Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A

Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport. Using live-cell confocal and single-molecule imaging of rat hippocampal neurons cultured in microfluidic devices, we show that the activity-dependent uptake of the binding domain of the BoNT/A heavy chain (BoNT/A-Hc) is followed by a delayed increase in retrograde axonal transport of BoNT/A-Hc carriers. Consistent with a role of presynaptic activity in initiating transport of the active toxin, activity-dependent uptake of BoNT/A in the terminal led to a significant increase in SNAP25 cleavage detected in the soma chamber compared with nonstimulated neurons. Surprisingly, most endocytosed BoNT/A-Hc was incorporated into LC3-positive autophagosomes generated in the nerve terminals, which then underwent retrograde transport to the cell soma, where they fused with lysosomes both in vitro and in vivo. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A1, respectively, inhibited the activity-dependent retrograde trafficking of BoNT/A-Hc. Our data demonstrate that both the presynaptic formation of autophagosomes and the initiation of their retrograde trafficking are tightly regulated by presynaptic activity

Aurigaia: mock Gaia DR2 stellar catalogues from the Auriga cosmological simulations

We present and analyse mock stellar catalogues that match the selection criteria and observables (including uncertainties) of the Gaia satellite data release 2 (DR2). The source are six cosmological high-resolution magneto-hydrodynamic ΛCDM zoom simulations of the formation of Milky Way analogues from the AURIGA project. Mock data are provided for stars with V 20 deg. The mock catalogues are made using two different methods: the public SNAPDRAGONS code, and a method based on that of Lowing et al. (2015) that preserves the phase-space distribution of the model stars. These publicly available catalogues contain five-parameter astrometry, radial velocities, multiband photometry, stellar parameters, dust extinction values, and uncertainties in all these quantities. In addition, we provide the gravitational potential and information on the origin of each star. By way of demonstration, we apply the mock catalogues to analyses of the young stellar disc and the stellar halo. We show that (i) the young outer stellar disc exhibits a flared distribution that is detectable in the height and vertical velocity distribution of A - and B -dwarf stars up to radii of ∼15 kpc, and (ii) the spin of the stellar halo out to 100 kpc can be accurately measured with Gaia DR2 RR Lyrae stars. These catalogues are well suited for comparisons with observations and should help to (i) develop and test analysis methods for the Gaia DR2 data, (ii) gauge the limitations and biases of the data, and (iii) interpret the data in the light of theoretical predictions from realistic ab initio simulations of galaxy formation in the ΛCDM cosmological model

Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function

BRCC36 is a Zn²⁺-dependent deubiquitinating enzyme (DUB) that hydrolyzes lysine-63-linked ubiquitin chains as part of distinct macromolecular complexes that participate in either interferon signaling or DNA-damage recognition. The MPN⁺ domain protein BRCC36 associates with pseudo DUB MPN⁻ proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity. To understand the basis for BRCC36 regulation, we have solved the structure of an active BRCC36-KIAA0157 heterodimer and an inactive BRCC36 homodimer. Structural and functional characterizations show how BRCC36 is switched to an active conformation by contacts with KIAA0157. Higher-order association of BRCC36 and KIAA0157 into a dimer of heterodimers (super dimers) was required for DUB activity and interaction with targeting proteins SHMT2 and RAP80. These data provide an explanation of how an inactive pseudo DUB allosterically activates a cognate DUB partner and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity, subcellular localization, and biological function

Failures in transport infrastructure embankments

To ensure that road and rail transport networks remain operational, both highway and railway embankments require continual maintenance and renewal to mitigate against ongoing deterioration and repair any sections damaged by realised failures. This paper provides a review of recent developments in the understanding of highway and railway embankment degradation and failure. Failures due to pore water pressure increase, seasonal shrink-swell deformation and progressive failure are considered. The material composition and construction of highway and railway embankments differ, which influences the dominant type and timing of embankment failure. There is evidence for highway embankment failures induced by pore water pressure increase, but not seasonal deformation and progressive failure. Some railway embankments are susceptible to pore water pressure increase, seasonal shrink-swell deformation and progressive failure due to the age and nature of the dumped clay fill used in their construction. The approaches used to measure and explore embankment failure mechanisms are compared and discussed. Field observations have been used to understand pore water pressure increase and seasonal shrink-swell deformation in embankments, while the investigation of progressive embankment failure has mainly utilised physical and numerical modelling approaches. Further field and laboratory investigation is required before the rigorous analysis of embankment failure can be routinely undertaken. However, progress is being made to empirically identify and evaluate the various risk factors affecting transport infrastructure embankment failure

Improved W boson mass measurement with the D0 detector

We have measured the W boson mass using the D0 detector and a data sample of 82 pb^-1 from the Tevatron collider. This measurement used W -> e nu decays, where the electron is close to a boundary of a central electromagnetic calorimeter module. Such 'edge' electrons have not been used in any previous D0 analysis, and represent a 14% increase in the W boson sample size. For these electrons, new response and resolution parameters are determined, and revised backgrounds and underlying event energy flow measurements are made. When the current measurement is combined with previous D0 W boson mass measurements, we obtain M_W = 80.483 +/- 0.084 GeV. The 8% improvement from the previous D0 measurement is primarily due to the improved determination of the response parameters for non-edge electrons using the sample of Z bosons with non-edge and edge electrons.Comment: submitted to Phys. Rev. D; 20 pages, 18 figures, 9 table

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters