess of 1,538 degrees Celsius (ref. 10). Second, under anodic polarization most metals inevitably corrode in such conditions. Third, iron oxide undergoes spontaneous reduction on contact with most refractory metals and even carbon. Here we show that anodes comprising chromium-based alloys exhibit limited consumption during iron extraction and oxygen evolution by MOE. The anode stability is due to the formation of an electronically conductive solid solution of chromium(iii) and aluminium oxides in the corundum structure. These findings make practicable larger-scale evaluation of MOE for the production of steel, and potentially provide a key material component enabling mitigation of greenhouse-gas emissions while producing metal of superior metallurgical quality.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657254&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23657253 Publication Date: 2013 May 16 PMID: 23657253<br/>Authors: Fray, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23657253&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23646365 Publication Date: 2013 May 2 PMID: 23646365<br/>Authors: Kaplan, K.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23646365&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23646364 Publication Date: 2013 May 2 PMID: 23646364<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23646364&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23646363 Publication Date: 2013 May 2 PMID: 23646363<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23646363&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23646362 Publication Date: 2013 May 2 PMID: 23646362<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23646362&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23644460 Publication Date: 2013 May 5 PMID: 23644460<br/>Authors: Yadlapalli, S. - Yamashita, Y. M.<br/>Journal: Nature<br/><br/>Adult stem cells undergo asymmetric cell division to self-renew and give rise to differentiated cells that comprise mature tissue. Sister chromatids may be distinguished and segregated nonrandomly in asymmetrically dividing stem cells, although the underlying mechanism and the purpose it may serve remain elusive. Here we develop the CO-FISH (chromosome orientation fluorescence in situ hybridization) technique with single-chromosome resolution and show that sister chromatids of X and Y chromosomes, but not autosomes, are segregated nonrandomly during asymmetric divisions of Drosophila male germline stem cells. This provides the first direct evidence, to our knowledge, that two sister chromatids containing identical genetic information can be distinguished and segregated nonrandomly during asymmetric stem-cell divisions. We further show that the centrosome, SUN-KASH nuclear envelope proteins and Dnmt2 (also known as Mt2) are required for nonrandom sister chromatid segregation. Our data indicate that the information on X and Y chromosomes that enables nonrandom segregation is primed during gametogenesis in the parents. Moreover, we show that sister chromatid segregation is randomized in germline stem cell overproliferation and dedifferentiated germline stem cells. We propose that nonrandom sister chromatid segregation may serve to transmit distinct information carried on two sister chromatids to the daughters of asymmetrically dividing stem cells.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23644460&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23644459 Publication Date: 2013 May 16 PMID: 23644459<br/>Authors: Dvinge, H. - Git, A. - Graf, S. - Salmon-Divon, M. - Curtis, C. - Sottoriva, A. - Zhao, Y. - Hirst, M. - Armisen, J. - Miska, E. A. - Chin, S. F. - Provenzano, E. - Turashvili, G. - Green, A. - Ellis, I. - Aparicio, S. - Caldas, C.<br/>Journal: Nature<br/><br/>MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23644459&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23644458 Publication Date: 2013 May 5 PMID: 23644458<br/>Authors: Ho, C. Y. - Jaalouk, D. E. - Vartiainen, M. K. - Lammerding, J.<br/>Journal: Nature<br/><br/>Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison-Gilford progeria syndrome. Most LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and altered interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes. Here we report in mice that lamin-A/C-deficient (Lmna-/-) and LmnaN195K/N195K mutant cells have impaired nuclear translocation and downstream signalling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function. Altered nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna-/- and LmnaN195K/N195K mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmna mutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease aetiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23644458&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23644457 Publication Date: 2013 May 5 PMID: 23644457<br/>Authors: Park, S. - Li, X. - Kim, H. M. - Singh, C. R. - Tian, G. - Hoyt, M. A. - Lovell, S. - Battaile, K. P. - Zolkiewski, M. - Coffino, P. - Roelofs, J. - Cheng, Y. - Finley, D.<br/>Journal: Nature<br/><br/>The proteasomal ATPase ring, comprising Rpt1-Rpt6, associates with the heptameric alpha-ring of the proteasome core particle (CP) in the mature proteasome, with the Rpt carboxy-terminal tails inserting into pockets of the alpha-ring. Rpt ring assembly is mediated by four chaperones, each binding a distinct Rpt subunit. Here we report that the base subassembly of the Saccharomyces cerevisiae proteasome, which includes the Rpt ring, forms a high-affinity complex with the CP. This complex is subject to active dissociation by the chaperones Hsm3, Nas6 and Rpn14. Chaperone-mediated dissociation was abrogated by a non-hydrolysable ATP analogue, indicating that chaperone action is coupled to nucleotide hydrolysis by the Rpt ring. Unexpectedly, synthetic Rpt tail peptides bound alpha-pockets with poor specificity, except for Rpt6, which uniquely bound the alpha2/alpha3-pocket. Although the Rpt6 tail is not visualized within an alpha-pocket in mature proteasomes, it inserts into the alpha2/alpha3-pocket in the base-CP complex and is important for complex formation. Thus, the Rpt-CP interface is reconfigured when the lid complex joins the nascent proteasome to form the mature holoenzyme.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23644457&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23644456 Publication Date: 2013 May 5 PMID: 23644456<br/>Authors: Styrkarsdottir, U. - Thorleifsson, G. - Sulem, P. - Gudbjartsson, D. F. - Sigurdsson, A. - Jonasdottir, A. - Jonasdottir, A. - Oddsson, A. - Helgason, A. - Magnusson, O. T. - Walters, G. B. - Frigge, M. L. - Helgadottir, H. T. - Johannsdottir, H. - Bergsteinsdottir, K. - Ogmundsdottir, M. H. - Center, J. R. - Nguyen, T. V. - Eisman, J. A. - Christiansen, C. - Steingrimsson, E. - Jonasson, J. G. - Tryggvadottir, L. - Eyjolfsson, G. I. - Theodors, A. - Jonsson, T. - Ingvarsson, T. - Olafsson, I. - Rafnar, T. - Kong, A. - Sigurdsson, G. - Masson, G. - Thorsteinsdottir, U. - Stefansson, K.<br/>Journal: Nature<br/><br/>Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23644456&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23644455 Publication Date: 2013 May 5 PMID: 23644455<br/>Authors: Fukuda, T. - Takeda, S. - Xu, R. - Ochi, H. - Sunamura, S. - Sato, T. - Shibata, S. - Yoshida, Y. - Gu, Z. - Kimura, A. - Ma, C. - Xu, C. - Bando, W. - Fujita, K. - Shinomiya, K. - Hirai, T. - Asou, Y. - Enomoto, M. - Okano, H. - Okawa, A. - Itoh, H.<br/>Journal: Nature<br/><br/>Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a-/- mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a-/- mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1-/- and Sema3aosx-/- mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin-/- and Sema3anestin-/- mice) had low bone mass, similar to Sema3a-/- mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin-/- mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin-/- mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a-/- mice, such as olfactory development, were identified in Sema3asynasin-/- mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a-/- mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23644455&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23644454 Publication Date: 2013 May 5 PMID: 23644454<br/>Authors: Kasuga, H. - Fukuyama, M. - Kitazawa, A. - Kontani, K. - Katada, T.<br/>Journal: Nature<br/><br/>The coordination of stem- and blast-cell behaviours, such as self-renewal, differentiation and quiescence, with physiological changes underlies growth, regeneration and tissue homeostasis. Germline stem and somatic blast cells in newly hatched Caenorhabditis elegans larvae can suspend postembryonic development, which consists of diverse cellular events such as migration, proliferation and differentiation, until the nutritional state becomes favourable (termed L1 diapause). Although previous studies showed that the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway regulates this developmental quiescence, the detailed mechanism by which the IIS pathway enables these multipotent cells to respond to nutrient availability is unknown. Here we show in C. elegans that the microRNA (miRNA) miR-235, a sole orthologue of mammalian miR-92 from the oncogenic miR-17-92 cluster, acts in the hypodermis and glial cells to arrest postembryonic developmental events in both neuroblasts and mesoblasts. Expression of mir-235 persists during L1 diapause, and decreases upon feeding in a manner dependent on the IIS pathway. Upregulation of one of the miR-235 targets, nhr-91, which encodes an orthologue of mammalian germ cell nuclear factor, is responsible for defects caused by loss of the miRNA. Our findings establish a novel role of a miR-92 orthologue in coupling blast-cell behaviours to the nutritional state.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23644454&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636401 Publication Date: 2013 May 2 PMID: 23636401<br/>Authors: Song, Y. M. - Xie, Y. - Malyarchuk, V. - Xiao, J. - Jung, I. - Choi, K. J. - Liu, Z. - Park, H. - Lu, C. - Kim, R. H. - Li, R. - Crozier, K. B. - Huang, Y. - Rogers, J. A.<br/>Journal: Nature<br/><br/>In arthropods, evolution has created a remarkably sophisticated class of imaging systems, with a wide-angle field of view, low aberrations, high acuity to motion and an infinite depth of field. A challenge in building digital cameras with the hemispherical, compound apposition layouts of arthropod eyes is that essential design requirements cannot be met with existing planar sensor technologies or conventional optics. Here we present materials, mechanics and integration schemes that afford scalable pathways to working, arthropod-inspired cameras with nearly full hemispherical shapes (about 160 degrees). Their surfaces are densely populated by imaging elements (artificial ommatidia), which are comparable in number (180) to those of the eyes of fire ants (Solenopsis fugax) and bark beetles (Hylastes nigrinus). The devices combine elastomeric compound optical elements with deformable arrays of thin silicon photodetectors into integrated sheets that can be elastically transformed from the planar geometries in which they are fabricated to hemispherical shapes for integration into apposition cameras. Our imaging results and quantitative ray-tracing-based simulations illustrate key features of operation. These general strategies seem to be applicable to other compound eye devices, such as those inspired by moths and lacewings (refracting superposition eyes), lobster and shrimp (reflecting superposition eyes), and houseflies (neural superposition eyes).<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636401&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636400 Publication Date: 2013 May 2 PMID: 23636400<br/>Authors: Yin, C. - Rancic, M. - de Boo, G. G. - Stavrias, N. - McCallum, J. C. - Sellars, M. J. - Rogge, S.<br/>Journal: Nature<br/><br/>The detection of electron spins associated with single defects in solids is a critical operation for a range of quantum information and measurement applications under development. So far, it has been accomplished for only two defect centres in crystalline solids: phosphorus dopants in silicon, for which electrical read-out based on a single-electron transistor is used, and nitrogen-vacancy centres in diamond, for which optical read-out is used. A spin read-out fidelity of about 90 per cent has been demonstrated with both electrical read-out and optical read-out; however, the thermal limitations of the former and the poor photon collection efficiency of the latter make it difficult to achieve the higher fidelities required for quantum information applications. Here we demonstrate a hybrid approach in which optical excitation is used to change the charge state (conditional on its spin state) of an erbium defect centre in a silicon-based single-electron transistor, and this change is then detected electrically. The high spectral resolution of the optical frequency-addressing step overcomes the thermal broadening limitation of the previous electrical read-out scheme, and the charge-sensing step avoids the difficulties of efficient photon collection. This approach could lead to new architectures for quantum information processing devices and could drastically increase the range of defect centres that can be exploited. Furthermore, the efficient electrical detection of the optical excitation of single sites in silicon represents a significant step towards developing interconnects between optical-based quantum computing and silicon technologies.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636400&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636399 Publication Date: 2013 May 2 PMID: 23636399<br/>Authors: Anger, A. M. - Armache, J. P. - Berninghausen, O. - Habeck, M. - Subklewe, M. - Wilson, D. N. - Beckmann, R.<br/>Journal: Nature<br/><br/>Protein synthesis in all cells is carried out by macromolecular machines called ribosomes. Although the structures of prokaryotic, yeast and protist ribosomes have been determined, the more complex molecular architecture of metazoan 80S ribosomes has so far remained elusive. Here we present structures of Drosophila melanogaster and Homo sapiens 80S ribosomes in complex with the translation factor eEF2, E-site transfer RNA and Stm1-like proteins, based on high-resolution cryo-electron-microscopy density maps. These structures not only illustrate the co-evolution of metazoan-specific ribosomal RNA with ribosomal proteins but also reveal the presence of two additional structural layers in metazoan ribosomes, a well-ordered inner layer covered by a flexible RNA outer layer. The human and Drosophila ribosome structures will provide the basis for more detailed structural, biochemical and genetic experiments.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636399&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636398 Publication Date: 2013 May 2 PMID: 23636398<br/>Authors: Kandoth, C. - Schultz, N. - Cherniack, A. D. - Akbani, R. - Liu, Y. - Shen, H. - Robertson, A. G. - Pashtan, I. - Shen, R. - Benz, C. C. - Yau, C. - Laird, P. W. - Ding, L. - Zhang, W. - Mills, G. B. - Kucherlapati, R. - Mardis, E. R. - Levine, D. A.<br/>Journal: Nature<br/><br/>We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and approximately 25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636398&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636397 Publication Date: 2013 May 2 PMID: 23636397<br/>Authors: Schroeder, J. I. - Delhaize, E. - Frommer, W. B. - Guerinot, M. L. - Harrison, M. J. - Herrera-Estrella, L. - Horie, T. - Kochian, L. V. - Munns, R. - Nishizawa, N. K. - Tsay, Y. F. - Sanders, D.<br/>Journal: Nature<br/><br/>With the global population predicted to grow by at least 25 per cent by 2050, the need for sustainable production of nutritious foods is critical for human and environmental health. Recent advances show that specialized plant membrane transporters can be used to enhance yields of staple crops, increase nutrient content and increase resistance to key stresses, including salinity, pathogens and aluminium toxicity, which in turn could expand available arable land.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636397&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636396 Publication Date: 2013 May 2 PMID: 23636396<br/>Authors: Helbing, D.<br/>Journal: Nature<br/><br/>Today's strongly connected, global networks have produced highly interdependent systems that we do not understand and cannot control well. These systems are vulnerable to failure at all scales, posing serious threats to society, even when external shocks are absent. As the complexity and interaction strengths in our networked world increase, man-made systems can become unstable, creating uncontrollable situations even when decision-makers are well-skilled, have all data and technology at their disposal, and do their best. To make these systems manageable, a fundamental redesign is needed. A 'Global Systems Science' might create the required knowledge and paradigm shift in thinking.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636396&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636394 Publication Date: 2013 May 2 PMID: 23636394<br/>Authors: Clague, M. J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636394&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636393 Publication Date: 2013 May 2 PMID: 23636393<br/>Authors: Borst, A. - Plett, J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636393&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636392 Publication Date: 2013 May 2 PMID: 23636392<br/>Authors: Weis, C. D. - Schenkel, T.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636392&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636391 Publication Date: 2013 May 2 PMID: 23636391<br/>Authors: Halliday, A. N.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636391&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636390 Publication Date: 2013 May 2 PMID: 23636390<br/>Authors: Bayry, J.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636390&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636389 Publication Date: 2013 May 2 PMID: 23636389<br/>Authors: Huang, X. - Qiao, G. - Favret, C.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636389&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636388 Publication Date: 2013 May 2 PMID: 23636388<br/>Authors: DeCoursey, T. E.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636388&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636387 Publication Date: 2013 May 2 PMID: 23636387<br/>Authors: Bosch, X.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636387&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636386 Publication Date: 2013 May 2 PMID: 23636386<br/>Authors: Grunewald, W. - Bury, J. - Inze, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636386&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636381 Publication Date: 2013 May 2 PMID: 23636381<br/>Authors: Zhang, F. - Chen, X. - Vitousek, P.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636381&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636380 Publication Date: 2013 May 2 PMID: 23636380<br/>Authors: Whitty, C. J. - Jones, M. - Tollervey, A. - Wheeler, T.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636380&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636379 Publication Date: 2013 May 2 PMID: 23636379<br/>Authors: Cressey, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636379&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636378 Publication Date: 2013 May 2 PMID: 23636378<br/>Authors: Gilbert, N.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636378&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636377 Publication Date: 2013 May 2 PMID: 23636377<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636377&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636376 Publication Date: 2013 May 2 PMID: 23636376<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636376&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636375 Publication Date: 2013 May 2 PMID: 23636375<br/>Authors: Van Noorden, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636375&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636373 Publication Date: 2013 May 2 PMID: 23636373<br/>Authors: Mole, B.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636373&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636372 Publication Date: 2013 May 2 PMID: 23636372<br/>Authors: Ledford, H.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636372&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636371 Publication Date: 2013 May 2 PMID: 23636371<br/>Authors: Abbott, A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636371&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636370 Publication Date: 2013 May 2 PMID: 23636370<br/>Authors: Butler, D. - Cyranoski, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636370&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636369 Publication Date: 2013 May 2 PMID: 23636369<br/>Authors: Monastersky, R.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636369&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636356 Publication Date: 2013 May 2 PMID: 23636356<br/>Authors: Hilton, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636356&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636333 Publication Date: 2013 May 1 PMID: 23636333<br/>Authors: Znamenskiy, P. - Zador, A. M.<br/>Journal: Nature<br/><br/>The neural pathways by which information about the acoustic world reaches the auditory cortex are well characterized, but how auditory representations are transformed into motor commands is not known. Here we use a perceptual decision-making task in rats to study this transformation. We demonstrate the role of corticostriatal projection neurons in auditory decisions by manipulating the activity of these neurons in rats performing an auditory frequency-discrimination task. Targeted channelrhodopsin-2 (ChR2)-mediated stimulation of corticostriatal neurons during the task biased decisions in the direction predicted by the frequency tuning of the stimulated neurons, whereas archaerhodopsin-3 (Arch)-mediated inactivation biased decisions in the opposite direction. Striatal projections are widespread in cortex and may provide a general mechanism for the control of motor decisions by sensory cortex.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636333&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636332 Publication Date: 2013 May 1 PMID: 23636332<br/>Authors: Law, J. A. - Du, J. - Hale, C. J. - Feng, S. - Krajewski, K. - Palanca, A. M. - Strahl, B. D. - Patel, D. J. - Jacobsen, S. E.<br/>Journal: Nature<br/><br/>DNA methylation is an epigenetic modification that has critical roles in gene silencing, development and genome integrity. In Arabidopsis, DNA methylation is established by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and targeted by 24-nucleotide small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). This pathway requires two plant-specific RNA polymerases: Pol-IV, which functions to initiate siRNA biogenesis, and Pol-V, which functions to generate scaffold transcripts that recruit downstream RdDM factors. To understand the mechanisms controlling Pol-IV targeting we investigated the function of SAWADEE HOMEODOMAIN HOMOLOG 1 (SHH1), a Pol-IV-interacting protein. Here we show that SHH1 acts upstream in the RdDM pathway to enable siRNA production from a large subset of the most active RdDM targets, and that SHH1 is required for Pol-IV occupancy at these same loci. We also show that the SHH1 SAWADEE domain is a novel chromatin-binding module that adopts a unique tandem Tudor-like fold and functions as a dual lysine reader, probing for both unmethylated K4 and methylated K9 modifications on the histone 3 (H3) tail. Finally, we show that key residues within both lysine-binding pockets of SHH1 are required in vivo to maintain siRNA and DNA methylation levels as well as Pol-IV occupancy at RdDM targets, demonstrating a central role for methylated H3K9 binding in SHH1 function and providing the first insights into the mechanism of Pol-IV targeting. Given the parallels between methylation systems in plants and mammals, a further understanding of this early targeting step may aid our ability to control the expression of endogenous and newly introduced genes, which has broad implications for agriculture and gene therapy.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636332&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636331 Publication Date: 2013 May 1 PMID: 23636331<br/>Authors: Min, S. K. - Zhang, X. - Zwiers, F. W. - Hegerl, G. C.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636331&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636330 Publication Date: 2013 May 9 PMID: 23636330<br/>Authors: Zhang, G. - Li, J. - Purkayastha, S. - Tang, Y. - Zhang, H. - Yin, Y. - Li, B. - Liu, G. - Cai, D.<br/>Journal: Nature<br/><br/>Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IkappaB kinase-beta (IKK-beta), nuclear factor kappaB (NF-kappaB) and related microglia-neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-beta and NF-kappaB activation. Mechanistic studies further revealed that IKK-beta and NF-kappaB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636330&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636329 Publication Date: 2013 May 16 PMID: 23636329<br/>Authors: Shen, J. - Xia, W. - Khotskaya, Y. B. - Huo, L. - Nakanishi, K. - Lim, S. O. - Du, Y. - Wang, Y. - Chang, W. C. - Chen, C. H. - Hsu, J. L. - Wu, Y. - Lam, Y. C. - James, B. P. - Liu, X. - Liu, C. G. - Patel, D. J. - Hung, M. C.<br/>Journal: Nature<br/><br/>MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumour cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here we show that epidermal growth factor receptor (EGFR), which is the product of a well-characterized oncogene in human cancers, suppresses the maturation of specific tumour-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs. We also identify a long-loop structure in precursor miRNAs as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Furthermore, AGO2-Y393 phosphorylation mediates EGFR-enhanced cell survival and invasiveness under hypoxia, and correlates with poorer overall survival in breast cancer patients. Our study reveals a previously unrecognized function of EGFR in miRNA maturation and demonstrates how EGFR is likely to function as a regulator of AGO2 through novel post-translational modification. These findings suggest that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636329&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636328 Publication Date: 2013 May 9 PMID: 23636328<br/>Authors: Ritz, R. - Halder, M. - Wagner, M. - Franz, C. - Bauer, A. - Pfleiderer, C.<br/>Journal: Nature<br/><br/>Fermi liquid theory provides a remarkably powerful framework for the description of the conduction electrons in metals and their ordering phenomena, such as superconductivity, ferromagnetism, and spin- and charge-density-wave order. A different class of ordering phenomena of great interest concerns spin configurations that are topologically protected, that is, their topology can be destroyed only by forcing the average magnetization locally to zero. Examples of such configurations are hedgehogs (points at which all spins are either pointing inwards or outwards) and vortices. A central question concerns the nature of the metallic state in the presence of such topologically distinct spin textures. Here we report a high-pressure study of the metallic state at the border of the skyrmion lattice in MnSi, which represents a new form of magnetic order composed of topologically non-trivial vortices. When long-range magnetic order is suppressed under pressure, the key characteristic of the skyrmion lattice--that is, the topological Hall signal due to the emergent magnetic flux associated with the topological winding--is unaffected in sign or magnitude and becomes an important characteristic of the metallic state. The regime of the topological Hall signal in temperature, pressure and magnetic field coincides thereby with the exceptionally extended regime of a pronounced non-Fermi-liquid resistivity. The observation of this topological Hall signal in the regime of the NFL resistivity suggests empirically that spin correlations with non-trivial topological character may drive a breakdown of Fermi liquid theory in pure metals.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636328&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636327 Publication Date: 2013 May 1 PMID: 23636327<br/>Authors: Bouchard, K. E. - Mesgarani, N. - Johnson, K. - Chang, E. F.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636327&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636326 Publication Date: 2013 May 9 PMID: 23636326<br/>Authors: Yang, H. - Rudge, D. G. - Koos, J. D. - Vaidialingam, B. - Yang, H. J. - Pavletich, N. P.<br/>Journal: Nature<br/><br/>The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636326&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636325 Publication Date: 2013 May 16 PMID: 23636325<br/>Authors: Salazar-Ciudad, I. - Marin-Riera, M.<br/>Journal: Nature<br/><br/>It is not known whether natural selection can encounter any given phenotype that can be produced by genetic variation. There has been a long-lasting debate about the processes that limit adaptation and, consequently, about how well adapted phenotypes are. Here we examine how development may affect adaptation, by decomposing the genotype-fitness map-the association between each genotype and its fitness-into two: one mapping genotype to phenotype by means of a computational model of organ development, and one mapping phenotype to fitness. In the map of phenotype and fitness, the fitness of each individual is based on the similarity between realized morphology and optimal morphology. We use three different simulations to map phenotype to fitness, and these differ in the way in which similarity is calculated: similarity is calculated for each trait (in terms of each cell position individually), for a large or a small number of phenotypic landmarks (the 'many-traits' and 'few-traits' phenotype-fitness maps), and by measuring the overall surface roughness of morphology (the 'roughness' phenotype-fitness map). Evolution is simulated by applying the genotype-phenotype map and one phenotype-fitness map to each individual in the population, as well as random mutation and drift. We show that the complexity of the genotype-phenotype map prevents substantial adaptation in some of the phenotype-fitness maps: sustained adaptation is only possible using 'roughness' or 'few-traits' phenotype-fitness maps. The results contribute developmental understanding to the long-standing question of which aspects of phenotype can be effectively optimized by natural selection.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636325&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636324 Publication Date: 2013 May 16 PMID: 23636324<br/>Authors: Wang, C. - Wu, H. - Katritch, V. - Han, G. W. - Huang, X. P. - Liu, W. - Siu, F. Y. - Roth, B. L. - Cherezov, V. - Stevens, R. C.<br/>Journal: Nature<br/><br/>The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 A resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636324&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636323 Publication Date: 2013 May 16 PMID: 23636323<br/>Authors: Polly, P. D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636323&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636322 Publication Date: 2013 May 9 PMID: 23636322<br/>Authors: Alessi, D. R. - Kulathu, Y.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636322&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636321 Publication Date: 2013 May 9 PMID: 23636321<br/>Authors: Gabuzda, D. - Yankner, B. A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636321&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23636320 Publication Date: 2013 May 1 PMID: 23636320<br/>Authors: Shirey, K. A. - Lai, W. - Scott, A. J. - Lipsky, M. - Mistry, P. - Pletneva, L. M. - Karp, C. L. - McAlees, J. - Gioannini, T. L. - Weiss, J. - Chen, W. H. - Ernst, R. K. - Rossignol, D. P. - Gusovsky, F. - Blanco, J. C. - Vogel, S. N.<br/>Journal: Nature<br/><br/>There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4-/- mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)-a potent, well-tolerated, synthetic TLR4 antagonist-blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23636320&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23627003 Publication Date: 2013 Apr 25 PMID: 23627003<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Congresses as Topic, Functional Neuroimaging, Humans, Mental Disorders/classification/*diagnosis/genetics, Psychiatry/methods/*trends, *Reference Books, Medical<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23627003&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23627002 Publication Date: 2013 Apr 25 PMID: 23627002<br/>Authors: <br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Animals, Birds/*virology, China/epidemiology, Humans, Influenza A virus/*physiology, Influenza in Birds/*epidemiology/*prevention & control/transmission/virology, Influenza, Human/diagnosis/*epidemiology/*prevention & control/virology, Information Dissemination/ethics, Pandemics/prevention & control/statistics & numerical data/veterinary, Zoonoses/epidemiology/transmission/virology<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23627002&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23626997 Publication Date: 2013 Apr 25 PMID: 23626997<br/>Authors: Gewin, V.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: *Art, *Creativity, Hobbies, *Interdisciplinary Communication, Interdisciplinary Studies/*trends, Research Personnel/education/*psychology, Science/education/manpower/methods/*trends, Synthetic Biology/methods<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23626997&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23624375 Publication Date: 2013 Apr 28 PMID: 23624375<br/>Authors: Dewan, A. - Pacifico, R. - Zhan, R. - Rinberg, D. - Bozza, T.<br/>Journal: Nature<br/><br/>Many species are critically dependent on olfaction for survival. In the main olfactory system of mammals, odours are detected by sensory neurons that express a large repertoire of canonical odorant receptors and a much smaller repertoire of trace amine-associated receptors (TAARs). Odours are encoded in a combinatorial fashion across glomeruli in the main olfactory bulb, with each glomerulus corresponding to a specific receptor. The degree to which individual receptor genes contribute to odour perception is unclear. Here we show that genetic deletion of the olfactory Taar gene family, or even a single Taar gene (Taar4), eliminates the aversion that mice display to low concentrations of volatile amines and to the odour of predator urine. Our findings identify a role for the TAARs in olfaction, namely, in the high-sensitivity detection of innately aversive odours. In addition, our data reveal that aversive amines are represented in a non-redundant fashion, and that individual main olfactory receptor genes can contribute substantially to odour perception.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23624375&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23624374 Publication Date: 2013 May 9 PMID: 23624374<br/>Authors: Cebula, A. - Seweryn, M. - Rempala, G. A. - Pabla, S. S. - McIndoe, R. A. - Denning, T. L. - Bry, L. - Kraj, P. - Kisielow, P. - Ignatowicz, L.<br/>Journal: Nature<br/><br/>Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4(+) Foxp3(+) regulatory T (Treg) cells generated in the thymus or extrathymically by induction of naive CD4(+) Foxp3(-) T cells. Previous studies suggested that the T-cell receptor repertoires of thymic Treg cells and induced Treg cells are biased towards self and non-self antigens, respectively, but their relative contribution in controlling immunopathology, such as colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved. The intestine, and especially the colon, is a particularly suitable organ to study this question, given the variety of self-, microbiota- and food-derived antigens to which Treg cells and other T-cell populations are exposed. Intestinal environments can enhance conversion to a regulatory lineage and favour tolerogenic presentation of antigens to naive CD4(+) T cells, suggesting that intestinal homeostasis depends on microbiota-specific induced Treg cells. Here, to identify the origin and antigen-specificity of intestinal Treg cells, we performed single-cell and high-throughput sequencing of the T-cell receptor repertoires of CD4(+) Foxp3(+) and CD4(+) Foxp3(-) T cells, and analysed their reactivity against specific commensal species. We show that thymus-derived Treg cells constitute most Treg cells in all lymphoid and intestinal organs, including the colon, where their repertoire is heavily influenced by the composition of the microbiota. Our results suggest that thymic Treg cells, and not induced Treg cells, dominantly mediate tolerance to antigens produced by intestinal commensals.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23624374&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23624373 Publication Date: 2013 May 9 PMID: 23624373<br/>Authors: Moore, J. D. - Deschenes, M. - Furuta, T. - Huber, D. - Smear, M. C. - Demers, M. - Kleinfeld, D.<br/>Journal: Nature<br/><br/>Whisking and sniffing are predominant aspects of exploratory behaviour in rodents. Yet the neural mechanisms that generate and coordinate these and other orofacial motor patterns remain largely uncharacterized. Here we use anatomical, behavioural, electrophysiological and pharmacological tools to show that whisking and sniffing are coordinated by respiratory centres in the ventral medulla. We delineate a distinct region in the ventral medulla that provides rhythmic input to the facial motor neurons that drive protraction of the vibrissae. Neuronal output from this region is reset at each inspiration by direct input from the pre-Botzinger complex, such that high-frequency sniffing has a one-to-one relationship with whisking, whereas basal respiration is accompanied by intervening whisks that occur between breaths. We conjecture that the respiratory nuclei, which project to other premotor regions for oral and facial control, function as a master clock for behaviours that coordinate with breathing.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23624373&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23624372 Publication Date: 2013 Apr 28 PMID: 23624372<br/>Authors: Sanders, T. A. - Llagostera, E. - Barna, M.<br/>Journal: Nature<br/><br/>The ability of signalling proteins to traverse tissues containing tightly packed cells is of fundamental importance for cell specification and tissue development; however, how this is achieved at a cellular level remains poorly understood. For more than a century, the vertebrate limb bud has served as a model for studying cell signalling during embryonic development. Here we optimize single-cell real-time imaging to delineate the cellular mechanisms for how signalling proteins, such as sonic hedgehog (SHH), that possess membrane-bound covalent lipid modifications traverse long distances within the vertebrate limb bud in vivo. By directly imaging SHH ligand production under native regulatory control in chick (Gallus gallus) embryos, our findings show that SHH is unexpectedly produced in the form of a particle that remains associated with the cell via long cytoplasmic extensions that span several cell diameters. We show that these cellular extensions are a specialized class of actin-based filopodia with novel cytoskeletal features that have not been previously described. Notably, particles containing SHH travel along these extensions with a net anterograde movement within the field of SHH cell signalling. We further show that in SHH-responding cells, specific subsets of SHH co-receptors, including cell adhesion molecule downregulated by oncogenes (CDO) and brother of CDO (BOC), actively distribute and co-localize in specific micro-domains within filopodial extensions, far from the cell body. Stabilized interactions are formed between filopodia containing SHH ligand and those containing co-receptors over a long range. These results suggest that contact-mediated release propagated by specialized filopodia contributes to the delivery of SHH at a distance. Together, these studies identify an important mode of communication between cells that considerably extends our understanding of ligand movement and reception during vertebrate tissue patterning.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23624372&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619696 Publication Date: 2013 Apr 25 PMID: 23619696<br/>Authors: Xu, H. - Li, X. - Liu, D. - Li, J. - Zhang, X. - Chen, X. - Hou, S. - Peng, L. - Xu, C. - Liu, W. - Zhang, L. - Qi, H.<br/>Journal: Nature<br/><br/>Germinal centres support antibody affinity maturation and memory formation. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.<br/><br/>MeSH Categories: Animals, B-Lymphocytes/*immunology/metabolism, Bystander Effect/*immunology, *Cell Movement, DNA-Binding Proteins/metabolism, Genotype, Germinal Center/*cytology/immunology, Inducible T-Cell Co-Stimulator Ligand/metabolism, Inducible T-Cell Co-Stimulator Protein/*metabolism, Lymphocyte Activation, Mice, Pseudopodia/metabolism, Receptors, CXCR5, T-Lymphocytes, Helper-Inducer/*cytology/*immunology<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619696&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619695 Publication Date: 2013 Apr 25 PMID: 23619695<br/>Authors: Cabral, R. A. - Jackson, M. G. - Rose-Koga, E. F. - Koga, K. T. - Whitehouse, M. J. - Antonelli, M. A. - Farquhar, J. - Day, J. M. - Hauri, E. H.