A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles

Poly(MePEG₂₀₀₀cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1. The high values of transendothelial electrical resistance and low permeability coefficients of marker molecules demonstrated the functionality of this model. The comparative passage of polyhexadecylcyanoacrylate and PEG-PHDCA nanoparticles through this model was investigated, showing a higher passage of PEGylated nanoparticles, presumably by endocytosis. This result was confirmed by confocal microscopy. Thanks to a good in vitro/in vivo correlation, this rat BBB model will help in understanding the mechanisms of nanoparticle translocation and in designing new types of colloidal carriers as brain delivery systems.Received 4 March 2005; accepted 14 April 2005     

Global estimate of aerosol direct radiative forcing from satellite measurements

Atmospheric aerosols cause scattering and absorption of incoming solar radiation. Additional anthropogenic aerosols released into the atmosphere thus exert a direct radiative forcing on the climate system. The degree of present-day aerosol forcing is estimated from global models that incorporate a representation of the aerosol cycles. Although the models are compared and validated against observations, these estimates remain uncertain. Previous satellite measurements of the direct effect of aerosols contained limited information about aerosol type, and were confined to oceans only. Here we use state-of-the-art satellite-based measurements of aerosols and surface wind speed to estimate the clear-sky direct radiative forcing for 2002, incorporating measurements over land and ocean. We use a Monte Carlo approach to account for uncertainties in aerosol measurements and in the algorithm used. Probability density functions obtained for the direct radiative forcing at the top of the atmosphere give a clear-sky, global, annual average of -1.9 W m(-2) with standard deviation, +/- 0.3 W m(-2). These results suggest that present-day direct radiative forcing is stronger than present model estimates, implying future atmospheric warming greater than is presently predicted, as aerosol emissions continue to decline.     

Ice-sheet collapse and sea-level rise at the Bølling warming 14,600 years ago

Past sea-level records provide invaluable information about the response of ice sheets to climate forcing. Some such records suggest that the last deglaciation was punctuated by a dramatic period of sea-level rise, of about 20?metres, in less than 500?years. Controversy about the amplitude and timing of this meltwater pulse (MWP-1A) has, however, led to uncertainty about the source of the melt water and its temporal and causal relationships with the abrupt climate changes of the deglaciation. Here we show that MWP-1A started no earlier than 14,650 years ago and ended before 14,310 years ago, making it coeval with the B?lling warming. Our results, based on corals drilled offshore from Tahiti during Integrated Ocean Drilling Project Expedition 310, reveal that the increase in sea level at Tahiti was between 12 and 22 metres, with a most probable value between 14 and 18 metres, establishing a significant meltwater contribution from the Southern Hemisphere. This implies that the rate of eustatic sea-level rise exceeded 40 millimetres per year during MWP-1A.     

Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.     

Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene

The independent evolution of morphological similarities is widespread. For simple traits, such as overall body colour, repeated transitions by means of mutations in the same gene may be common. However, for more complex traits, the possible genetic paths may be more numerous; the molecular mechanisms underlying their independent origins and the extent to which they are constrained to follow certain genetic paths are largely unknown. Here we show that a male wing pigmentation pattern involved in courtship display has been gained and lost multiple times in a Drosophila clade. Each of the cases we have analysed (two gains and two losses) involved regulatory changes at the pleiotropic pigmentation gene yellow. Losses involved the parallel inactivation of the same cis-regulatory element (CRE), with changes at a few nucleotides sufficient to account for the functional divergence of one element between two sibling species. Surprisingly, two independent gains of wing spots resulted from the co-option of distinct ancestral CREs. These results demonstrate how the functional diversification of the modular CREs of pleiotropic genes contributes to evolutionary novelty and the independent evolution of morphological similarities.     

Improper ferroelectricity in perovskite oxide artificial superlattices

Ferroelectric thin films and superlattices are currently the subject of intensive research because of the interest they raise for technological applications and also because their properties are of fundamental scientific importance. Ferroelectric superlattices allow the tuning of the ferroelectric properties while maintaining perfect crystal structure and a coherent strain, even throughout relatively thick samples. This tuning is achieved in practice by adjusting both the strain, to enhance the polarization, and the composition, to interpolate between the properties of the combined compounds. Here we show that superlattices with very short periods possess a new form of interface coupling, based on rotational distortions, which gives rise to 'improper' ferroelectricity. These observations suggest an approach, based on interface engineering, to produce artificial materials with unique properties. By considering ferroelectric/paraelectric PbTiO3/SrTiO3 multilayers, we first show from first principles that the ground-state of the system is not purely ferroelectric but also primarily involves antiferrodistortive rotations of the oxygen atoms in a way compatible with improper ferroelectricity. We then demonstrate experimentally that, in contrast to pure PbTiO3 and SrTiO3 compounds, the multilayer system indeed behaves like a prototypical improper ferroelectric and exhibits a very large dielectric constant of epsilon(r) approximately 600, which is also fairly temperature-independent. This behaviour, of practical interest for technological applications, is distinct from that of normal ferroelectrics, for which the dielectric constant is typically large but strongly evolves around the phase transition temperature and also differs from that of previously known improper ferroelectrics that exhibit a temperature-independent but small dielectric constant only.     

Quantum phase transition in a single-molecule quantum dot

Quantum criticality is the intriguing possibility offered by the laws of quantum mechanics when the wave function of a many-particle physical system is forced to evolve continuously between two distinct, competing ground states. This phenomenon, often related to a zero-temperature magnetic phase transition, is believed to govern many of the fascinating properties of strongly correlated systems such as heavy-fermion compounds or high-temperature superconductors. In contrast to bulk materials with very complex electronic structures, artificial nanoscale devices could offer a new and simpler means of understanding quantum phase transitions. Here we demonstrate this possibility in a single-molecule quantum dot, where a gate voltage induces a crossing of two different types of electron spin state (singlet and triplet) at zero magnetic field. The quantum dot is operated in the Kondo regime, where the electron spin on the quantum dot is partially screened by metallic electrodes. This strong electronic coupling between the quantum dot and the metallic contacts provides the strong electron correlations necessary to observe quantum critical behaviour. The quantum magnetic phase transition between two different Kondo regimes is achieved by tuning gate voltages and is fundamentally different from previously observed Kondo transitions in semiconductor and nanotube quantum dots. Our work may offer new directions in terms of control and tunability for molecular spintronics.     

Elastic wave velocity in rocks from Dabieshan and its constraints for lithospheric composition and crust-mantle recycling

P-and S-wave velocities in eclogites and granulites from the Dabie ultrahigh pressures (UHP) meta morphic belt, China, were measured at room temperature under the hydrostatic pressures up to 1.0 GPa. The ultrahigh pressure eclogites had the highest densities (3.3 ～ 3.6 g.cm-3) , high velocities and the lowest anisotropy (1.4%c ～ 2.6 % ) . The lowest densities (2.8 ～ 3.1 g. cm-3 ) and the highest Poisson' s ratios (0.28 ～ 0.29) were found in gran ulites, whereas the strongest anisotropies (6. 1 % ～8.4% ) were found in the high-pressure (HP) eclogites. Compari son of the velocities in rocks with that observed in the deep seismic sounding profile crossing Dabieshan suggests that e clogites might exist in the lower crust of Dabieshan, but the quantity might be small. The upper mantle has very similar velocities as the UHP eclogites and serpentinizated/water-bearing dunite. The formation of eclogite represents the crust mantle recycling processes. Crustal material is delaminated and sinks into the mantle by way of eclogite, whereas only a small part of the eclogite could return to the crust.     

Initial sequencing and comparative analysis of the mouse genome

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.