Centrosome polarization delivers secretory granules to the immunological synapse

Cytotoxic T lymphocytes (CTLs) destroy virally infected and tumorigenic cells by releasing the contents of specialized secretory lysosomes--termed 'lytic granules'--at the immunological synapse formed between the CTL and the target. On contact with the target cell, the microtubule organizing centre of the CTL polarizes towards the target and granules move along microtubules in a minus-end direction towards the polarized microtubule organizing centre. However, the final steps of secretion have remained unclear. Here we show that CTLs do not require actin or plus-end microtubule motors for secretion, but instead the centrosome moves to and contacts the plasma membrane at the central supramolecular activation cluster of the immunological synapse. Actin and IQGAP1 are cleared away from the synapse, and granules are delivered directly to the plasma membrane. These data show that CTLs use a previously unreported mechanism for delivering secretory granules to the immunological synapse, with granule secretion controlled by centrosome delivery to the plasma membrane.     

Resonance in the electron-doped high-transition-temperature superconductor Pr0.88LaCe0.12CuO4-delta

In conventional superconductors, the interaction that pairs the electrons to form the superconducting state is mediated by lattice vibrations (phonons). In high-transition-temperature (high-T(c)) copper oxides, it is generally believed that magnetic excitations might play a fundamental role in the superconducting mechanism because superconductivity occurs when mobile 'electrons' or 'holes' are doped into the antiferromagnetic parent compounds. Indeed, a sharp magnetic excitation termed 'resonance' has been observed by neutron scattering in a number of hole-doped materials. The resonance is intimately related to superconductivity, and its interaction with charged quasi-particles observed by photoemission, optical conductivity, and tunnelling suggests that it might play a part similar to that of phonons in conventional superconductors. The relevance of the resonance to high-T(c) superconductivity, however, has been in doubt because so far it has been found only in hole-doped materials. Here we report the discovery of the resonance in electron-doped superconducting Pr0.88LaCe0.12CuO4-delta (T(c) = 24 K). We find that the resonance energy (E(r)) is proportional to T(c) via E(r) approximately 5.8k(B)T(c) for all high-T(c) superconductors irrespective of electron- or hole-doping. Our results demonstrate that the resonance is a fundamental property of the superconducting copper oxides and therefore must be essential in the mechanism of superconductivity.     

A high-performance brain-computer interface

Recent studies have demonstrated that monkeys and humans can use signals from the brain to guide computer cursors. Brain-computer interfaces (BCIs) may one day assist patients suffering from neurological injury or disease, but relatively low system performance remains a major obstacle. In fact, the speed and accuracy with which keys can be selected using BCIs is still far lower than for systems relying on eye movements. This is true whether BCIs use recordings from populations of individual neurons using invasive electrode techniques or electroencephalogram recordings using less- or non-invasive techniques. Here we present the design and demonstration, using electrode arrays implanted in monkey dorsal premotor cortex, of a manyfold higher performance BCI than previously reported. These results indicate that a fast and accurate key selection system, capable of operating with a range of keyboard sizes, is possible (up to 6.5 bits per second, or approximately 15 words per minute, with 96 electrodes). The highest information throughput is achieved with unprecedentedly brief neural recordings, even as recording quality degrades over time. These performance results and their implications for system design should substantially increase the clinical viability of BCIs in humans.     

Direct observation of individual RecA filaments assembling on single DNA molecules

Escherichia coli RecA is essential for the repair of DNA double-strand breaks by homologous recombination. Repair requires the formation of a RecA nucleoprotein filament. Previous studies have indicated a mechanism of filament assembly whereby slow nucleation of RecA protein on DNA is followed by rapid growth. However, many aspects of this process remain unclear, including the rates of nucleation and growth and the involvement of ATP hydrolysis, largely because visualization at the single-filament level is lacking. Here we report the direct observation of filament assembly on individual double-stranded DNA molecules using fluorescently modified RecA. The nucleoprotein filaments saturate the DNA and extend it approximately 1.6-fold. At early time points, discrete RecA clusters are seen, permitting analysis of single-filament growth from individual nuclei. Formation of nascent RecA filaments is independent of ATP hydrolysis but is dependent on the type of nucleotide cofactor and the RecA concentration, suggesting that nucleation involves binding of approximately 4-5 ATP-RecA monomers to DNA. Individual RecA filaments grow at rates of 3-10 nm s(-1). Growth is bidirectional and, in contrast to nucleation, independent of nucleotide cofactor, suggesting addition of approximately 2-7 monomers s(-1). These results are in accord with extensive genetic and biochemical studies, and indicate that assembly in vivo is controlled at the nucleation step. We anticipate that our approach and conclusions can be extended to the related eukaryotic counterpart, Rad51 (see ref.), and to regulation by assembly mediators.     

