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Src family kinases (SFKs) are key regulators of cell proliferation, differentiation, and survival. The expression of these non-receptor tyrosine kinases is strongly correlated with cancer development and tumor progression. Thus, this family of proteins serves as an attractive drug target. The activation of SFKs can occur via multiple signaling pathways, yet many of them are poorly understood. Here, we summarize the current knowledge on G protein-coupled receptor (GPCR)- mediated regulation of SFKs, which is of considerable interest because GPCRs are among the most widely used pharmaceutical targets. This type of activation can occur through a direct interaction between the two proteins or be allosterically regulated by arrestins and G proteins. We postulate that a rearrangement of binding motifs within the active conformation of arrestin-3 mediates Src regulation by comparison of available crystal structures. Therefore, we hypothesize a potentially different activation mechanism compared to arrestin-2. Furthermore, we discuss the probable direct regulation of SFK by GPCRs and investigate the intracellular domains of exemplary GPCRs with conserved polyproline binding motifs that might serve as scaffolding domains to allow such a direct interaction. Large intracellular domains in GPCRs are often understudied and, in general, not much is known of their contribution to different signaling pathways. The suggested direct interaction between a GPCR and a SFK could allow for a potential immediate allosteric regulation of SFKs by GPCRs and thereby unravel a novel mechanism of SFK signaling. This overview will help to identify new GPCR–SFK interactions, which could serve to explain biological functions or be used to modulate downstream effectors.

In the past decade, the integration of spatiotemporal constraints into control systems has emerged as a crucial necessity, driven by the demand for enhanced performance, guaranteed safety, and the execution of complex tasks. Spatiotemporal constraints involve criteria that are dependent on both space and time, which can be represented by time-varying constraints in nonlinear control systems. Funnel-based control methods provide computationally tractable and robust feedback control laws to enforce time-varying constraints in uncertain nonlinear systems. This thesis begins by exploring the application of funnel-based control designs to address performance specifications in coordinate-free formation control of multi-agent systems. Moreover, we develop new robust feedback control schemes dealing with coupled spatiotemporal constraints in uncertain nonlinear systems that cannot be directly addressed by conventional funnel-based control methods. In the first part of the thesis, we present a novel coordinate-free formation control scheme for directed leader-follower multi-agent systems, exhibiting almost global convergence to the desired shape. The synthesis of fully decentralized robust controllers for agents is achieved through the application of the Prescribed Performance Control (PPC) method. This method imposes spatiotemporal funnel constraints on each agent's formation errors, ensuring a predefined transient and steady-state performance while maintaining robustness to system uncertainties. The core idea in this work is the utilization of bipolar coordinates to achieve orthogonal (decoupled) formation errors for each follower agent. This approach not only ensures the global convergence to the desired shape but also facilitates the effective application of the PPC method. In the second part of the thesis, first, we introduce a novel approach that extends funnel-based control schemes to deal with a specific class of time-varying hard and soft constraints. In this work, we employ an online Constraint Consistent Funnel (CCF) planning scheme to tackle couplings between hard and soft constraints. By satisfying these CCF constraints, we ensure adherence to hard (safety) constraints, while soft (performance) constraints are met only when they do not conflict with the hard constraints. Subsequently, we directly employ the PPC design method to craft a robust, low-complexity control law, ensuring that the system's outputs consistently stay within the online planned CCF constraints. In subsequent work, we tackle the challenge of satisfying a generalized class of potentially coupled time-varying output constraints. We show that addressing multiple constraints effectively boils down to formulating a single consolidating constraint. Ensuring the fulfillment of this consolidating constraint guarantees both convergence to and invariance of the time-varying output-constrained set within a user-defined finite time. Building on the PPC design method, we introduce a novel, robust low-complexity feedback control framework to handle this issue in uncertain high-order MIMO nonlinear control systems. Additionally, we present a mechanism for online modification of the consolidating constraint to secure a least-violating solution when constraint infeasibilities occur for an unknown time interval. / Under det senaste decenniet har integrationen av bivillkor i tid och rum för reglersystem framstått som en nödvändighet, driven av efterfrågan på förbättrad prestanda, garanterad säkerhet och utförandet av komplexa uppgifter. Bivillkor i tid och rum för icke-linjära reglersystem kan representeras av tidsvarierande bivillkor. Trattbaserade reglermetoder ("funnel-based control") tillhandahåller beräkningsmässigt hanterbara och robusta återkopplingslagar för att garantera tidsvarier-ande bivillkor i osäkra icke-linjära system. Denna avhandling börjar med att utforska tillämpningen av trattbaserade kontrollmetoder för att hantera prestanda-specifikationer i koordinatfri formationskontroll av multiagentsystem. Dessutom utvecklar vi nya robusta återkopplingslagar som hanterar kopplade bivillkor i tid och rum för osäkra icke-linjära system som inte direkt kan hanteras av konventionella trattbaserade kontrollmetoder. I den första delen av avhandlingen presenterar vi en ny koordinatfri formationskontrollmetod för riktade ledare-följare multiagentsystem, vilken uppvisar nästan global konvergens till den önskade formen. Syntesen av helt decentraliserade robusta regulatorer för agenter uppnås genom tillämpning av Prescribed Performance Control (PPC)-metoden. Denna metod lägger på trattbivillkor i tid och rum på varje agents formationsfel och säkerställer en fördefinierad transient och stationär prestanda samtidigt som robusthet mot systemosäkerheter bibehålls. Kärnan i detta arbete är användningen av bipolära koordinater för att uppnå ortogonala (frikopplade) formationsfel för varje följande agent. Detta tillvägagångssätt säkerställer inte bara global konvergens till den önskade formen utan underlättar också en effektiva tillämpning av PPC-metoden. I den andra delen av avhandlingen introducerar vi först ett nytt tillvägagångssätt som utökar trattbaserade kontrollmetoder för att hantera en specifik klass av tidsvar-ierande hårda och mjuka bivillkor. I detta arbete använder vi en online Constraint Consistent Funnel (CCF)-planeringsmetod för att tackla sammankopplingar mellan hårda och mjuka bivillkor. Genom att uppfylla dessa CCF-bivillkor säkerställer vi efterlevnad av hårda (säkerhets-) bivillkor, medan mjuka (prestanda-) bivillkor uppfylls endast när de inte strider mot de hårda bivillkoren. Därefter tillämpar vi direkt PPC-designmetoden för att utforma en robust reglerlag med låg komplexitet som säkerställer att systemets utsignal konsekvent håller sig inom de online planerade CCF-bivillkoren. Därefter hanterar vi utmaningen med att uppfylla en generaliserad klass av potentiellt kopplade tidsvarierande utsignals-bivillkor. Vi visar att effektiv hantering av flera bivillkor i grund och botten handlar om att formulera ett sammanfattande bivillkor. Uppfyllandet av detta sammanfattande bivillkor garanterar både konvergens till och invarians av den tidsvarierande mängden som uppfyller utsignalsbivillkoren, inom en användardefinierad begränsad tid. Baserat på PPC-designmetoden introducerar vi en ny, robust återkopplingsregulatorstruktur för att hantera detta problem i osäkra högordnings MIMO icke-linjära reglersystem. Dessutom presenterar vi en mekanism för online-modifiering av det sammanfattande bivillkoret för att säkra en lösning med minsta möjliga kränkning då bivillkoren blir omöjliga att uppfylla under en okänd tidsperiod. / <p>QC 20231229</p>

<p>The thesis intends to explain in full detail the developed techniques and approaches for the modeling, design, and sensitivity analysis of nano-plasmoic structures. However, some examples are included for audiences of general microwave background. Although the thesis is mainly focused on simulation-based techniques, analytical and convex optimization approaches are also demonstrated. The thesis is organized into two parts. Part 1 includes Chapters 2-4, which cover the simulation-based modeling and sensitivity analysis approaches and their applications. Part 2 includes Chapters 5 and 6, which cover the analytical optimization approaches.</p> / <p>We propose novel techniques for modeling, adjoint sensitivity analysis, and optimization of photonic and nano-plasmonic devices. The scope of our work is generalized to cover microwave, terahertz and optical regimes. It contains original approaches developed for different categories of materials including dispersive and plasmonic materials. Artificial materials (metamaterials) are also investigated and modeled. The modeling technique exploits the time-domain transmission line modeling (TD-TLM) technique. Generalized adjoint variable method (AVM) techniques are developed for sensitivity analysis of the modeled devices. Although TLM-based, they can be generalized to other time-domain modeling techniques like finite difference time-domain method (FDTD) and time-domain finite element method (FEM).</p> <p>We propose to extend the application of TLM-based AVM to photonic devices. We develop memory efficient approaches that overcome the limitation of excessive memory requirement in TLM-based AVM. A memory reduction of 90% can be achieved without loss of accuracy and at a more efficient calculation procedure. The developed technique is applied to slot waveguide Bragg gratings and a challenging dielectric resonator antenna problem.</p> <p>We also introduce a novel sensitivity analysis approach for materials with dispersive constitutive parameters. To our knowledge, this is the first wide-band AVM approach that takes into consideration the dependence of material properties on the frequency. The approach can be utilized for design optimization of innovative nano-plasmonic structures. The design of engineered metamaterial is systematic and efficient. Beside working with engineered new designs, dispersive AVM can be utilized in bio-imaging applications. The sensitivity of the objective function with respect to dispersive material properties enables the exploitation of parameter and gradient based optimization for imaging in the terahertz and optical regimes. Material resonance interaction can be easily investigated by the provided sensitivity information.</p> <p>In addition to the developed techniques for simulation-based optimization, several analytical optimization algorithms are proposed to foster the parameter extraction and design optimization in terahertz and optical regimes. In terahertz time-domain spectroscopy, we have developed an efficient parameter based approach that utilizes the pre-known information about the material. The algorithm allows for the estimation of the optical properties of sample materials of unknown thicknesses. The approach has been developed based on physical analytical dispersive models. It has been applied with the Debye, Lorentz, Cole-Cole, and Drude model.</p> <p>Furthermore, we propose various algorithms for design optimization of coupled resonators. The proposed algorithms are utilized to transform a highly non-linear optimization problem into a linear one. They exploit an approximate transfer function of the coupled resonators that avoids negligible multiple reflections among them. The algorithms are successful for the optimization of very large-scale coupled microcavities (150 coupled ring resonators).</p> / Doctor of Philosophy (PhD)