<br/>Journal: Nature<br/><br/>Basaltic lavas erupted at some oceanic intraplate hotspot volcanoes are thought to sample ancient subducted crustal materials. However, the residence time of these subducted materials in the mantle is uncertain and model-dependent, and compelling evidence for their return to the surface in regions of mantle upwelling beneath hotspots is lacking. Here we report anomalous sulphur isotope signatures indicating mass-independent fractionation (MIF) in olivine-hosted sulphides from 20-million-year-old ocean island basalts from Mangaia, Cook Islands (Polynesia), which have been suggested to sample recycled oceanic crust. Terrestrial MIF sulphur isotope signatures (in which the amount of fractionation does not scale in proportion with the difference in the masses of the isotopes) were generated exclusively through atmospheric photochemical reactions until about 2.45 billion years ago. Therefore, the discovery of MIF sulphur in these young plume lavas suggests that sulphur--probably derived from hydrothermally altered oceanic crust--was subducted into the mantle before 2.45 billion years ago and recycled into the mantle source of Mangaia lavas. These new data provide evidence for ancient materials, with negative Delta(33)S values, in the mantle source for Mangaia lavas. Our data also complement evidence for recycling of the sulphur content of ancient sedimentary materials to the subcontinental lithospheric mantle that has been identified in diamond-hosted sulphide inclusions. This Archaean age for recycled oceanic crust also provides key constraints on the length of time that subducted crustal material can survive in the mantle, and on the timescales of mantle convection from subduction to upwelling beneath hotspots.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619695&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619694 Publication Date: 2013 Apr 25 PMID: 23619694<br/>Authors: Le Sage, D. - Arai, K. - Glenn, D. R. - DeVience, S. J. - Pham, L. M. - Rahn-Lee, L. - Lukin, M. D. - Yacoby, A. - Komeili, A. - Walsworth, R. L.<br/>Journal: Nature<br/><br/>Magnetic imaging is a powerful tool for probing biological and physical systems. However, existing techniques either have poor spatial resolution compared to optical microscopy and are hence not generally applicable to imaging of sub-cellular structure (for example, magnetic resonance imaging), or entail operating conditions that preclude application to living biological samples while providing submicrometre resolution (for example, scanning superconducting quantum interference device microscopy, electron holography and magnetic resonance force microscopy). Here we demonstrate magnetic imaging of living cells (magnetotactic bacteria) under ambient laboratory conditions and with sub-cellular spatial resolution (400 nanometres), using an optically detected magnetic field imaging array consisting of a nanometre-scale layer of nitrogen-vacancy colour centres implanted at the surface of a diamond chip. With the bacteria placed on the diamond surface, we optically probe the nitrogen-vacancy quantum spin states and rapidly reconstruct images of the vector components of the magnetic field created by chains of magnetic nanoparticles (magnetosomes) produced in the bacteria. We also spatially correlate these magnetic field maps with optical images acquired in the same apparatus. Wide-field microscopy allows parallel optical and magnetic imaging of multiple cells in a population with submicrometre resolution and a field of view in excess of 100 micrometres. Scanning electron microscope images of the bacteria confirm that the correlated optical and magnetic images can be used to locate and characterize the magnetosomes in each bacterium. Our results provide a new capability for imaging bio-magnetic structures in living cells under ambient conditions with high spatial resolution, and will enable the mapping of a wide range of magnetic signals within cells and cellular networks.<br/><br/>MeSH Categories: Bacteria/*cytology/metabolism, *Diamond/chemistry, Magnetic Fields, *Magnetic Phenomena, Magnetosomes/chemistry/metabolism, *Microbial Viability, Microscopy/instrumentation/*methods, Nanoparticles/analysis/chemistry, Nitrogen<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619694&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619693 Publication Date: 2013 Apr 25 PMID: 23619693<br/>Authors: Rambo, R. P. - Tainer, J. A.<br/>Journal: Nature<br/><br/>Modern small-angle scattering (SAS) experiments with X-rays or neutrons provide a comprehensive, resolution-limited observation of the thermodynamic state. However, methods for evaluating mass and validating SAS-based models and resolution have been inadequate. Here we define the volume of correlation, Vc, a SAS invariant derived from the scattered intensities that is specific to the structural state of the particle, but independent of concentration and the requirements of a compact, folded particle. We show that Vc defines a ratio, QR, that determines the molecular mass of proteins or RNA ranging from 10 to 1,000 kilodaltons. Furthermore, we propose a statistically robust method for assessing model-data agreements (chi(2)free) akin to cross-validation. Our approach prevents over-fitting of the SAS data and can be used with a newly defined metric, RSAS, for quantitative evaluation of resolution. Together, these metrics (Vc, QR, chi(2)free and RSAS) provide analytical tools for unbiased and accurate macromolecular structural characterizations in solution.<br/><br/>MeSH Categories: Aldose-Ketose Isomerases/chemistry, DNA-Binding Proteins/chemistry, Models, Chemical, *Models, Molecular, Molecular Conformation, Molecular Weight, Pliability, RNA, Viral/chemistry, Reproducibility of Results, Riboswitch/genetics, *Scattering, Small Angle, Solutions<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619693&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619692 Publication Date: 2013 Apr 25 PMID: 23619692<br/>Authors: Reichardt, B. W. - Unger, F. - Vazirani, U.<br/>Journal: Nature<br/><br/>Quantum computation and cryptography both involve scenarios in which a user interacts with an imperfectly modelled or 'untrusted' system. It is therefore of fundamental and practical interest to devise tests that reveal whether the system is behaving as instructed. In 1969, Clauser, Horne, Shimony and Holt proposed an experimental test that can be passed by a quantum-mechanical system but not by a system restricted to classical physics. Here we extend this test to enable the characterization of a large quantum system. We describe a scheme that can be used to determine the initial state and to classically command the system to evolve according to desired dynamics. The bipartite system is treated as two black boxes, with no assumptions about their inner workings except that they obey quantum physics. The scheme works even if the system is explicitly designed to undermine it; any misbehaviour is detected. Among its applications, our scheme makes it possible to test whether a claimed quantum computer is truly quantum. It also advances towards a goal of quantum cryptography: namely, the use of 'untrusted' devices to establish a shared random key, with security based on the validity of quantum physics.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619692&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619691 Publication Date: 2013 Apr 25 PMID: 23619691<br/>Authors: Wynn, T. A. - Chawla, A. - Pollard, J. W.<br/>Journal: Nature<br/><br/>Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.<br/><br/>MeSH Categories: Animals, Cell Lineage, *Disease, Fibrosis/metabolism/pathology, *Growth and Development, *Homeostasis, Humans, Macrophages/cytology/immunology/*pathology/*physiology<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619691&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619690 Publication Date: 2013 Apr 25 PMID: 23619690<br/>Authors: Posfai, M. - Dunin-Borkowski, R. E.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Bacteria/*cytology, *Diamond, *Magnetic Phenomena, *Microbial Viability, Microscopy/*methods<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619690&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619688 Publication Date: 2013 Apr 25 PMID: 23619688<br/>Authors: Wilczek, F.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619688&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619687 Publication Date: 2013 Apr 25 PMID: 23619687<br/>Authors: Pironio, S. - Aharonov, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619687&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619686 Publication Date: 2013 Apr 25 PMID: 23619686<br/>Authors: Gann, A. - Witkowski, J. A.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Crystallography, X-Ray/*history, DNA/*history, *Nobel Prize<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619686&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619685 Publication Date: 2013 Apr 25 PMID: 23619685<br/>Authors: Wilkins, G.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: *Nucleic Acids<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619685&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619676 Publication Date: 2013 Apr 25 PMID: 23619676<br/>Authors: Fishell, G.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Animals, *Animals, Laboratory, *Cyclonic Storms, Disasters/*history, History, 21st Century, Laboratories/*history, Mice, Mice, Transgenic, New York City, Research/*history<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619676&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619675 Publication Date: 2013 Apr 25 PMID: 23619675<br/>Authors: Ball, P.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Anniversaries and Special Events, DNA/*chemistry/*genetics, Evolution, Molecular, Genes/genetics, Genomics/*trends, Genotype, *Human Genome Project, National Human Genome Research Institute (U.S.), Phenotype, RNA, Untranslated/genetics, Transcription, Genetic/genetics, Uncertainty, United States<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619675&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619674 Publication Date: 2013 Apr 25 PMID: 23619674<br/>Authors: Adam, D.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Humans, Mental Disorders/*classification/*diagnosis/genetics, Psychiatry/standards/trends, *Reference Books, Medical, Uncertainty<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619674&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619673 Publication Date: 2013 Apr 25 PMID: 23619673<br/>Authors: Wadman, M.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Centers for Disease Control and Prevention (U.S.)/economics, Emergency Medicine, Firearms/*statistics & numerical data, History, 20th Century, History, 21st Century, Homicide/*prevention & control/*statistics & numerical data, Humans, *Research/economics/manpower/statistics & numerical data, *Research Personnel, Suicide/prevention & control/statistics & numerical data, United States/epidemiology, Violence/*prevention & control/psychology/*statistics & numerical data<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619673&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619672 Publication Date: 2013 Apr 25 PMID: 23619672<br/>Authors: Hayden, E. C.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Advisory Committees, *Blogging, *Guidelines as Topic, Human Experimentation/standards, Humans, Research/*standards, Research Personnel/standards, Sociology/*standards, United States, United States Dept. of Health and Human Services<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619672&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619671 Publication Date: 2013 Apr 25 PMID: 23619671<br/>Authors: Perkins, S.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619671&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619670 Publication Date: 2013 Apr 25 PMID: 23619670<br/>Authors: Cyranoski, D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619670&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619669 Publication Date: 2013 Apr 25 PMID: 23619669<br/>Authors: Cressey, D.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Animals, Bees/*drug effects/parasitology, Environmental Exposure/adverse effects/analysis/*statistics & numerical data, Environmental Monitoring, Europe, Guanidines/poisoning/toxicity, Imidazoles/poisoning/toxicity, Insecticides/administration & dosage/poisoning/*toxicity, Nitro Compounds/poisoning/toxicity, Oxazines/poisoning/toxicity, Risk Assessment, Thiazoles/poisoning/toxicity, *Uncertainty<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619669&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619668 Publication Date: 2013 Apr 25 PMID: 23619668<br/>Authors: Witze, A.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619668&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619667 Publication Date: 2013 Apr 25 PMID: 23619667<br/>Authors: Tollefson, J.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Atmosphere/chemistry, Carbon Cycle/*drug effects, Carbon Dioxide/metabolism/*pharmacology, Carbon Sequestration/drug effects, Climate Change/*statistics & numerical data, Droughts/statistics & numerical data, Ecology/*methods, Models, Theoretical, Pilot Projects, Research Design, Trees/*drug effects/metabolism, *Tropical Climate<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619667&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23619655 Publication Date: 2013 Apr 25 PMID: 23619655<br/>Authors: Horby, P.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Adaptation, Physiological, Animals, China/epidemiology, Disease Transmission, Infectious/statistics & numerical data, Host Specificity, Humans, Influenza A Virus, H1N1 Subtype/pathogenicity/physiology, Influenza A Virus, H5N1 Subtype/pathogenicity/physiology, Influenza A virus/pathogenicity/*physiology, Influenza, Human/*epidemiology/prevention & control/transmission/*virology, Poultry/virology, Swine/virology, Zoonoses/*epidemiology/transmission/*virology<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23619655&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615618 Publication Date: 2013 May 2 PMID: 23615618<br/>Authors: Caron, S. J. - Ruta, V. - Abbott, L. F. - Axel, R.