Event-driven simulation in SELMON: An overview of EDSE

EDSE (event-driven simulation engine), a model-based event-driven simulator implemented for SELMON, a tool for sensor selection and anomaly detection in real-time monitoring is described. The simulator is used in conjunction with a causal model to predict future behavior of the model from observed data. The behavior of the causal model is interpreted as equivalent to the behavior of the physical system being modeled. An overview of the functionality of the simulator and the model-based event-driven simulation paradigm on which it is based is provided. Included are high-level descriptions of the following key properties: event consumption and event creation, iterative simulation, synchronization and filtering of monitoring data from the physical system. Finally, how EDSE stands with respect to the relevant open issues of discrete-event and model-based simulation is discussed

Conceptual Model of Quantities, Units, Dimensions, and Values

JPL collaborated with experts from industry and other organizations to develop a conceptual model of quantities, units, dimensions, and values based on the current work of the ISO 80000 committee revising the International System of Units & Quantities based on the International Vocabulary of Metrology (VIM). By providing support for ISO 80000 in SysML via the International Vocabulary of Metrology (VIM), this conceptual model provides, for the first time, a standard-based approach for addressing issues of unit coherence and dimensional analysis into the practice of systems engineering with SysML-based tools. This conceptual model provides support for two kinds of analyses specified in the International Vocabulary of Metrology (VIM): coherence of units as well as of systems of units, and dimension analysis of systems of quantities. To provide a solid and stable foundation, the model for defining quantities, units, dimensions, and values in SysML is explicitly based on the concepts defined in VIM. At the same time, the model library is designed in such a way that extensions to the ISQ (International System of Quantities) and SI Units (Systeme International d Unites) can be represented, as well as any alternative systems of quantities and units. The model library can be used to support SysML user models in various ways. A simple approach is to define and document libraries of reusable systems of units and quantities for reuse across multiple projects, and to link units and quantity kinds from these libraries to Unit and QuantityKind stereotypes defined in SysML user models

Integrating Analytical Models with Descriptive System Models: Implementation of the OMG SyML Standard for the Tool-specific Case of MapleSim and MagicDraw

AbstractThe Jet Propulsion Laboratory (JPL) is investing heavily in the development of an infrastructure for building system models using the Systems Modeling Language (SysML). An essential component is a transformation apparatus that permits diverse models to be integrated independently of their nature (e.g. declarative, analytical and statistical). This paper presents one useful case: the integration of analytical models expressed using the Modelica language. Modelica is an open standard, declarative, multi-domain modeling language that allows for complex dynamic systems to be modeled. Maplesoft's MapleSim is one software tool that supports the Modelica language. The tool-neutral specification for the transformation between the languages Modelica and SysML is defined in the SysML-Modelica transformation specification (SyML) standard published by the Object Management Group (OMG). As part of the development efforts, said specification has been implemented using the Query-View- Transformation Operational (QVTO) language. During the process, several critical changes to the current SyML standard were proposed. Furthermore, a number of current limitations related to MapleSim were identified. Despite these issues, a proof-of- concept transformation was successfully implemented. In conclusion, the integration of complex simulation models conforming to the Modelica language with SysML-based system models has shown great promise and is a highly useful tool to support the decision making process in design

Requirements Analysis for an Integrated OCL Development Environment

An Integrated OCL Development Environment (IDE4OCL) can significantly improve the pragmatics and praxis of OCL. We present the domain concepts, toolâlevel interactions with OCL and the use cases we identified in a systematic analysis of requirements for an IDE4OCL. The domain concepts is an important contribution of our work as it attempts to clarify inconsistencies in the relevant specifications. Because OCL is not a standâalone language, the OCL landscape includes several interacting tools including an IDE4OCL. The use cases describe our vision of the desired functionality unique to an IDE4OCL. The results of our analysis and the long term vision of our work should be relevant to developers of OCL tools as well as to the OMG Request for Information regarding the UML Futures1. Our work is relevant to the UML Futures Roadmap because providing OCL for the constraints in the UML specification has been a longstanding problem at the OMG

Listeria pathogenesis and molecular virulence determinants

The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal indivuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research

Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer

International audienceObjectives: Tumor mutational burden is an emerging biomarker of response to immune checkpoint inhibitors (ICI), whose clinical adoption is challenging. We hypothesized that targeting limited but relevant genetic alterations in plasma cell-free DNA along with early monitoring may non-invasively predict response to ICI in advanced non-small cell lung cancer (NSCLC).Material and methods: Plasma samples from patients with progressive NSCLC collected before ICI initiation and at 1 month were profiled from responders (R: PFS > 6 months) and non-responders (NR: progressive disease at first evaluation) using amplicon sequencing of hotspots and coding regions from 36 genes. The molecular profile of ctDNA, and its early kinetics were analyzed.Results: 97 patients were analyzed, of which 86 (39 R, 47 NR) were evaluable. Alterations in ctDNA were detectable in 67/86 baseline samples (78%). The detection of a targetable oncogenic driver was associated with a 2 months PFS. The presence of a PTEN or STK11 mutation was correlated with early progression (HR 8.9, p = 0.09 for PTEN, HR 4.7, p = 0.003 for STK11), while transversion mutations (Tv) in KRAS and TP53 predicted better outcomes (HR 0.36, p = 0.011 for TP53 Tv; HR 0.46, p = 0.11 for KRAS Tv). Patients with a low "immune score" (driver and/or PTEN or STK11 mutation and/or without KRAS or TP53 Tv) derived poor outcomes (median PFS 2 months), compared with patients with a high immune score (no driver, no PTEN or STK11 and with KRAS or TP53 Tv (median PFS 14 months, p = 0.0001, HR 2.96). Early changes in the ctDNA allele fraction (AF) of 65 specimens were correlated with clinical outcomes (14 months PFS if AF decreases vs. 2 months if AF increases, p < 0.0001).Conclusion: Targeted sequencing of plasma ctDNA and monitoring its early variations can predict response to ICI