Coevolution of variability models and related software artifacts

Variant-rich software systems offer a large degree of customization, allowing users to configure the target system according to their preferences and needs. Facing high degrees of variability, these systems often employ variability models to explicitly capture user-configurable features (e.g., systems options) and the constraints they impose. The explicit representation of features allows them to be referenced in different variation points across different artifacts, enabling the latter to vary according to specific feature selections. In such settings, the evolution of variability models interplays with the evolution of related artifacts, requiring the two to evolve together, or coevolve. Interestingly, little is known about how such coevolution occurs in real-world systems, as existing research has focused mostly on variability evolution as it happens in variability models only. Furthermore, existing techniques supporting variability evolution are usually validated with randomly-generated variability models or evolution scenarios that do not stem from practice. As the community lacks a deep understanding of how variability evolution occurs in real-world systems and how it relates to the evolution of different kinds of software artifacts, it is not surprising that industry reports existing tools and solutions ineffective, as they do not handle the complexity found in practice. Attempting to mitigate this overall lack of knowledge and to support tool builders with insights on how variability models coevolve with other artifact types, we study a large and complex real-world variant-rich software system: the Linux kernel. Specifically, we extract variability-coevolution patterns capturing changes in the variability model of the Linux kernel with subsequent changes in Makefiles and C source code. From the analysis of the patterns, we report on findings concerning evolution principles found in the kernel, and we reveal deficiencies in existing tools and theory when handling changes captured by our patterns

The Resource Usage Aware Backfilling

Abstract. Job scheduling policies for HPC centers have been extensively stud-ied in the last few years, especially backfilling based policies. Almost all of these studies have been done using simulation tools. All the existent simulators use the runtime (either estimated or real) provided in the workload as a basis of their sim-ulations. In our previous work we analyzed the impact on system performance of considering the resource sharing (memory bandwidth) of running jobs including a new resource model in the Alvio simulator. Based on this studies we proposed the LessConsume and LessConsume Threshold resource selection policies. Both are oriented to reduce the saturation of the shared resources thus increasing the performance of the system. The results showed how both resource allocation poli-cies shown how the performance of the system can be improved by considering where the jobs are finally allocated. Using the LessConsume Threshold Resource Selection Policy, we propose a new backfilling strategy: the Resource Usage Aware Backfilling job scheduling policy. This is a backfilling based scheduling policy where the algorithms which decide which job has to be executed and how jobs have to be backfilled are based on a different Threshold configurations. This backfilling variant that considers how the shared resources are used by the scheduled jobs. Rather than backfilling the first job that can moved to the run queue based on the job arrival time or job size, it looks ahead to the next queued jobs, and tries to allocate jobs that would experience lower penalized runtime caused by the resource sharing saturation. In the paper we demostrate how the exchange of scheduling information between the local resource manager and the scheduler can improve substantially the per-formance of the system when the resource sharing is considered. We show how it can achieve a close response time performance that the shorest job first Back-filling with First Fit (oriented to improve the start time for the allocated jobs) providing a qualitative improvement in the number of killed jobs and in the per-centage of penalized runtime.

Formal Reduction Potential of 3,5-Difluorotyrosine in a Structured Protein: Insight into Multistep Radical Transfer

The reversible Y–O•/Y–OH redox properties of the α[subscript 3]Y model protein allow access to the electrochemical and thermodynamic properties of 3,5-difluorotyrosine. The unnatural amino acid has been incorporated at position 32, the dedicated radical site in α[subscript 3]Y, by in vivo nonsense codon suppression. Incorporation of 3,5-difluorotyrosine gives rise to very minor structural changes in the protein scaffold at pH values below the apparent pK (8.0 ± 0.1) of the unnatural residue. Square-wave voltammetry on α[subscript 3](3,5)F[subscript 2]Y provides an E°′(Y–O•/Y–OH) of 1026 ± 4 mV versus the normal hydrogen electrode (pH 5.70 ± 0.02) and shows that the fluoro substitutions lower the E°′ by −30 ± 3 mV. These results illustrate the utility of combining the optimized α[subscript 3]Y tyrosine radical system with in vivo nonsense codon suppression to obtain the formal reduction potential of an unnatural aromatic residue residing within a well-structured protein. It is further observed that the protein E°′ values differ significantly from peak potentials derived from irreversible voltammograms of the corresponding aqueous species. This is notable because solution potentials have been the main thermodynamic data available for amino acid radicals. The findings in this paper are discussed relative to recent mechanistic studies of the multistep radical-transfer process in Escherichia coli ribonucleotide reductase site-specifically labeled with unnatural tyrosine residues.National Institutes of Health (U.S.) (Grant GM29595

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Benchmarks and Standards for the Evaluation of Parallel Job Schedulers

The evaluation of parallel job schedulers hinges on the workloads used. It is suggested that this be standardized, in terms of both format and content, so as to ease the evaluation and comparison of different systems. The question remains whether this can encompass both traditional parallel systems and metacomputing systems. This paper is based on a panel on this subject that was held at the workshop, and the ensuing discussion; its authors are both the panel members and participants from the audience. Naturally, not all of us agree with all the opinions expressed here..

Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. SFRP1 (the secreted frizzled-related protein 1), a putative tumor suppressor gene mapped onto chromosome 8p12-p11.1, the frequent loss of heterozygosity (LOH) region in human HCC, encodes a Wingless-type (Wnt) signaling antagonist and is frequently inactivated by promoter methylation in many human cancers. However, whether the down-regulation of SFRP1 can contribute to hepatocarcinogenesis still remains unclear.</p> <p>Methods</p> <p>We investigated the expression of SFRP1 through real time RT-PCR and immunohistochemistry staining. The cell growth and colony formation were observed as the overexpression and knockdown of SFRP1. The DNA methylation status within SFRP1 promoter was analyzed through methylation-specific PCR or bisulphate-treated DNA sequencing assays. Loss of heterozygosity was here detected with microsatellite markers.</p> <p>Results</p> <p>SFRP1 was significantly down-regulated in 76.1% (35/46) HCC specimens at mRNA level and in 30% (30/100) HCCs indicated by immunohistochemistry staining, as compared to adjacent non-cancerous livers. The overexpression of SFRP1 can significantly inhibit the cell growth and colony formation of YY-8103, SMMC7721, and Hep3B cells. The RNA interference against the constitutional SFRP1 in the offspring SMMC7721 cells, which were stably transfected by ectopic SFRP1, can markedly promote cell growth of these cells. LOH of both microsatellite markers D8S532 and D8SAC016868 flanking the gene locus was found in 13% (6 of 46 HCCs) and 6.5% (3 of 46 HCCs) of the informative cases, respectively, where 5 of 8 HCC specimens with LOH showed the down-regulation of SFRP1. DNA hypermethylation within SFRP1 promoter was identified in two of three HCC specimens without SFRP1 expression. Moreover, the DNA methylation of SFRP1 promoter was significantly reduced, along with the re-expression of the gene, in those HCC cell lines, Bel7404, QGY7701, and MHCC-H, as treated by DAC.</p> <p>Conclusion</p> <p>Our data suggested that the down-regulation of SFRP1 as a candidate tumor suppressor gene, triggered by the epigenetic and/or genetic events, could contribute to the oncogenesis of HCC.</p

Aflatoxin-Induced TP53 R249S Mutation in HepatoCellular Carcinoma in Thailand: Association with Tumors Developing in the Absence of Liver Cirrhosis

Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3rd among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G→T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection