Fault Tolerant Scheduling of Precedence Task Graphs on Heterogeneous Platforms

Fault tolerance and latency are important requirements in several applications which are time critical in nature: such applications require guaranties in terms of latency, even when processors are subject to failures. In this paper, we propose a fault tolerant scheduling heuristic for mapping precedence task graphs on heterogeneous systems. Our approach is based on an active replication scheme, capable of supporting $\varepsilon$ arbitrary fail-silent (fail-stop) processor failures, hence valid results will be provided even if $\varepsilon$ processors fail. We focus on a bi-criteria approach, where we aim at minimizing the latency given a fixed number of failures supported in the system, or the other way round. Major achievements include a low complexity, and a drastic reduction of the number of additional communications induced by the replication mechanism. Experimental results demonstrate that our heuristics, despite their lower complexity, outperform their direct competitor, the FTBAR scheduling algorithm[8].La tolérance aux pannes et la latence sont deux critères importants pour plusieurs applications qui sont critiques par nature. Ce type d’applications exige des garanties en terme de temps de latence, même lorsque les processeurs sont sujets aux pannes. Dans ce rapport, nous proposons une heuristique tolérante aux pannes pour l’ordonnancement de graphes de tâches sur des systèmes hétérogènes. Notre approche est basée sur un mécanisme de réplication active, capable de supporter " pannes arbitraires de type silence sur défaillance. En d’autres termes, des résultats valides seront fournis même si " processeurs tombent en panne. Nous nous concentrons sur une approche bi-critère, où nous avons pour objectif de minimiser le temps de latence pour un nombre donné (fixé) de pannes tolérées dans le système, ou l’inverse. Les principales contributions incluent une faible complexité en temps d’exécution, et une réduction importante du nombre de communications induites par le mécanisme de réplication.Les résultats expérimentaux montrent que notre algorithme, en dépit de sa faible complexité temporelle, est meilleur que son direct compétiteur,l’algorithme FTBA

Iso-Level CAFT: How to Tackle the Combination of Communication Overhead Reduction and Fault Tolerance Scheduling

To schedule precedence task graphs in a more realistic framework, we introduce an efficient fault tolerant scheduling algorithm that is both contention-aware and capable of supporting $\varepsilon$ arbitrary fail-silent (fail-stop) processor failures. The design of the proposed algorithm which we call Iso-Level CAFT, is motivated by (i) the search for a better load-balance and (ii) the generation of fewer communications. These goals are achieved by scheduling a chunk of ready tasks simultaneously, which enables for a global view of the potential communications. Our goal is to minimize the total execution time, or latency, while tolerating an arbitrary number of processor failures. Our approach is based on an active replication scheme to mask failures, so that there is no need for detecting and handling such failures. Major achievements include a low complexity, and a drastic reduction of the number of additional communications induced by the replication mechanism. The experimental results fully demonstrate the usefulness of Iso-Level~CAFT

Caspase-8 Inactivation in T Cells Increases Necroptosis and Suppresses Autoimmunity in Bim−/−Bim^{−/−} Mice

Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of $Bim^{−/−}$ mice restrained their autoimmunity and extended their life span. We show that, similar to $caspase-8^{−/−}$ T cells, $Bim^{−/−}$ T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of $Bim^{−/−}$ T cells and restrains autoimmunity in $Bim^{−/−}$ mice

Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer

Signaling and repair of DNA double-strand breaks (DSBs) are critical for preventing immunodeficiency and cancer. These DNA breaks result from exogenous and endogenous DNA insults but are also programmed to occur during physiological processes such as meiosis and immunoglobulin heavy chain (IgH) class switch recombination (CSR). Recent studies reported that the E3 ligase RNF8 plays important roles in propagating DNA DSB signals and thereby facilitating the recruitment of various DNA damage response proteins, such as 53BP1 and BRCA1, to sites of damage. Using mouse models for Rnf8 mutation, we report that Rnf8 deficiency leads to impaired spermatogenesis and increased sensitivity to ionizing radiation both in vitro and in vivo. We also demonstrate the existence of alternative Rnf8-independent mechanisms that respond to irradiation and accounts for the partial recruitment of 53bp1 to sites of DNA damage in activated Rnf8−/− B cells. Remarkably, IgH CSR is impaired in a gene dose-dependent manner in Rnf8 mutant mice, revealing that these mice are immunodeficient. In addition, Rnf8−/− mice exhibit increased genomic instability and elevated risks for tumorigenesis indicating that Rnf8 is a novel tumor suppressor. These data unravel the in vivo pleiotropic effects of Rnf8

The Tumor Suppressor Gene Brca1 Is Required for Embryonic Cellular Proliferation in the Mouse

AbstractMutations of the BRCA1 gene in humans are associated with predisposition to breast and ovarian cancers. We show here that Brca1+/− mice are normal and fertile and lack tumors by age eleven months. Homozygous Brca15-6 mutant mice die before day 7.5 of embryogenesis. Mutant embryos are poorly developed, with no evidence of mesoderm formation. The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality. In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity. The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos. Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro. Thus, the death of Brca15-6 mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers

Impaired Negative Selection of T Cells in Hodgkin's Disease Antigen CD30–Deficient Mice

AbstractCD30 is found on Reed–Sternberg cells of Hodgkin's disease and on a variety of non-Hodgkin's lymphoma cells and is up-regulated on cells after Epstein–Barr virus, human T cell leukemia virus, and HIV infections. We report here that the thymus in CD30-deficient mice contains elevated numbers of thymocytes. Activation-induced death of thymocytes after CD3 cross-linking is impaired both in vitro and in vivo. Breeding the CD30 mutation separately into αβTCR- or γδTCR-transgenic mice revealed a gross defect in negative but not positive selection. Thus, like TNF-receptors and Fas/Apo-1, the CD30 receptor is involved in cell death signaling. It is also an important coreceptor that participates in thymic deletion

Inactivation of Chk2 and Mus81 Leads to Impaired Lymphocytes Development, Reduced Genomic Instability, and Suppression of Cancer

Chk2 is an effector kinase important for the activation of cell cycle checkpoints, p53, and apoptosis in response to DNA damage. Mus81 is required for the restart of stalled replication forks and for genomic integrity. Mus81Δex3-4/Δex3-4 mice have increased cancer susceptibility that is exacerbated by p53 inactivation. In this study, we demonstrate that Chk2 inactivation impairs the development of Mus81Δex3-4/Δex3-4 lymphoid cells in a cell-autonomous manner. Importantly, in contrast to its predicted tumor suppressor function, loss of Chk2 promotes mitotic catastrophe and cell death, and it results in suppressed oncogenic transformation and tumor development in Mus81Δex3-4/Δex3-4 background. Thus, our data indicate that an important role for Chk2 is maintaining lymphocyte development and that dual inactivation of Chk2 and Mus81 remarkably inhibits cancer

RhoA and RhoC have distinct roles in migration and invasion by acting through different targets

Although closely related, RhoA and RhoC have distinct molecular targets and functional roles in cell migration and invasion

Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations