Old World Arenaviruses Enter the Host Cell via the Multivesicular Body and Depend on the Endosomal Sorting Complex Required for Transport

The highly pathogenic Old World arenavirus Lassa virus (LASV) and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) use α-dystroglycan as a cellular receptor and enter the host cell by an unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Upon internalization, the viruses are delivered to acidified endosomes in a Rab5-independent manner bypassing classical routes of incoming vesicular trafficking. Here we sought to identify cellular factors involved in the unusual and largely unknown entry pathway of LASV and LCMV. Cell entry of LASV and LCMV required microtubular transport to late endosomes, consistent with the low fusion pH of the viral envelope glycoproteins. Productive infection with recombinant LCMV expressing LASV envelope glycoprotein (rLCMV-LASVGP) and LCMV depended on phosphatidyl inositol 3-kinase (PI3K) as well as lysobisphosphatidic acid (LBPA), an unusual phospholipid that is involved in the formation of intraluminal vesicles (ILV) of the multivesicular body (MVB) of the late endosome. We provide evidence for a role of the endosomal sorting complex required for transport (ESCRT) in LASV and LCMV cell entry, in particular the ESCRT components Hrs, Tsg101, Vps22, and Vps24, as well as the ESCRT-associated ATPase Vps4 involved in fission of ILV. Productive infection with rLCMV-LASVGP and LCMV also critically depended on the ESCRT-associated protein Alix, which is implicated in membrane dynamics of the MVB/late endosomes. Our study identifies crucial cellular factors implicated in Old World arenavirus cell entry and indicates that LASV and LCMV invade the host cell passing via the MVB/late endosome. Our data further suggest that the virus-receptor complexes undergo sorting into ILV of the MVB mediated by the ESCRT, possibly using a pathway that may be linked to the cellular trafficking and degradation of the cellular receptor

Multi-objective lot splitting for a single product m-machine flowshop line

In this paper, the mean flowtime and the makespan objectives are simultaneously investigated in a single product, m-machine, flowshop system. For this purpose, an efficiency frontier approach is applied and an optimal algorithm for generating all efficient solutions is developed. A comprehensive computational experiment is performed for analyzing the tradeoff between the two objectives and evaluating the proposed algorithm performance. The most-balanced-solution, MinMax, is defined and recommended as a desirable alternative for either the flowtime or the makespan optimal solutions. Results show that when the system is optimized for either the mean flowtime or the makespan, a significant loss in the nonoptimized objective value is observed. On the other hand, adopting the MinMax solution obtains a close to optimal solution in both objectives

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Requirements for Hybrid Cosimulation Standards

This paper defines a suite of requirements for future hybrid cosimulation standards, and specifically provides guidance for development of a hybrid cosimulation version of the Functional Mockup Interface (FMI). A cosimulation standard defines interfaces that enable diverse simulation tools to interoperate. Specifically, one tool defines a component that forms part of a simulation model in another tool. We focus on components with inputs and outputs that are functions of time, and specifically on mixtures of discrete events and continuous time signals. This hybrid mixture is not well supported by existing cosimulation standards, and specifically not by FMI 2.0, for reasons that are explained in this paper. The paper defines a suite of test components, giving a mathematical model of an ideal behavior, plus a discussion of practical implementation considerations. The discussion includes acceptance criteria by which we can determine whether a standard supports definition of each component. In addition, we define a set of test compositions that define requirements for coordination between components, including consistent handling of timed events.QC 20150602</p