5,353 research outputs found
Spatial adaptive settlement systems in archaeology. Modelling long-term settlement formation from spatial micro interactions
Despite research history spanning more than a century, settlement patterns still hold a promise to contribute to the theories of large-scale processes in human history. Mostly they have been presented as passive imprints of past human activities and spatial interactions they shape have not been studied as the driving force of historical processes. While archaeological knowledge has been used to construct geographical theories of evolution of settlement there still exist gaps in this knowledge. Currently no theoretical framework has been adopted to explore them as spatial systems emerging from micro-choices of small population units.
The goal of this thesis is to propose a conceptual model of adaptive settlement systems based on complex adaptive systems framework. The model frames settlement system formation processes as an adaptive system containing spatial features, information flows, decision making population units (agents) and forming cross scale feedback loops between location choices of individuals and space modified by their aggregated choices. The goal of the model is to find new ways of interpretation of archaeological locational data as well as closer theoretical integration of micro-level choices and meso-level settlement structures.
The thesis is divided into five chapters, the first chapter is dedicated to conceptualisation of the general model based on existing literature and shows that settlement systems are inherently complex adaptive systems and therefore require tools of complexity science for causal explanations. The following chapters explore both empirical and theoretical simulated settlement patterns based dedicated to studying selected information flows and feedbacks in the context of the whole system.
Second and third chapters explore the case study of the Stone Age settlement in Estonia comparing residential location choice principles of different periods. In chapter 2 the relation between environmental conditions and residential choice is explored statistically. The results confirm that the relation is significant but varies between different archaeological phenomena. In the third chapter hunter-fisher-gatherer and early agrarian Corded Ware settlement systems were compared spatially using inductive models. The results indicated a large difference in their perception of landscape regarding suitability for habitation. It led to conclusions that early agrarian land use significantly extended land use potential and provided a competitive spatial benefit. In addition to spatial differences, model performance was compared and the difference was discussed in the context of proposed adaptive settlement system model. Last two chapters present theoretical agent-based simulation experiments intended to study effects discussed in relation to environmental model performance and environmental determinism in general. In the fourth chapter the central place foragingmodel was embedded in the proposed model and resource depletion, as an environmental modification mechanism, was explored. The study excluded the possibility that mobility itself would lead to modelling effects discussed in the previous chapter.
The purpose of the last chapter is the disentanglement of the complex relations between social versus human-environment interactions. The study exposed non-linear spatial effects expected population density can have on the system and the general robustness of environmental inductive models in archaeology to randomness and social effect. The model indicates that social interactions between individuals lead to formation of a group agency which is determined by the environment even if individual cognitions consider the environment insignificant. It also indicates that spatial configuration of the environment has a certain influence towards population clustering therefore providing a potential pathway to population aggregation. Those empirical and theoretical results showed the new insights provided by the complex adaptive systems framework. Some of the results, including the explanation of empirical results, required the conceptual model to provide a framework of interpretation
Beam scanning by liquid-crystal biasing in a modified SIW structure
A fixed-frequency beam-scanning 1D antenna based on Liquid Crystals (LCs) is designed for application in 2D scanning with lateral alignment. The 2D array environment imposes full decoupling of adjacent 1D antennas, which often conflicts with the LC requirement of DC biasing: the proposed design accommodates both. The LC medium is placed inside a Substrate Integrated Waveguide (SIW) modified to work as a Groove Gap Waveguide, with radiating slots etched on the upper broad wall, that radiates as a Leaky-Wave Antenna (LWA). This allows effective application of the DC bias voltage needed for tuning the LCs. At the same time, the RF field remains laterally confined, enabling the possibility to lay several antennas in parallel and achieve 2D beam scanning. The design is validated by simulation employing the actual properties of a commercial LC medium
A survey on reconfigurable intelligent surfaces: wireless communication perspective
Using reconfigurable intelligent surfaces (RISs) to improve the coverage and the data rate of future wireless networks is a viable option. These surfaces are constituted of a significant number of passive and nearly passive components that interact with incident signals in a smart way, such as by reflecting them, to increase the wireless system's performance as a result of which the notion of a smart radio environment comes to fruition. In this survey, a study review of RIS-assisted wireless communication is supplied starting with the principles of RIS which include the hardware architecture, the control mechanisms, and the discussions of previously held views about the channel model and pathloss; then the performance analysis considering different performance parameters, analytical approaches and metrics are presented to describe the RIS-assisted wireless network performance improvements. Despite its enormous promise, RIS confronts new hurdles in integrating into wireless networks efficiently due to its passive nature. Consequently, the channel estimation for, both full and nearly passive RIS and the RIS deployments are compared under various wireless communication models and for single and multi-users. Lastly, the challenges and potential future study areas for the RIS aided wireless communication systems are proposed
Rational development of stabilized cyclic disulfide redox probes and bioreductive prodrugs to target dithiol oxidoreductases
Countless biological processes allow cells to develop, survive, and proliferate. Among these, tightly balanced regulatory enzymatic pathways that can respond rapidly to external impacts maintain dynamic physiological homeostasis. More specifically, redox homeostasis broadly affects cellular metabolism and proliferation, with major contributions by thiol/disulfide oxidoreductase systems, in particular, the Thioredoxin Reductase Thioredoxin (TrxR/Trx) and the Glutathione Reductase-Glutathione-Glutaredoxin (GR/GSH/Grx) systems.
These cascades drive vital cellular functions in many ways through signaling, regulating other proteins' activity by redox switches, and by stoichiometric reductant transfers in metabolism and antioxidant systems. Increasing evidence argues that there is a persistent alteration of the redox environment in certain pathological states, such as cancer, that heavily involve the Trx system: upregulation and/or overactivity of the Trx system may support or drive cancer progression, making both TrxR and Trx promising targets for anti-cancer drug development.
Understanding the biochemical mechanisms and connections between certain redox cascades requires research tools that interact with them. The state-of-the-art genetic tools are mostly ratiometric reporters that measure reduced:oxidized ratios of selected redox pairs or the general thiol pool. However, the precise cellular roles of the central oxidoreductase systems, including TrxR and Trx, remain inaccessible due to the lack of probes to selectively measure turnover by either of these proteins. However, such probes would allow measuring their effective reductive activity apart from expression levels in native systems, including in cells, animals, or patient samples. They are also of high interest to identify chemical inhibitors for TrxR/Trx in cells and to validate their potential use as anti-cancer agents (to date, there is no selective cellular Trx inhibitor, and most known TrxR inhibitors were not comprehensively evaluated considering selectivity and potential off-targets). However, small molecule redox imaging tools are underdeveloped: their protein specificity, spectral properties, and applicability remain poorly precedented.
This work aimed to address this opportunity gap and develop novel, small molecule diagnostic and therapeutic tools to selectively target the Trx system based on a modular trigger cargo design: artificial cyclic disulfide substrates (trigger) for oxidoreductases are tethered to molecular agents (cargo) such that the cargo’s activity is masked and is re-established only through reduction by a target protein.
The rational design of these novel reduction sensors to target the cell's strongest disulfide-reducing enzymes was driven by the following principles: (i) cyclic disulfide triggers with stabilized ring systems were used to gain low reduction potentials that should resist reduction except by the strongest cellular reductases, such as Trx; and (ii) the cyclic topology also offers the potential for kinetic reversibility that should select for dithiol-type redox proteins over the cellular monothiol background. Creating imaging agents based on such two-component designs to selectively measure redox protein activity in native cells required to combine the correct trigger reducibility, probe activation kinetics, and imaging modalities and to consider the overall molecular architecture.
The major prior art in this field has applied cyclic 5-membered disulfides (1,2 dithiolanes) as substrates for TrxR in a similar way to create such tools. However, this motif was described elsewhere as thermodynamically instable and was due to widely used for dynamic covalent cascade reactions. By comparing a novel 1,2 dithiolane-based probe to the state-of-the-art probes, including commercial TrxR sensors, by screening a conclusive assay panel of cellular TrxR modulations, I clarified that 1,2 dithiolanes are not selective substrates for TrxR in biological settings (Nat Commun 2022).
Instead, aiming for more stable ring systems and thus more robust redox probes, during this work, I developed bicyclic 6 membered disulfides (piperidine fused 1,2 dithianes) with remarkably low reduction potentials. I showed that molecular probes using them as reduction sensors can be mostly processed by thioredoxins while being stable against reduction by GSH. The thermodynamically stabilized decalin like topology of the cis-annelated 1,2 dithianes requires particularly strong reductants to be cleaved. They also select for dithiol type redox proteins, like Trx, based on kinetic reversibility and offer fast cyclization due to the preorganization by annelation (JACS 2021).
This work further expanded the system’s modularity with structural cores based on piperazine-fused 1,2 dithianes with the two amines allowing independent derivatization. Diagnostic tools using them as reduction sensors proved equally robust but with highly improved activation kinetics and were thus cellularly activated. Cellular studies evolved that they are substrates for both Trxs and their protein cousins Grxs, so measuring the cellular dithiol protein pool rather than solely Trx activity (preprint 2023).
Finally, a trigger based on a slightly adapted reduction sensor, a desymmetrized 1,2 thiaselenane, was designed for selective reduction by TrxR’s selenol/thiol active site, then combined with a precipitating large Stokes’ shift fluorophore and a solubilizing group, to evolve the first selective probe RX1 to measure cellular TrxR activity, which even allowed high throughput inhibitor screening (Chem 2022).
The central principle of this work was further advanced to therapeutic prodrugs based on the duocarmycin cargo (CBI) with tunable potency (JACS Au 2022) that can be used to create off-to-on therapeutic prodrugs. Such CBI prodrugs employing stabilized 1,2 dichalcogenide triggers proved to be cytotoxins that depend on Trx system activity in cells. They could further be exploited for cell-line dependent reductase activity profiling by screening their redox activation indices, the reduction-dependent part of total prodrug activation, in 177 cell lines. Beyond that, these prodrugs were well-tolerated in animals and showed anti-cancer efficacy in vivo in two distinct mouse tumor models (preprint 2022).
Taken together, I introduced unique monothiol-resistant reducible motifs to target the cellular Trx system with chemocompatible units for each for TrxR and Trx/Grx, where the cyclic nature of the dichalcogenides avoids activation by GSH. By using them with distinct molecular cargos, I developed novel selective fluorescent reporter probes; and introduced a new class of bioreductive therapeutic constructs based on a common modular design. These were either applied to selectively measure cellular reductase activity or to deliver cytotoxic anti cancer agents in vivo. Ongoing work aims to differentiate between the two major redox effector proteins Trx and Grx, requiring additional layers of selectivity that may be addressed by tuned molecular recognition. The flexible use of various molecular cargos allows harnessing the same cellular redox machinery by either probes or prodrugs. This allows predictive conclusions from diagnostics to be directly translated into therapy and offers great potential for future adaptation to other enzyme classes and therapeutic venues.Die zelluläre Redox-Homöostase hängt von Thiol/Disulfid-Oxidoreduktasen ab, die den Stoffwechsel, die Proliferation und die antioxidative Antwort von Zellen beeinflussen. Die wichtigsten Netzwerke sind die Thioredoxin Reduktase-Thioredoxin (TrxR/Trx) und Glutathion Reduktase-Glutathion-Glutaredoxin (GR/GSH/Grx) Systeme, die über Redox-Schalter in Substratproteinen lebenswichtige zelluläre Funktionen steuern und so an der Redox-Regulation und -Signalübertragung beteiligt sind. Persistente Veränderungen des Redoxmilieus in pathologischen Zuständen, wie z. B. bei Krebs, sind in hohem Maße mit dem Trx-System verbunden. Eine Hochregulierung und/oder Überaktivität des Trx-Systems, die bei vielen Krebsarten auftreten, unterstützt zudem das Fortschreiten des Krebswachstums, was TrxR/Trx zu vielversprechenden Zielproteinen für die Entwicklung neuer Krebsmedikamente macht.
Um die biochemischen Prozesse dahinter zu erforschen, sind spezielle Techniken zur Visualisierung und Messung enzymatischer Aktivität nötig. Die hierzu geeigneten, meist genetischen Sensoren messen ratiometrisch das Verhältnis reduzierter/oxidierter Spezies in zellulärem Umfeld oder spezifisch ausgewählte Redoxpaare. Die weitere Erforschung der exakten Funktion von TrxR/Trx und deren Substrate ist jedoch durch mangelnde Nachweismethoden limitiert. Diese sind außerdem zur Validierung chemischer Hemmstoffe für TrxR/Trx in Zellen und deren potenziellen Verwendung als Krebsmittel von großem Interesse. Bislang gibt es keinen selektiven zellulären Trx-Inhibitor und potenzielle Off-Target-Effekte der bekannten TrxR-Inhibitoren wurden nicht abschließend bewertet.
Ziel dieser Arbeit ist die Entwicklung niedermolekularer, diagnostischer und therapeutischer Werkzeuge, die selektiv auf das Trx-System abzielen und auf einem modularen Trigger-Cargo Design basieren. Hierzu werden zyklische Disulfid-Substrate (Trigger) für Oxidoreduktasen so mit molekularen Wirkstoffen (Cargo) verknüpft, dass dabei die Wirkstoffaktivität maskiert, und erst nach Reduktion durch ein Zielprotein wiederhergestellt wird. Diese neuartigen, synthetischen Reduktionssensoren basieren auf den folgenden Grundprinzipien: (i) Zyklische Disulfide sind thermodynamisch stabilisiert und können nur durch die stärksten Reduktasen gespalten werden; und (ii) die zyklische Topologie ermöglicht die kinetische Reversibilität der zwei Thiol-Disulfid-Austauschreaktionen, die eine erste Reaktion mit Monothiolen, wie z. B. GSH, sofort umkehrt und so eine vollständige Reduktion verhindert.
