Time delay of light signals in an energy-dependent spacetime metric

In this note we review the problem of time delay of photons propagating in a spacetime with a metric that explicitly depends on the energy of the particles (Gravity-Rainbow approach). We show that corrections due to this approach -- which is closely related to DSR proposal -- produce for small redshifts ($z<<1$) smaller time delays than in the generic Lorentz Invariance Violating case.Comment: 5 pages. This version contains two new references with respect to the published versio

Approaching Space Time Through Velocity in Doubly Special Relativity

We discuss the definition of velocity as dE/dp, where E,p are the energy and momentum of a particle, in Doubly Special Relativity (DSR). If this definition matches dx/dt appropriate for the space-time sector, then space-time can in principle be built consistently with the existence of an invariant length scale. We show that, within different possible velocity definitions, a space-time compatible with momentum-space DSR principles can not be derived.Comment: 11 pages, no figures, minor changes, references added, final version to appear in PR

Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity.

The endocytic delivery of macromolecules from the mammalian cell surface for degradation by lysosomal acid hydrolases requires traffic through early endosomes to late endosomes followed by transient (kissing) or complete fusions between late endosomes and lysosomes. Transient or complete fusion results in the formation of endolysosomes, which are hybrid organelles from which lysosomes are re-formed. We have used synthetic membrane-permeable cathepsin substrates, which liberate fluorescent reporters upon proteolytic cleavage, as well as acid phosphatase cytochemistry to identify which endocytic compartments are acid hydrolase active. We found that endolysosomes are the principal organelles in which acid hydrolase substrates are cleaved. Endolysosomes also accumulated acidotropic probes and could be distinguished from terminal storage lysosomes, which were acid hydrolase inactive and did not accumulate acidotropic probes. Using live-cell microscopy, we have demonstrated that fusion events, which form endolysosomes, precede the onset of acid hydrolase activity. By means of sucrose and invertase uptake experiments, we have also shown that acid-hydrolase-active endolysosomes and acid-hydrolase-inactive, terminal storage lysosomes exist in dynamic equilibrium. We conclude that the terminal endocytic compartment is composed of acid-hydrolase-active, acidic endolysosomes and acid hydrolase-inactive, non-acidic, terminal storage lysosomes, which are linked and function in a lysosome regeneration cycle.This work was supported by MRC research grant MR/M010007/1. The CIMR is supported by Wellcome Trust Strategic Award 100140. The Cellomics ArrayScan™ VTi High Content Screening Microscope, Zeiss LSM710 confocal microscope and FEI Tecnai G2 Spirit BioTWIN transmission EM were purchased with Wellcome Trust grants 079919 and 093026. LJD is supported by a BBSRC industrial CASE studentship with GSK Research and Development Ltd. We thank Sally Gray for preparing and sequencing pLXIN constructs and Matthew Gratian for help with light microscopy and analytical software.This is the final version of the article. It first appeared from Elsevier via https://doi.org/ 10.1016/j.cub.2016.06.04

Tertiary creep in concrete

Time dependent concrete fracture is simulated using a rate type creep model coupled with a discrete concrete model. The numerical study uses experimental data, of various tests, three point bending, relaxation, tensile, performed on concrete. This contribution demonstrates the capability of the model to capture the time dependent fracture behavior of concrete, and predicts the critical time of failure

Recruitment of VPS33A to HOPS by VPS16 Is Required for Lysosome Fusion with Endosomes and Autophagosomes.

The mammalian homotypic fusion and vacuole protein sorting (HOPS) complex is comprised of six subunits: VPS11, VPS16, VPS18, VPS39, VPS41 and the Sec1/Munc18 (SM) family member VPS33A. Human HOPS has been predicted to be a tethering complex required for fusion of intracellular compartments with lysosomes, but it remains unclear whether all HOPS subunits are required. We showed that the whole HOPS complex is required for fusion of endosomes with lysosomes by monitoring the delivery of endocytosed fluorescent dextran to lysosomes in cells depleted of individual HOPS proteins. We used the crystal structure of the VPS16/VPS33A complex to design VPS16 and VPS33A mutants that no longer bind each other and showed that, unlike the wild-type proteins, these mutants no longer rescue lysosome fusion with endosomes or autophagosomes in cells depleted of the endogenous proteins. There was no effect of depleting either VIPAR or VPS33B, paralogs of VPS16 and VPS33A, on fusion of lysosomes with either endosomes or autophagosomes and immunoprecipitation showed that they form a complex distinct from HOPS. Our data demonstrate the necessity of recruiting the SM protein VPS33A to HOPS via its interaction with VPS16 and that HOPS proteins, but not VIPAR or VPS33B, are essential for fusion of endosomes or autophagosomes with lysosomes.We thank Folma Buss and David Tumbarello for HeLaM cells stably expressing mRFP-GFP-LC3, Reiner Schulte and Michal Maj for help with FACS analysis, Sally Gray for technical assistance and David Owen for discussing experiments and critical reading of the manuscript. L. W. was supported by European Molecular Biology Organization (EMBO) and Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Long-Term Fellowships, S. C. G. by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant: 098406/Z/12/Z) and U. G. is a Marie Skłodowska-Curie fellow. The work was funded by UK Medical Research Council programme grant to J. P. L. (G0900113) and the Cambridge Institute for Medical Research is supported by a Wellcome Trust Strategic Award (100140). The Zeiss LSM710 confocal system and the Thermo(Cellomics) ArrayScan™ VTi High Content Screening Microscope (Cellomics) were purchased with Wellcome Trust support (grants: 079919 and 093026).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/tra.1228

