Automated Synthesis of Distributed Self-Stabilizing Protocols

In this paper, we introduce an SMT-based method that automatically synthesizes a distributed self-stabilizing protocol from a given high-level specification and network topology. Unlike existing approaches, where synthesis algorithms require the explicit description of the set of legitimate states, our technique only needs the temporal behavior of the protocol. We extend our approach to synthesize ideal-stabilizing protocols, where every state is legitimate. We also extend our technique to synthesize monotonic-stabilizing protocols, where during recovery, each process can execute an most once one action. Our proposed methods are fully implemented and we report successful synthesis of well-known protocols such as Dijkstra's token ring, a self-stabilizing version of Raymond's mutual exclusion algorithm, ideal-stabilizing leader election and local mutual exclusion, as well as monotonic-stabilizing maximal independent set and distributed Grundy coloring

Álgebras de estabilização

Tese de mestrado, Matemática, Universidade de Lisboa, Faculdade de Ciências, 2018Este trabalho explora uma generalização da teoria algébrica das Linguagens Formais. Tendo os trabalhos de Thomas Colcombet e de Laure Daviaud, Denis Kuperberg e Jean-Éric Pin sobre funções de custo como ponto de partida, apresentamos os conceitos de ideal de ordem, álgebra de estabilização e autómato de estabilização. Obtemos generalizações de resultados conhecidos no âmbito das Linguagens Formais, como por exemplo do Teorema de Eilenberg e do Teorema de Schützenberger sobre identidades associadas a variedades, e também obtemos uma resposta para o Problema da Igualdade. Provamos também que o conceito de ideal de ordem reconhecível é uma generalização do conceito de função custo reconhecível pelo que a teoria desenvolvida se aplica também no estudo das funções de custo.This thesis explores a generalisation of the algebraic theory of Formal Languages. Having the work of Thomas Colcombet and of Laure Daviaud, Denis Kuperberg and Jean-Éric Pin about cost functions as a starting point, we present the concepts of ordered ideal, stabilisation algebra and stabilisation automata. We generalize various known results in Formal Languages, for example, the Eilenberg Theorem and the Schützenberger Theorem about identities associated to varieties, besides we answer to the Equality Problem. We also prove that the concept of recognisable ordered ideal is a generalisation of the concept of recognizable cost function, whence the theory developed in this thesis also applies to the study of cost functions

Saturated ideal modes in advanced tokamak regimes in MAST

MAST plasmas with a safety factor above unity and a profile with either weakly reversed shear or broad low-shear regions, regularly exhibit long-lived saturated ideal magnetohydrodynamic (MHD) instabilities. The toroidal rotation is flattened in the presence of such perturbations and the fast ion losses are enhanced. These ideal modes, distinguished as such by the notable lack of islands or signs of reconnection, are driven unstable as the safety factor approaches unity. This could be of significance for advanced scenarios, or hybrid scenarios which aim to keep the safety factor just above rational surfaces associated with deleterious resistive MHD instabilities, especially in spherical tokamaks which are more susceptible to such ideal internal modes. The role of rotation, fast ions and ion diamagnetic effects in determining the marginal mode stability is discussed, as well as the role of instabilities with higher toroidal mode numbers as the safety factor evolves to lower values

