Evaluation of the therapeutic potential of ant-TLR4-antibody MTS510 in experimental stroke and significa of different routes of application

Toll-like receptors (TLRs) are central sensors for the inflammatory response in ischemia-reperfusion injury. We therefore investigated whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia. Anti-TLR4/MD2-antibody (mAb clone MTS510) blocked TLR4-induced cell activation in vitro, as reported previously. Here, different routes of MTS510 application in vivo were used to study the effects on stroke outcome up to 2d after occlusion of the middle cerebral artery (MCAO) for 45 min in adult male C57Bl/6 wild-type mice. Improved neurological performance, reduced infarct volumes, and reduced brain swelling showed that intravascular application of MTS510 had a protective effect in the model of 45 min MCAO. Evaluation of potential long-term adverse effects of anti-TLR4-mAb-treament revealed no significant deleterious effect on infarct volumes nor neurological deficit after 14d of reperfusion in a mild model of stroke (15 min MCAO). Interestingly, inhibition of TLR4 resulted in an altered adaptive immune response at 48 hours after reperfusion. We conclude that blocking TLR4 by the use of specific mAb is a promising strategy for stroke therapy. However, long-term studies with increased functional sensitivity, larger sampling sizes and use of other species are required before a clinical use could be envisaged

Shutdown is a component of the Drosophila piRNA biogenesis machinery

In animals, the piRNA pathway preserves the integrity of gametic genomes, guarding them against the activity of mobile genetic elements. This innate immune mechanism relies on distinct genomic loci, termed piRNA clusters, to provide a molecular definition of transposons, enabling their discrimination from genes. piRNA clusters give rise to long, single-stranded precursors, which are processed into primary piRNAs through an unknown mechanism. These can engage in an adaptive amplification loop, the ping-pong cycle, to optimize the content of small RNA populations via the generation of secondary piRNAs.Many proteins have been ascribed functions in either primary biogenesis or the ping-pong cycle, though for the most part the molecular functions of proteins implicated in these pathways remain obscure. Here, we link shutdown (shu), a gene previously shown to be required for fertility in Drosophila, to the piRNA pathway. Analysis of knockdown phenotypes in both the germline and somatic compartments of the ovary demonstrate important roles for shutdown in both primary biogenesis and the ping-pong cycle. shutdown is a member of the FKBP family of immunophilins. Shu contains domains implicated in peptidyl-prolyl cis-trans isomerase activity and in the binding of HSP90-family chaperones, though the relevance of these domains to piRNA biogenesis is unknown. Published by Cold Spring Harbor Laboratory Press. Copyright © 2012 RNA Society

Analysis of the atmospheric distribution, sources, and sinks of oxygenated volatile organic chemicals based on measurements over the Pacific during TRACE-P

Airborne measurements of a large number of oxygenated volatile organic chemicals (OVOC) were carried out in the Pacific troposphere (0.1 - 12 km) in winter/spring of 2001 (24 February to 10 April). Specifically, these measurements included acetone (CH3COCHA3), methylethyl ketone (CH3COC2H5, MEK), methanol (CH3OH), ethanol (C2H5OH), acetaldehyde (CH3CHO), propionaldehyde C2H 5CHO), peroxyacylnitrates (PANs) (CnH 2n+1COO2NO2), and organic nitrates (CnH2n+1ONO2). Complementary measurements of formaldehyde (HCHO), methyl hydroperoxide (CH 3OOH), and selected tracers were also available. OVOC were abundant in the clean troposphere and were greatly enhanced in the outflow regions from Asia. Background mixing ratios were typically highest in the lower troposphere and declined toward the upper troposphere and the lowermost stratosphere. Their total abundance (ΣOVOC) was nearly twice that of nonmethane hydrocarbons (Σ C2-C8 NMHC. Throughout the troposphere, the OH reactivity of OVOC is comparable to that of methane and far exceeds that of NMHC. A comparison of these data with western Pacific observations collected some 7 years earlier (February-March 1994) did not reveal significant differences. Mixing ratios of OVOC were strongly correlated with each other as well as with tracers of fossil and biomass/biofuel combustion. Analysis of the relative enhancement of selected OVOC with respect to CH 3Cl and CO in 12 plumes originating from fires and sampled in the free troposphere (3-11 km) is used to assess their primary and secondary emissions from biomass combustion. The composition of these plumes also indicates a large shift of reactive nitrogen into the PAN reservoir thereby limiting ozone formation. A three-dimensional global model that uses state of the art chemistry and source information is used to compare measured and simulated mixing ratios of selected OVOC. While there is reasonable agreement in many cases, measured aldehyde concentrations are significantly larger than predicted. At their observed levels, acetaldehyde mixing ratios are shown to be an important source of HCHO (and HOx) and PAN in the troposphere. On the basis of presently known chemistry, measured mixing ratios of aldehydes and PANs are mutually incompatible. We provide rough estimates of the global sources of several OVOC and conclude that collectively these are extremely large (150-500 Tg C yr-1) but remain poorly quantified. Copyright 2004 by the American Geophysical Union

Polarizing Bubble Collisions

We predict the polarization of cosmic microwave background (CMB) photons that results from a cosmic bubble collision. The polarization is purely E-mode, symmetric around the axis pointing towards the collision bubble, and has several salient features in its radial dependence that can help distinguish it from a more conventional explanation for unusually cold or hot features in the CMB sky. The anomalous "cold spot" detected by the Wilkinson Microwave Anisotropy Probe (WMAP) satellite is a candidate for a feature produced by such a collision, and the Planck satellite and other proposed surveys will measure the polarization on it in the near future. The detection of such a collision would provide compelling evidence for the string theory landscape.Comment: Published version. 15 pages, 8 figure

Bubble collisions and measures of the multiverse

To compute the spectrum of bubble collisions seen by an observer in an eternally-inflating multiverse, one must choose a measure over the diverging spacetime volume, including choosing an "initial" hypersurface below which there are no bubble nucleations. Previous calculations focused on the case where the initial hypersurface is pushed arbitrarily deep into the past. Interestingly, the observed spectrum depends on the orientation of the initial hypersurface, however one's ability observe the effect rapidly decreases with the ratio of inflationary Hubble rates inside and outside one's bubble. We investigate whether this conclusion might be avoided under more general circumstances, in particular placing the observer's bubble near the initial hypersurface. We find that it is not. As a point of reference, a substantial appendix reviews relevant aspects of the measure problem of eternal inflation.Comment: 24 pages, two figures, plus 16-page appendix with one figure; v2: minor improvements and clarifications, conclusions unchanged (version to appear in JCAP

Processing of Drosophila endo-siRNAs depends on a specific Loquacious isoform

Drosophila melanogaster expresses three classes of small RNAs, which are classified according to their mechanisms of biogenesis. MicroRNAs are ∼22-23 nucleotides (nt), ubiquitously expressed small RNAs that are sequentially processed from hairpin-like precursors by Drosha/Pasha and Dcr-1/Loquacious complexes. MicroRNAs usually associate with AGO1 and regulate the expression of protein-coding genes. Piwi-interacting RNAs (piRNAs) of ∼24-28 nt associate with Piwi-family proteins and can arise from single-stranded precursors. piRNAs function in transposon silencing and are mainly restricted to gonadal tissues. Endo-siRNAs are found in both germline and somatic tissues. These ∼21-nt RNAs are produced by a distinct Dicer, Dcr-2, and do not depend on Drosha/Pasha complexes. They predominantly bind to AGO2 and target both mobile elements and protein-coding genes. Surprisingly, a subset of endo-siRNAs strongly depend for their production on the dsRNA-binding protein Loquacious (Loqs), thought generally to be a partner for Dcr-1 and a cofactor for miRNA biogenesis. Endo-siRNA production depends on a specific Loqs isoform, Loqs-PD, which is distinct from the one, Loqs-PB, required for the production of microRNAs. Paralleling their roles in the biogenesis of distinct small RNA classes, Loqs-PD and Loqs-PB bind to different Dicer proteins, with Dcr-1/Loqs-PB complexes and Dcr-2/Loqs-PD complexes driving microRNA and endo-siRNA biogenesis, respectively. Copyright © 2009 RNA Society

The Gravity Dual of a Density Matrix

For a state in a quantum field theory on some spacetime, we can associate a density matrix to any subset of a given spacelike slice by tracing out the remaining degrees of freedom. In the context of the AdS/CFT correspondence, if the original state has a dual bulk spacetime with a good classical description, it is natural to ask how much information about the bulk spacetime is carried by the density matrix for such a subset of field theory degrees of freedom. In this note, we provide several constraints on the largest region that can be fully reconstructed, and discuss specific proposals for the geometric construction of this dual region.Comment: 19 pages, LaTeX, 8 figures, v2: footnote and reference adde