Natural killer cells act as rheostats modulating antiviral T cells

Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection, implying that NK cells have a role in these T-cell-associated diseases. Although direct NK-cell-mediated lysis of virus-infected cells may contribute to antiviral defence during some virus infections--especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans--NK cells have also been suspected of having immunoregulatory functions. For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells. In contrast to MCMV, lymphocytic choriomeningitis virus (LCMV) infection in mice seems to be resistant to any direct antiviral effects of NK cells. Here we examine the roles of NK cells in regulating T-cell-dependent viral persistence and immunopathology in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus doses, NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at medium doses NK cells paradoxically facilitated lethal T-cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.     

Photosensitized reduction of nitrogen dioxide on humic acid as a source of nitrous acid

Nitrous acid is a significant photochemical precursor of the hydroxyl radical, the key oxidant in the degradation of most air pollutants in the troposphere. The sources of nitrous acid in the troposphere, however, are still poorly understood. Recent atmospheric measurements revealed a strongly enhanced formation of nitrous acid during daytime via unknown mechanisms. Here we expose humic acid films to nitrogen dioxide in an irradiated tubular gas flow reactor and find that reduction of nitrogen dioxide on light-activated humic acids is an important source of gaseous nitrous acid. Our findings indicate that soil and other surfaces containing humic acid exhibit an organic surface photochemistry that produces reductive surface species, which react selectively with nitrogen dioxide. The observed rate of nitrous acid formation could explain the recently observed high daytime concentrations of nitrous acid in the boundary layer, the photolysis of which accounts for up to 60 per cent of the integrated hydroxyl radical source strengths. We suggest that this photo-induced nitrous acid production on humic acid could have a potentially significant impact on the chemistry of the lowermost troposphere.     

Dynamical fracture instabilities due to local hyperelasticity at crack tips

As the speed of a crack propagating through a brittle material increases, a dynamical instability leads to an increased roughening of the fracture surface. Cracks moving at low speeds create atomically flat mirror-like surfaces; at higher speeds, rougher, less reflective ('mist') and finally very rough, irregularly faceted ('hackle') surfaces are formed. The behaviour is observed in many different brittle materials, but the underlying physical principles, though extensively debated, remain unresolved. Most existing theories of fracture assume a linear elastic stress-strain law. However, the relation between stress and strain in real solids is strongly nonlinear due to large deformations near a moving crack tip, a phenomenon referred to as hyperelasticity. Here we use massively parallel large-scale atomistic simulations--employing a simple atomistic material model that allows a systematic transition from linear elastic to strongly nonlinear behaviour--to show that hyperelasticity plays a governing role in the onset of the instability. We report a generalized model that describes the onset of instability as a competition between different mechanisms controlled by the local stress field and local energy flow near the crack tip. Our results indicate that such instabilities are intrinsic to dynamical fracture and they help to explain a range of controversial experimental and computational results.     

Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion

Peripheral infection is the natural route of transmission in most prion diseases. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis, but the mechanisms of prion transfer from the immune to the nervous system are unknown. Here we show that ablation of the chemokine receptor CXCR5 juxtaposes follicular dendritic cells (FDCs) to major splenic nerves, and accelerates the transfer of intraperitoneally administered prions into the spinal cord. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves: transfer of CXCR5-/- bone marrow to wild-type mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to CXCR5-/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5-/- mice. This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.     

AAV serotype 2 vectors preferentially integrate into active genes in mice

Recombinant adeno-associated virus serotype 2 (rAAV2) is a promising vector for gene therapy because it can achieve long-term stable transgene expression in animals and human subjects after direct administration of vectors into various target tissues. In the liver, although stable transgene expression primarily results from extrachromosomal vector genomes, a series of experiments has shown that vector genomes integrate into host chromosomes in hepatocytes at a low frequency. Despite the low integration efficiency, recent reports of retroviral insertional mutagenesis in mice and two human subjects have raised concerns about the potential for rAAV2-mediated insertional mutagenesis. Here we characterize rAAV2-targeted chromosomal integration sites isolated from selected or non-selected hepatocytes in vector-injected mouse livers. We document frequent chromosomal deletions of up to 2 kb at integration sites (14 of 14 integrations, 100%; most of the deletions were <0.3 kb) and preferred integration into genes (21 of 29 integrations, 72%). In addition, all of the targeted genes analyzed (20 of 20 targeted genes, 100%) were expressed in the liver. This is the first report to our knowledge on host chromosomal effects of rAAV2 integration in animals, and it provides insights into the nature of rAAV2 vector integration into chromosomes in quiescent somatic cells in animals and human subjects.     

Communications: quantum teleportation across the Danube

Efficient long-distance quantum teleportation is crucial for quantum communication and quantum networking schemes. Here we describe the high-fidelity teleportation of photons over a distance of 600 metres across the River Danube in Vienna, with the optimal efficiency that can be achieved using linear optics. Our result is a step towards the implementation of a quantum repeater, which will enable pure entanglement to be shared between distant parties in a public environment and eventually on a worldwide scale.     

Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking

Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) has an important function in cell regulation both as a precursor of second messenger molecules and by means of its direct interactions with cytosolic and membrane proteins. Biochemical studies have suggested a role for PtdIns(4,5)P2 in clathrin coat dynamics, and defects in its dephosphorylation at the synapse produce an accumulation of coated endocytic intermediates. However, the involvement of PtdIns(4,5)P2 in synaptic vesicle exocytosis remains unclear. Here, we show that decreased levels of PtdIns(4,5)P2 in the brain and an impairment of its depolarization-dependent synthesis in nerve terminals lead to early postnatal lethality and synaptic defects in mice. These include decreased frequency of miniature currents, enhanced synaptic depression, a smaller readily releasable pool of vesicles, delayed endocytosis and slower recycling kinetics. Our results demonstrate a critical role for PtdIns(4,5)P2 synthesis in the regulation of multiple steps of the synaptic vesicle cycle.