Light-sensitive nanocarriers for drug delivery in photodynamic therapy

Aquesta tesi aprofundeix en l’estudi de nanotransportadors com a sistemes de vehiculització i en alguns casos, alliberació de fotosensibilitzadors emprats en teràpia fotodinàmica. S’han fet servir dos nanotransportadors de naturalesa diferent: proteïnes i liposomes. En primer lloc s’ha investigat els complexos formats entre la hipericina i les proteïnes apomioglobina i β-lactoglobulina. S’han estudiat les característiques fisicoquímiques i fotofísiques, avaluant l’activitat antimicrobiana en front a bacteris gram-positius i gram-negatius. En ambdues matrius proteiques el fotosensibilitzador es troba majoritàriament en forma monomèrica, preservant les seves propietats fotofísiques i formant un complex estable. En el cas de la β-lactoglobulina s’estudia a més, la formació del complex amb l’adició d’un 20% de DMSO com a co-solvent, fet que millora les propietats fotofísiques en detriment de la capacitat antimicrobiana. Ambdós complexos proteics son efectius contra bacteris gram-positius però no contra gram-negatius. Per altra banda, es demostra que la hipericina incorporada a la cavitat de l’apomioglobina pot ser utilitzada en microscòpia de super-resolució STED. Amb aquesta tècnica es pot monitoritzar els llocs d’unió del fotosensibilitzador a la membrana dels bacteris. Així mateix, s’estudia l’ús de la β-lactoglobulina com a portador dual d’hipericina i àcid retinoic. En aquest últim sistema multi-component s’avaluen les propietats fotofísiques per a verificar la formació i estabilitat del complex. En segon lloc, es desenvolupa un nanovehicle per la seva aplicació en teràpia combinada en el qual s’incorporen fàrmacs quimioterapèutics convencionals amb agents fotosensibilitzants, per superar resistències i millorar l’eficàcia dels tractaments individuals. Amb aquest objectiu, s’han dissenyat i estudiat dues formulacions liposomals diferents, ambdues amb el mateix fotosensibilitzador però encapsulant diferents agents quimioterapèutics. Es preparen formulacions bimodals on s’incorporen els dos agents al mateix vehicle i els seus homòlegs unimodals, amb la incorporació única d’un dels dos agents. S’han avaluat les característiques fisicoquímiques, fotofísiques i fotobiològiques de les suspensions bimodals i unimodals. La lozalització subcel·lular demostra que cada principi actiu es localitza a orgànuls diferents desencadenant rutes de senyalització cel·lular diferents, eludint els possibles mecanismes de resistència. El tractament in vitro en cèl·lules cancerígenes amb aquests sistemes tenen un efecte prometedor, ja que com a mínim presenten un comportament additiu respecte els tractaments individuals. Finalment, s’ha avaluat el potencial de la vehiculització activa mitjançant la unió covalent d’un anticòs monoclonal a la superfície, el que millora lleugerament els resultats per una de les dues formulacions.Esta tesis profundiza en el estudio de nanotransportadores como sistema de vehiculización y en algunos casos, liberación de fotosensibilizadores empleados en terapia fotodinámica. Se emplean dos nanotransportadores de naturaleza distinta: proteínas y liposomas. En primer lugar se han investigado los complejos formados entre hipericina y las proteínas apomioglobina y β-lactoglobulina. Se han estudiado las características fisicoquímicas y fotofísicas, evaluando la actividad antimicrobiana frente bacterias gram-positivas y gram-negativas. En ambas matrices proteicas el fotosensibilizador se encuentra mayoritariamente en forma monomérica, preservando sus propiedades fotofísicas y formando un complejo estable. En el caso de la β-lactoglobulina se estudia además, la formación del complejo con la adición del 20% de DMSO como co-solvente, lo que mejora las propiedades físicas pero sorprendentemente, empeora la capacidad antimicrobiana. Ambos complejos proteicos son efectivos contra bacterias gram-positivas, pero no contra gram-negativas. Además, se demuestra que la hipericina en la cavidad de la apomioglobina es capaz de realizar microscopía de super-resolución STED, mediante la cual se puede monitorizar los sitios de unión a las bacterias. Asimismo, se ha estudiado la β-lactoglobulina como portador dual de hipericina y ácido retinoico. En este último sistema multi-componente se evalúan las propiedades fotofísicas para verificar la formación y estabilidad del complejo. En segundo lugar, se desarrolla un nanovehículo para su uso en terapia combinada en el que se incorpora fármacos quimioterapéuticos convencionales con agentes fotosensibilizantes, para superar las resistencias y mejorar la eficacia de los tratamientos individuales. Con este objetivo, se han diseñado y estudiado dos formulaciones liposomales diferentes, ambas con el mismo fotosensibilizador, pero con diferentes agentes quimioterapéuticos. Se preparan las formulaciones bimodales con ambos agentes en el mismo vehículo además de sus homólogos unimodales, con la incorporación única de uno de los dos agentes. Se han evaluado las características fisicoquímicas, fotofísicas y fotobiológicas de las suspensiones bimodales y unimodales. La localización subcelular demuestra que cada principio activo se localiza en orgánulos diferentes desencadenando rutas de señalización celular diferentes, eludiendo los posibles mecanismos de resistencia. El tratamiento in vitro en células cancerígenas de estos sistemas tiene un efecto prometedor siendo al menos aditivo en comparación con los tratamientos individuales. Finalmente, se ha evaluado el potencial de la vehiculización activa mediante la unión covalente de un anticuerpo monoclonal en la superficie, lo que lleva a resultados ligeramente superiores para una de las dos formulaciones.This thesis reports the study of nanocarriers as drug delivery systems for photosensitisers in photodynamic therapy. Proteins and liposomes are the two nanovehicles of different nature used for this purpose. Beginning with the proteins, the complexes formed between hypericin and the proteins apomyoglobin and β-lactoglobulin have been explored. The physicochemical and photophysical properties have been studied, as also assessing their photoantibacterial activity against Gram-positive and Gram-negative bacteria. In both protein scaffolds the photosensitiser is found mainly in monomeric form, preserving its fluorescence and singlet oxygen photosensitising properties and yielding a stable complex. In the case of β-lactoglobulin, the complex formation has also been tested with the addition of a 20% DMSO as a co-solvent, which improves the photophysical properties but surprisingly, worsens its antimicrobial activity. Both protein complexes are effective against Gram-positive but not against Gram-negative bacteria. Moreover, it has been proved that hypericin, inside the apomyoglobin cavity, can perform STED microscopy through which its localization in bacteria can be monitored. Additionally, the suitability of β-lactoglobulin as a dual carrier for hypericin and acid retinoic has also been exploited. In this last multi-component system, the photophysical properties have been evaluated to confirm the formation and complex stability. Secondly, a nanocarrier for its use in combined therapy has been developed, in which conventional chemotherapeutic drugs are combined with photosensitising agents to overcome resistance and improve the effectiveness of the individual treatments. For this purpose, two different liposome formulations have been designed and studied with a common photosensitiser but different anti tumour drugs. The bimodal formulations with both agents entrapped and their unimodal counterparts, having each drug loaded in separate liposomes, have been evaluated. The physicochemical, photophysical and photobiological properties of bimodal and unimodal suspensions have been studied. The subcellular localization shows different organelle accumulation by each agent, triggering different key signals transduction pathways, eluding the cellular resistance mechanisms. The treatment in vitro of these multi-component liposomes with cancer cells has a promising effect, since at least an additive outcome is observed when compared with the individual treatments. Finally, we have explored the potential of active targeting strategies by covalently linking a monoclonal antibody to the surface, leading to slightly greater outcomes for one of the liposomal formulations