<br/>Journal: Nature<br/><br/>The mushroom body in the fruitfly Drosophila melanogaster is an associative brain centre that translates odour representations into learned behavioural responses. Kenyon cells, the intrinsic neurons of the mushroom body, integrate input from olfactory glomeruli to encode odours as sparse distributed patterns of neural activity. We have developed anatomic tracing techniques to identify the glomerular origin of the inputs that converge onto 200 individual Kenyon cells. Here we show that each Kenyon cell integrates input from a different and apparently random combination of glomeruli. The glomerular inputs to individual Kenyon cells show no discernible organization with respect to their odour tuning, anatomic features or developmental origins. Moreover, different classes of Kenyon cells do not seem to preferentially integrate inputs from specific combinations of glomeruli. This organization of glomerular connections to the mushroom body could allow the fly to contextualize novel sensory experiences, a feature consistent with the role of this brain centre in mediating learned olfactory associations and behaviours.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615618&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615617 Publication Date: 2013 May 2 PMID: 23615617<br/>Authors: Bernien, H. - Hensen, B. - Pfaff, W. - Koolstra, G. - Blok, M. S. - Robledo, L. - Taminiau, T. H. - Markham, M. - Twitchen, D. J. - Childress, L. - Hanson, R.<br/>Journal: Nature<br/><br/>Quantum entanglement between spatially separated objects is one of the most intriguing phenomena in physics. The outcomes of independent measurements on entangled objects show correlations that cannot be explained by classical physics. As well as being of fundamental interest, entanglement is a unique resource for quantum information processing and communication. Entangled quantum bits (qubits) can be used to share private information or implement quantum logical gates. Such capabilities are particularly useful when the entangled qubits are spatially separated, providing the opportunity to create highly connected quantum networks or extend quantum cryptography to long distances. Here we report entanglement of two electron spin qubits in diamond with a spatial separation of three metres. We establish this entanglement using a robust protocol based on creation of spin-photon entanglement at each location and a subsequent joint measurement of the photons. Detection of the photons heralds the projection of the spin qubits onto an entangled state. We verify the resulting non-local quantum correlations by performing single-shot readout on the qubits in different bases. The long-distance entanglement reported here can be combined with recently achieved initialization, readout and entanglement operations on local long-lived nuclear spin registers, paving the way for deterministic long-distance teleportation, quantum repeaters and extended quantum networks.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615617&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615616 Publication Date: 2013 May 2 PMID: 23615616<br/>Authors: Allen, V. - Bates, K. T. - Li, Z. - Hutchinson, J. R.<br/>Journal: Nature<br/><br/>Locomotion in living birds (Neornithes) has two remarkable features: feather-assisted flight, and the use of unusually crouched hindlimbs for bipedal support and movement. When and how these defining functional traits evolved remains controversial. However, the advent of computer modelling approaches and the discoveries of exceptionally preserved key specimens now make it possible to use quantitative data on whole-body morphology to address the biomechanics underlying this issue. Here we use digital body reconstructions to quantify evolutionary trends in locomotor biomechanics (whole-body proportions and centre-of-mass position) across the clade Archosauria. We use three-dimensional digital reconstruction to estimate body shape from skeletal dimensions for 17 archosaurs along the ancestral bird line, including the exceptionally preserved, feathered taxa Microraptor, Archaeopteryx, Pengornis and Yixianornis, which represent key stages in the evolution of the avian body plan. Rather than a discrete transition from more-upright postures in the basal-most birds (Avialae) and their immediate outgroup deinonychosauria, our results support hypotheses of a gradual, stepwise acquisition of more-crouched limb postures across much of theropod evolution, although we find evidence of an accelerated change within the clade Maniraptora (birds and their closest relatives, such as deinonychosaurs). In addition, whereas reduction of the tail is widely accepted to be the primary morphological factor correlated with centre-of-mass position and, hence, evolution of hindlimb posture, we instead find that enlargement of the pectoral limb and several associated trends have a much stronger influence. Intriguingly, our support for the onset of accelerated morpho-functional trends within Maniraptora is closely correlated with the evolution of flight. Because we find that the evolution of enlarged forelimbs is strongly linked, via whole-body centre of mass, to hindlimb function during terrestrial locomotion, we suggest that the evolution of avian flight is linked to anatomical novelties in the pelvic limb as well as the pectoral.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615616&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615615 Publication Date: 2013 May 16 PMID: 23615615<br/>Authors: Xiong, X. - Coombs, P. J. - Martin, S. R. - Liu, J. - Xiao, H. - McCauley, J. W. - Locher, K. - Walker, P. A. - Collins, P. J. - Kawaoka, Y. - Skehel, J. J. - Gamblin, S. J.<br/>Journal: Nature<br/><br/>Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets, the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA-receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4), 1968 (ref. 5) and 2009 (ref. 6) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615615&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615614 Publication Date: 2013 May 9 PMID: 23615614<br/>Authors: Yu, S. F. - Baylies, M. K.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615614&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615613 Publication Date: 2013 May 2 PMID: 23615613<br/>Authors: Reinhard, C. T. - Planavsky, N. J. - Lyons, T. W.<br/>Journal: Nature<br/><br/>The accumulation of substantial quantities of O2 in the atmosphere has come to control the chemistry and ecological structure of Earth's surface. Non-mass-dependent (NMD) sulphur isotope anomalies in the rock record are the central tool used to reconstruct the redox history of the early atmosphere. The generation and initial delivery of these anomalies to marine sediments requires low partial pressures of atmospheric O2 (p(O2); refs 2, 3), and the disappearance of NMD anomalies from the rock record 2.32 billion years ago is thought to have signalled a departure from persistently low atmospheric oxygen levels (less than about 10(-5) times the present atmospheric level) during approximately the first two billion years of Earth's history. Here we present a model study designed to describe the long-term surface recycling of crustal NMD anomalies, and show that the record of this geochemical signal is likely to display a 'crustal memory effect' following increases in atmospheric p(O2) above this threshold. Once NMD anomalies have been buried in the upper crust they are extremely resistant to removal, and can be erased only through successive cycles of weathering, dilution and burial on an oxygenated Earth surface. This recycling results in the residual incorporation of NMD anomalies into the sedimentary record long after synchronous atmospheric generation of the isotopic signal has ceased, with dynamic and measurable signals probably surviving for as long as 10-100 million years subsequent to an increase in atmospheric p(O2) to more than 10(-5) times the present atmospheric level. Our results can reconcile geochemical evidence for oxygen production and transient accumulation with the maintenance of NMD anomalies on the early Earth, and suggest that future work should investigate the notion that temporally continuous generation of new NMD sulphur isotope anomalies in the atmosphere was likely to have ceased long before their ultimate disappearance from the rock record.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615613&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615612 Publication Date: 2013 May 16 PMID: 23615612<br/>Authors: Benner, E. J. - Luciano, D. - Jo, R. - Abdi, K. - Paez-Gonzalez, P. - Sheng, H. - Warner, D. S. - Liu, C. - Eroglu, C. - Kuo, C. T.<br/>Journal: Nature<br/><br/>Postnatal/adult neural stem cells (NSCs) within the rodent subventricular zone (SVZ; also called subependymal zone) generate doublecortin (Dcx)(+) neuroblasts that migrate and integrate into olfactory bulb circuitry. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche. It is generally thought that enhancing the neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear whether there are conditions that favour astrogenesis over neurogenesis in the SVZ niche, and whether astrocytes produced there have different properties compared with astrocytes produced elsewhere in the brain. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4), a secreted homopentameric glycoprotein, in contrast to cortical astrocytes, which express low levels of Thbs4. We found that localized photothrombotic/ischaemic cortical injury initiates a marked increase in Thbs4(hi) astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creER(tm)4 lineage tracing demonstrated that it is these SVZ-generated Thbs4(hi) astrocytes, and not Dcx(+) neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production. Consequently, Thbs4 homozygous knockout mice (Thbs4(KO/KO)) showed severe defects in cortical-injury-induced SVZ astrogenesis, instead producing cells expressing Dcx migrating from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular haemorrhage into the brain parenchyma of Thbs4(KO/KO) mice. Taken together, these findings have important implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members have important roles.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615612&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615610 Publication Date: 2013 May 2 PMID: 23615610<br/>Authors: Kamat, S. S. - Williams, H. J. - Dangott, L. J. - Chakrabarti, M. - Raushel, F. M.<br/>Journal: Nature<br/><br/>Methane is a potent greenhouse gas that is produced in significant quantities by aerobic marine organisms. These bacteria apparently catalyse the formation of methane through the cleavage of the highly unreactive carbon-phosphorus bond in methyl phosphonate (MPn), but the biological or terrestrial source of this compound is unclear. However, the ocean-dwelling bacterium Nitrosopumilus maritimus catalyses the biosynthesis of MPn from 2-hydroxyethyl phosphonate and the bacterial C-P lyase complex is known to convert MPn to methane. In addition to MPn, the bacterial C-P lyase complex catalyses C-P bond cleavage of many alkyl phosphonates when the environmental concentration of phosphate is low. PhnJ from the C-P lyase complex catalyses an unprecedented C-P bond cleavage reaction of ribose-1-phosphonate-5-phosphate to methane and ribose-1,2-cyclic-phosphate-5-phosphate. This reaction requires a redox-active [4Fe-4S]-cluster and S-adenosyl-L-methionine, which is reductively cleaved to L-methionine and 5'-deoxyadenosine. Here we show that PhnJ is a novel radical S-adenosyl-L-methionine enzyme that catalyses C-P bond cleavage through the initial formation of a 5'-deoxyadenosyl radical and two protein-based radicals localized at Gly 32 and Cys 272. During this transformation, the pro-R hydrogen from Gly 32 is transferred to the 5'-deoxyadenosyl radical to form 5'-deoxyadenosine and the pro-S hydrogen is transferred to the radical intermediate that ultimately generates methane. A comprehensive reaction mechanism is proposed for cleavage of the C-P bond by the C-P lyase complex that uses a covalent thiophosphate intermediate for methane and phosphate formation.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615610&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615609 Publication Date: 2013 May 2 PMID: 23615609<br/>Authors: Pelechano, V. - Wei, W. - Steinmetz, L. M.<br/>Journal: Nature<br/><br/>Transcript function is determined by sequence elements arranged on an individual RNA molecule. Variation in transcripts can affect messenger RNA stability, localization and translation, or produce truncated proteins that differ in localization or function. Given the existence of overlapping, variable transcript isoforms, determining the functional impact of the transcriptome requires identification of full-length transcripts, rather than just the genomic regions that are transcribed. Here, by jointly determining both transcript ends for millions of RNA molecules, we reveal an extensive layer of isoform diversity previously hidden among overlapping RNA molecules. Variation in transcript boundaries seems to be the rule rather than the exception, even within a single population of yeast cells. Over 26 major transcript isoforms per protein-coding gene were expressed in yeast. Hundreds of short coding RNAs and truncated versions of proteins are concomitantly encoded by alternative transcript isoforms, increasing protein diversity. In addition, approximately 70% of genes express alternative isoforms that vary in post-transcriptional regulatory elements, and tandem genes frequently produce overlapping or even bicistronic transcripts. This extensive transcript diversity is generated by a relatively simple eukaryotic genome with limited splicing, and within a genetically homogeneous population of cells. Our findings have implications for genome compaction, evolution and phenotypic diversity between single cells. These data also indicate that isoform diversity as well as RNA abundance should be considered when assessing the functional repertoire of genomes.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615609&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615608 Publication Date: 2013 May 9 PMID: 23615608<br/>Authors: Hochreiter-Hufford, A. E. - Lee, C. S. - Kinchen, J. M. - Sokolowski, J. D. - Arandjelovic, S. - Call, J. A. - Klibanov, A. L. - Yan, Z. - Mandell, J. W. - Ravichandran, K. S.<br/>Journal: Nature<br/><br/>Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibres. Although conserved transcription factors and signalling proteins involved in myogenesis have been identified, upstream regulators are less well understood. Here we report an unexpected discovery that the membrane protein BAI1, previously linked to recognition of apoptotic cells by phagocytes, promotes myoblast fusion. Endogenous BAI1 expression increased during myoblast fusion, and BAI1 overexpression enhanced myoblast fusion by means of signalling through ELMO/Dock180/Rac1 proteins. During myoblast fusion, a fraction of myoblasts within the population underwent apoptosis and exposed phosphatidylserine, an established ligand for BAI1 (ref. 3). Blocking apoptosis potently impaired myoblast fusion, and adding back apoptotic myoblasts restored fusion. Furthermore, primary human myoblasts could be induced to form myotubes by adding apoptotic myoblasts, even under normal growth conditions. Mechanistically, apoptotic cells did not directly fuse with the healthy myoblasts, rather the apoptotic cells induced a contact-dependent signalling with neighbours to promote fusion among the healthy myoblasts. In vivo, myofibres from Bai1(-/-) mice are smaller than those from wild-type littermates. Muscle regeneration after injury was also impaired in Bai1(-/-)mice, highlighting a role for BAI1 in mammalian myogenesis. Collectively, these data identify apoptotic cells as a new type of cue that induces signalling via the phosphatidylserine receptor BAI1 to promote fusion of healthy myoblasts, with important implications for muscle development and repair.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615608&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23615607 Publication Date: 2013 May 2 PMID: 23615607<br/>Authors: Pugh, B. F.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23615607&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23604256 Publication Date: 2013 May 2 PMID: 23604256<br/>Authors: Campbell, C. S. - Desai, A.<br/>Journal: Nature<br/><br/>Accurate segregation of the replicated genome requires chromosome biorientation on the spindle. Biorientation is ensured by Aurora B kinase (Ipl1), a member of the four-subunit chromosomal passenger complex (CPC). Localization of the CPC to the inner centromere is central to the current model for how tension ensures chromosome biorientation: kinetochore-spindle attachments that are not under tension remain close to the inner centromere and are destabilized by Aurora B phosphorylation, whereas kinetochores under tension are pulled away from the influence of Aurora B, stabilizing their microtubule attachments. Here we show that an engineered truncation of the Sli15 (known as INCENP in humans) subunit of budding yeast CPC that eliminates association with the inner centromere nevertheless supports proper chromosome segregation during both mitosis and meiosis. Truncated Sli15 suppresses the deletion phenotypes of the inner-centromere-targeting proteins survivin (Bir1), borealin (Nbl1), Bub1 and Sgo1 (ref. 6). Unlike wild-type Sli15, truncated Sli15 localizes to pre-anaphase spindle microtubules. Premature targeting of full-length Sli15 to microtubules by preventing Cdk1 (also known as Cdc28) phosphorylation also suppresses the inviability of Bir1 deletion. These results suggest that activation of Aurora B kinase by clustering either on chromatin or on microtubules is sufficient for chromosome biorientation.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23604256&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23604255 Publication Date: 2013 May 2 PMID: 23604255<br/>Authors: Borshchevskiy, V. - Buldt, G.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23604255&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23604254 Publication Date: 2013 May 2 PMID: 23604254<br/>Authors: Shukla, A. K. - Manglik, A. - Kruse, A. C. - Xiao, K. - Reis, R. I. - Tseng, W. C. - Staus, D. P. - Hilger, D. - Uysal, S. - Huang, L. Y. - Paduch, M. - Tripathi-Shukla, P. - Koide, A. - Koide, S. - Weis, W. I. - Kossiakoff, A. A. - Kobilka, B. K. - Lefkowitz, R. J.<br/>Journal: Nature<br/><br/>The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of beta-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of beta-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate beta-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of beta-arrestin-1. The structure of the beta-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in beta-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of beta-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on beta-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23604254&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23604253 Publication Date: 2013 May 2 PMID: 23604253<br/>Authors: Kim, Y. J. - Hofmann, K. P. - Ernst, O. P. - Scheerer, P. - Choe, H. W. - Sommer, M. E.<br/>Journal: Nature<br/><br/>Arrestins interact with G-protein-coupled receptors (GPCRs) to block interaction with G proteins and initiate G-protein-independent signalling. Arrestins have a bi-lobed structure that is stabilized by a long carboxy-terminal tail (C-tail), and displacement of the C-tail by receptor-attached phosphates activates arrestins for binding active GPCRs. Structures of the inactive state of arrestin are available, but it is not known how C-tail displacement activates arrestin for receptor coupling. Here we present a 3.0 A crystal structure of the bovine arrestin-1 splice variant p44, in which the activation step is mimicked by C-tail truncation. The structure of this pre-activated arrestin is profoundly different from the basal state and gives insight into the activation mechanism. p44 displays breakage of the central polar core and other interlobe hydrogen-bond networks, leading to a approximately 21 degrees rotation of the two lobes as compared to basal arrestin-1. Rearrangements in key receptor-binding loops in the central crest region include the finger loop, loop 139 (refs 8, 10, 11) and the sequence Asp 296-Asn 305 (or gate loop), here identified as controlling the polar core. We verified the role of these conformational alterations in arrestin activation and receptor binding by site-directed fluorescence spectroscopy. The data indicate a mechanism for arrestin activation in which C-tail displacement releases critical central-crest loops from restricted to extended receptor-interacting conformations. In parallel, increased flexibility between the two lobes facilitates a proper fitting of arrestin to the active receptor surface. Our results provide a snapshot of an arrestin ready to bind the active receptor, and give an insight into the role of naturally occurring truncated arrestins in the visual system.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23604253&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594744 Publication Date: 2013 May 2 PMID: 23594744<br/>Authors: Pfeiffer, B. E. - Foster, D. J.<br/>Journal: Nature<br/><br/>Effective navigation requires planning extended routes to remembered goal locations. Hippocampal place cells have been proposed to have a role in navigational planning, but direct evidence has been lacking. Here we show that before goal-directed navigation in an open arena, the rat hippocampus generates brief sequences encoding spatial trajectories strongly biased to progress from the subject's current location to a known goal location. These sequences predict immediate future behaviour, even in cases in which the specific combination of start and goal locations is novel. These results indicate that hippocampal sequence events characterized previously in linearly constrained environments as 'replay' are also capable of supporting a goal-directed, trajectory-finding mechanism, which identifies important places and relevant behavioural paths, at specific times when memory retrieval is required, and in a manner that could be used to control subsequent navigational behaviour.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594744&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594743 Publication Date: 2013 Apr 25 PMID: 23594743<br/>Authors: Howe, K. - Clark, M. D. - Torroja, C. F. - Torrance, J. - Berthelot, C. - Muffato, M. - Collins, J. E. - Humphray, S. - McLaren, K. - Matthews, L. - McLaren, S. - Sealy, I. - Caccamo, M. - Churcher, C. - Scott, C. - Barrett, J. C. - Koch, R. - Rauch, G. J. - White, S. - Chow, W. - Kilian, B. - Quintais, L. T. - Guerra-Assuncao, J. A. - Zhou, Y. - Gu, Y. - Yen, J. - Vogel, J. H. - Eyre, T. - Redmond, S. - Banerjee, R. - Chi, J. - Fu, B. - Langley, E. - Maguire, S. F. - Laird, G. K. - Lloyd, D. - Kenyon, E. - Donaldson, S. - Sehra, H. - Almeida-King, J. - Loveland, J. - Trevanion, S. - Jones, M. - Quail, M. - Willey, D. - Hunt, A. - Burton, J. - Sims, S. - McLay, K. - Plumb, B. - Davis, J. - Clee, C. - Oliver, K. - Clark, R. - Riddle, C. - Eliott, D. - Threadgold, G. - Harden, G. - Ware, D. - Mortimer, B. - Kerry, G. - Heath, P. - Phillimore, B. - Tracey, A. - Corby, N. - Dunn, M. - Johnson, C. - Wood, J. - Clark, S. - Pelan, S. - Griffiths, G. - Smith, M. - Glithero, R. - Howden, P. - Barker, N. - Stevens, C. - Harley, J. - Holt, K. - Panagiotidis, G. - Lovell, J. - Beasley, H. - Henderson, C. - Gordon, D. - Auger, K. - Wright, D. - Collins, J. - Raisen, C. - Dyer, L. - Leung, K. - Robertson, L. - Ambridge, K. - Leongamornlert, D. - McGuire, S. - Gilderthorp, R. - Griffiths, C. - Manthravadi, D. - Nichol, S. - Barker, G. - Whitehead, S. - Kay, M. - Brown, J. - Murnane, C. - Gray, E. - Humphries, M. - Sycamore, N. - Barker, D. - Saunders, D. - Wallis, J. - Babbage, A. - Hammond, S. - Mashreghi-Mohammadi, M. - Barr, L. - Martin, S. - Wray, P. - Ellington, A. - Matthews, N. - Ellwood, M. - Woodmansey, R. - Clark, G. - Cooper, J. - Tromans, A. - Grafham, D. - Skuce, C. - Pandian, R. - Andrews, R. - Harrison, E. - Kimberley, A. - Garnett, J. - Fosker, N. - Hall, R. - Garner, P. - Kelly, D. - Bird, C. - Palmer, S. - Gehring, I. - Berger, A. - Dooley, C. M. - Ersan-Urun, Z. - Eser, C. - Geiger, H. - Geisler, M. - Karotki, L. - Kirn, A. - Konantz, J. - Konantz, M. - Oberlander, M. - Rudolph-Geiger, S. - Teucke, M. - Osoegawa, K. - Zhu, B. - Rapp, A. - Widaa, S. - Langford, C. - Yang, F. - Carter, N. P. - Harrow, J. - Ning, Z. - Herrero, J. - Searle, S. M. - Enright, A. - Geisler, R. - Plasterk, R. H. - Lee, C. - Westerfield, M. - de Jong, P. J. - Zon, L. I. - Postlethwait, J. H. - Nusslein-Volhard, C. - Hubbard, T. J. - Roest Crollius, H. - Rogers, J. - Stemple, D. L.<br/>Journal: Nature<br/><br/>Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.<br/><br/>MeSH Categories: Animals, Chromosomes/genetics, Conserved Sequence/*genetics, Evolution, Molecular, Female, Genes/genetics, Genome/*genetics, Genome, Human/genetics, Genomics, Humans, Male, Meiosis/genetics, Molecular Sequence Annotation, Pseudogenes/genetics, Reference Standards, Sex Determination Processes/genetics, Zebrafish/*genetics, Zebrafish Proteins/genetics<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594743&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594742 Publication Date: 2013 Apr 25 PMID: 23594742<br/>Authors: Kettleborough, R. N. - Busch-Nentwich, E. M. - Harvey, S. A. - Dooley, C. M. - de Bruijn, E. - van Eeden, F. - Sealy, I. - White, R. J. - Herd, C. - Nijman, I. J. - Fenyes, F. - Mehroke, S. - Scahill, C. - Gibbons, R. - Wali, N. - Carruthers, S. - Hall, A. - Yen, J. - Cuppen, E. - Stemple, D. L.<br/>Journal: Nature<br/><br/>Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.<br/><br/>MeSH Categories: Alleles, Animals, Exome/genetics, Female, Gene Knockout Techniques, Genetic Complementation Test, Genome/*genetics, Genomics, Male, Molecular Sequence Annotation, Mutagenesis, Mutation/genetics, Phenotype, Polymorphism, Single Nucleotide/genetics, Zebrafish/*genetics/physiology, Zebrafish Proteins/*genetics/metabolism<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594742&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594741 Publication Date: 2013 Apr 25 PMID: 23594741<br/>Authors: Schier, A. F.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Animals, Conserved Sequence/*genetics, Female, Genome/*genetics, Humans, Male, Zebrafish/*genetics, Zebrafish Proteins/*genetics<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594741&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594740 Publication Date: 2013 May 2 PMID: 23594740<br/>Authors: Schmidt, B. - Redish, A. D.<br/>Journal: Nature<br/><br/><br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594740&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594739 Publication Date: 2013 Apr 25 PMID: 23594739<br/>Authors: Abdumalikov, A. A. Jr - Fink, J. M. - Juliusson, K. - Pechal, M. - Berger, S. - Wallraff, A. - Filipp, S.