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ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.

This paper investigates how state diagrams can be best represented in the polychronous model of computation (MoC) and proposes to use this model for code validation of behavior specifications in Architecture Analysis & Design Language (AADL). In this relational MoC, the basic objects are signals, which are related through dataflow equations. Signals are associated with logical clocks, which provide the capability to describe systems in which components obey multiple clock rates. We propose a model of finite-state automata, called polychronous automata, which is based on clock relationships. A specificity of this model is that an automaton is submitted to clock constraints, which allows one to specify a wide range of control-related configurations, being either reactive or restrictive with respect to their control environment. A semantic model is defined for these polychronous automata, which relies on boolean algebra of clocks. Based on a previously defined modeling method for AADL software architectures using the polychronous MoC, the proposed model is used as a formal model for the AADL behavior annex. This is illustrated with a case study involving an adaptive cruise control system.

Translation validation was invented in the 90’s by Pnueli et al. as a technique to formally verify the correctness of code generators. Rather than certifying the code generator or exhaustively qualifying it, translation validators attempt to verify that program transformations preserve semantics. In this work, we adopt this approach to formally verify that the clock semantics and data dependence are preserved during the compilation of the Signal compiler. Translation validation is implemented for every compilation phase from the initial phase until the latest phase where the executable code is generated, by proving the transformation in each phase of the compiler preserves the semantics. We represent the clock semantics, the data dependence of a program and its transformed counterpart as first-order formulas which are called clock models and synchronous dependence graphs (SDGs), respectively. We then introduce clock refinement and dependence refinement relations which express the preservations of clock semantics and dependence, as a relation on clock models and SDGs, respectively. Our validator does not require any instrumentation or modification of the compiler, nor any rewriting of the source program.

Architecture analysis & design language (AADL) has been increasingly adopted in the design of embedded systems, and corresponding scheduling and formal verification have been well studied. However, little work takes code distribution and architecture exploration into account, particularly considering clock constraints, for distributed multi-processor systems. In this paper, we present an overview of our approach to handle these concerns, together with the associated toolchain, AADL-Polychrony-SynDEx. First, in order to avoid semantic ambiguities of AADL, the polychronous/multiclock semantics of AADL, based on a polychronous model of computation, is considered. Clock synthesis is then carried out in Polychrony, which bridges the gap between the polychronous semantics and the synchronous semantics of SynDEx. The same timing semantics is always preserved in order to ensure the correctness of the transformations between different formalisms. Code distribution and corresponding scheduling is carried out on the obtained SynDExmodel in the last step, which enables the exploration of architectures originally specified in AADL. Our contribution provides a fast yet efficient architecture exploration approach for the design of distributed real-time and embedded systems. An avionic case study is used here to illustrate our approach.

We studied the chromosome periphery in human HeLa and TG cells using cryomethods in electron microscopy. A contrasted layer of peripheral chromosomal material (PCM) was visible in cryo-ultrathin sections of mitotic cells. This PCM was composed of closely packed fibrils associated with granules. The PCM did not cover the entire chromosome surface but was found around most of the chromosomes and even between two chromatids. The organization of the PCM was not affected by colchicine treatment of mitotic cells. In cells prepared by quick-freezing, the PCM appeared to be a fibrous material at the chromosome periphery, and was also associated with granules that resembled interchromatin granules in size and shape. At higher magnification, direct contacts between the chromosomes and the fibrils of the PCM were observed. The cryotechniques used are known to preserve the native organization of cells. Therefore, the architecture of the perichromosomal region analysed presumably corresponds to that in vivo during mitosis. These observations show that in HeLa and TG cells, a particular structure present at the chromosome periphery in the form of PCM is persistent and ubiquitous. In addition, we showed by immunolabelling that the PCM is the specific site of accumulation of nucleolar antigens during mitosis. These two results, i.e. the identification of specific morphological structures and the compartmentation of proteins, indicate that this layer is a specific region of mitotic cells.

Different point mutations in the nucleolar protein fibrillarin (Nop1p in Saccharomyces cerevisiae) can inhibit different steps in ribosome synthesis. A screen for mutations that are synthetically lethal (sl) with the nop1-5allele, which inhibits pre-rRNA processing, identified NOP56. An independent sl mutation screen with nop1-3, which inhibits pre-rRNA methylation, identified a mutation in NOP58. Strikingly, Nop56p and Nop58p are highly homologous (45% identity). Both proteins were found to be essential and localized to the nucleolus. A temperature-sensitive lethal mutant allele, nop56-2, inhibited many steps in pre-rRNA processing, particularly on the pathway of 25S/5.8S rRNA synthesis, and led to defects in 60S subunit assembly. Epitope-tagged constructs show that both Nop56p and Nop58p are associated with Noplp in complexes, Nop56p and Nop1p exhibiting a stoichiometric association. These physical interactions presumably underlie the observed sl phenotypes. Well-conserved homologs are present in a range of organisms, including humans (52% identity between human hNop56p and yeast Nop56p), suggesting that these complexes have been conserved in evolution.

The behaviour of nucleolar antigens known to associate with chromosomes at mitosis was investigated in mammalian cells (HeLa, HEp-2, PtK1, CHO) by immunofluorescence and confocal laser scanning microscopy. Serial optical sections through mitotic cells, from prophase to telophase, were used to generate threedimensional images of the antigen distribution. Our results indicate that, at the onset of mitosis, these antigens leave the nucleoli in a highly ordered manner to form a network extending from the nucleoli towards the nuclear envelope. The migration begins at very early prophase, when the condensation of the chromosomes is not yet visible. After completion of the migration at late prophase, the labelling is found at the chromosome periphery. The antigens remain distributed as a sheath surrounding the chromosomes from prophase to telophase. Therefore, the proteins involved in the formation of this perichromosomal layer have different behaviour than those of the prenucleolar bodies. The antigens appear to interact strongly with chromosomes, since they are not lost during chromosome isolation in hypotonic buffer. Each chromosome is entirely covered from one telomere to the other, except in the centromeric region. Thus the relocation of these nucleolar proteins does not appear to be the result of a passive accumulation at the chromosome periphery, but seems rather to be due to an active targeting to specific sites. Consequently, these proteins may have a determining function in the progression of the cells through mitosis, possibly by participating in the protection and stabilization of the chromosomes.

Solving large sparse linear systems is a time-consuming step in basin modeling or reservoir simulation. The choice of a robust preconditioner strongly impact the performance of the overall simulation. Heterogeneous architectures based on General Purpose computing on Graphic Processing Units (GPGPU) or many-core architectures introduce programming challenges which can be managed in a transparent way for developer with the use of runtime systems. Nevertheless, algorithms need to be well suited for these massively parallel architectures. In this paper, we present preconditioning techniques which enable to take advantage of emerging architectures. We also present our task-based implementations through the use of the HARTS (Heterogeneous Abstract RunTime System) runtime system, which aims to manage the recent architectures. We focus on two preconditoners. The first is ILU(0) preconditioner implemented on distributing memory systems. The second one is a multi-level domain decomposition method implemented on a shared-memory system. Obtained results are then presented on corresponding architectures, which open the way to discuss on the scalability of such methods according to numerical performances while keeping in mind that the next step is to propose a massively parallel implementations of these techniques.