Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Chronogram:an R package for data curation and analysis of infection and vaccination cohort studies

Motivation: Observational cohort studies that track vaccine and infection responses offer real-world data to inform pandemic policy. Translating biological hypotheses, such as whether different patterns of accumulated antigenic exposures confer differing antibody responses, into analysis code can be onerous, particularly when source data is dis-aggregated. Results: The R package chronogram introduces the class chronogram, where metadata is seamlessly aggregated with sparse infection episode, clinical and laboratory data. Each experimental modality is added sequentially, allowing the incorporation of new data, such as specialized time-consuming research assays, or their downstream analyses. Source data can be any rectangular data format, including database tables (such as structured query language databases). This supports annotations that aggregate data types/sources, for example, combining symptoms, molecular testing, and sequencing of one or more infectious episodes in a pathogen-agnostic manner. Chronogram arranges observational data to allow the translation of biological hypotheses into their corresponding code via a shared vocabulary. Availability and implementation: Chronogram is implemented R and available under an MIT licence at: https://www.github.com/FrancisCrickInstitute/chronogram; a user manual is available at: https://franciscrickinstitute.github.io/chronogram

Chronogram:an R package for data curation and analysis of infection and vaccination cohort studies

Motivation: Observational cohort studies that track vaccine and infection responses offer real-world data to inform pandemic policy. Translating biological hypotheses, such as whether different patterns of accumulated antigenic exposures confer differing antibody responses, into analysis code can be onerous, particularly when source data is dis-aggregated. Results: The R package chronogram introduces the class chronogram, where metadata is seamlessly aggregated with sparse infection episode, clinical and laboratory data. Each experimental modality is added sequentially, allowing the incorporation of new data, such as specialized time-consuming research assays, or their downstream analyses. Source data can be any rectangular data format, including database tables (such as structured query language databases). This supports annotations that aggregate data types/sources, for example, combining symptoms, molecular testing, and sequencing of one or more infectious episodes in a pathogen-agnostic manner. Chronogram arranges observational data to allow the translation of biological hypotheses into their corresponding code via a shared vocabulary. Availability and implementation: Chronogram is implemented R and available under an MIT licence at: https://www.github.com/FrancisCrickInstitute/chronogram; a user manual is available at: https://franciscrickinstitute.github.io/chronogram

Effective Scenario of Loop Quantum Cosmology

Semiclassical states in isotropic loop quantum cosmology are employed to show that the improved dynamics has the correct classical limit. The effective Hamiltonian for the quantum cosmological model with a massless scalar field is thus obtained, which incorporates also the next to leading order quantum corrections. The possibility that the higher order correction terms may lead to significant departure from the leading order effective scenario is revealed. If the semiclassicality of the model is maintained in the large scale limit, there are great possibilities for $k=0$ Friedmann expanding universe to undergo a collapse in the future due to the quantum gravity effect. Thus the quantum bounce and collapse may contribute a cyclic universe in the new scenario.Comment: 4 pages, 2 figures; version published in PR

Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10−11 for rs4733781; P = 1.0 × 10−10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis–infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB

Measurements of Compression and Emittance Growth after the First LCLS Bunch Compressor Chicane

The Linac Coherent Light Source (LCLS) is a SASE xray free-electron laser project presently under construction at SLAC. The injector section from RF photocathode gun through first bunch compressor chicane was installed during the fall of 2006. The first bunch compressor is located at 250 MeV and nominally compresses a 1-nC electron bunch from an rms length of about 1 mm to 0.2 mm. Transverse phase space and bunch length diagnostics are located immediately after the chicane. We present preliminary measurements and simulations of the longitudinal and transverse phase space after the chicane in various beam conditions, including extreme compression with micron-scale current spikes

Spatiotemporal dynamics of ultrarelativistic beam-plasma instabilities

An electron or electron-positron beam streaming through a plasma is notoriously prone to micro-instabilities. For a dilute ultrarelativistic infinite beam, the dominant instability is a mixed mode between longitudinal two-stream and transverse filamentation modes, with a phase velocity oblique to the beam velocity. A spatiotemporal theory describing the linear growth of this oblique mixed instability is proposed, which predicts that spatiotemporal effects generally prevail for finite-length beams, leading to a significantly slower instability evolution than in the usually assumed purely temporal regime. These results are accurately supported by particle-in-cell (PIC) simulations. Furthermore, we show that the self-focusing dynamics caused by the plasma wakefields driven by finite-width beams can compete with the oblique instability. Analyzed through PIC simulations, the interplay of these two processes in realistic systems bears important implications for upcoming accelerator experiments on ultrarelativistic beam-plasma interactions