Transiting extrasolar planetary candidates in the Galactic bulge

More than 200 extrasolar planets have been discovered around relatively nearby stars, primarily through the Doppler line shifts owing to reflex motions of their host stars, and more recently through transits of some planets across the faces of the host stars. The detection of planets with the shortest known periods, 1.2-2.5 days, has mainly resulted from transit surveys which have generally targeted stars more massive than 0.75 M(o), where M(o) is the mass of the Sun. Here we report the results from a planetary transit search performed in a rich stellar field towards the Galactic bulge. We discovered 16 candidates with orbital periods between 0.4 and 4.2 days, five of which orbit stars of masses in the range 0.44-0.75 M(o). In two cases, radial-velocity measurements support the planetary nature of the companions. Five candidates have orbital periods below 1.0 day, constituting a new class of ultra-short-period planets, which occur only around stars of less than 0.88 M(o). This indicates that those orbiting very close to more-luminous stars might be evaporatively destroyed or that jovian planets around stars of lower mass might migrate to smaller radii.     

Eastern Pacific cooling and Atlantic overturning circulation during the last deglaciation

Surface ocean conditions in the equatorial Pacific Ocean could hold the clue to whether millennial-scale global climate change during glacial times was initiated through tropical ocean-atmosphere feedbacks or by changes in the Atlantic thermohaline circulation. North Atlantic cold periods during Heinrich events and millennial-scale cold events (stadials) have been linked with climatic changes in the tropical Atlantic Ocean and South America, as well as the Indian and East Asian monsoon systems, but not with tropical Pacific sea surface temperatures. Here we present a high-resolution record of sea surface temperatures in the eastern tropical Pacific derived from alkenone unsaturation measurements. Our data show a temperature drop of approximately 1 degrees C, synchronous (within dating uncertainties) with the shutdown of the Atlantic meridional overturning circulation during Heinrich event 1, and a smaller temperature drop of approximately 0.5 degrees C synchronous with the smaller reduction in the overturning circulation during the Younger Dryas event. Both cold events coincide with maxima in surface ocean productivity as inferred from 230Th-normalized carbon burial fluxes, suggesting increased upwelling at the time. From the concurrence of equatorial Pacific cooling with the two North Atlantic cold periods during deglaciation, we conclude that these millennial-scale climate changes were probably driven by a reorganization of the oceans' thermohaline circulation, although possibly amplified by tropical ocean-atmosphere interaction as suggested before.     

Ecology: mechanisms for consumer diversity

A variety of mechanisms can theoretically produce competitive coexistence in nature, making it hard to identify a single explanation for the maintenance of diversity in any particular system. Based on laboratory experiments with a consumer-resource system of crustacean Daphnia eating algae, Nelson et al. suggest that maintenance of genetic diversity in the consumer populations they studied depends only on the dynamics of the population structure of the consumer. We suggest that the differences in Daphnia genetic diversity that they find for different experimental treatments could equally be explained by a simple, well known mechanism: the number of coexisting competitors cannot exceed the number of shared resources. Here we confirm this possibility by using a simple mathematical model and suggest that more than one mechanism may account for the maintenance of genetic diversity observed by Nelson et al. in their system.     

Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.     

Independent evolution of bitter-taste sensitivity in humans and chimpanzees

It was reported over 65 years ago that chimpanzees, like humans, vary in taste sensitivity to the bitter compound phenylthiocarbamide (PTC). This was suggested to be the result of a shared balanced polymorphism, defining the first, and now classic, example of the effects of balancing selection in great apes. In humans, variable PTC sensitivity is largely controlled by the segregation of two common alleles at the TAS2R38 locus, which encode receptor variants with different ligand affinities. Here we show that PTC taste sensitivity in chimpanzees is also controlled by two common alleles of TAS2R38; however, neither of these alleles is shared with humans. Instead, a mutation of the initiation codon results in the use of an alternative downstream start codon and production of a truncated receptor variant that fails to respond to PTC in vitro. Association testing of PTC sensitivity in a cohort of captive chimpanzees confirmed that chimpanzee TAS2R38 genotype accurately predicts taster status in vivo. Therefore, although Fisher et al.'s observations were accurate, their explanation was wrong. Humans and chimpanzees share variable taste sensitivity to bitter compounds mediated by PTC receptor variants, but the molecular basis of this variation has arisen twice, independently, in the two species.     

Kant and the nature of matter: Mechanics,chemistry, and the life sciences

Kant believed that the ultimate processes that regulate the behavior of material bodies can be characterized exclusively in terms of mechanics. In 1790, turning his attention to the life sciences, he raised a potential problem for his mechanically-based account, namely that many of the operations described in the life sciences seemed to operate teleologically. He argued that the life sciences do indeed require us to think in teleological terms, but that this is a fact about us, not about the processes themselves. Nevertheless, even were we to concede his account of the life sciences, this would not secure the credentials of mechanics as a general theory of matter. Hardly any material properties studied in the second half of the eighteenth century were, or could have been, conceived in mechanical terms. Kant's concern with teleology is tangential to the problems facing a general matter theory grounded in mechanics, for the most pressing issues have nothing to do with teleology. They derive rather from a lack of any connection between mechanical forces and material properties. This is evident in chemistry, which Kant dismisses as being unscientific on the grounds that it cannot be formulated in mechanical terms.