<br/>Journal: Nature<br/><br/>The geometric aspects of quantum mechanics are emphasized most prominently by the concept of geometric phases, which are acquired whenever a quantum system evolves along a path in Hilbert space, that is, the space of quantum states of the system. The geometric phase is determined only by the shape of this path and is, in its simplest form, a real number. However, if the system has degenerate energy levels, then matrix-valued geometric state transformations, known as non-Abelian holonomies--the effect of which depends on the order of two consecutive paths--can be obtained. They are important, for example, for the creation of synthetic gauge fields in cold atomic gases or the description of non-Abelian anyon statistics. Moreover, there are proposals to exploit non-Abelian holonomic gates for the purposes of noise-resilient quantum computation. In contrast to Abelian geometric operations, non-Abelian ones have been observed only in nuclear quadrupole resonance experiments with a large number of spins, and without full characterization of the geometric process and its non-commutative nature. Here we realize non-Abelian non-adiabatic holonomic quantum operations on a single, superconducting, artificial three-level atom by applying a well-controlled, two-tone microwave drive. Using quantum process tomography, we determine fidelities of the resulting non-commuting gates that exceed 95 per cent. We show that two different quantum gates, originating from two distinct paths in Hilbert space, yield non-equivalent transformations when applied in different orders. This provides evidence for the non-Abelian character of the implemented holonomic quantum operations. In combination with a non-trivial two-quantum-bit gate, our method suggests a way to universal holonomic quantum computing.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594739&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594738 Publication Date: 2013 May 9 PMID: 23594738<br/>Authors: Chang, H. M. - Triboulet, R. - Thornton, J. E. - Gregory, R. I.<br/>Journal: Nature<br/><br/>The pluripotency factor Lin28 blocks the expression of let-7 microRNAs in undifferentiated cells during development, and functions as an oncogene in a subset of cancers. Lin28 binds to let-7 precursor (pre-let-7) RNAs and recruits 3' terminal uridylyl transferases to selectively inhibit let-7 biogenesis. Uridylated pre-let-7 is refractory to processing by Dicer, and is rapidly degraded by an unknown RNase. Here we identify Dis3l2 as the 3'-5' exonuclease responsible for the decay of uridylated pre-let-7 in mouse embryonic stem cells. Biochemical reconstitution assays show that 3' oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3' oligouridylation as an RNA decay signal for Dis3l2, and identifies the first physiological RNA substrate of this new exonuclease, which is mutated in the Perlman syndrome of fetal overgrowth and causes a predisposition to Wilms' tumour development.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594738&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23594737 Publication Date: 2013 May 9 PMID: 23594737<br/>Authors: Mahmoud, A. I. - Kocabas, F. - Muralidhar, S. A. - Kimura, W. - Koura, A. S. - Thet, S. - Porrello, E. R. - Sadek, H. A.<br/>Journal: Nature<br/><br/>The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown. Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes, and for re-activation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16 and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23594737&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23584590 Publication Date: 2013 May 9 PMID: 23584590<br/>Authors: Giustina, M. - Mech, A. - Ramelow, S. - Wittmann, B. - Kofler, J. - Beyer, J. - Lita, A. - Calkins, B. - Gerrits, T. - Nam, S. W. - Ursin, R. - Zeilinger, A.<br/>Journal: Nature<br/><br/>The violation of a Bell inequality is an experimental observation that forces the abandonment of a local realistic viewpoint--namely, one in which physical properties are (probabilistically) defined before and independently of measurement, and in which no physical influence can propagate faster than the speed of light. All such experimental violations require additional assumptions depending on their specific construction, making them vulnerable to so-called loopholes. Here we use entangled photons to violate a Bell inequality while closing the fair-sampling loophole, that is, without assuming that the sample of measured photons accurately represents the entire ensemble. To do this, we use the Eberhard form of Bell's inequality, which is not vulnerable to the fair-sampling assumption and which allows a lower collection efficiency than other forms. Technical improvements of the photon source and high-efficiency transition-edge sensors were crucial for achieving a sufficiently high collection efficiency. Our experiment makes the photon the first physical system for which each of the main loopholes has been closed, albeit in different experiments.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23584590&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23584589 Publication Date: 2013 May 9 PMID: 23584589<br/>Authors: Xu, K. - Zhang, M. - Zhao, Q. - Yu, F. - Guo, H. - Wang, C. - He, F. - Ding, J. - Zhang, P.<br/>Journal: Nature<br/><br/>ATP-binding cassette (ABC) transporters, composed of importers and exporters, form one of the biggest protein superfamilies that transport a variety of substrates across the membrane, powered by ATP hydrolysis. Most ABC transporters are composed of two transmembrane domains and two cytoplasmic nucleotide-binding domains. Also, importers from prokaryotes usually have extra solute-binding proteins in the periplasm that are responsible for the binding of substrates. Structures of importers have been reported that suggested a two-state model for the transport mechanism. Energy-coupling factor (ECF) transporters belong to a new class of ATP-binding cassette importers. Each ECF transporter comprises an energy-coupling module consisting of a transmembrane T protein (EcfT), two nucleotide-binding proteins (EcfA and EcfA'), and another transmembrane substrate-specific binding S protein (EcfS). Despite the similarities with ABC transporters, ECF transporters have different organizational and functional properties. The lack of solute-binding proteins in ECF transporters differentiates them clearly from the canonical ABC importers. Previously reported structures of the EcfS proteins RibU and ThiT clearly demonstrated the binding site of substrate riboflavin and thiamine, respectively. However, the organization of the four different components and the transport mechanism of ECF transporters remain unknown. Here we present the structure of an intact folate ECF transporter from Lactobacillus brevis at a resolution of 3 A. This structure was captured in an inward-facing, nucleotide-free conformation with no bound substrate. The folate-binding protein FolT is nearly parallel to the membrane and is bound almost entirely by EcfT, which adopts an L shape and connects to EcfA and EcfA' through two coupling helices. Two conserved XRX motifs from the coupling helices of EcfT have a vital role in energy coupling by docking into EcfA-EcfA'. We propose a transport model that involves a substantial conformational change of FolT.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23584589&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23584588 Publication Date: 2013 May 9 PMID: 23584588<br/>Authors: Sampson, T. R. - Saroj, S. D. - Llewellyn, A. C. - Tzeng, Y. L. - Weiss, D. S.<br/>Journal: Nature<br/><br/>CRISPR/Cas (clustered regularly interspaced palindromic repeats/CRISPR-associated) systems are a bacterial defence against invading foreign nucleic acids derived from bacteriophages or exogenous plasmids. These systems use an array of small CRISPR RNAs (crRNAs) consisting of repetitive sequences flanking unique spacers to recognize their targets, and conserved Cas proteins to mediate target degradation. Recent studies have suggested that these systems may have broader functions in bacterial physiology, and it is unknown if they regulate expression of endogenous genes. Here we demonstrate that the Cas protein Cas9 of Francisella novicida uses a unique, small, CRISPR/Cas-associated RNA (scaRNA) to repress an endogenous transcript encoding a bacterial lipoprotein. As bacterial lipoproteins trigger a proinflammatory innate immune response aimed at combating pathogens, CRISPR/Cas-mediated repression of bacterial lipoprotein expression is critical for F. novicida to dampen this host response and promote virulence. Because Cas9 proteins are highly enriched in pathogenic and commensal bacteria, our work indicates that CRISPR/Cas-mediated gene regulation may broadly contribute to the regulation of endogenous bacterial genes, particularly during the interaction of such bacteria with eukaryotic hosts.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23584588&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23584587 Publication Date: 2013 May 9 PMID: 23584587<br/>Authors: Wang, T. - Fu, G. - Pan, X. - Wu, J. - Gong, X. - Wang, J. - Shi, Y.<br/>Journal: Nature<br/><br/>The energy-coupling factor (ECF) transporters constitute a novel family of conserved membrane transporters in prokaryotes that have a similar domain organization to the ATP-binding cassette transporters. Each ECF transporter comprises a pair of cytosolic ATPases (the A and A' components, or EcfA and EcfA'), a membrane-embedded substrate-binding protein (the S component, or EcfS) and a transmembrane energy-coupling component (the T component, or EcfT) that links the EcfA-EcfA' subcomplex to EcfS. The structure and transport mechanism of the quaternary ECF transporter remain largely unknown. Here we report the crystal structure of a nucleotide-free ECF transporter from Lactobacillus brevis at a resolution of 3.5 A. The T component has a horseshoe-shaped open architecture, with five alpha-helices as transmembrane segments and two cytoplasmic alpha-helices as coupling modules connecting to the A and A' components. Strikingly, the S component, thought to be specific for hydroxymethyl pyrimidine, lies horizontally along the lipid membrane and is bound exclusively by the five transmembrane segments and the two cytoplasmic helices of the T component. These structural features suggest a plausible working model for the transport cycle of the ECF transporters.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23584587&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23575636 Publication Date: 2013 May 9 PMID: 23575636<br/>Authors: Mossadegh-Keller, N. - Sarrazin, S. - Kandalla, P. K. - Espinosa, L. - Stanley, E. R. - Nutt, S. L. - Moore, J. - Sieweke, M. H.<br/>Journal: Nature<br/><br/>Under stress conditions such as infection or inflammation the body rapidly needs to generate new blood cells that are adapted to the challenge. Haematopoietic cytokines are known to increase output of specific mature cells by affecting survival, expansion and differentiation of lineage-committed progenitors, but it has been debated whether long-term haematopoietic stem cells (HSCs) are susceptible to direct lineage-specifying effects of cytokines. Although genetic changes in transcription factor balance can sensitize HSCs to cytokine instruction, the initiation of HSC commitment is generally thought to be triggered by stochastic fluctuation in cell-intrinsic regulators such as lineage-specific transcription factors, leaving cytokines to ensure survival and proliferation of the progeny cells. Here we show that macrophage colony-stimulating factor (M-CSF, also called CSF1), a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 and instruct myeloid cell-fate change in mouse HSCs, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified HSCs with M-CSF in culture resulted in activation of the PU.1 promoter and an increased number of PU.1(+) cells with myeloid gene signature and differentiation potential. In vivo, high systemic levels of M-CSF directly stimulated M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs and induced a PU.1-dependent myeloid differentiation preference. Our data demonstrate that lineage-specific cytokines can act directly on HSCs in vitro and in vivo to instruct a change of cell identity. This fundamentally changes the current view of how HSCs respond to environmental challenge and implicates stress-induced cytokines as direct instructors of HSC fate.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23575636&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23575631 Publication Date: 2013 May 16 PMID: 23575631<br/>Authors: Chung, K. - Wallace, J. - Kim, S. Y. - Kalyanasundaram, S. - Andalman, A. S. - Davidson, T. J. - Mirzabekov, J. J. - Zalocusky, K. A. - Mattis, J. - Denisin, A. K. - Pak, S. - Bernstein, H. - Ramakrishnan, C. - Grosenick, L. - Gradinaru, V. - Deisseroth, K.<br/>Journal: Nature<br/><br/>Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked to a three-dimensional network of hydrophilic polymers) that is fully assembled but optically transparent and macromolecule-permeable. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters. CLARITY also enables intact-tissue in situ hybridization, immunohistochemistry with multiple rounds of staining and de-staining in non-sectioned tissue, and antibody labelling throughout the intact adult mouse brain. Finally, we show that CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and disease.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23575631&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23575629 Publication Date: 2013 Apr 25 PMID: 23575629<br/>Authors: Paddon, C. J. - Westfall, P. J. - Pitera, D. J. - Benjamin, K. - Fisher, K. - McPhee, D. - Leavell, M. D. - Tai, A. - Main, A. - Eng, D. - Polichuk, D. R. - Teoh, K. H. - Reed, D. W. - Treynor, T. - Lenihan, J. - Fleck, M. - Bajad, S. - Dang, G. - Dengrove, D. - Diola, D. - Dorin, G. - Ellens, K. W. - Fickes, S. - Galazzo, J. - Gaucher, S. P. - Geistlinger, T. - Henry, R. - Hepp, M. - Horning, T. - Iqbal, T. - Jiang, H. - Kizer, L. - Lieu, B. - Melis, D. - Moss, N. - Regentin, R. - Secrest, S. - Tsuruta, H. - Vazquez, R. - Westblade, L. F. - Xu, L. - Yu, M. - Zhang, Y. - Zhao, L. - Lievense, J. - Covello, P. S. - Keasling, J. D. - Reiling, K. K. - Renninger, N. S. - Newman, J. D.<br/>Journal: Nature<br/><br/>In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.