Syftet med fallstudien var att undersöka möjligheterna och nyttan med att implementera en höjdmodell med högre upplösning i SMHI:s översvämningsmodellering som tillämpar den hydrauliska modellen LISFLOOD-FP. SMHI utfärdar översvämningsvarningar och det är därför av vikt att översvämningsmodelleringen håller hög kvalitet. Samtidigt kräver modelleringen tid och resurser från Nationellt Superdatorcentrum i Linköping, NSC. Därför vägdes de potentiella fördelarna med högre upplösning mot förlängd körtid. Fallstudien bestod av två delar där en höjdmodell på två meters upplösning i xy-planet implementerades och jämfördes med den i dagsläget uppställda modellen på fem meters upplösning. Detta gjordes genom att återskapa översvämningstillfällen med dess flöden från S-HYPE och mätningar. I studiens första del hämtades satellitdata från Copernicus från två tidigare översvämningstillfällen för validering av över-svämningsmodelleringen. De tidigare översvämningstillfällena var dels i Emån i Småland år 2012 och dels i Västerdalälven i Dalarna år 2018. Ett index för passning beräknades mellan översvämningskartorna producerade med två respektive fem meters upplösning gentemot satellitbilderna för att kvantifiera överlappande ytor. Därtill beräknades vattendragens lutning för att undersöka om det fanns indikationer på något samband med förändring i index med ökad upplösning på höjdmodellen. Studiens andra del bestod i att undersöka hur höjdmodellens upplösning påverkar vattnets spridning kring översvämningsvallar i modellen. I undersökningen återskapades ett översvämningstillfälle från 2020 i Helige å i Småland. Ett antal delavrinningsområden visade sig instabila för den högre upplösta höjdmodellen och kunde därför endast simuleras med lägre flöden. Erhållna resultat visade dock på att översvämningskarteringen förbättrades med upplösningen två meter vid jämförelse med data från Copernicus. Körtiden ökade dock med över 12 gånger vid simulering av högre upplösning. Vidare visades tröskeleffekter i studiens resultat, då översvämnings-vallen stoppade vattnet i den högre upplösta höjdmodellen men inte i den med lägre upplösning. På grund av stabilitetsproblemet och studiens begränsade omfattning, kunde slutsats inte dras om huruvida SMHI bör implementera en höjdmodell med två meters upplösning i systemet för översvämningsvarningar. Däremot kunde konstateras att stabiliteten i modellen måste öka för att det ska vara möjligt. Slutligen drogs slutsatsen att det förekommer tröskeleffekter mellan de två höjdmodellerna och att prestandan ökar generellt för den högre upplösningen när det kommer till precisionen i översvämningsmodelleringen. / The purpose of this case study was to examine the possibilities and advantages of implementing a DEM with higher resolution in inundation modelling at SMHI, the Swedish Meteorological and Hydrological Institute, which uses the hydraulic model LISFLOOD-FP. The institute issues flood warnings and therefore it is of high importance that the innundation modelling gives adequate results. On the other hand, running the models at a higher spatial resolution takes more time and resources. Therefore, potentially improved modelling results were discussed in a context of prolonged runtime. The case study consisted of two parts where a Digital Elevation Model, DEM of two meter resolution was implemented and compared to the five meter DEM that is currently in use. This was done by recreating previous flooding events by using discharge data from S-HYPE. In the first part, satellite data from Copernicus from two previous flooding events in Sweden were used for model validation in comparison with the results from inundation models of SMHI for the different DEM:s. An index was calculated to quantify the overlapping inundation areas. The events were at the river Emån in 2012 and at Västerdalälven in 2018. Moreover, the slope of the rivers within each study area was calculated to investigate correlation between improved flood modelling results for higher DEM resolution and slope of the rivers. The second part of the study investigated flood embankments for the two different DEM:s around Helige å river. A flooding event which took place in 2020 was recreated and the water flow around the built embankments was compared for the two resolutions.  Running the models, it turned out that simulations of several subcatchment areas were unstable with the two meter DEM, and could only be run with lower flow. The obtained results, however, revealed an improved inundation modelling for the DEM with a resolution of 2 m for all study areas in comparison to the data from Copernicus; however the runtime was increased by over 12 times. Moreover, the results also showed threshold effects, where the flooding was impeded by the flooding embankment with the two meter DEM but not at the lower resolution. Due to the stability issue and the limited scope of this study, it cannot be concluded whether SMHI should implement the two meter DEM in their flood warnings system. However, it was concluded that the stability has to be increased to make it feasible. It was also concluded that there are threshold effects between the two DEM:s and that the performance seems to increase overall for the higher resolution when it comes to precision of the modelling.