Is there an association between NPY and neuroticism?
Nature 458, E6 (2009). doi:10.1038/nature07927
Authors: Colleen H. Cotton, Jonathan Flint & Thomas G. Campbell
Arising from: Z. Zhou et al.Nature452, 997–1001 (2008); Zhou et al.replyPsychiatric genetics has been hampered by the fact that initially exciting findings from underpowered studies are so often not replicated in larger, more powerful, data sets. Here we show that the claims of Zhou et al. that neuropeptide Y (NPY) diplotype-predicted expression is correlated with trait anxiety (neuroticism) is not replicated in a data set consisting of phenotypically extreme individuals drawn from a large (n = 88,142) non-clinical population. We found no association between NPY diplotype or diplotype-predicted expression and neuroticism. Our reply to Zhou and colleagues forms part of a larger debate (see, for example, http://www.nature.com/news/2008/080709/full/454154a.html) about the efficacy and replicability of candidate driven versus genome wide approaches to psychiatric genetics.
]]>Nature 458, E7 (2009). doi:10.1038/nature07928
Authors: Zhifeng Zhou, Guanshan Zhu, Ahmad R. Hariri, Mary-Anne Enoch, David Scott, Rajita Sinha, Matti Virkkunen, Deborah C. Mash, Robert H. Lipsky, Xian-Zhang Hu, Colin A. Hodgkinson, Ke Xu, Beata Buzas, Qiaoping Yuan, Pei-Hong Shen, Robert E. Ferrell, Stephen B. Manuck, Sarah M. Brown, Richard L. Hauger, Christian S. Stohler, Jon-Kar Zubieta & David Goldman
Replying to: C. H. Cotton, J. Flint & T. G. Campbell Nature458, 10.1038/nature07927 (2009)The inability of Cotton et al. to detect an effect of a functional haplotype (and locus) of neuropeptide Y (NPY), a stress regulatory neuropeptide, on neuroticism is interesting. Although it is important to measure effects of functional loci on complex behaviours, the strength of our study, and primary basis of its conclusions, was the larger and convergent effects of NPY on intermediate phenotypes, including regional brain responses to emotional stimuli and pain, and brain NPY messenger RNA and plasma NPY levels. Eysenck Neuroticism is a trait that we did not directly investigate. We reported modest association of NPY with two Harm Avoidance subscales from the Tridimensional Personality Questionnaire. Association of NPY with the complex trait of anxiety, especially when measured differently, is not the first place we would look to validate our results.
]]>Nature 458, 548 (2009). doi:10.1038/7238548a
An experiment to detect high-energy positrons pays off.
]]>Nature 458, 548 (2009). doi:10.1038/7238548b
Last authorBeing able to read another person's mind is still science fiction. But Frank Tong, a cognitive neuroscientist at Vanderbilt University in Nashville, Tennessee, and his colleague Stephenie Harrison might have brought this fantasy a little closer to reality. Researchers thought that brain areas
]]>Nature 458, 548 (2009). doi:10.1038/7238548c
Nature Chemistry (http://www.nature.com/nchem/index.html) has finally arrived! In a post in The Sceptical Chymist (http://tinyurl.com/c73cc8), associate editor Neil Withers announces the first issue, which is “freely available for everyone to read and (hopefully) enjoy”.Uppsala University postdoc and blogger Egon Willighagen
]]>Nature 458, 549 (2009). doi:10.1038/458549a
Nuclear non-proliferation's moment has come. Scientists must help governments to seize a historic opportunity to avoid future apocalypses.
]]>Nature 458, 549 (2009). doi:10.1038/458549b
The e-textbook is only one part of a bigger revolution in online learning.
]]>Nature 458, 550 (2009). doi:10.1038/458550a
Italy's Senate has approved a bill that ignores patients' wishes and the country's own constitution.
