Agoric computation: trust and cyber-physical systems

In the past two decades advances in miniaturisation and economies of scale have led to the emergence of billions of connected components that have provided both a spur and a blueprint for the development of smart products acting in specialised environments which are uniquely identifiable, localisable, and capable of autonomy. Adopting the computational perspective of multi-agent systems (MAS) as a technological abstraction married with the engineering perspective of cyber-physical systems (CPS) has provided fertile ground for designing, developing and deploying software applications in smart automated context such as manufacturing, power grids, avionics, healthcare and logistics, capable of being decentralised, intelligent, reconfigurable, modular, flexible, robust, adaptive and responsive. Current agent technologies are, however, ill suited for information-based environments, making it difficult to formalise and implement multiagent systems based on inherently dynamical functional concepts such as trust and reliability, which present special challenges when scaling from small to large systems of agents. To overcome such challenges, it is useful to adopt a unified approach which we term agoric computation, integrating logical, mathematical and programming concepts towards the development of agent-based solutions based on recursive, compositional principles, where smaller systems feed via directed information flows into larger hierarchical systems that define their global environment. Considering information as an integral part of the environment naturally defines a web of operations where components of a systems are wired in some way and each set of inputs and outputs are allowed to carry some value. These operations are stateless abstractions and procedures that act on some stateful cells that cumulate partial information, and it is possible to compose such abstractions into higher-level ones, using a publish-and-subscribe interaction model that keeps track of update messages between abstractions and values in the data. In this thesis we review the logical and mathematical basis of such abstractions and take steps towards the software implementation of agoric modelling as a framework for simulation and verification of the reliability of increasingly complex systems, and report on experimental results related to a few select applications, such as stigmergic interaction in mobile robotics, integrating raw data into agent perceptions, trust and trustworthiness in orchestrated open systems, computing the epistemic cost of trust when reasoning in networks of agents seeded with contradictory information, and trust models for distributed ledgers in the Internet of Things (IoT); and provide a roadmap for future developments of our research

Deorphanization of Adhesion GPCRs overexpressed in Glioblastoma

G-protein-coupled receptors (GPCRs) represent, nowadays, one of the most productive source of drug targets. Some GPCRs members are, however, poorly studied and hence cannot be targeted for therapies yet. Among these, there are more than 90 GPCRs still orphan, i.e. with no described endogenous ligand and no clearly defined function. The orphan receptors CELSR2 and Frizzled4 (Fz4), have recently drawn the attention of the scientific community in virtue of their involvement in cancer progression. CELSR2 is an adhesion GPCR (class B GPCRs) overexpressed in glioblastoma. Until now, CELSR2 endogenous ligands have not yet been identified. Fz4 belongs to class F GPCRs and it is activated by the lipoproteins WNTs and Norrin. Misregulation of Fz4 activity is involved in tumor proliferation and cancer stem cell genesis in many types of malignancies, such as glioblastoma, colorectal and breast cancer. To date, the existence of low-molecular-weight organic molecules binding to and modulating Fz4 has not been reported. Thus, the identification of ligands/modulators of CELSR2 and Fz4 activity could pave the way for new therapeutic strategies to treat cancer. In this thesis, I attempted to identify CELSR2 and Fz4 ligands by using the “Pharmacological chaperone readout”, an innovative screening platform (PC-platform) that identifies ligands in virtue of their potency in affecting the tridimensional structure and the intracellular localization of a protein target. The first chapter of the thesis describes the results obtained in the attempt of identifying new ligands of Fz4 receptor. To achieve this aim, a cell line expressing a Fz4 mutant, Fz4-L501fsX533, was generated. This frameshift mutation is responsible in vivo for the occurrence of the Familial Exudative Vitreoretinopathy (FEVR), a pathology of the retina. The resulting mutant, here referred to as Fz4-FEVR, aggregates intracellularly in the Endoplasmic Reticulum (ER) without reaching the Plasma Membrane (PM) of the cell where, in contrast, the wt receptor localizes at steady state. To identify Fz4 wt modulators, a library of organic molecules has been screened for pharmacological chaperones of Fz4-FEVR, i.e. for molecules able to rescue the folding and correct localization of Fz4-FEVR at PM. Using such read-out, the organic molecule FzM1 has been thus identified as Fz4-FEVR pharmacological chaperone. The pharmacological chaperone FzM1 acts as allosteric inhibitor of the Fz4-wt receptor, binding directly to the wt receptor and inhibiting the signalling pathway Fz4 is involved in. I also performed a structure-activity relationship (SAR) analysis using FzM1 as lead to identify the first allosteric agonist of Fz4, FzM1.8. As discussed in the second chapter of this thesis, a specific PC-platform was developed for the identification of ligands of CELSR2. To achieve this aim, a misfolded version of CELSR2 was generated and then a library of metabolites was screened looking for compounds binding to the receptor and correcting its folding. Zebrafish eggs were used as biomass to obtain a library of metabolites which were screened for pharmacological chaperone efficiency. The outcome of the screening identified three compounds acting as modulators of CELSR2: cholesterol, PGE2 and β-carotene. They do not target the orthosteric binding site of CELSR2 but they are located in an hydrophobic region of the receptor at the interface between the TM-bundle and the lipid bilayer. The potential ability of these molecules to allosterically modulate CELSR2 function could have important implications both in physiological and pathological cell conditions