Hierarchical Self-Assembly of Halogen-Bonded Block Copolymer Complexes into Upright Cylindrical Domains

Self-assembly of block copolymers into well-defined, ordered arrangements of chemically distinct domains is a reliable strategy for preparing tailored nanostructures. Microphase separation results from the system, minimizing repulsive interactions between dissimilar blocks and maximizing attractive interactions between similar blocks. Supramolecular methods have also achieved this separation by introducing small-molecule additives binding specifically to one block by noncovalent interactions. Here, we use halogen bonding as a supramolecular tool that directs the hierarchical self-assembly of low-molecular-weight perfluorinated molecules and diblock copolymers. Microphase separation results in a lamellar-within-cylindrical arrangement and promotes upright cylindrical alignment in films upon rapid casting and without further annealing. Such cylindrical domains with internal lamellar self-assemblies can be cleaved by solvent treatment of bulk films, resulting in separated and segmented cylindrical micelles stabilized by halogen-bond-based supramolecular crosslinks. These features, alongside the reversible nature of halogen bonding, provide a robust modular approach for nanofabricatio

Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion.

Mutations in the gene encoding the microtubule (MT)-severing protein spastin are the most common cause of hereditary spastic paraplegia, a genetic condition in which axons of the corticospinal tracts degenerate. We show that not only does endogenous spastin colocalize with MTs, but that it is also located on the early secretory pathway, can be recruited to endosomes and is present in the cytokinetic midbody. Spastin has two main isoforms, a 68 kD full-length isoform and a 60 kD short form. These two isoforms preferentially localize to different membrane traffic pathways with 68 kD spastin being principally located at the early secretory pathway, where it regulates endoplasmic reticulum-to-Golgi traffic. Sixty kiloDalton spastin is the major form recruited to endosomes and is also present in the midbody, where its localization requires the endosomal sorting complex required for transport-III-interacting MIT domain. Loss of midbody MTs accompanies the abscission stage of cytokinesis. In cells lacking spastin, a MT disruption event that normally accompanies abscission does not occur and abscission fails. We suggest that this event represents spastin-mediated MT severing. Our results support a model in which membrane traffic and MT regulation are coupled through spastin. This model is relevant in the axon, where there also is co-ordinated MT regulation and membrane traffic

Deformed Special Relativity as an effective theory of measurements on quantum gravitational backgrounds

In this article we elaborate on a recently proposed interpretation of DSR as an effective measurement theory in the presence of non-negligible (albeit small) quantum gravitational fluctuations. We provide several heuristic arguments to explain how such a new theory can emerge and discuss the possible observational consequences of this framework.Comment: 11 pages, no figure

A Genetic Screen Identifies a Critical Role for the WDR81-WDR91 Complex in the Trafficking and Degradation of Tetherin.

Tetherin (BST2/CD317) is a viral restriction factor that anchors enveloped viruses to host cells and limits viral spread. The HIV-1 Vpu accessory protein counteracts tetherin by decreasing its cell surface expression and targeting it for ubiquitin-dependent endolysosomal degradation. Although the Vpu-mediated downregulation of tetherin has been extensively studied, the molecular details are not completely elucidated. We therefore used a forward genetic screen in human haploid KBM7 cells to identify novel genes required for tetherin trafficking. Our screen identified WDR81 as a novel gene required for tetherin trafficking and degradation in both the presence and absence of Vpu. WDR81 is a BEACH-domain containing protein that is also required for the degradation of EGF-stimulated epidermal growth factor receptor (EGFR) and functions in a complex with the WDR91 protein. In the absence of WDR81 the endolysosomal compartment appears swollen, with enlarged early and late endosomes and reduced delivery of endocytosed dextran to cathepsin-active lysosomes. Our data suggest a role for the WDR81-WDR91 complex in the fusion of endolysosomal compartments and the absence of WDR81 leads to impaired receptor trafficking and degradation.This work was supported by the Wellcome Trust, through a Principal Research Fellowship to PJL (084957/Z/08/Z) and Ph.D studentship to RR (079895/Z/06/Z), by MRC research grant MR/M010007/1 to JPL and by a BBSRC industrial CASE studentship with GSK Research and Development Ltd to LJD. The CIMR is in receipt of a Wellcome Trust strategic award 100140.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1111/tra.1240

The localization of myosin VI at the golgi complex and leading edge of fibroblasts and its phosphorylation and recruitment into membrane ruffles of A431 cells after growth factor stimulation.

Myosin VI is an unconventional myosin that may play a role in vesicular membrane traffic through actin rich regions of the cytoplasm in eukaryotic cells. In this study we have cloned and sequenced a cDNA encoding a chicken intestinal brush border myosin VI. Polyclonal antisera were raised to bacterially expressed fragments of this myosin VI. The affinity purified antibodies were highly specific for myosin VI by immunoblotting and immunoprecipitation and were used to study the localization of the protein by immunofluorescence and immunoelectron microscopy. It was found that in NRK and A431 cells, myosin VI was associated with both the Golgi complex and the leading, ruffling edge of the cell as well as being present in a cytosolic pool. In A431 cells in which cell surface ruffling was stimulated by EGF, myosin VI was phosphorylated and recruited into the newly formed ruffles along with ezrin and myosin V. In vitro experiments suggested that a p21-activated kinase (PAK) might be the kinase responsible for phosphorylation in the motor domain. These results strongly support a role for myosin VI in membrane traffic on secretory and endocytic pathways