]]>Nature 458, 552 (2009). doi:10.1038/458552a
Science323, 1734–1737 (2009) 10.1126/science.1169441It is difficult to study what triggers shoaling in sea fish as the conglomerations can be tens of kilometres across and yet are still hard to find in the vast oceans. Nicholas Makris of
]]>Nature 458, 552 (2009). doi:10.1038/458552b
Genome Res. doi:10.1101/gr.083188.108 (2009)Blood-sucking lice are common. Genetically, they are also unusual, say Renfu Shao at the University of Queensland, Australia, and his colleagues. Using information from the Human Body Louse Genome Project, the team found that the mitochondrial
]]>Nature 458, 552 (2009). doi:10.1038/458552c
Nature Nanotechnol. doi:10.1038/nnano.2009.55 (2009) Even the strongest molecular bonds break if yanked hard enough. But studying this effect requires a delicate tugging mechanism that can focus force controllably on individual bonds.Roman Boulatov and his colleagues at the University of
]]>Nature 458, 552 (2009). doi:10.1038/458552d
Science323, 1698–1701 (2009) 10.1126/science.1169399The joints in human elbows, knees and the like exhibit very little friction even at moderately high pressure — man-made materials can offer nothing as good. Zwitterions might put that right.Zwitterions are molecules
]]>Nature 458, 552 (2009). doi:10.1038/458552e
Astrophys. J.694, 130–143 (2009) 10.1088/0004-637X/694/1/130Galactic archaeologists have identified a component of the Milky Way's halo that had been predicted but not seen before. The team, led by Heather Morrison at Case Western Reserve University in Cleveland, sifted
]]>Nature 458, 553 (2009). doi:10.1038/458553a
Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0810875106 (2009)The longevity of deep-sea corals has been much debated: radiocarbon dating provides estimates of millennia, but counting growth rings gives ages of only a few hundred years. Brendan Roark at Texas A&M University
]]>Nature 458, 553 (2009). doi:10.1038/458553b
iv
]]>Nature 458, 553 (2009). doi:10.1038/458553c
Nature Geosci. doi:10.1038/ngeo474 (2009)During the ice ages there was much more dust in the air over Antarctica than there is now, but its supply was sometimes rapidly curtailed.David Sugden of the University of Edinburgh, UK, and his colleagues
]]>Nature 458, 553 (2009). doi:10.1038/458553d
Ecol. Appl.19, 505–514 (2009)The number of birds killed by crashing into communication towers could be reduced by about 50–70% by simply changing the towers' lighting systems, researchers say.Millions of night-migrating songbirds collide with these towers each year. Joelle Gehring of Michigan
]]>Nature 458, 553 (2009). doi:10.1038/458553e
Author: Anthony J. Ryan
A chemist welcomes an ingenious advance in plastics technology.It's a rare joy to come across a communication that is truly concise, with a genuinely surprising but ultimately logical result, and compellingly modest conclusions that could materially benefit our society. Anne Hiltner at Case Western
]]>Nature 458, 571 (2009). doi:10.1038/458571a
Authors: Michael Freissmuth & Sigismund Huck
SirBecause of uncertainty about this year's science budget, as expressed in your News in Brief story 'Austrian scientists rattled by threat to funding' (Nature457 648; 2009), the Austrian science fund FWF has postponed its first two board meetings of 2009.
]]>Nature 458, 571 (2009). doi:10.1038/458571b
Author: Jerome H. L. Hui
SirYour News story 'Hong Kong evolution curriculum row' (Nature457, 1067; 2009) reports a call by faculty members at Hong Kong University for a sentence to be removed from new guidelines for secondary-school biology education. At present, these state: “In addition
]]>Nature 458, 571 (2009). doi:10.1038/458571c
Author: Dave Bienus
SirIn your Editorial 'Against vicious activism' (Nature457, 636; 10.1038/457636a2009), you call for scientists and the authorities to stand up for animal research in basic and applied science. However, you may be putting the cart before the horse in
]]>Nature 458, 571 (2009). doi:10.1038/458571d
Author: Thomas C. Mettenleiter
SirYour News story 'Britain hits a hurdle in replacing key animal-pathogen facility' (Nature457, 769; 2009) describes the problems faced by the Institute for Animal Health in Pirbright. It is deplorable that this world-class institute is uncertain of being able to
]]>Nature 458, 572 (2009). doi:10.1038/458572a
Author: Robert Dallek
Barack Obama's choice of science advisers is cause for celebration. Yet history shows that an impressive academic record doesn't guarantee good, impartial advice, cautions Robert Dallek.
]]>Nature 458, 574 (2009). doi:10.1038/458574a
Author: George Perkovich
Since acquiring atomic weapons, India, Pakistan and North Korea have not engaged in major warfare. But nuclear deterrence alone does not buy peace — diplomacy must keep the balance, says George Perkovich.
]]>Nature 458, 575 (2009). doi:10.1038/458575a
Author: Andrew Robinson
After years of backsliding on nuclear-weapons proliferation by the world's superpowers, President Barack Obama has stated that he intends to “make the goal of eliminating all nuclear weapons a central element” in nuclear policy. His recently appointed chief science adviser, physicist John Holdren, spent ten
]]>Nature 458, 577 (2009). doi:10.1038/458577a
Author: James Acord
James Acord is the only sculptor licensed to work with radioactive materials. Formally trained in nuclear physics, he tells Nature why he thinks contaminated nuclear sites should be marked for future generations and explains his obsession with the nuclear age.
]]>Nature 458, 579 (2009). doi:10.1038/458579a
Authors: Shahid Naeem
An elaborate microcosm study has a message for the wider world: declining distributional equity among species, where the rare become rarer, and the dominant become more dominant, can put ecosystems at risk.
]]>Nature 458, 580 (2009). doi:10.1038/458580a
Authors: Jaroslav Fabian
Electrons in semiconductors are subject to forces that make their spins flip. According to new evidence, if an ensemble of spins curls into a helix, the collective spin lifetime can be greatly enhanced.
]]>Nature 458, 581 (2009). doi:10.1038/458581a
Authors: Jiri Lukas & Jiri Bartek
Modifications of DNA-associated histone proteins maintain genome integrity. On damage to DNA, phosphorylation of histone H2A.X determines whether repair is justified or if the damaged cell must die.
]]>Nature 458, 583 (2009). doi:10.1038/458583a
Authors: Werner Aeschbach-Hertig
Subsurface storage of carbon dioxide is a major option for mitigating climate change. On one account, much of the gas sequestered in this way would end up as carbonic acid in the pore waters of the host rock.
]]>Nature 458, 583 (2009). doi:10.1038/458583b
50 Years agoIt often happens that investigators, particularly in the social sciences, must try to collect the information which they need by using questionnaires. One of the many problems that are apt to arise concerns the reliability of answers to questions which require an
]]>Nature 458, 584 (2009). doi:10.1038/458584a
Authors: Dennis R. Burton & Pascal Poignard
An impressive system for retrieving large numbers of antibodies from memory B cells has been developed. It has been put into practice in an investigation of immune responses to the human immunodeficiency virus.
]]>Nature 458, 585 (2009). doi:10.1038/458585a
Authors: Alexander C. Jackson & Roger A. Nicoll
In mediating fast synaptic communication in the brain, AMPA receptors require TARP auxiliary proteins. It seems that another distinct class of proteins also bind to AMPA receptors and regulate their function.
]]>Nature 458, 587 (2009). doi:10.1038/458587a
Authors: Robert Caldwell & Marc Kamionkowski
Observations continue to indicate that the Universe is dominated by invisible components — dark matter and dark energy. Shedding light on this cosmic darkness is a priority for astronomers and physicists.
]]>Nature 458, 591 (2009). doi:10.1038/nature07849
Authors: Peter J. Cook, Bong Gun Ju, Francesca Telese, Xiangting Wang, Christopher K. Glass & Michael G. Rosenfeld
Life and death fate decisions allow cells to avoid massive apoptotic death in response to genotoxic stress. Although the regulatory mechanisms and signalling pathways controlling DNA repair and apoptosis are well characterized, the precise molecular strategies that determine the ultimate choice of DNA repair and
]]>Nature 458, 597 (2009). doi:10.1038/nature07869
Authors: Shoji Maeda, So Nakagawa, Michihiro Suga, Eiki Yamashita, Atsunori Oshima, Yoshinori Fujiyoshi & Tomitake Tsukihara
Gap junctions consist of arrays of intercellular channels between adjacent cells that permit the exchange of ions and small molecules. Here we report the crystal structure of the gap junction channel formed by human connexin 26 (Cx26, also known as GJB2) at 3.5 Å resolution, and
]]>Nature 458, 603 (2009). doi:10.1038/nature07865
Authors: Chris A. Collins, John P. Stott, Matt Hilton, Scott T. Kay, S. Adam Stanford, Michael Davidson, Mark Hosmer, Ben Hoyle, Andrew Liddle, Ed Lloyd-Davies, Robert G. Mann, Nicola Mehrtens, Christopher J. Miller, Robert C. Nichol, A. Kathy Romer, Martin Sahlén, Pedro T. P. Viana & Michael J. West
The current consensus is that galaxies begin as small density fluctuations in the early Universe and grow by in situ star formation and hierarchical merging. Stars begin to form relatively quickly in sub-galactic-sized building blocks called haloes which are subsequently assembled into galaxies. However, exactly when this assembly takes place is a matter of some debate. Here we report that the stellar masses of brightest cluster galaxies, which are the most luminous objects emitting stellar light, some 9 billion years ago are not significantly different from their stellar masses today. Brightest cluster galaxies are almost fully assembled 4-5 billion years after the Big Bang, having grown to more than 90 per cent of their final stellar mass by this time. Our data conflict with the most recent galaxy formation models based on the largest simulations of dark-matter halo development. These models predict protracted formation of brightest cluster galaxies over a Hubble time, with only 22 per cent of the stellar mass assembled at the epoch probed by our sample. Our findings suggest a new picture in which brightest cluster galaxies experience an early period of rapid growth rather than prolonged hierarchical assembly.
]]>Nature 458, 607 (2009). doi:10.1038/nature07942
Authors: O. Adriani, G. C. Barbarino, G. A. Bazilevskaya, R. Bellotti, M. Boezio, E. A. Bogomolov, L. Bonechi, M. Bongi, V. Bonvicini, S. Bottai, A. Bruno, F. Cafagna, D. Campana, P. Carlson, M. Casolino, G. Castellini, M. P. De Pascale, G. De Rosa, N. De Simone, V. Di Felice, A. M. Galper, L. Grishantseva, P. Hofverberg, S. V. Koldashov, S. Y. Krutkov, A. N. Kvashnin, A. Leonov, V. Malvezzi, L. Marcelli, W. Menn, V. V. Mikhailov, E. Mocchiutti, S. Orsi, G. Osteria, P. Papini, M. Pearce, P. Picozza, M. Ricci, S. B. Ricciarini, M. Simon, R. Sparvoli, P. Spillantini, Y. I. Stozhkov, A. Vacchi, E. Vannuccini, G. Vasilyev, S. A. Voronov, Y. T. Yurkin, G. Zampa, N. Zampa & V. G. Zverev
Antiparticles account for a small fraction of cosmic rays and are known to be produced in interactions between cosmic-ray nuclei and atoms in the interstellar medium, which is referred to as a ‘secondary source’. Positrons might also originate in objects such as pulsars and microquasars or through dark matter annihilation, which would be ‘primary sources’. Previous statistically limited measurements of the ratio of positron and electron fluxes have been interpreted as evidence for a primary source for the positrons, as has an increase in the total electron+positron flux at energies between 300 and 600 GeV (ref. 8). Here we report a measurement of the positron fraction in the energy range 1.5–100 GeV. We find that the positron fraction increases sharply over much of that range, in a way that appears to be completely inconsistent with secondary sources. We therefore conclude that a primary source, be it an astrophysical object or dark matter annihilation, is necessary.
]]>Nature 458, 610 (2009). doi:10.1038/nature07871
Authors: J. D. Koralek, C. P. Weber, J. Orenstein, B. A. Bernevig, Shou-Cheng Zhang, S. Mack & D. D. Awschalom
According to Noether’s theorem, for every symmetry in nature there is a corresponding conservation law. For example, invariance with respect to spatial translation corresponds to conservation of momentum. In another well-known example, invariance with respect to rotation of the electron’s spin, or SU(2) symmetry, leads to conservation of spin polarization. For electrons in a solid, this symmetry is ordinarily broken by spin–orbit coupling, allowing spin angular momentum to flow to orbital angular momentum. However, it has recently been predicted that SU(2) can be achieved in a two-dimensional electron gas, despite the presence of spin–orbit coupling. The corresponding conserved quantities include the amplitude and phase of a helical spin density wave termed the ‘persistent spin helix’. SU(2) is realized, in principle, when the strengths of two dominant spin–orbit interactions, the Rashba (strength parameterized by α) and linear Dresselhaus (β1) interactions, are equal. This symmetry is predicted to be robust against all forms of spin-independent scattering, including electron–electron interactions, but is broken by the cubic Dresselhaus term (β3) and spin-dependent scattering. When these terms are negligible, the distance over which spin information can propagate is predicted to diverge as α approaches β1. Here we report experimental observation of the emergence of the persistent spin helix in GaAs quantum wells by independently tuning α and β1. Using transient spin-grating spectroscopy, we find a spin-lifetime enhancement of two orders of magnitude near the symmetry point. Excellent quantitative agreement with theory across a wide range of sample parameters allows us to obtain an absolute measure of all relevant spin–orbit terms, identifying β3 as the main SU(2)-violating term in our samples. The tunable suppression of spin relaxation demonstrated in this work is well suited for application to spintronics.
]]>Nature 458, 614 (2009). doi:10.1038/nature07852
Authors: Stuart M. V. Gilfillan, Barbara Sherwood Lollar, Greg Holland, Dave Blagburn, Scott Stevens, Martin Schoell, Martin Cassidy, Zhenju Ding, Zheng Zhou, Georges Lacrampe-Couloume & Chris J. Ballentine
Injecting CO2 into deep geological strata is proposed as a safe and economically favourable means of storing CO2 captured from industrial point sources. It is difficult, however, to assess the long-term consequences of CO2 flooding in the subsurface from decadal observations of existing disposal sites. Both the site design and long-term safety modelling critically depend on how and where CO2 will be stored in the site over its lifetime. Within a geological storage site, the injected CO2 can dissolve in solution or precipitate as carbonate minerals. Here we identify and quantify the principal mechanism of CO2 fluid phase removal in nine natural gas fields in North America, China and Europe, using noble gas and carbon isotope tracers. The natural gas fields investigated in our study are dominated by a CO2 phase and provide a natural analogue for assessing the geological storage of anthropogenic CO2 over millennial timescales. We find that in seven gas fields with siliciclastic or carbonate-dominated reservoir lithologies, dissolution in formation water at a pH of 5–5.8 is the sole major sink for CO2. In two fields with siliciclastic reservoir lithologies, some CO2 loss through precipitation as carbonate minerals cannot be ruled out, but can account for a maximum of 18 per cent of the loss of emplaced CO2. In view of our findings that geological mineral fixation is a minor CO2 trapping mechanism in natural gas fields, we suggest that long-term anthropogenic CO2 storage models in similar geological systems should focus on the potential mobility of CO2 dissolved in water.
]]>Nature 458, 619 (2009). doi:10.1038/nature07857
Authors: Claude Herzberg & Esteban Gazel
Geological mapping and geochronological studies have shown much lower eruption rates for ocean island basalts (OIBs) in comparison with those of lavas from large igneous provinces (LIPs) such as oceanic plateaux and continental flood provinces. However, a quantitative petrological comparison has never been made between mantle source temperature and the extent of melting for OIB and LIP sources. Here we show that the MgO and FeO contents of Galapagos-related lavas and their primary magmas have decreased since the Cretaceous period. From petrological modelling, we infer that these changes reflect a cooling of the Galapagos mantle plume from a potential temperature of 1,560–1,620 °C in the Cretaceous to 1,500 °C at present. Iceland also exhibits secular cooling, in agreement with previous studies. Our work provides quantitative petrological evidence that, in general, mantle plumes for LIPs with Palaeocene–Permian ages were hotter and melted more extensively than plumes of more modern ocean islands. We interpret this to reflect episodic flow from lower-mantle domains that are lithologically and geochemically heterogeneous.
]]>Nature 458, 623 (2009). doi:10.1038/nature07840
Authors: Lieven Wittebolle, Massimo Marzorati, Lieven Clement, Annalisa Balloi, Daniele Daffonchio, Kim Heylen, Paul De Vos, Willy Verstraete & Nico Boon
Owing to the present global biodiversity crisis, the biodiversity–stability relationship and the effect of biodiversity on ecosystem functioning have become major topics in ecology. Biodiversity is a complex term that includes taxonomic, functional, spatial and temporal aspects of organismic diversity, with species richness (the number of species) and evenness (the relative abundance of species) considered among the most important measures. With few exceptions (see, for example, ref. 6), the majority of studies of biodiversity-functioning and biodiversity–stability theory have predominantly examined richness. Here we show, using microbial microcosms, that initial community evenness is a key factor in preserving the functional stability of an ecosystem. Using experimental manipulations of both richness and initial evenness in microcosms with denitrifying bacterial communities, we found that the stability of the net ecosystem denitrification in the face of salinity stress was strongly influenced by the initial evenness of the community. Therefore, when communities are highly uneven, or there is extreme dominance by one or a few species, their functioning is less resistant to environmental stress. Further unravelling how evenness influences ecosystem processes in natural and humanized environments constitutes a major future conceptual challenge.
]]>Nature 458, 627 (2009). doi:10.1038/nature07721
Authors: Prakash Kara & Jamie D. Boyd
In invertebrate predators such as the praying mantis and vertebrate predators such as wild cats the ability to detect small differences in inter-ocular retinal disparities is a critical means for accurately determining the depth of moving objects such as prey. In mammals, the first neurons along the visual pathway that encode binocular disparities are found in the visual cortex. However, a precise functional architecture for binocular disparity has never been demonstrated in any species, and coarse maps for disparity have been found in only one primate species. Moreover, the dominant approach for assaying the developmental plasticity of binocular cortical neurons used monocular tests of ocular dominance to infer binocular function. The few studies that examined the relationship between ocular dominance and binocular disparity of individual cells used single-unit recordings and have provided conflicting results regarding whether ocular dominance can predict the selectivity or sensitivity to binocular disparity. We used two-photon calcium imaging to sample the response to monocular and binocular visual stimuli from nearly every adjacent neuron in a small region of the cat visual cortex, area 18. Here we show that local circuits for ocular dominance always have smooth and graded transitions from one apparently monocular functional domain to an adjacent binocular region. Most unexpectedly, we discovered a new map in the cat visual cortex that had a precise functional micro-architecture for binocular disparity selectivity. At the level of single cells, ocular dominance was unrelated to binocular disparity selectivity or sensitivity. When the local maps for ocular dominance and binocular disparity both had measurable gradients at a given cortical site, the two gradient directions were orthogonal to each other. Together, these results indicate that, from the perspective of the spiking activity of individual neurons, ocular dominance cannot predict binocular disparity tuning. However, the precise local arrangement of ocular dominance and binocular disparity maps provide new clues regarding how monocular and binocular depth cues may be combined and decoded.
]]>Nature 458, 632 (2009). doi:10.1038/nature07832
Authors: Stephenie A. Harrison & Frank Tong
Visual working memory provides an essential link between perception and higher cognitive functions, allowing for the active maintenance of information about stimuli no longer in view. Research suggests that sustained activity in higher-order prefrontal, parietal, inferotemporal and lateral occipital areas supports visual maintenance, and may account for the limited capacity of working memory to hold up to 3–4 items. Because higher-order areas lack the visual selectivity of early sensory areas, it has remained unclear how observers can remember specific visual features, such as the precise orientation of a grating, with minimal decay in performance over delays of many seconds. One proposal is that sensory areas serve to maintain fine-tuned feature information, but early visual areas show little to no sustained activity over prolonged delays. Here we show that orientations held in working memory can be decoded from activity patterns in the human visual cortex, even when overall levels of activity are low. Using functional magnetic resonance imaging and pattern classification methods, we found that activity patterns in visual areas V1–V4 could predict which of two oriented gratings was held in memory with mean accuracy levels upwards of 80%, even in participants whose activity fell to baseline levels after a prolonged delay. These orientation-selective activity patterns were sustained throughout the delay period, evident in individual visual areas, and similar to the responses evoked by unattended, task-irrelevant gratings. Our results demonstrate that early visual areas can retain specific information about visual features held in working memory, over periods of many seconds when no physical stimulus is present.
]]>Nature 458, 636 (2009). doi:10.1038/nature07930
Authors: Johannes F. Scheid, Hugo Mouquet, Niklas Feldhahn, Michael S. Seaman, Klara Velinzon, John Pietzsch, Rene G. Ott, Robert M. Anthony, Henry Zebroski, Arlene Hurley, Adhuna Phogat, Bimal Chakrabarti, Yuxing Li, Mark Connors, Florencia Pereyra, Bruce D. Walker, Hedda Wardemann, David Ho, Richard T. Wyatt, John R. Mascola, Jeffrey V. Ravetch & Michel C. Nussenzweig
Antibodies to conserved epitopes on the human immunodeficiency virus (HIV) surface protein gp140 can protect against infection in non-human primates, and some infected individuals show high titres of broadly neutralizing immunoglobulin (Ig)G antibodies in their serum. However, little is known about the specificity and activity of these antibodies. To characterize the memory antibody responses to HIV, we cloned 502 antibodies from HIV envelope-binding memory B cells from six HIV-infected patients with broadly neutralizing antibodies and low to intermediate viral loads. We show that in these patients, the B-cell memory response to gp140 is composed of up to 50 independent clones expressing high affinity neutralizing antibodies to the gp120 variable loops, the CD4-binding site, the co-receptor-binding site, and to a new neutralizing epitope that is in the same region of gp120 as the CD4-binding site. Thus, the IgG memory B-cell compartment in the selected group of patients with broad serum neutralizing activity to HIV is comprised of multiple clonal responses with neutralizing activity directed against several epitopes on gp120.
]]>Nature 458, 641 (2009). doi:10.1038/nature07746
Authors: Yuka Kawashima, Katja Pfafferott, John Frater, Philippa Matthews, Rebecca Payne, Marylyn Addo, Hiroyuki Gatanaga, Mamoru Fujiwara, Atsuko Hachiya, Hirokazu Koizumi, Nozomi Kuse, Shinichi Oka, Anna Duda, Andrew Prendergast, Hayley Crawford, Alasdair Leslie, Zabrina Brumme, Chanson Brumme, Todd Allen, Christian Brander, Richard Kaslow, James Tang, Eric Hunter, Susan Allen, Joseph Mulenga, Songee Branch, Tim Roach, Mina John, Simon Mallal, Anthony Ogwu, Roger Shapiro, Julia G. Prado, Sarah Fidler, Jonathan Weber, Oliver G. Pybus, Paul Klenerman, Thumbi Ndung’u, Rodney Phillips, David Heckerman, P. Richard Harrigan, Bruce D. Walker, Masafumi Takiguchi & Philip Goulder
The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host–pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8+ T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8+ T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128–135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8+ T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.
]]>Nature 458, 646 (2009). doi:10.1038/nature07686
Authors: Ilya Gertsman, Lu Gan, Miklos Guttman, Kelly Lee, Jeffrey A. Speir, Robert L. Duda, Roger W. Hendrix, Elizabeth A. Komives & John E. Johnson
Lambda-like double-stranded (ds) DNA bacteriophage undergo massive conformational changes in their capsid shell during the packaging of their viral genomes. Capsid shells are complex organizations of hundreds of protein subunits that assemble into intricate quaternary complexes that ultimately are able to withstand over 50 atm of pressure during genome packaging. The extensive integration between subunits in capsids requires the formation of an intermediate complex, termed a procapsid, from which individual subunits can undergo the necessary refolding and structural rearrangements needed to transition to the more stable capsid. Although various mature capsids have been characterized at atomic resolution, no such procapsid structure is available for a dsDNA virus or bacteriophage. Here we present a procapsid X-ray structure at 3.65 Å resolution, termed prohead II, of the lambda-like bacteriophage HK97, the mature capsid structure of which was previously solved to 3.44 Å (ref. 2). A comparison of the two largely different capsid forms has unveiled an unprecedented expansion mechanism that describes the transition. Crystallographic and hydrogen/deuterium exchange data presented here demonstrate that the subunit tertiary structures are significantly different between the two states, with twisting and bending motions occurring in both helical and β-sheet regions. We also identified subunit interactions at each three-fold axis of the capsid that are maintained throughout maturation. The interactions sustain capsid integrity during subunit refolding and provide a fixed hinge from which subunits undergo rotational and translational motions during maturation. Previously published calorimetric data of a closely related bacteriophage, P22, showed that capsid maturation was an exothermic process that resulted in a release of 90 kJ mol-1 of energy. We propose that the major tertiary changes presented in this study reveal a structural basis for an exothermic maturation process probably present in many dsDNA bacteriophage and possibly viruses such as herpesvirus, which share the HK97 subunit fold.