Characterising the Multi-Scale Properties of Flocculated Sediment by X-ray and Focused Ion Beam Nano-Tomography

PhDThe hydrodynamic behaviour of fine suspended aqueous sediments, and stability of the bedforms they create once settled, are governed by the physical properties (e.g., size, shape, porosity and density) of the flocculated particles in suspension (flocs). Consequently, accurate prediction of the transport and fate of sediments and of the nutrients and pollutants they carry depends on our ability to characterise aqueous flocs. Current research primarily focuses on characterising flocs based on their external gross-scale (>1 μm) properties (e.g., gross morphology, size and settling velocity) using in situ techniques such as photography and videography. Whilst these techniques provide valuable information regarding the outward behaviour of flocculated sediment (i.e. transport and settling), difficulties associated with extracting 3D geometries from 2D projections raises concerns regarding their accuracy and key parameters such as density can only be estimated. In addition, they neglect to inform on the internal micro- and nano-scale structure of flocs, responsible for much of their behaviour and development. Transmission electron microscope (TEM) and environmental electron microscope may be used to obtain nano-scale information in, essentially, 2D but there is a large scale gap between this information and the macro-scale of optical techniques. To address this issue this study uses 3D tomographic imaging over a range of spatial scales. Whilst commonly used in materials science and the life sciences, correlative tomography has yet to be applied in the environmental sciences. Threading together 3D Xray micro-computed tomography (X-ray μCT) and focused ion beam nano-tomography (FIBnt) with 2D TEM makes material characterisation from the centimetre to nanometre-scale possible. Here, this correlative imaging strategy is combined with a non-destructive stabilisation procedure and applied to the investigation of flocculated estuarine sediment, enabling the multi length-scale properties of flocs to be accurately described for the first time. This work has demonstrated that delicate aqueous flocs can be successfully stabilised via a resin embedding process and contrasted for both electron microscopy and X-ray tomography imaging. The 3D information obtained can be correlated across all length-scales from nm to mm revealing new information about the structure and morphology of flocs. A new system of characterising floc structure can be defined based on the association of particles and their stability in the structure rather than simply their size. This new model refutes the postulate that floc structures are fractal in nature.Engineering and Physical Sciences Research Council (EPSRC) Queen Mary University London (through the Post Graduate Research Fund) Environment Canad