Low-energy acoustic plasmons at metal surfaces

Nearly two-dimensional (2D) metallic systems formed in charge inversion layers and artificial layered materials permit the existence of low-energy collective excitations, called 2D plasmons, which are not found in a three-dimensional (3D) metal. These excitations have caused considerable interest because their low energy allows them to participate in many dynamical processes involving electrons and phonons, and because they might mediate the formation of Cooper pairs in high-transition-temperature superconductors. Metals often support electronic states that are confined to the surface, forming a nearly 2D electron-density layer. However, it was argued that these systems could not support low-energy collective excitations because they would be screened out by the underlying bulk electrons. Rather, metallic surfaces should support only conventional surface plasmons-higher-energy modes that depend only on the electron density. Surface plasmons have important applications in microscopy and sub-wavelength optics, but have no relevance to the low-energy dynamics. Here we show that, in contrast to expectations, a low-energy collective excitation mode can be found on bare metal surfaces. The mode has an acoustic (linear) dispersion, different to the dependence of a 2D plasmon, and was observed on Be(0001) using angle-resolved electron energy loss spectroscopy. First-principles calculations show that it is caused by the coexistence of a partially occupied quasi-2D surface-state band with the underlying 3D bulk electron continuum and also that the non-local character of the dielectric function prevents it from being screened out by the 3D states. The acoustic plasmon reported here has a very general character and should be present on many metal surfaces. Furthermore, its acoustic dispersion allows the confinement of light on small surface areas and in a broad frequency range, which is relevant for nano-optics and photonics applications.     

Annealing-induced interfacial toughening using a molecular nanolayer

Self-assembled molecular nanolayers (MNLs) composed of short organic chains and terminated with desired functional groups are attractive for modifying surface properties for a variety of applications. For example, organosilane MNLs are used as lubricants, in nanolithography, for corrosion protection and in the crystallization of biominerals. Recent work has explored uses of MNLs at thin-film interfaces, both as active components in molecular devices, and as passive layers, inhibiting interfacial diffusion, promoting adhesion and toughening brittle nanoporous structures. The relatively low stability of MNLs on surfaces at temperatures above 350-400 degrees C (refs 12, 13), as a result of desorption or degradation, limits the use of surface MNLs in high-temperature applications. Here we harness MNLs at thin-film interfaces at temperatures higher than the MNL desorption temperature to fortify copper-dielectric interfaces relevant to wiring in micro- and nano-electronic devices. Annealing Cu/MNL/SiO2 structures at 400-700 degrees C results in interfaces that are five times tougher than pristine Cu/SiO2 structures, yielding values exceeding approximately 20 J m(-2). Previously, similarly high toughness values have only been obtained using micrometre-thick interfacial layers. Electron spectroscopy of fracture surfaces and density functional theory modelling of molecular stretching and fracture show that toughening arises from thermally activated interfacial siloxane bridging that enables the MNL to be strongly linked to both the adjacent layers at the interface, and suppresses MNL desorption. We anticipate that our findings will open up opportunities for molecular-level tailoring of a variety of interfacial properties, at processing temperatures higher than previously envisaged, for applications where microlayers are not a viable option-such as in nanodevices or in thermally resistant molecular-inorganic hybrid devices.     

Visualizing single-molecule diffusion in mesoporous materials

Periodic mesoporous materials formed through the cooperative self-assembly of surfactants and framework building blocks can assume a variety of structures, and their widely tuneable properties make them attractive hosts for numerous applications. Because the molecular movement in the pore system is the most important and defining characteristic of porous materials, it is of interest to learn about this behaviour as a function of local structure. Generally, individual fluorescent dye molecules can be used as molecular beacons with which to explore the structure of--and the dynamics within--these porous hosts, and single-molecule fluorescence techniques provide detailed insights into the dynamics of various processes, ranging from biology to heterogeneous catalysis. However, optical microscopy methods cannot directly image the mesoporous structure of the host system accommodating the diffusing molecules, whereas transmission electron microscopy provides detailed images of the porous structure, but no dynamic information. It has therefore not been possible to 'see' how molecules diffuse in a real nanoscale pore structure. Here we present a combination of electron microscopic mapping and optical single-molecule tracking experiments to reveal how a single luminescent dye molecule travels through linear or strongly curved sections of a mesoporous channel system. In our approach we directly correlate porous structures detected by transmission electron microscopy with the diffusion dynamics of single molecules detected by optical microscopy. This opens up new ways of understanding the interactions of host and guest.     