]]>Nature 458, 651 (2009). doi:10.1038/nature07753
Authors: Judith M. Neugebauer, Jeffrey D. Amack, Annita G. Peterson, Brent W. Bisgrove & H. Joseph Yost
Cilia are cell surface organelles found on most epithelia in vertebrates. Specialized groups of cilia have critical roles in embryonic development, including left–right axis formation. Recently, cilia have been implicated as recipients of cell–cell signalling. However, little is known about cell–cell signalling pathways that control the length of cilia. Here we provide several lines of evidence showing that fibroblast growth factor (FGF) signalling regulates cilia length and function in diverse epithelia during zebrafish and Xenopus development. Morpholino knockdown of FGF receptor 1 (Fgfr1) in zebrafish cell-autonomously reduces cilia length in Kupffer’s vesicle and perturbs directional fluid flow required for left–right patterning of the embryo. Expression of a dominant-negative FGF receptor (DN-Fgfr1), treatment with SU5402 (a pharmacological inhibitor of FGF signalling) or genetic and morpholino reduction of redundant FGF ligands Fgf8 and Fgf24 reproduces this cilia length phenotype. Knockdown of Fgfr1 also results in shorter tethering cilia in the otic vesicle and shorter motile cilia in the pronephric ducts. In Xenopus, expression of a dn-fgfr1 results in shorter monocilia in the gastrocoel roof plate that control left–right patterning and in shorter multicilia in external mucociliary epithelium. Together, these results indicate a fundamental and highly conserved role for FGF signalling in the regulation of cilia length in multiple tissues. Abrogation of Fgfr1 signalling downregulates expression of two ciliogenic transcription factors, foxj1 and rfx2, and of the intraflagellar transport gene ift88 (also known as polaris), indicating that FGF signalling mediates cilia length through an Fgf8/Fgf24–Fgfr1–intraflagellar transport pathway. We propose that a subset of developmental defects and diseases ascribed to FGF signalling are due in part to loss of cilia function.
]]>Nature 458, 655 (2009). doi:10.1038/nature07763
Authors: Taufiq-Ur-Rahman, Alexander Skupin, Martin Falcke & Colin W. Taylor
The versatility of Ca2+ signals derives from their spatio-temporal organization. For Ca2+ signals initiated by inositol-1,4,5-trisphosphate (InsP3), this requires local interactions between InsP3 receptors (InsP3Rs) mediated by their rapid stimulation and slower inhibition by cytosolic Ca2+. This allows hierarchical recruitment of Ca2+ release events as the InsP3 concentration increases. Single InsP3Rs respond first, then clustered InsP3Rs open together giving a local ‘Ca2+ puff’, and as puffs become more frequent they ignite regenerative Ca2+ waves. Using nuclear patch-clamp recording, here we demonstrate that InsP3Rs are initially randomly distributed with an estimated separation of ∼1 μm. Low concentrations of InsP3 cause InsP3Rs to aggregate rapidly and reversibly into small clusters of about four closely associated InsP3Rs. At resting cytosolic [Ca2+], clustered InsP3Rs open independently, but with lower open probability, shorter open time, and less InsP3 sensitivity than lone InsP3Rs. Increasing cytosolic [Ca2+] reverses the inhibition caused by clustering, InsP3R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes InsP3Rs to local Ca2+ rises and increases the effects of Ca2+. Dynamic regulation of clustering by InsP3 retunes InsP3R sensitivity to InsP3 and Ca2+, facilitating hierarchical recruitment of the elementary events that underlie all InsP3-evoked Ca2+ signals.
]]>Nature 458, 660 (2009). doi:10.1038/nature07964
Authors: Hyun Chul Lee, Su-Jin Kim, Kyung-Sup Kim, Hang-Cheol Shin & Ji-Won Yoon
Nature408, 483–488 (2000)Three of the authors (H.C.L., K.-S.K. and H.-C.S.) wish to retract this Letter on the grounds that they have been unable to reproduce the results. The retraction has not been signed by Ji-Won Yoon (deceased)
]]>Nature 458, 668 (2009). doi:10.1038/458668a
Author: Gregory Benford
Future-proof.
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