The Tropos Modeling Language. A User Guide

Tropos e` una nuova metodologia basata sul paradigma dei sistemi multi-agente che supporta il progettista in tutto il processo di sviluppo del software, dall'analisi dei requisiti all'implementazione del sistema. Essa vuole offrire un approccio strutturato allo sviluppo del software, basato sulla costruzione di modelli concettuali definiti secondo un linguaggio di modellazione visuale, i cui elementi base sono concetti quali agente (attore), credenze, obiettivi, piani e intenzioni. Tropos si caratterizza per tre idee chiave: (i) le nozioni di agente, goal, piani e altre nozioni mentalistiche sono usate lungo tutte le fasi di sviluppo del software; (ii) l'adozione di un approccio allo sviluppo del software guidato dai requisiti anziché dai vincoli dettati dalla piattaforma di implementazione scelta; (iii) la costruzione di modelli concettuali seguendo un approccio trasformazionale di tipo incrementale. Questo lavoro si colloca all'interno di un progetto che coinvolge diverse università e istituti di ricerca nel mondo, tra le quali l'Università degli Studi di Trento e l'ITC-irst. Obiettivo di questo documento è quello di fornire una guida all'uso della metodologia Tropos lungo tutte le fasi del processo di sviluppo del software con particolare enfasi al linguaggio di modellazione visuale. Il linguaggio utilizzato in Tropos è un linguaggio di specifica semiformale caratterizzato da un'ontologia, un meta-modello, una notazione grafica e un insieme di regole. L'ontologia è rappresentata da un insieme di concetti per la modellazione (attori, goal, piani) e di relazioni tra questi (dipendenze). Il meta-modello (descritto tramite diagrammi delle classi UML) è necessario per la specifica dei modelli Tropos. Ciascun concetto definito all'interno del meta-modello dispone della propria rappresentazione grafica che lo identifica lungo tutte le fasi del processo. Sono disponibili vari diagrammi che catturano aspetti statici e dinamici dei modelli da più punti di vista. Ogni diagramma è costruito seguendo un insieme di regole precise che guidano all'uso dei concetti durante le diverse fasi del processo di sviluppo del software

Panoramic Overview on the Enantioselection Performance of Inherently Chiral Surfaces: a Comparison between Systems with Different Atropisomeric Cores and Stereogenic Elements

Enantiorecognition is a key issue in advanced analytical chemistry, particularly concerning the biological and pharmaceutical field. Enantiomeric molecules, being mirror-image structures, have identical physico-chemical scalar properties, but opposite pseudo-scalar ones. When interacting with a racemic probe, chiral molecules are able to recognize the enantiomers through diasteromeric interactions. Similarly, chiral electrodes are required for enantioselective electroanalysis, and the development of "intelligent" electrodes capable of discriminating enantiomers, in particular molecules of biological and pharmaceutical importance, remains as one of the major challenges in electroanalysis. We have recently proposed the first synthetic inherently chiral electrode surfaces able to neatly discriminate as separate peaks (in terms of potential values) the antipodes of model chiral probes, also drugs, both as enantiopure and racemate. [1-2] We have also verified the general validity of the inherently chiral concept, which does not depend from the chemical nature of the atropisomeric scaffold, testing chiral surfaces electrooligomerized from starting monomers with different molecular design (i.e. bithiophene, bibenzothiophene, biindole and paracyclophane cores) and different stereogenic elements (stereogenic axis vs helix vs plane). In order to fully elucidate the enantioselection capability of all of these heteroaromatic systems we propose a detailed comparison (an example in Figure) of our inherently chiral surfaces with different atropisomeric core vs thiahelicene-based films vs \u201ctwo floor\u201d paracyclophanic oligomers. Figure. Enantioselection properties of inherently chiral oligomers with bibenzothiophene and biindole units towards L- and D-DOPA probes. The support of Fondazione Cariplo/Regione Lombardia "Avviso congiunto per l\u2019incremento dell\u2019attrattivit\ue0 del sistema di ricerca lombardo e della competitivit\ue0 dei ricercatori candidati su strumenti ERC - edizione 2016\u201d (Project 2016-0923) is gratefully acknowledged. References: [1] F. Sannicol\uf2, S. Arnaboldi, T. Benincori, V. Bonometti,R. Cirilli, L. Dunsch, W. Kutner, G. Longhi, P. R. Mussini, M. Panigati, M. Pierini, S. Rizzo, Angew Chem. Int. Ed., 53 (2014) 2623-2627. [2] S. Arnaboldi, T. Benincori, R. Cirilli, W. Kutner, M. Magni, P. R. Mussini, K. Noworyta, F. Sannicol\uf2, Chem. Sci., 6 (2015) 1706-171

Consensus-Based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1

Purpose of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects approximately 1 in 2,500 individuals globally [Ashizawa et al.: Neurol Clin Pract 2018;8(6):507-20]. In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death in this patient population, followed by cardiac complications [de Die-Smulders et al.: Brain 1998;121(Pt 8):1557-63], [Mathieu et al.: Neurology 1999;52(8):1658-62], [Groh et al.: Muscle Nerve 2011;43(5):648-51]. This paper provides a more detailed outline on the diagnostic and management protocols, which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists discussed respiratory testing and management at baseline and during follow-up visits, based on their clinical experience with patients with DM1. The details are presented in this report. Recent Findings: Myotonic recruited 66 international clinicians experienced in the treatment of people living with DM1 to develop and publish consensus-based care recommendations targeting all body systems affected by this disease [Ashizawa et al.: Neurol Clin Pract. 2018;8(6):507-20]. Myotonic then worked with 12 international respiratory therapists, pulmonologists and neurologists with long-standing experience in DM respiratory care to develop consensus-based care recommendations for pulmonologists using a methodology called the Single Text Procedure. This process generated a 7-page document that provides detailed respiratory care recommendations for the management of patients living with DM1. This consensus is completely based on expert opinion and not backed up by empirical evidence due to limited clinical care data available for respiratory care management in DM patients. Nevertheless, we believe it is of relevance for professionals treating adults with myotonic dystrophy because it addresses practical issues related to respiratory management and care, which have been adapted to meet the specific issues in patients with DM1. Summary: The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of untoward respiratory complications and mortality by providing pulmonologist who are less experienced with DM1 with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related to this multiorgan disease

Strategies for High Enantioselectivity in Electroanalysis: Implementing Inherently Chiral Selectors as Electrode Surfaces or at Electrode|Ionic Liquid Interfaces

Strategies for High Enantioselectivity in Electroanalysis: Implementing Inherently Chiral Selectors as Electrode Surfaces or at Electrode|Ionic Liquid Interfaces Patrizia R. Mussini,*1 Serena Arnaboldi1, Mirko Magni1, Sara Grecchi1, Tiziana Benincori2, Simona Rizzo3, Emanuela Licandro1, Silvia Cauteruccio1, Francesco Sannicol\uf21 1Universit\ue0 degli Studi di Milano, Dip. di Chimica, Via Golgi 19, 20133 Milano, Italy, 2 Universit\ue0 degli Studi dell'Insubria, Dip. di Scienza e Alta Tecnologia, Como, Italy 3 Istituto di Scienze e Tecnologie Molecolari, CNR, Milano, Italy E-mail: [email protected] Chiral electroanalysis could be regarded as the highest recognition degree in electrochemical sensing, implying the ability to discriminate between specular images of a given electroactive molecule in terms of significant peak potential difference. A groundbreaking strategy was recently proposed, based on the use of "inherently chiral" molecular selectors, i.e. with chirality and key functional properties originating from the same structural element. Large differences in peak potentials have been observed for the enantiomers of different chiral probes: (a) working on inherently chiral electrode surfaces consisting of thin electroactive oligomer films1 (often including macrocycle terms) electrodeposited from enantiopure inherently chiral monomers with atropisomeric or helical scaffolds; (b) working on achiral electrodes, implementing inherent chirality in their interphase with an ionic liquid medium2 exploiting the latter's peculiarly high order. Inherently chiral ionic liquids ICILs were developed as double salts of an atropisomeric 3,3\u2032-bipyridine scaffold with long alkyl chains and a suitable anion, Even more convenient, the new ICILs as well as other family terms solid at room temperature but of easier synthesis, or other inherently chiral salts, can be efficiently applied as low-concentration chiral additives in commercial achiral ionic liquids: large peak potential differences, regularly increasing with additive concentration, have been observed for the enantiomers of different probes on achiral electrodes. Work is in progress to strengthen and rationalize the first proofs of concepts by developing, characterizing and testing a wider variety of inherently chiral selectors with different chiral probes, particularly of pharmaceutical interest, with more optimized and detailed protocols, and with the support of other techniques, particularly aiming to the recognition mechanism elucidation.. The inherent chirality research is currently supported by Regione Lombardia and Fondazione Cariplo (Avviso congiunto per l\u2019incremento dell\u2019attrattivit\ue0 del sistema di ricerca lombardo e della competitivit\ue0 dei ricercatori candidati su strumenti ERC-edizione 2016, Project 2016-0923). 1 Angew. Chem., 2014, 53, 2623. Chem. Eur J. 2014, 20, 15298; Chem. Sci. 2015, 6, 1706; Anal. Bional. Chem. 2016, 408, 7243; Chem. Eur J. 2016, 22, 10839 2 Angew. Chem. 2017, 56, 2079; Electrochem. Comm. 2018, 89, 57

Electrochemistry of inherently chiral molecular materials with bisindole atropisomeric cores: interacting equivalent redox sites, configurational stability, and enantioselection ability for different chiral probes

In "inherently chiral" molecules chirality and key functional properties originate from the same structural element, and are thus strictly linked together. In the case of poly(hetero)aromatic electroactive molecules, this can be achieved by inserting in the main conjugated backbone a tailored torsion with an energy barrier too high to be overcome at room temperature, while not entirely hampering conjugation. This strategy results in outstanding chirality manifestations. including e.g. circularly polarized luminescence as well as outstanding enantiorecognition ability in CV experiments. For instance, large peak potential differences were observed for the enantiomers of different chiral probes on electroactive surfaces obtained by electrooligomerization of inherently chiral monomers having atropisomeric (= with hindered rotation between two moieties) bibenzothiophene (Fig 1A) or bithiophene cores. [1-4]. An interesting option is also to change the thiophene-based atropisomeric cores with 2,2'-bisindole and 3,3'-bisindole ones (Fig 1B and 1C), on account of the easy functionalization of the core e.g. with long alkyl chains, modulating solubility and processability. A B C Figure 1 R = H or C1-C6 alkyl chains; Spacer = phenyl or nothing (oligothiophene wing attached to core) The change also leads to quite interesting modifications in the electrochemical activity. Since indole is electron richer than thiophene, the first two oxidations take place at significantly less positive potentials than in the former cases, and are localized on the two interacting moieties of the bisindole core rather than on the terminal wings; thus, they are chemically reversible (oligomerization can be achieved cycling around the third oxidation peak). A peculiar attractive feature concerns the interaction between the two equivalent redox centers in the biindole core, which can be evaluated from the potential difference between the corresponding oxidation peak: it can be shown that it can account for the atropisomeric energy barrier (depending on the 2,2' or 3,3' connectivity and on the N-alkyl substituents), and is also modulated by temperature and the solvent polarity. Thus electrochemistry can provide information on the torsional energy barrier and on the enantiomer stability, as confirmed by other approaches. Besides the intrinsic interest of these inherently chiral families, they are also quite attractive from the applicative point of view, since enantioselectivity test on films obtained by electrooligomerization of the more stable 2,2' monomers yield large potential differences for the antipodes of very different chiral probes, also of pharmaceutical interest. The current support of Fondazione Cariplo/Regione Lombardia "Avviso congiunto per l\u2019incremento dell\u2019attrattivit\ue0 del sistema di ricerca lombardo e della competitivit\ue0 dei ricercatori candidati su strumenti ERC - edizione 2016\u201d (Project 2016-0923) to our inherently chiral research is gratefully acknowledged. References: 1. Angew. Chem. Int. Ed. 2014, 53, 2623. 2. Chem. Eur. J. 2014, 20, 15298. 3. Chem. Sci. 2015, 6,1706. 4. Chem. Eur.2016 , 22,10839. 5. Anal. Bioanal. Chem. 2016, 408, 7243

Knowledge Level Software Engineering

We contend that, at least in the first stages of definition of the early and late requirements, the software development process should be articulated using knowledge level concepts. These concepts include actors, who can be (social, organizational, human or software) agents, positions or roles, goals, and social dependencies for defining the obligations of actors to other actors. The goal of this paper is to instantiate this claim by describing how Tropos, an agent-oriented software engineering methodology based on knowledge level concepts, can be used in the development of a substantial case study consisting of the meeting scheduler problem

Électrodes transparentes à base de réseaux de nanofils d'argent : percolation électrique, propriétés physiques et applications

Transparent electrodes attract intense attention in many technological fields, including optoelectronic devices (solar cells, LEDs, touch screens), transparent film heaters (TFHs) and electromagnetic (EM) applications. New generation transparent electrodes are expected to have three main physical properties: high electrical conductivity, high transparency and mechanical flexibility. The most efficient and widely-used transparent conducting material is currently indium tin oxide (ITO). However the scarcity of indium associated with ITO’s lack of flexibility and the relatively high manufacturing costs have prompted search into alternative materials. With their outstanding physical properties, silver nanowire (AgNW)-based percolating networks appear to be one of the most promising alternatives to ITO. They also have several other advantages, such as solution-based processing, and compatibility with large area deposition techniques. First cost estimates are lower for AgNW based technology compared to current ITO fabrication processes. Unlike ITO, AgNW are indeed directly compatible with solution processes, never requiring vacuum conditions. Moreover, due to very large aspect ratio of the NWs, smaller quantities of raw materials are needed to reach industrial performance criteria.The present thesis aims at investigating important physical assets of AgNW networks – unexplored (or not explored enough) so far – in order to increase the robustness, reliability, and industrial compatibility of such technology. This thesis work investigates first optimization methods to decrease the electrical resistance of AgNW networks. In situ electrical measurements performed during thermal ramp annealing and/or chemical treatments provided useful information regarding the activation process at the NW-NW junctions. At the scale of the entire network, our ability to distinguish NW areas taking part in the electrical conduction from inactive areas is a critical issue. In the case where the network density is close to the percolation threshold, a discontinuous activation process of efficient percolating pathways through the network was evidenced, giving rise to a geometrical quantized percolation phenomenon. More generally, the influence of several parameters (networks density, applied voltage, optimization level) on the electrical and thermal homogeneity and stability of AgNW networks is investigated via a dual approach combining electrical mapping techniques and simulations. A thermal runaway process leading to a vertical crack and associated to electrical failure at high voltage could be visually evidenced via in situ electrical mapping of AgNW networks during voltage plateaus. Moreover many efforts using Matlab and Comsol softwares were devoted to construct reliable models able to fit with experimental results. Due to the increasing demand for portable and wearable electronics, preliminary tests were also conducted to investigate the stretching capability of AgNW networks when transferred to elastomeric substrates. Finally, integrations of AgNW networks in several devices were performed. Specifically, studies were conducted to understand the mechanisms leading to failure in AgNW-based transparent film heaters, and to improve their overall stability. Preliminary investigations of the benefits of incorporating of AgNW networks into electromagnetic devices such as antennas and EM shielding devices are also discussed at the end of the manuscript.L’intérêt pour les électrodes transparentes (TEs) concerne un large spectre de domaines technologiques, tels que les dispositifs optoélectroniques (cellules solaires, LEDs, écrans tactiles), les films chauffants transparents, ou les applications électromagnétiques. Les TEs de nouvelle génération auront à combiner à la fois un très haut niveau de conduction électrique, de transparence optique, mais aussi de flexibilité mécanique. L’oxyde d’Indium dopé Etain (ITO) domine actuellement le marché des matériaux transparents conducteurs (TCMs). Cependant, la rareté de l’Indium, combinée à ses faibles performances en flexion mécaniques et ses coûts de fabrication élevés ont orienté les recherches vers des TCMs alternatifs. Les réseaux percolants de nanofils métalliques, en particulier les nanofils d’argent (AgNWs), se sont imposés comme l’une des alternatives les plus sérieuses à l’ITO, en raison de leurs propriétés physiques très attractives. Ces réseaux interconnectés offrent également la possibilité d’utiliser des méthodes de synthèse en voie chimique et d’impression à bas coût, sur de grandes surfaces. De manière générale, les premières estimations concernant les coûts de fabrication sont inférieures à celles de l’ITO. De plus, grâce au très haut facteur de forme des nanofils et à la nature percolante des réseaux, les besoins en quantité de matières premières nécessaires pour atteindre un haut niveau de performance sont moindres.Ce travail de thèse s’intéresse à l’étude des propriétés physiques fondamentales – inexplorées ou non encore suffisamment étudiées – des réseaux d’AgNWs, afin d’améliorer la robustesse, la fiabilité et la compatibilité de ce type d’électrodes avec les critères de performance industriels. La première partie est consacrée à l’étude des méthodes d’optimisation utilisées pour diminuer au mieux la résistance électrique des électrodes. Les mesures électriques in situ effectuées au court d’un recuit thermique et/ou après traitement chimique fournissent de précieuses informations concernant les mécanismes d’activation au niveau des jonctions entre nanofils. A l’échelle du réseau, notre capacité à distinguer les zones qui participent efficacement à la conduction électrique de celles qui seraient potentiellement inactives est un défi majeur. Pour les réseaux dont la densité en nanofils est proche du seuil de percolation, un processus d’activation discontinu de chemins efficaces de percolation à travers le réseau a pu être mis en évidence. De manière générale, l’influence de plusieurs paramètres (densité du réseau, tension, niveau d’optimisation) sur l’homogénéité et la stabilité électrique et thermique des électrodes a été étudiée, à l’aide de techniques de cartographie électrique et de simulations. A tension élevée, un processus d’emballement thermique conduisant à la formation d’une fissure physique à travers un réseau d’AgNWs soumis à des plateaux de tension croissants a pu être détecté visuellement. Des modèles de simulation via les logiciels Matlab et Comsol ont aussi été construits afin de confirmer, voire anticiper, les phénomènes observés expérimentalement. Par ailleurs, encouragés par la demande croissante pour les dispositifs électroniques portatifs en toute circonstance, des tests préliminaires ont été conduit pour évaluer le comportement des réseaux d’AgNWs sous contrainte d’étirement mécanique lorsqu’ils sont transférés sur des substrats élastiques. Ce travail de thèse a également donné lieu à l’intégration de réseaux d’AgNWs dans des dispositifs. Des études ont été menées afin d’améliorer la stabilité des films chauffants transparents à base d’AgNWs et de mieux appréhender les mécanismes favorisant l’émergence de défauts. L’utilisation des réseaux d’AgNWs pour des applications électromagnétiques (antennes, blindage) a également fait l’objet de tentatives préliminaires dont les résultats sont commentés à la fin du manuscrit

Identification d’une signature métabolique prédictive de réponse aux inhibiteurs des points de contrôle immunitaires chez les patients atteints d’un cancer bronchique non à petites cellules : protocole et analyse intermédiaire

Immune Checkpoint lnhibitors (ICI) are becoming new standards of care in Oncology, especially for the non-small cell lung cancer (NSCLC). Actually, no biomarker is sensitive and specific enough to predict their effectiveness. As the composition of the microbiota can influence the response to these treatments, we hypothesized that the metabolome, reflecting the function of the microbiota, could represent an effective biomarker. METABO-IPCI is a monocentric and prospective at University Hospital Grenoble Alpes whose main objective is to identify a metabolic signature predictive of response to ICI in patients with NSCLC. Secondary objectives are re to show an association between metabolome, microbiota composition, immunological profile and clinical response to ICI. The protocol includes 60 patients followed for NSCLC and treated with ICI as first line alone (Cohort 1 ), as second line or more (Cohort 2) or as first line in combination with chemotherapy (Cohort 3). At the 30th June 2021, 30 patients were included: 1 in Cohort 1, 19 in Cohort 2 and 10 in Cohort 3. The median age was 68 years old, 80% were adenocarcinoma. As part of the study, 94% of blood samples were collected, 72% of stool samples. At 2 months after the start of treatment, 9 patients (30%) had progressive disease, 15 (50%) stable disease and 6 (20%) had partial response disease. Given the delay in inclusions, the inclusion period has been extended to June 2022. Ali biological analyses will ail be performed 6 months after the last inclusion (starting in the first half of 2023).Les inhibiteurs des points de contrôle immunitaires (IPCI) sont des nouveaux standards de soins en oncologie, notamment dans le cancer bronchique non à petites cellules (CBNPC). Aujourd'hui, aucun biomarqueur n'est assez sensible et spécifique pour prédire leur efficacité. La composition du microbiote pouvant influencer la réponse à ces traitements, nous avons émis l'hypothèse que le métabolome, reflet de sa fonction, pouvait représenter un biomarqueur efficace. METABO-IPCI est une étude monocentrique prospective au CHU Grenoble Alpes dont l'objectif principal est la mise en évidence d'une signature métabolique prédictive de réponse aux IPCI chez les patients avec un CBNPC. Les objectifs secondaires sont de révéler un lien entre le métabolome, la composition du microbiote, le profil immunologique et la réponse clinique aux IPCI. Le protocole prévoit l'inclusion de 60 patients suivis pour un CBNPC et traités par IPCI seul en première ligne (Cohorte 1 ), en deuxième ligne ou plus (Cohorte 2) ou en association avec la chimiothérapie en première ligne (Cohorte 3). Au 30 juin 2021, 30 patients étaient inclus: 1 dans la cohorte 1, 19 dans la Cohorte 2 et 10 dans la Cohorte 3. L'âge médian est de 68 ans, 80% sont des adénocarcinomes. 94% des échantillons de sang ont été recueillis, 72% des échantillons de selles. A 2 mois de traitement, 9 patients (30%) présentaient une maladie en progression, 15 (50%) une maladie stable et 6 (20%) une maladie en réponse partielle. Du fait un rythme d'inclusion plus lent que prévu, la période d'inclusion a ainsi été prolongée jusqu'en juin 2022. L'ensemble des analyses biologiques sera réalisé 6 mois après la dernière inclusion (à partir du 1er semestre 2023)