Die meisten früheren Arbeiten auf diesem Gebiet verwendeten ein zyklisches, fünfgliedriges Disulfid (1,2 Dithiolan) als Substrat für TrxR. Das gleiche Strukturmotiv wurde jedoch an anderer Stelle als thermodynamisch instabil beschrieben und aufgrund dieser Eigenschaft explizit für dynamische Kaskadenreaktionen verwendet. Deshalb vergleicht diese Arbeit zu Beginn einen neuen 1,2 Dithiolan basierten fluorogenen Indikator mit bestehenden, z. T. kommerziellen, Redox Sonden für TrxR in einer Reihe von Zellkultur-Experimenten unter Modulation der zellulären TrxR Aktivität und stellt so einen Widerspruch in der Literatur klar: 1,2 Dithiolane eignen sich nicht als selektive Substrate für TrxR, da sie labil sowohl gegen die Reduktion durch andere Redoxproteine, als auch gegen den Monothiol Hintergrund in Zellen sind (Nat. Commun. 2022).
Als alternatives Strukturmotiv wird in dieser Arbeit ein bizyklisches sechsgliedriges Disulfid (anneliertes 1,2 Dithian) etabliert. Durch sein niedriges Reduktionspotenzial, also seine hohe Resistenz gegen Reduktion, werden molekulare Sonden basierend auf diesem 1,2 Dithian als Reduktionssensor fast ausschließlich von Trx aktiviert, nicht aber von TrxR oder GSH (JACS 2021). Dieses Kernmotiv bestimmt dabei die Reduzierbarkeit, und damit die Enzymspezifität, durch seine zyklische Natur und die Annelierung, auch unter Verwendung unterschiedlicher Farb-/Wirkstoffe. Auf dieser Grundlage konnte die molekulare Struktur durch einen weiteren Modifikationspunkt für die flexible Verwendung weiterer funktioneller Einheiten ergänzt werden. Obwohl zelluläre Studien ergaben, dass diese neuartigen 1,2 Dithian Einheiten in Zellen sowohl Trx als auch das strukturell verwandte Grx adressieren, sind die daraus resultierenden diagnostischen Moleküle wertvoll, um den katalytischen Umsatz zellulärer Dithiol-Reduktasen, der sogenannten Trx Superfamilie, selektiv anzuzeigen (Preprint 2023).
Begünstigt durch das modulare Moleküldesign stellt diese Arbeit zudem das erste Reportersystem RX1 zum selektiven Nachweis der TrxR-Aktivität in Zellen vor. Es basiert auf der Verwendung eines zyklischen, unsymmetrischen Selenenylsulfid-Sensors (1,2 Thiaselenan), der selektiv von dem einzigartigen Selenolat der TrxR angegriffen wird, und dadurch letztlich nur von TrxR reduziert werden kann. RX1 eignete sich zudem für eine Hochdurchsatz-Validierung bestehender TrxR Inhibitoren und unterstreicht dadurch den kommerziellen Nutzen derartiger Diagnostika (Chem 2022).
Das zentrale Trigger-Cargo Konzept dieser Arbeit wurde für therapeutische Zwecke weiterentwickelt und nutzt dabei den einzigartigen Wirkmechanismus der Duocarmycin-Naturstoffklasse (CBI) (JACS Au 2022) zur Entwicklung reduktiv aktivierbarer Therapeutika. CBI Prodrugs basierend auf stabilisierten Redox-Schaltern (1,2 Dithiane für Trx; 1,2 Thiaselenan für TrxR) reagierten signifikant auf TrxR-Modulation in Zellen. Sie wurden darüber hinaus durch das Referenzieren ihrer Aktivität gegenüber nicht-reduzierbaren Kontrollmoleküle für die Erstellung zelllinienabhängiger Profile der Reduktaseaktivität in 177 Zelllinien genutzt. Schließlich waren diese neuen Krebsmittel im Tiermodell gut verträglich und zeigten in zwei verschiedenen Mausmodellen eine krebshemmende Wirkung (Preprint 2022b).
Zusammenfassend präsentiert diese Dissertation monothiol-resistente reduzierbare Trigger-Einheiten für das zelluläre Trx-System zur Entwicklung neuartiger, selektiver Reporter-Sonden, sowie eine neue Klasse reduktiv aktivierbarer Krebsmittel auf Basis eines adaptierbaren Trigger-Cargo Designs. Diese fanden entweder zur selektiven Messung zellulärer Proteinaktivität oder zum Einsatz als Antikrebsmittel Verwendung. Es wurden chemokompatible Motive sowohl für TrxR als auch für Trx/Grx identifiziert, wobei deren zyklische Natur eine Aktivierung durch GSH verhindert. Eine weitere Differenzierung zwischen den beiden Redox-Proteinen Trx und Grx und anderen Proteinen der Trx-Superfamilie erfordert eine zusätzliche Ebene der Selektierung, z. B. durch molekulare Erkennung, und ist Gegenstand laufender Arbeiten.
Die flexible Verwendung verschiedener molekularer Wirkstoffe ermöglicht dabei die „Pipeline-Entwicklung“ von Diagnostika und Therapeutika, die von der zellulären Redox-Maschinerie analog umgesetzt werden, und dadurch Schlussfolgerungen aus der Diagnostik direkt auf eine Therapie übertragbar machen. Dies birgt großes Potenzial für künftige Entwicklungen bei einer potenziellen Übertragung des modularen Konzepts auf andere Enzymklassen und therapeutische Einsatzgebiete
Tradition and Innovation in Construction Project Management
This book is a reprint of the Special Issue 'Tradition and Innovation in Construction Project Management' that was published in the journal Buildings
Modelling of tuna around fish aggregating devices: The importance of ocean flow and prey
Catch and distribution of tuna in the ocean are typically investigated with ocean basin-scale models. Due to their large scale, such models must greatly simplify tuna behaviour occurring at a scale below 100 km, despite interactions at this level potentially being important to both catch and distribution of tuna. For example, the associative behaviour of tuna with man-made floating objects, that are deployed by fishers to improve their catch rates (Fish Aggregating Devices; FADs), are usually ignored or simplified. Here we present a model that can be used to investigate the influence of tuna dynamics below the 100 km scale on larger scales. It is an Individual-Based Model (IBM) of a hypothetical, tuna-like species, that includes their interactions with each other, free-floating FADs and prey. In this IBM, both tuna and FADs are represented by Lagrangian particles that are advected by an ocean flow field, with tuna also exhibiting active swimming based on internal states such as stomach fullness. We apply the IBM in multiple configurations of idealized flow and prey fields, alongside differing interaction strengths between agents. When tuna swimming behaviour is influenced equally by prey and FADs, we find that the model simulations compare well with observations at the km scale. For instance, compared to observations, tuna particles have a similar stomach fullness when associated or non-associated to a FAD, tuna colonize at similar timescales at FADs after their deployment and tuna particles exhibit similar variations in continuous residence times. However, we find large differences in emergent dynamics such as residence and catch among different flow configurations, because the flow determines the time scale at which tuna encounter FADs. These findings are discussed in the context of directing future research, and an improved interpretation of tuna catch and other data for the sustainable management of these economically important species
Complexity Science in Human Change
This reprint encompasses fourteen contributions that offer avenues towards a better understanding of complex systems in human behavior. The phenomena studied here are generally pattern formation processes that originate in social interaction and psychotherapy. Several accounts are also given of the coordination in body movements and in physiological, neuronal and linguistic processes. A common denominator of such pattern formation is that complexity and entropy of the respective systems become reduced spontaneously, which is the hallmark of self-organization. The various methodological approaches of how to model such processes are presented in some detail. Results from the various methods are systematically compared and discussed. Among these approaches are algorithms for the quantification of synchrony by cross-correlational statistics, surrogate control procedures, recurrence mapping and network models.This volume offers an informative and sophisticated resource for scholars of human change, and as well for students at advanced levels, from graduate to post-doctoral. The reprint is multidisciplinary in nature, binding together the fields of medicine, psychology, physics, and neuroscience
Ciguatoxins
Ciguatoxins (CTXs), which are responsible for Ciguatera fish poisoning (CFP), are liposoluble toxins produced by microalgae of the genera Gambierdiscus and Fukuyoa. This book presents 18 scientific papers that offer new information and scientific evidence on: (i) CTX occurrence in aquatic environments, with an emphasis on edible aquatic organisms; (ii) analysis methods for the determination of CTXs; (iii) advances in research on CTX-producing organisms; (iv) environmental factors involved in the presence of CTXs; and (v) the assessment of public health risks related to the presence of CTXs, as well as risk management and mitigation strategies
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