<br/><br/>MeSH Categories: Antimalarials/economics/isolation & purification/metabolism/supply & distribution, Artemisinins/chemistry/economics/isolation & purification/*metabolism/*supply &, distribution, *Biosynthetic Pathways, Biotechnology, Fermentation, Genetic Engineering, Malaria, Falciparum/drug therapy, Molecular Sequence Data, Saccharomyces cerevisiae/classification/genetics/growth & development/*metabolism, Singlet Oxygen/metabolism<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23575629&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23563269 Publication Date: 2013 May 2 PMID: 23563269<br/>Authors: Murtaza, M. - Dawson, S. J. - Tsui, D. W. - Gale, D. - Forshew, T. - Piskorz, A. M. - Parkinson, C. - Chin, S. F. - Kingsbury, Z. - Wong, A. S. - Marass, F. - Humphray, S. - Hadfield, J. - Bentley, D. - Chin, T. M. - Brenton, J. D. - Caldas, C. - Rosenfeld, N.<br/>Journal: Nature<br/><br/>Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23563269&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23563267 Publication Date: 2013 May 2 PMID: 23563267<br/>Authors: Ko, M. - An, J. - Bandukwala, H. S. - Chavez, L. - Aijo, T. - Pastor, W. A. - Segal, M. F. - Li, H. - Koh, K. P. - Lahdesmaki, H. - Hogan, P. G. - Aravind, L. - Rao, A.<br/>Journal: Nature<br/><br/>TET (ten-eleven-translocation) proteins are Fe(ii)- and alpha-ketoglutarate-dependent dioxygenases that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, potential intermediates in the active erasure of DNA-methylation marks. Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling that has been implicated in malignant renal cell carcinoma and colonic villous adenoma, regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity.<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23563267&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23563266 Publication Date: 2013 Apr 25 PMID: 23563266<br/>Authors: Bhatt, S. - Gething, P. W. - Brady, O. J. - Messina, J. P. - Farlow, A. W. - Moyes, C. L. - Drake, J. M. - Brownstein, J. S. - Hoen, A. G. - Sankoh, O. - Myers, M. F. - George, D. B. - Jaenisch, T. - Wint, G. R. - Simmons, C. P. - Scott, T. W. - Farrar, J. J. - Hay, S. I.<br/>Journal: Nature<br/><br/>Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.<br/><br/>MeSH Categories: Cohort Studies, Databases, Factual/standards, Dengue/*epidemiology/transmission/virology, Dengue Virus/physiology, Humans, Incidence, Public Health/statistics & numerical data, Quality Control, Rain, Risk Factors, Temperature, Tropical Climate, Urbanization, World Health/*statistics & numerical data, World Health Organization<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23563266&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23552894 Publication Date: 2013 Apr 25 PMID: 23552894<br/>Authors: Mouquet, H. - Nussenzweig, M. C.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Antibodies, Neutralizing/*chemistry/*immunology, *Evolution, Molecular, HIV Antibodies/*chemistry/*immunology, HIV-1/*chemistry/*immunology, Humans<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23552894&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23552891 Publication Date: 2013 Apr 25 PMID: 23552891<br/>Authors: Russell, A. B. - LeRoux, M. - Hathazi, K. - Agnello, D. M. - Ishikawa, T. - Wiggins, P. A. - Wai, S. N. - Mougous, J. D.<br/>Journal: Nature<br/><br/>Membranes allow the compartmentalization of biochemical processes and are therefore fundamental to life. The conservation of the cellular membrane, combined with its accessibility to secreted proteins, has made it a common target of factors mediating antagonistic interactions between diverse organisms. Here we report the discovery of a diverse superfamily of bacterial phospholipase enzymes. Within this superfamily, we defined enzymes with phospholipase A1 and A2 activity, which are common in host-cell-targeting bacterial toxins and the venoms of certain insects and reptiles. However, we find that the fundamental role of the superfamily is to mediate antagonistic bacterial interactions as effectors of the type VI secretion system (T6SS) translocation apparatus; accordingly, we name these proteins type VI lipase effectors. Our analyses indicate that PldA of Pseudomonas aeruginosa, a eukaryotic-like phospholipase D, is a member of the type VI lipase effector superfamily and the founding substrate of the haemolysin co-regulated protein secretion island II T6SS (H2-T6SS). Although previous studies have specifically implicated PldA and the H2-T6SS in pathogenesis, we uncovered a specific role for the effector and its secretory machinery in intra- and interspecies bacterial interactions. Furthermore, we find that this effector achieves its antibacterial activity by degrading phosphatidylethanolamine, the major component of bacterial membranes. The surprising finding that virulence-associated phospholipases can serve as specific antibacterial effectors suggests that interbacterial interactions are a relevant factor driving the continuing evolution of pathogenesis.<br/><br/>MeSH Categories: Anti-Bacterial Agents/*metabolism, *Antibiosis, *Bacterial Secretion Systems, Cell Membrane/chemistry/metabolism, Evolution, Molecular, Phosphatidylethanolamines/metabolism, Phospholipase D/chemistry/classification/*metabolism, Phylogeny, Pseudomonas aeruginosa/*enzymology/metabolism/pathogenicity, Species Specificity, Substrate Specificity, Virulence Factors/chemistry/metabolism<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23552891&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23552890 Publication Date: 2013 Apr 25 PMID: 23552890<br/>Authors: Liao, H. X. - Lynch, R. - Zhou, T. - Gao, F. - Alam, S. M. - Boyd, S. D. - Fire, A. Z. - Roskin, K. M. - Schramm, C. A. - Zhang, Z. - Zhu, J. - Shapiro, L. - Mullikin, J. C. - Gnanakaran, S. - Hraber, P. - Wiehe, K. - Kelsoe, G. - Yang, G. - Xia, S. M. - Montefiori, D. C. - Parks, R. - Lloyd, K. E. - Scearce, R. M. - Soderberg, K. A. - Cohen, M. - Kamanga, G. - Louder, M. K. - Tran, L. M. - Chen, Y. - Cai, F. - Chen, S. - Moquin, S. - Du, X. - Joyce, M. G. - Srivatsan, S. - Zhang, B. - Zheng, A. - Shaw, G. M. - Hahn, B. H. - Kepler, T. B. - Korber, B. T. - Kwong, P. D. - Mascola, J. R. - Haynes, B. F.<br/>Journal: Nature<br/><br/>Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.<br/><br/>MeSH Categories: AIDS Vaccines/immunology, Africa, Amino Acid Sequence, Antibodies, Monoclonal/chemistry/genetics/immunology, Antibodies, Neutralizing/*chemistry/genetics/*immunology, Antigens, CD4/chemistry/immunology, Cell Lineage, Cells, Cultured, Clone Cells/cytology, Cross Reactions/immunology, Crystallography, X-Ray, Epitopes/chemistry/immunology, *Evolution, Molecular, HIV Antibodies/*chemistry/genetics/*immunology, HIV Envelope Protein gp120/chemistry/genetics/immunology/metabolism, HIV-1/*chemistry/classification/*immunology, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Neutralization Tests, Phylogeny, Protein Structure, Tertiary<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23552890&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23542591 Publication Date: 2013 Apr 25 PMID: 23542591<br/>Authors: Pedersen, B. P. - Kumar, H. - Waight, A. B. - Risenmay, A. J. - Roe-Zurz, Z. - Chau, B. H. - Schlessinger, A. - Bonomi, M. - Harries, W. - Sali, A. - Johri, A. K. - Stroud, R. M.<br/>Journal: Nature<br/><br/>Phosphate is crucial for structural and metabolic needs, including nucleotide and lipid synthesis, signalling and chemical energy storage. Proton-coupled transporters of the major facilitator superfamily (MFS) are essential for phosphate uptake in plants and fungi, and also have a function in sensing external phosphate levels as transceptors. Here we report the 2.9 A structure of a fungal (Piriformospora indica) high-affinity phosphate transporter, PiPT, in an inward-facing occluded state, with bound phosphate visible in the membrane-buried binding site. The structure indicates both proton and phosphate exit pathways and suggests a modified asymmetrical 'rocker-switch' mechanism of phosphate transport. PiPT is related to several human transporter families, most notably the organic cation and anion transporters of the solute carrier family (SLC22), which are implicated in cancer-drug resistance. We modelled representative cation and anion SLC22 transporters based on the PiPT structure to surmise the structural basis for substrate binding and charge selectivity in this important family. The PiPT structure demonstrates and expands on principles of substrate transport by the MFS transporters and illuminates principles of phosphate uptake in particular.<br/><br/>MeSH Categories: Basidiomycota/*chemistry, Binding Sites, Crystallography, X-Ray, Eukaryotic Cells/*chemistry, Humans, Models, Biological, Models, Molecular, Phosphate Transport Proteins/*chemistry/metabolism, Phosphates/metabolism, Protein Conformation, Protons, Structure-Activity Relationship<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23542591&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23467095 Publication Date: 2013 Apr 25 PMID: 23467095<br/>Authors: Kleinewietfeld, M. - Manzel, A. - Titze, J. - Kvakan, H. - Yosef, N. - Linker, R. A. - Muller, D. N. - Hafler, D. A.<br/>Journal: Nature<br/><br/>There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-alpha and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.<br/><br/>MeSH Categories: Animals, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental/*chemically, induced/*immunology/pathology, Gene Silencing, Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis, Humans, Immediate-Early Proteins/metabolism, Interleukin-2/biosynthesis, MAP Kinase Signaling System/drug effects, Mice, Mice, Inbred C57BL, Phenotype, Protein-Serine-Threonine Kinases/metabolism, Sodium Chloride, Dietary/*pharmacology, Th17 Cells/*drug effects/*immunology/pathology, Transcription Factors/metabolism, Tumor Necrosis Factor-alpha/biosynthesis, p38 Mitogen-Activated Protein Kinases/deficiency/genetics/metabolism<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23467095&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23467089 Publication Date: 2013 Apr 25 PMID: 23467089<br/>Authors: Yosef, N. - Shalek, A. K. - Gaublomme, J. T. - Jin, H. - Lee, Y. - Awasthi, A. - Wu, C. - Karwacz, K. - Xiao, S. - Jorgolli, M. - Gennert, D. - Satija, R. - Shakya, A. - Lu, D. Y. - Trombetta, J. J. - Pillai, M. R. - Ratcliffe, P. J. - Coleman, M. L. - Bix, M. - Tantin, D. - Park, H. - Kuchroo, V. K. - Regev, A.<br/>Journal: Nature<br/><br/>Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4(+) T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation.<br/><br/>MeSH Categories: Animals, Antigens, CD95/metabolism, Cell Differentiation/*genetics, Cells, Cultured, DNA/genetics/metabolism, Forkhead Transcription Factors/metabolism, Gene Knockdown Techniques, Gene Regulatory Networks/*genetics, Genome/genetics, Interferon-gamma/biosynthesis, Interleukin-2/genetics, Mice, Mice, Inbred C57BL, Nanowires, Neoplasm Proteins/metabolism, Nuclear Proteins/metabolism, RNA, Messenger/genetics/metabolism, Reproducibility of Results, Silicon, Th17 Cells/*cytology/immunology/*metabolism, Time Factors, Trans-Activators/metabolism, Transcription Factors/metabolism, Transcription, Genetic/genetics<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23467089&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23467087 Publication Date: 2013 Apr 25 PMID: 23467087<br/>Authors: O'Shea, J. J. - Jones, R. G.<br/>Journal: Nature<br/><br/><br/><br/>MeSH Categories: Animals, Cell Differentiation/*drug effects, Encephalomyelitis, Autoimmune, Experimental/*chemically induced/*immunology, Humans, Immediate-Early Proteins/*metabolism, Interleukin-17/*metabolism, Protein-Serine-Threonine Kinases/*metabolism, Sodium Chloride/*pharmacology, Sodium Chloride, Dietary/*pharmacology, Th17 Cells/*drug effects/*immunology/*pathology<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23467087&title=Entrez+Pubmed">CiteULike</a> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23467085 Publication Date: 2013 Apr 25 PMID: 23467085<br/>Authors: Wu, C. - Yosef, N. - Thalhamer, T. - Zhu, C. - Xiao, S. - Kishi, Y. - Regev, A. - Kuchroo, V. K.<br/>Journal: Nature<br/><br/>TH17 cells (interleukin-17 (IL-17)-producing helper T cells) are highly proinflammatory cells that are critical for clearing extracellular pathogens and for inducing multiple autoimmune diseases. IL-23 has a critical role in stabilizing and reinforcing the TH17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing TH17 cells with pathogenic effector functions. However, the precise molecular mechanism by which IL-23 sustains the TH17 response and induces pathogenic effector functions has not been elucidated. Here we used transcriptional profiling of developing TH17 cells to construct a model of their signalling network and nominate major nodes that regulate TH17 development. We identified serum glucocorticoid kinase 1 (SGK1), a serine/threonine kinase, as an essential node downstream of IL-23 signalling. SGK1 is critical for regulating IL-23R expression and stabilizing the TH17 cell phenotype by deactivation of mouse Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na(+) transport and salt (NaCl) homeostasis in other cells. We show here that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances TH17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na(+)-mediated TH17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 has a critical role in the induction of pathogenic TH17 cells and provide a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers TH17 development and promotes tissue inflammation.<br/><br/>MeSH Categories: Animals, Cell Differentiation/*drug effects, Encephalomyelitis, Autoimmune, Experimental/chemically, induced/immunology/metabolism/pathology, Forkhead Transcription Factors/metabolism, HEK293 Cells, Humans, Immediate-Early Proteins/deficiency/genetics/*metabolism, Interferon-gamma/biosynthesis/immunology, Interleukin-17/biosynthesis/immunology/*metabolism, Mice, Phenotype, Phosphorylation/drug effects, Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism, Receptors, Interleukin/biosynthesis/immunology, Sodium Chloride/*pharmacology, Sodium Chloride, Dietary/pharmacology, Th17 Cells/*drug effects/enzymology/immunology/*pathology<br/><br/>post to: <a href = "http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D23467085&title=Entrez+Pubmed">CiteULike</a>