TRIM5α requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription

TRIM5α is an antiviral, cytoplasmic, E3 ubiquitin (Ub) ligase that assembles on incoming retroviral capsids and induces their premature dissociation. It inhibits reverse transcription of the viral genome and can also synthesize unanchored polyubiquitin (polyUb) chains to stimulate innate immune responses. Here, we show that TRIM5α employs the E2 Ub-conjugating enzyme Ube2W to anchor the Lys63-linked polyUb chains in a process of TRIM5α auto-ubiquitination. Chain anchoring is initiated, in cells and in vitro, through Ube2W-catalyzed monoubiquitination of TRIM5α. This modification serves as a substrate for the elongation of anchored Lys63-linked polyUb chains, catalyzed by the heterodimeric E2 enzyme Ube2N/Ube2V2. Ube2W targets multiple TRIM5α internal lysines with Ub especially lysines 45 and 50, rather than modifying the N-terminal amino group, which is instead αN-acetylated in cells. E2 depletion or Ub mutation inhibits TRIM5α ubiquitination in cells and restores restricted viral reverse transcription, but not infection. Our data indicate that the stepwise formation of anchored Lys63-linked polyUb is a critical early step in the TRIM5α restriction mechanism and identify the E2 Ub-conjugating cofactors involved

Mean-Payoff Optimization in Continuous-Time Markov Chains with Parametric Alarms

Continuous-time Markov chains with alarms (ACTMCs) allow for alarm events that can be non-exponentially distributed. Within parametric ACTMCs, the parameters of alarm-event distributions are not given explicitly and can be subject of parameter synthesis. An algorithm solving the $\varepsilon$-optimal parameter synthesis problem for parametric ACTMCs with long-run average optimization objectives is presented. Our approach is based on reduction of the problem to finding long-run average optimal strategies in semi-Markov decision processes (semi-MDPs) and sufficient discretization of parameter (i.e., action) space. Since the set of actions in the discretized semi-MDP can be very large, a straightforward approach based on explicit action-space construction fails to solve even simple instances of the problem. The presented algorithm uses an enhanced policy iteration on symbolic representations of the action space. The soundness of the algorithm is established for parametric ACTMCs with alarm-event distributions satisfying four mild assumptions that are shown to hold for uniform, Dirac and Weibull distributions in particular, but are satisfied for many other distributions as well. An experimental implementation shows that the symbolic technique substantially improves the efficiency of the synthesis algorithm and allows to solve instances of realistic size.Comment: This article is a full version of a paper accepted to the Conference on Quantitative Evaluation of SysTems (QEST) 201

Manufacturing Development of the NCSX Modular Coil Windings

The modular coils on the National Compact Stellarator Experiment (NCSX) present a number of significant engineering challenges due to their complex shapes, requirements for high dimensional accuracy and the high current density required in the modular coils due to space constraints. In order to address these challenges, an R&D program was established to develop the conductor, insulation scheme, manufacturing techniques, and procedures. A prototype winding named Twisted Racetrack Coil (TRC) was of particular importance in dealing with these challenges. The TRC included a complex shaped winding form, conductor, insulation scheme, leads and termination, cooling system and coil clamps typical of the modular coil design. Even though the TRC is smaller in size than a modular coil, its similar complex geometry provided invaluable information in developing the final design, metrology techniques and development of manufacturing procedures. In addition a discussion of the development of the copper rope conductor including "Keystoning" concerns; the epoxy impregnation system (VPI) plus the tooling and equipment required to manufacture the modular coils will be presented

Dirac Gauginos, Negative Supertraces and Gauge Mediation

In an attempt to maximize General Gauge Mediated parameter space, I propose simple models in which gauginos and scalars are generated from disconnected mechanisms. In my models Dirac gauginos are generated through the supersoft mechanism, while independent R-symmetric scalar masses are generated through operators involving non-zero messenger supertrace. I propose several new methods for generating negative messenger supertraces which result in viable positive mass squareds for MSSM scalars. The resultant spectra are novel, compressed and may contain light fermionic SM adjoint fields.Comment: 16 pages 3 figure

Timing of Intervention Affects Brain Electrical Activity in Children Exposed to Severe Psychosocial Neglect

Background: Early psychosocial deprivation has profound effects on brain activity in the young child. Previous reports have shown increased power in slow frequencies of the electroencephalogram (EEG), primarily in the theta band, and decreased power in higher alpha and beta band frequencies in infants and children who have experienced institutional care. Methodology/Principal Findings: We assessed the consequences of removing infants from institutions and placing them into a foster care intervention on brain electrical activity when children were 8 years of age. We found the intervention was successful for increasing high frequency EEG alpha power, with effects being most pronounced for children placed into foster care before 24 months of age. Conclusions/Significance: The dependence on age of placement for the effects observed on high frequency EEG alpha power suggests a sensitive period after which brain activity in the face of severe psychosocial deprivation is less amenabl

Divergent mathematical treatments in utility theory

In this paper I study how divergent mathematical treatments affect mathematical modelling, with a special focus on utility theory. In particular I examine recent work on the ranking of information states and the discounting of future utilities, in order to show how, by replacing the standard analytical treatment of the models involved with one based on the framework of Nonstandard Analysis, diametrically opposite results are obtained. In both cases, the choice between the standard and nonstandard treatment amounts to a selection of set-theoretical parameters that cannot be made on purely empirical grounds. The analysis of this phenomenon gives rise to a simple logical account of the relativity of impossibility theorems in economic theory, which concludes the paper