Identification of Tim4 as a phosphatidylserine receptor

In programmed cell death, a large number of cells undergo apoptosis, and are engulfed by macrophages to avoid the release of noxious materials from the dying cells. In definitive erythropoiesis, nuclei are expelled from erythroid precursor cells and are engulfed by macrophages. Phosphatidylserine is exposed on the surface of apoptotic cells and on the nuclei expelled from erythroid precursor cells; it works as an 'eat me' signal for phagocytes. Phosphatidylserine is also expressed on the surface of exosomes involved in intercellular signalling. Here we established a library of hamster monoclonal antibodies against mouse peritoneal macrophages, and found an antibody that strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells. The antigen recognized by the antibody was identified by expression cloning as a type I transmembrane protein called Tim4 (T-cell immunoglobulin- and mucin-domain-containing molecule; also known as Timd4). Tim4 was expressed in Mac1+ cells in various mouse tissues, including spleen, lymph nodes and fetal liver. Tim4 bound apoptotic cells by recognizing phosphatidylserine via its immunoglobulin domain. The expression of Tim4 in fibroblasts enhanced their ability to engulf apoptotic cells. When the anti-Tim4 monoclonal antibody was administered into mice, the engulfment of apoptotic cells by thymic macrophages was significantly blocked, and the mice developed autoantibodies. Among the other Tim family members, Tim1, but neither Tim2 nor Tim3, specifically bound phosphatidylserine. Tim1- or Tim4-expressing Ba/F3 B cells were bound by exosomes via phosphatidylserine, and exosomes stimulated the interaction between Tim1 and Tim4. These results indicate that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signalling in which exosomes are involved.     

Enhanced biological carbon consumption in a high CO2 ocean

The oceans have absorbed nearly half of the fossil-fuel carbon dioxide (CO2) emitted into the atmosphere since pre-industrial times, causing a measurable reduction in seawater pH and carbonate saturation. If CO2 emissions continue to rise at current rates, upper-ocean pH will decrease to levels lower than have existed for tens of millions of years and, critically, at a rate of change 100 times greater than at any time over this period. Recent studies have shown effects of ocean acidification on a variety of marine life forms, in particular calcifying organisms. Consequences at the community to ecosystem level, in contrast, are largely unknown. Here we show that dissolved inorganic carbon consumption of a natural plankton community maintained in mesocosm enclosures at initial CO2 partial pressures of 350, 700 and 1,050 microatm increases with rising CO2. The community consumed up to 39% more dissolved inorganic carbon at increased CO2 partial pressures compared to present levels, whereas nutrient uptake remained the same. The stoichiometry of carbon to nitrogen drawdown increased from 6.0 at low CO2 to 8.0 at high CO2, thus exceeding the Redfield carbon:nitrogen ratio of 6.6 in today's ocean. This excess carbon consumption was associated with higher loss of organic carbon from the upper layer of the stratified mesocosms. If applicable to the natural environment, the observed responses have implications for a variety of marine biological and biogeochemical processes, and underscore the importance of biologically driven feedbacks in the ocean to global change.     

Innate versus learned odour processing in the mouse olfactory bulb

The mammalian olfactory system mediates various responses, including aversive behaviours to spoiled foods and fear responses to predator odours. In the olfactory bulb, each glomerulus represents a single species of odorant receptor. Because a single odorant can interact with several different receptor species, the odour information received in the olfactory epithelium is converted to a topographical map of multiple glomeruli activated in distinct areas in the olfactory bulb. To study how the odour map is interpreted in the brain, we generated mutant mice in which olfactory sensory neurons in a specific area of the olfactory epithelium are ablated by targeted expression of the diphtheria toxin gene. Here we show that, in dorsal-zone-depleted mice, the dorsal domain of the olfactory bulb was devoid of glomerular structures, although second-order neurons were present in the vacant areas. The mutant mice lacked innate responses to aversive odorants, even though they were capable of detecting them and could be conditioned for aversion with the remaining glomeruli. These results indicate that, in mice, aversive information is received in the olfactory bulb by separate sets of glomeruli, those dedicated for innate and those for learned responses.     

BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module

Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms. ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment. However, the receptor(s) upstream of the ELMO/Dock180/Rac module are still unknown. Here we identify brain-specific angiogenesis inhibitor 1 (BAI1) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a seven-transmembrane protein belonging to the adhesion-type G-protein-coupled receptor family, with an extended extracellular region and no known ligands. We show that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, we identify phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, decreased BAI1 expression or interference with BAI1 function inhibits the engulfment of apoptotic targets ex vivo and in vivo. Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.