Investigating the trade-off between the effectiveness and efficiency of process modeling

Despite recent efforts to improve the quality of process models, we still observe a significant dissimilarity in quality between models. This paper focuses on the syntactic condition of process models, and how it is achieved. To this end, a dataset of 121 modeling sessions was investigated. By going through each of these sessions step by step, a separate ‘revision’ phase was identified for 81 of them. Next, by cutting the modeling process off at the start of the revision phase, a partial process model was exported for these modeling sessions. Finally, each partial model was compared with its corresponding final model, in terms of time, effort, and the number of syntactic errors made or solved, in search for a possible trade-off between the effectiveness and efficiency of process modeling. Based on the findings, we give a provisional explanation for the difference in syntactic quality of process models

Considerations about quality in model-driven engineering

The final publication is available at Springer via http://dx.doi.org/10.1007/s11219-016-9350-6The virtue of quality is not itself a subject; it depends on a subject. In the software engineering field, quality means good software products that meet customer expectations, constraints, and requirements. Despite the numerous approaches, methods, descriptive models, and tools, that have been developed, a level of consensus has been reached by software practitioners. However, in the model-driven engineering (MDE) field, which has emerged from software engineering paradigms, quality continues to be a great challenge since the subject is not fully defined. The use of models alone is not enough to manage all of the quality issues at the modeling language level. In this work, we present the current state and some relevant considerations regarding quality in MDE, by identifying current categories in quality conception and by highlighting quality issues in real applications of the model-driven initiatives. We identified 16 categories in the definition of quality in MDE. From this identification, by applying an adaptive sampling approach, we discovered the five most influential authors for the works that propose definitions of quality. These include (in order): the OMG standards (e.g., MDA, UML, MOF, OCL, SysML), the ISO standards for software quality models (e.g., 9126 and 25,000), Krogstie, Lindland, and Moody. We also discovered families of works about quality, i.e., works that belong to the same author or topic. Seventy-three works were found with evidence of the mismatch between the academic/research field of quality evaluation of modeling languages and actual MDE practice in industry. We demonstrate that this field does not currently solve quality issues reported in industrial scenarios. The evidence of the mismatch was grouped in eight categories, four for academic/research evidence and four for industrial reports. These categories were detected based on the scope proposed in each one of the academic/research works and from the questions and issues raised by real practitioners. We then proposed a scenario to illustrate quality issues in a real information system project in which multiple modeling languages were used. For the evaluation of the quality of this MDE scenario, we chose one of the most cited and influential quality frameworks; it was detected from the information obtained in the identification of the categories about quality definition for MDE. We demonstrated that the selected framework falls short in addressing the quality issues. Finally, based on the findings, we derive eight challenges for quality evaluation in MDE projects that current quality initiatives do not address sufficiently.F.G, would like to thank COLCIENCIAS (Colombia) for funding this work through the Colciencias Grant call 512-2010. This work has been supported by the Gene-ralitat Valenciana Project IDEO (PROMETEOII/2014/039), the European Commission FP7 Project CaaS (611351), and ERDF structural funds.Giraldo-Velásquez, FD.; España Cubillo, S.; Pastor López, O.; Giraldo, WJ. (2016). Considerations about quality in model-driven engineering. Software Quality Journal. 1-66. https://doi.org/10.1007/s11219-016-9350-6S166(1985). Iso information processing—documentation symbols and conventions for data, program and system flowcharts, program network charts and system resources charts. ISO 5807:1985(E) (pp. 1–25).(2011). Iso/iec/ieee systems and software engineering – architecture description. 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The rice NLR pair Pikp-1/Pikp-2 initiates cell death through receptor cooperation rather than negative regulation

Plant NLR immune receptors are multidomain proteins that can function as specialized sensor/helper pairs. Paired NLR immune receptors are generally thought to function via negative regulation, where one NLR represses the activity of the second and detection of pathogen effectors relieves this repression to initiate immunity. However, whether this mechanism is common to all NLR pairs is not known. Here, we show that the rice NLR pair Pikp-1/Pikp-2, which confers resistance to strains of the blast pathogen Magnaporthe oryzae (syn. Pyricularia oryzae) expressing the AVR-PikD effector, functions via receptor cooperation, with effector-triggered activation requiring both NLRs to trigger the immune response. To investigate the mechanism of Pikp-1/Pikp-2 activation, we expressed truncated variants of these proteins, and made mutations in previously identified NLR sequence motifs. We found that any domain truncation, in either Pikp-1 or Pikp-2, prevented cell death in the presence of AVR-PikD, revealing that all domains are required for activity. Further, expression of individual Pikp-1 or Pikp-2 domains did not result in cell death. Mutations in the conserved P-loop and MHD sequence motifs in both Pikp-1 and Pikp-2 prevented cell death activation, demonstrating that these motifs are required for the function of the two partner NLRs. Finally, we showed that Pikp-1 and Pikp-2 associate to form homo- and hetero-complexes in planta in the absence of AVR-PikD; on co-expression the effector binds to Pikp-1 generating a tri-partite complex. Taken together, we provide evidence that Pikp-1 and Pikp-2 form a fine-tuned system that is activated by AVR-PikD via receptor cooperation rather than negative regulation

p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1.We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins

Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo

Recent studies have suggested that C-MYC may be an excellent therapeutic cancer target and a number of new agents targeting C-MYC are in preclinical development. Given most therapeutic regimes would combine C-MYC inhibition with genotoxic damage, it is important to assess the importance of C-MYC function for DNA damage signalling in vivo. In this study, we have conditionally deleted the c-Myc gene in the adult murine intestine and investigated the apoptotic response of intestinal enterocytes to DNA damage. Remarkably, c-Myc deletion completely abrogated the immediate wave of apoptosis following both ionizing irradiation and cisplatin treatment, recapitulating the phenotype of p53 deficiency in the intestine. Consistent with this, c-Myc-deficient intestinal enterocytes did not upregulate p53. Mechanistically, this was linked to an upregulation of the E3 Ubiquitin ligase Mdm2, which targets p53 for degradation in c-Myc-deficient intestinal enterocytes. Further, low level overexpression of c-Myc, which does not impact on basal levels of apoptosis, elicited sustained apoptosis in response to DNA damage, suggesting c-Myc activity acts as a crucial cell survival rheostat following DNA damage. We also identify the importance of MYC during DNA damage-induced apoptosis in several other tissues, including the thymus and spleen, using systemic deletion of c-Myc throughout the adult mouse. Together, we have elucidated for the first time in vivo an essential role for endogenous c-Myc in signalling DNA damage-induced apoptosis through the control of the p53 tumour suppressor protein

Unified Process Modeling with UPROM Tool

UPROM tool is a business process modeling tool designed to conduct business process and user requirements analysis in an integrated way to constitute a basis for process automation. Usually, business process models are not utilized systematically to develop related artifacts, specifically when a process-aware information system is to be developed to automate those processes. This results in completeness, consistency and maintainability problems for those artifacts. Unified business process modeling methodology, UPROM, is developed to integrate process modeling and practices. Enabling the application of UPROM, the tool provides editors for six different diagram types based on a common meta-model. It offers features so that modelers can develop a cohesive set of models. Using these models, UPROM tool can be used to automatically generate artifacts of user requirements document, COSMIC based software size estimation, process definition document and business glossary

Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov)