Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread ...evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
Coherent diffractive imaging of individual free nanoparticles has opened routes for the in situ analysis of their transient structural, optical, and electronic properties. So far, single-shot ...single-particle diffraction was assumed to be feasible only at extreme ultraviolet and X-ray free-electron lasers, restricting this research field to large-scale facilities. Here we demonstrate single-shot imaging of isolated helium nanodroplets using extreme ultraviolet pulses from a femtosecond-laser-driven high harmonic source. We obtain bright wide-angle scattering patterns, that allow us to uniquely identify hitherto unresolved prolate shapes of superfluid helium droplets. Our results mark the advent of single-shot gas-phase nanoscopy with lab-based short-wavelength pulses and pave the way to ultrafast coherent diffractive imaging with phase-controlled multicolor fields and attosecond pulses.Diffraction imaging studies of free individual nanoparticles have so far been restricted to XUV and X-ray free - electron laser facilities. Here the authors demonstrate the possibility of using table-top XUV laser sources to image prolate shapes of superfluid helium droplets.
A significant fraction of superfluid helium nanodroplets produced in a free-jet expansion has been observed to gain high angular momentum resulting in large centrifugal deformation. We measured ...single-shot diffraction patterns of individual rotating helium nanodroplets up to large scattering angles using intense extreme ultraviolet light pulses from the FERMI free-electron laser. Distinct asymmetric features in the wide-angle diffraction patterns enable the unique and systematic identification of the three-dimensional droplet shapes. The analysis of a large data set allows us to follow the evolution from axisymmetric oblate to triaxial prolate and two-lobed droplets. We find that the shapes of spinning superfluid helium droplets exhibit the same stages as classical rotating droplets while the previously reported metastable, oblate shapes of quantum droplets are not observed. Our three-dimensional analysis represents a valuable landmark for clarifying the interrelation between morphology and superfluidity on the nanometer scale.
The diversity of nanoparticle shapes generated by condensation from gaseous matter reflects the fundamental competition between thermodynamic equilibration and the persistence of metastable ...configurations during growth. In the kinetically limited regime, intermediate geometries that are favoured only in early formation stages can be imprinted in the finally observed ensemble of differently structured specimens. Here we demonstrate that single-shot wide-angle scattering of femtosecond soft X-ray free-electron laser pulses allows three-dimensional characterization of the resulting metastable nanoparticle structures. For individual free silver particles, which can be considered frozen in space for the duration of photon exposure, both shape and orientation are uncovered from measured scattering images. We identify regular shapes, including species with fivefold symmetry and surprisingly large aspect ratio up to particle radii of the order of 100 nm. Our approach includes scattering effects beyond Born's approximation and is remarkably efficient-opening up new routes in ultrafast nanophysics and free-electron laser science.
ATP has been indicated as a primary factor in microglial response to brain injury and inflammation. By acting on different purinergic receptors 2, ATP is known to induce chemotaxis and stimulate the ...release of several cytokines from these cells. The activation of purinergic receptors 2 in microglia can be triggered either by ATP deriving from dying cells, at sites of brain injury or by ATP released from astrocytes, in the absence of cell damage. By the use of a biochemical approach integrated with video microscopy experiments, we investigated the functional consequences triggered in microglia by ATP released from mechanically stimulated astrocytes, in mixed glial cocultures. Astrocyte-derived ATP induced in nearby microglia the formation and the shedding of membrane vesicles. Vesicle formation was inhibited by the ATP-degrading enzyme apyrase or by P2X(7)R antagonists. Isolation of shed vesicles, followed by IL-1beta evaluation by a specific ELISA revealed the presence of the cytokine inside the vesicular organelles and its subsequent efflux into the extracellular medium. IL-1beta efflux from shed vesicles was enhanced by ATP stimulation and inhibited by pretreatment with the P2X(7) antagonist oxidized ATP, thus indicating a crucial involvement of the pore-forming P2X(7)R in the release of the cytokine. Our data identify astrocyte-derived ATP as the endogenous factor responsible for microvesicle shedding in microglia and reveal the mechanisms by which astrocyte-derived ATP triggers IL-1beta release from these cells.
Neuropsychiatric disease in systemic lupus erythematosus (NPSLE) is a poorly understood, but potentially fatal, disease manifestation. A pathogenetic role for autoantibodies is suspected, but the ...mechanism is unclear. Since immune complexes in SLE can stimulate IFN-alpha and there is strong evidence in humans and in mice that IFN-alpha can cause neuropsychiatric manifestations, we asked whether NPSLE patient serum and/or cerebrospinal fluid (CSF) contain abnormally high IFN-alpha-inducing activity. In a bioassay containing plasmacytoid dendritic cells and a source of Ag, NPSLE CSF induced significantly higher IFN-alpha compared with CSF from patients with multiple sclerosis or other autoimmune disease controls. When normalized for IgG concentration, NPSLE CSF was 800-fold more potent at inducing IFN-alpha compared with paired serum due to inhibitors present in serum. Analysis of Ig-deficient patient serum, depletion of IgG from normal serum, as well as addition of purified IgG to NPSLE CSF and serum in the bioassays revealed that one inhibitor was contained within the IgG fraction itself. In addition to IFN-alpha, immune complexes formed by CSF autoantibodies produced significantly increased levels of IFN-gamma-inducible protein 10 (IP-10/CXCL), IL-8, and MCP-1, all of which have been reported to be elevated in CSF from NPSLE patients. Taken together, these findings are consistent with a two-step model of NPSLE whereby CSF autoantibodies bind to Ags released by neurocytotoxic Abs or other brain cell injury, and the resulting immune complexes stimulate IFN-alpha and proinflammatory cytokines and chemokines.
Recent theoretical work has identified functionalized diamondoids as promising candidates for the tailoring of fluorescent nanomaterials. However, experiments confirming that optical gap tuning can ...be achieved through functionalization have, up until now, found only systems where fluorescence is quenched. We address this shortcoming by investigating a series of methylated adamantanes. For the first time, a class of functionalized diamondoids is shown to fluoresce in the gas phase. In order to understand the evolution of the optical and electronic structure properties with degree of functionalization, photoelectron spectroscopy was used to map the occupied valence electronic structure, while absorption and fluorescence spectroscopies yielded information about the unoccupied electronic structure and postexcitation relaxation behavior. The resulting spectra were modeled by (time-dependent) density functional theory. These results show that it is possible to overcome fluorescence quenching when functionalizing diamondoids and represent a significant step toward tailoring the electronic structure of these and other semiconductor particles in a manner suitable to applications.
Abstract
The Large Magellanic Cloud (LMC) is the nearest laboratory for detailed studies on the formation and survival of complex organic molecules (COMs), including biologically important ones, in ...low-metallicity environments—typical of earlier cosmological epochs. We report the results of 1.2 mm continuum and molecular line observations of three fields in the star-forming region N 105 with the Atacama Large Millimeter/submillimeter Array. N 105 lies at the western edge of the LMC bar with ongoing star formation traced by H
2
O, OH, and CH
3
OH masers, ultracompact H
ii
regions, and young stellar objects. Based on the spectral line modeling, we estimated rotational temperatures, column densities, and fractional molecular abundances for 12 1.2 mm continuum sources. We identified sources with a range of chemical makeups, including two bona fide hot cores and four hot core candidates. The CH
3
OH emission is widespread and associated with all the continuum sources. COMs CH
3
CN and CH
3
OCH
3
are detected toward two hot cores in N 105 together with smaller molecules typically found in Galactic hot cores (e.g., SO
2
, SO, and HNCO) with the molecular abundances roughly scaling with metallicity. We report a tentative detection of the astrobiologically relevant formamide molecule (NH
2
CHO) toward one of the hot cores; if confirmed, this would be the first detection of NH
2
CHO in an extragalactic subsolar metallicity environment. We suggest that metallicity inhomogeneities resulting from the tidal interactions between the LMC and the Small Magellanic Cloud might have led to the observed large variations in COM abundances in LMC hot cores.
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