IL RIPOSIZIONAMENTO COMPETITIVO DI LOCMAN SPA

L’obiettivo della tesi è illustrare l’azione strategica di riposizionamento competitivo come strumento volto a superare stati di crisi aziendale e a ricercare la miglior posizione possibile in un contesto ambientale e strutturale in continuo divenire. In particolare l’analisi si concentra sull’evoluzione del settore dell’orologeria e sul suo rapporto con l’ambiente interno ed esterno, facendo specifico riferimento al riposizionamento competitivo attuato in una nota azienda toscana di segnatempo, la LOCMAN SPA. Questa ha reagito alla crisi, che pervade la nostra epoca, con azioni ad hoc intelligenti e innovative, che le hanno permesso di tornare in attivo, consolidarsi sul mercato e ottenere un migliore apprezzamento da parte dei clienti

The “Green Book” and a Black Sense of Movement: Black Mobilities and Motilities During the Jim Crow Era

Mobility is one of the most ubiquitous aspects of daily life around the globe, and is facilitated by various objects and spaces. The concept of motility, or the factors that contribute to the potential for movement, represents a holistic lens through which mobility can be examined. In the United States, black Americans have a particularly laborious relationship with mobility, as their movements have been regulated and constrained since the first enslaved Africans were brought to the country. Yet, African-Americans have struggled and worked to construct and perform their own movements in the face of a white supremacist society. This dissertation, therefore, seeks to investigate the relationship black Americans have with mobility by exploring examples of motility constructed during the Jim Crow era, a period of intense structural racism. Specifically, I use the Green Book, an African-American travel guide, to examine how black mobility and motility were enacted to create resistance and resilience to white supremacy. The first chapter seeks to develop a new framework for understanding black mobilities and motilities, termed a “black sense of movement.” Through a discourse analysis of the advertisements and essays published in various editions of the Green Book, I demonstrate how a “black sense of movement” is embodied in the guidebook and can better capture dialectical constructions of black geographies. The second chapter explores the intersection of black geographies and critical GIS through the spatial data collected within the pages of the Green Book. By (re)mapping spaces of black travel, I demonstrate how the Green Book served as a “counter map” that facilitated black travel within the city of New Orleans, Louisiana. The final chapter of this dissertation looks at a certain type of business listed in the Green Book, tourist homes, to understand how these private spaces rented to travelers aided in enabling black mobility and motility. I specifically employ the metaphor of hospitality as resistance to understand how iii welcoming black travelers into private homes subverted white supremacy. Overall, this dissertation provides a critical intervention in black geographic literature by centering the role of movement and developing a framework for understanding black mobilities

Postpartum Hemorrhage (PPH) Simulation Project

Postpartum Hemorrhage (PPH) is a problem of global significance; accounting for 25 percent of maternal deaths, it is a leading cause of maternal mortality, often occurring in healthy women devoid of significant risk factors. Because of its relative infrequency, student nurses may miss opportunities to practice critical PPH skills while in a supervised learning environment. Simulation offers students an arena to practice low-frequency, high-stakes events like PPH, in an environment where no harm results from missteps. This DNP Capstone Project investigated the effect of simulation on knowledge, confidence, and clinical judgment of 33 third semester traditionally enrolled baccalaureate nursing students. A one-group, pretest-posttest design assessing knowledge and confidence was performed; knowledge scores showed mixed improvement. Surveys revealed satisfaction with simulation improved (p\u3c .0 to .003 at .05), although confidence in skills and responsibility for learning did not. Student self-reflections correlated with researcher. Themes of importance emerged, including prioritization and communication

Droplet Memory on Liquid-Infused Surfaces

The knowledge of droplet friction on liquid-infused surfaces (LIS) is of paramount importance for applications involving liquid manipulation. While the possible dissipation mechanisms are well-understood, the effect of surface texture has thus far been mainly investigated on LIS with highly regular solid topographies. In this work, we aim to address this experimental gap by studying the friction experienced by water droplets on LIS based on both random and regular polysilsesquioxane nanostructures. We show that the available models apply to the tested surfaces, but we observe a previously unreported droplet memory effect: as consecutive droplets travel along the same path, their velocity increases up to a plateau value before returning to the original state after a sufficiently long time. We study the features of this phenomenon by evaluating the motion of droplets when they cross the path of a previous sequence of droplets, discovering that moving droplets create a low-friction trace in their wake, whose size matches their base diameter. Finally, we attribute this to the temporary smoothing out of an initially conformal lubricant layer by means of a Landau–Levich–Derjaguin liquid film deposition behind the moving droplet. The proposed mechanism might apply to any LIS with a conformal lubricant layer

Multi-agent based simulations of block-free distributed ledgers

In the past ten years distributed ledgers such as Bitcoin and smart contracts that can run code autonomously have seen an exponential growth both in terms of research interest and in terms of industrial and financial applications. These find a natural application in the area of Sensor Networks and Cyber-Physical Systems. However, the incentive architecture of blockchains requires massive computational resources for mining, delays in the confirmation of transactions and, more importantly, continuously growing transaction fees, which are ill-suited to systems in which services may be provided by resource-limited devices and confirmation times and transaction costs should be kept minimal, ideally absent. We focus on a new block-less, feeless paradigm for distributed ledgers suitable for the WSN, IoT and CPS in which transactions are nodes of a directed acyclic graph, that overcomes the limitations of blockchains for these applications, and where e.g. sensors can be at the same time issuers of transactions and validators of previous transactions. In particular, we present and release open-source a simulation environment that can be easily extended and analysed, and confirms the available results on the performance of the network