4,071 research outputs found

    Strategies to prevent Type 2 Diabetes in the postnatal period, in women with history of Gestational Diabetes Exploring different research methodologies based on dietary and pharmacological interventions

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    Aim and objectives The aim of this thesis is to investigate methods to prevent the progression to type 2 diabetes in the immediate postnatal period, in women diagnosed with gestational diabetes mellitus (GDM). The objectives of this thesis are to explore the views of pregnant women diagnosed with gestational diabetes and healthcare professionals, with regards to the use of an app in the postnatal period which will provide information about diet for type 2 diabetes prevention. The development of a protocol for a single-arm feasibility study on a Mediterranean-style diet for the prevention of type 2 diabetes in the postnatal period. To pilot the trial design and study processes and assess the feasibility of a large-scale trial on the effectiveness of a Mediterranean-style diet in postnatal period for type 2 diabetes prevention. To examine the acceptability of a Mediterranean-style diet for type 2 diabetes prevention in women taking part in a feasibility study and explore the opinions of women and healthcare professionals on trial processes. To develop a protocol for a pilot trial on metformin for the prevention of type 2 diabetes in the postnatal period. Pilot the trial design and study processes and assess the feasibility of a large-scale trial on the effectiveness of metformin in postnatal period for type 2 diabetes prevention. Methods The methods employed in this thesis include a cross-sectional survey, a single arm mixed method feasibility study with qualitative evaluation (which included the use of an app) and a mixed method randomised controlled double blind feasibility study with the use of metformin or placebo. Results Survey The survey demonstrated that app usage is part of everyday life, with 84% (85/101) of pregnant GDM women and 82% (71/87) of healthcare professionals using apps daily. All pregnant women who participated in this survey had a device by which they could access apps (100%, 101/101) and 95% (179/188) of the participants had a smartphone. The participants agreed that an app which provides dietary information in the postnatal period for diabetes prevention would be welcomed by postnatal women with GDM history. Single arm feasibility study on a Mediterranean-style diet for the prevention of T2D in the postnatal period (MERIT) A total of 69% (83/121) of eligible multi-ethnic women agreed to participate and 67% (56/83) of those initially recruited commenced the intervention. The last visit (12 months postnatally) was completed by 73.2% (41/56) of participants. A higher number of participants completed visit 2 (which is at 6 months postnatally) 80.4% (45/56), but this visit was completed remotely due to COVID-19 pandemic lockdown restrictions, whereas visit 3 was completed face-to-face. Participants had high engagement with the coach, both face-to-face and via phone-calls or text messages. Adherence based on the ESTEEM diet questionnaire was high at the end of the study. There was a trend of reduction of total dysglycaemia, and the participants weight was also reduced by 1.3kg, from visit 1 (6 to 13 weeks) to visit 3 (12 months postnatally). Clinical effectiveness discussion is exploratory due to the small sample size. The intervention and trial processes were acceptable to women and healthcare professionals, adherence was high when women had a supportive environment, provided by their family and the health coach. The group chat function was not successful in this study. Randomised double-blind placebo-controlled pilot trial on metformin for the prevention of T2D in the postnatal period (OMAhA) A total of 57.9% (175/302) of eligible multi-ethnic women agreed to take part in the study, out of those 82.3% (144/175) were randomised to receive metformin or placebo. The attendance rates for visits 2 (6 months) and 3 (12 months) were similar, with 54.6% (71/130) and 55.7 (64/115) attending each visit respectively. Due to the COVID-19 pandemic visit 3 was completed over the phone for 21.7% (39/115) of the participants which led to limited blood samples collection. Total dysglycaemia reduction was evident in the metformin group (18.3%) compared to the placebo group (24.7%) but this discussion is exploratory, and the study is not powered to measure effectiveness. The metformin group maintained their weight throughout the study, whereas the placebo group gained 400g. Adherence was 54.1% (participants who took at least 75% of the recommended dosage). The study was acceptable to both women and healthcare professionals, but the element of peer-support should be included in future studies. Conclusion It is feasible and acceptable to recruit women in the postnatal period in studies that are focused on diabetes prevention and introduce dietary or pharmacological interventions. The MERIT protocol will have to be revised to address how follow-up rates can be improved. The OMAhA protocol will also be revised to target improvement in adherence and follow-up rates. The COVID-19 pandemic lockdown restrictions and staffing issues have impacted data collection of both studies. More research is needed in this population with larger sample sizes to be able to prove efficacy. The strongest motivator that affects adherence and retention is the woman’s perception of her own risk of developing diabetes. Future studies should include the element of peer support and an education session about the risk of Type 2 Diabetes in postnatal period

    Communicating a Pandemic

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    This edited volume compares experiences of how the Covid-19 pandemic was communicated in the Nordic countries – Denmark, Finland, Iceland, Norway, and Sweden. The Nordic countries are often discussed in terms of similarities concerning an extensive welfare system, economic policies, media systems, and high levels of trust in societal actors. However, in the wake of a global pandemic, the countries’ coping strategies varied, creating certain question marks on the existence of a “Nordic model”. The chapters give a broad overview of crisis communication in the Nordic countries during the first year of the Covid-19 pandemic by combining organisational and societal theoretical perspectives and encompassing crisis response from governments, public health authorities, lobbyists, corporations, news media, and citizens. The results show several similarities, such as political and governmental responses highlighting solidarity and the need for exceptional measures, as expressed in press conferences, social media posts, information campaigns, and speeches. The media coverage relied on experts and was mainly informative, with few critical investigations during the initial phases. Moreover, surveys and interviews show the importance of news media for citizens’ coping strategies, but also that citizens mostly trusted both politicians and health authorities during the crisis. This book is of interest to all who are looking to understand societal crisis management on a comprehensive level. The volume contains chapters from leading experts from all the Nordic countries and is edited by a team with complementary expertise on crisis communication, political communication, and journalism, consisting of Bengt Johansson, Øyvind Ihlen, Jenny Lindholm, and Mark Blach-Ørsten. Publishe

    Beam scanning by liquid-crystal biasing in a modified SIW structure

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    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

    Overcoming drug resistance: targeting the BCL-2 family and the long non-coding RNA HCP5 in medulloblastoma and colorectal cancer

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    Colorectal cancer (CRC) is one of the most common cancers in the UK and medulloblastoma is a common cancer found in children. While there has been a progressive improvement in treatment outcomes, success has been marred by drug resistance and severe side effects. Therefore, this project focused on two aspects of chemotherapeutic drug resistance, the first using the antimitotic agent vincristine in combination with inhibitors of the anti-apoptotic Bcl-2 family proteins, while the second investigated the role of the long non-coding RNA (lncRNA), HCP5 in the resistance of cells to genotoxic agents. In the first part, three medulloblastoma cell lines (DAOY, MB03, ONS76) were analysed for the expression of Bcl-xL and ONS76 cells found to have the highest level of this anti-apoptotic protein. Subsequent results indicated that Bcl-xL encourages mitotic slippage and stemness and that knockdown of Bcl-xL in the high expressing ONS76 cells, reduces these and sensitizes the cells to the anti-mitotic agent vincristine. Thus, pharmacological inhibition of Bcl-xL should sensitize medulloblastoma cells to low doses of vincristine. Regarding the lncRNA HCP5, results showed that HCP5 was generally more highly expressed in a panel of CRC cell lines than the three medulloblastoma cell lines, corroborating data from an in-silico analysis for the corresponding tumours. One function of HCP5 is to translocate the multifunctional YB-1 protein from the cytoplasm to the nucleus where it carries out many of its functions. Knockdown of HCP5 followed by immunofluorescence indicated a reduction in the amount of YB-1 in the nucleus, confirming this function. Subsequently, HCP5 silencing sensitized all cell lines tested to the DNA damaging agents, cisplatin, oxaliplatin and tert-butyl hydroperoxide and also resulted in an increase in double-strand breaks as determined by H2AX formation. Finally, fluorescence activated cell sorting using Annexin V and propidium iodide confirmed a decrease in cell viability in HCP5 knockdown cells following treatment with genotoxic agents and that this was mirrored by an increased apoptotic fraction. Together, these studies indicate the possibilities of using novel therapeutics to increase the functionality of existing treatments to combat acquired drug resistance in cancer patients

    A clinical prognostic model for patients with esophageal squamous cell carcinoma based on circulating tumor DNA mutation features

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    BackgroundFew predictive models have included circulating tumor DNA (ctDNA) indicators to predict prognosis of esophageal squamous cell carcinoma (ESCC) patients. Here, we aimed to explore whether ctDNA can be used as a predictive biomarker in nomogram models to predict the prognosis of patients with ESCC.MethodsWe included 57 patients who underwent surgery and completed a 5-year follow-up. With next-generation sequencing, a 61-gene panel was used to evaluate plasma cell-free DNA and white blood cell genomic DNA from patients with ESCC. We analyzed the relationship between the mutation features of ctDNA and the prognosis of patients with ESCC, identified candidate risk predictors by Cox analysis, and developed nomogram models to predict the 2- and 5-year disease-free survival (DFS) and overall survival (OS). The area under the curve of the receiver operating characteristic (ROC) curve, concordance index (C-index), calibration plot, and integrated discrimination improvement (IDI) were used to evaluate the performance of the nomogram model. The model was compared with the traditional tumor-nodes-metastasis (TNM) staging system.ResultsThe ROC curve showed that the average mutant allele frequency (MAF) of ctDNA variants and the number of ctDNA variants were potential biomarkers for predicting the prognosis of patients with ESCC. The predictors included in the models were common candidate predictors of ESCC, such as lymph node stage, angiolymphatic invasion, drinking history, and ctDNA characteristics. The calibration curve demonstrated consistency between the observed and predicted results. Moreover, our nomogram models showed clear prognostic superiority over the traditional TNM staging system (based on C-index, 2-year DFS: 0.82 vs. 0.64; 5-year DFS: 0.78 vs. 0.65; 2-year OS: 0.80 vs. 0.66; 5-year OS: 0.77 vs. 0.66; based on IDI, 2-year DFS: 0.33, p <0.001; 5-year DFS: 0.18, p = 0.04; 2-year OS: 0.28, p <0.001; 5-year OS: 0.15, p = 0.04). The comprehensive scores of the nomogram models could be used to stratify patients with ESCC.ConclusionsThe novel nomogram incorporating ctDNA features may help predict the prognosis of patients with resectable ESCC. This model can potentially be used to guide the postoperative management of ESCC patients in the future, such as adjuvant therapy and follow-up

    Rational development of stabilized cyclic disulfide redox probes and bioreductive prodrugs to target dithiol oxidoreductases

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    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 zellulĂ€re Redox-Homöostase hĂ€ngt 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 ĂŒber Redox-Schalter in Substratproteinen lebenswichtige zellulĂ€re Funktionen steuern und so an der Redox-Regulation und -SignalĂŒbertragung beteiligt sind. Persistente VerĂ€nderungen des Redoxmilieus in pathologischen ZustĂ€nden, wie z. B. bei Krebs, sind in hohem Maße mit dem Trx-System verbunden. Eine Hochregulierung und/oder ÜberaktivitĂ€t des Trx-Systems, die bei vielen Krebsarten auftreten, unterstĂŒtzt zudem das Fortschreiten des Krebswachstums, was TrxR/Trx zu vielversprechenden Zielproteinen fĂŒr die Entwicklung neuer Krebsmedikamente macht. Um die biochemischen Prozesse dahinter zu erforschen, sind spezielle Techniken zur Visualisierung und Messung enzymatischer AktivitĂ€t nötig. Die hierzu geeigneten, meist genetischen Sensoren messen ratiometrisch das VerhĂ€ltnis reduzierter/oxidierter Spezies in zellulĂ€rem Umfeld oder spezifisch ausgewĂ€hlte 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 fĂŒr TrxR/Trx in Zellen und deren potenziellen Verwendung als Krebsmittel von großem Interesse. Bislang gibt es keinen selektiven zellulĂ€ren 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) fĂŒr Oxidoreduktasen so mit molekularen Wirkstoffen (Cargo) verknĂŒpft, dass dabei die WirkstoffaktivitĂ€t 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 stĂ€rksten Reduktasen gespalten werden; und (ii) die zyklische Topologie ermöglicht die kinetische ReversibilitĂ€t der zwei Thiol-Disulfid-Austauschreaktionen, die eine erste Reaktion mit Monothiolen, wie z. B. GSH, sofort umkehrt und so eine vollstĂ€ndige Reduktion verhindert. Die meisten frĂŒheren Arbeiten auf diesem Gebiet verwendeten ein zyklisches, fĂŒnfgliedriges Disulfid (1,2 Dithiolan) als Substrat fĂŒr TrxR. Das gleiche Strukturmotiv wurde jedoch an anderer Stelle als thermodynamisch instabil beschrieben und aufgrund dieser Eigenschaft explizit fĂŒr dynamische Kaskadenreaktionen verwendet. Deshalb vergleicht diese Arbeit zu Beginn einen neuen 1,2 Dithiolan basierten fluorogenen Indikator mit bestehenden, z. T. kommerziellen, Redox Sonden fĂŒr TrxR in einer Reihe von Zellkultur-Experimenten unter Modulation der zellulĂ€ren TrxR AktivitĂ€t und stellt so einen Widerspruch in der Literatur klar: 1,2 Dithiolane eignen sich nicht als selektive Substrate fĂŒr 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 EnzymspezifitĂ€t, durch seine zyklische Natur und die Annelierung, auch unter Verwendung unterschiedlicher Farb-/Wirkstoffe. Auf dieser Grundlage konnte die molekulare Struktur durch einen weiteren Modifikationspunkt fĂŒr die flexible Verwendung weiterer funktioneller Einheiten ergĂ€nzt werden. Obwohl zellulĂ€re 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 MolekĂŒle wertvoll, um den katalytischen Umsatz zellulĂ€rer Dithiol-Reduktasen, der sogenannten Trx Superfamilie, selektiv anzuzeigen (Preprint 2023). BegĂŒnstigt durch das modulare MolekĂŒldesign stellt diese Arbeit zudem das erste Reportersystem RX1 zum selektiven Nachweis der TrxR-AktivitĂ€t 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 fĂŒr eine Hochdurchsatz-Validierung bestehender TrxR Inhibitoren und unterstreicht dadurch den kommerziellen Nutzen derartiger Diagnostika (Chem 2022). Das zentrale Trigger-Cargo Konzept dieser Arbeit wurde fĂŒr 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 fĂŒr Trx; 1,2 Thiaselenan fĂŒr TrxR) reagierten signifikant auf TrxR-Modulation in Zellen. Sie wurden darĂŒber hinaus durch das Referenzieren ihrer AktivitĂ€t gegenĂŒber nicht-reduzierbaren KontrollmolekĂŒle fĂŒr die Erstellung zelllinienabhĂ€ngiger Profile der ReduktaseaktivitĂ€t in 177 Zelllinien genutzt. Schließlich waren diese neuen Krebsmittel im Tiermodell gut vertrĂ€glich und zeigten in zwei verschiedenen Mausmodellen eine krebshemmende Wirkung (Preprint 2022b). Zusammenfassend prĂ€sentiert diese Dissertation monothiol-resistente reduzierbare Trigger-Einheiten fĂŒr das zellulĂ€re 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 zellulĂ€rer ProteinaktivitĂ€t oder zum Einsatz als Antikrebsmittel Verwendung. Es wurden chemokompatible Motive sowohl fĂŒr TrxR als auch fĂŒr 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 zusĂ€tzliche 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 zellulĂ€ren Redox-Maschinerie analog umgesetzt werden, und dadurch Schlussfolgerungen aus der Diagnostik direkt auf eine Therapie ĂŒbertragbar machen. Dies birgt großes Potenzial fĂŒr kĂŒnftige Entwicklungen bei einer potenziellen Übertragung des modularen Konzepts auf andere Enzymklassen und therapeutische Einsatzgebiete

    Evaluation of Multi-frequency Synthetic Aperture Radar for Subsurface Archaeological Prospection in Arid Environments

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    The discovery of the subsurface paleochannels in the Saharan Desert with the 1981 Shuttle Imaging Radar (SIR-A) sensor was hugely significant in the field of synthetic aperture radar (SAR) remote sensing. Although previous studies had indicated the ability of microwaves to penetrate the earth’s surface in arid environments, this was the first applicable instance of subsurface imaging using a spaceborne sensor. And the discovery of the ‘radar rivers’ with associated archaeological evidence in this inhospitable environment proved the existence of an earlier less arid paleoclimate that supported past populations. Since the 1980’s SAR subsurface prospection in arid environments has progressed, albeit primarily in the fields of hydrology and geology, with archaeology being investigated to a lesser extent. Currently there is a lack of standardised methods for data acquisition and processing regarding subsurface imaging, difficulties in image interpretation and insufficient supporting quantitative verification. These barriers keep SAR technology from becoming as integral as other remote sensing techniques in archaeological practice The main objective of this thesis is to undertake a multi-frequency SAR analysis across different site types in arid landscapes to evaluate and enhance techniques for analysing SAR within the context of archaeological subsurface prospection. The analysis and associated fieldwork aim to address the gap in the literature regarding field verification of SAR image interpretation and contribute to the understanding of SAR microwave penetration in arid environments. The results presented in this thesis demonstrate successful subsurface imaging of subtle feature(s) at the site of ‘Uqdat al-Bakrah, Oman with X-band data. Because shorter wavelengths are often ignored due to their limited penetration depths as compared to the C-band or L-band data, the effectiveness of X-band sensors in archaeological prospection at this site is significant. In addition, the associated ground penetrating radar and excavation fieldwork undertaken at ‘Uqdat al-Bakrah confirm the image interpretation and support the quantitative information regarding microwave penetration

    Speciation and sex-biased gene expression in the scarce swallowtails

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    Speciation is the process by which closely related populations of organisms differentiate following reductions in the effective rate of genetic exchange between them over time. For most speciation events, population genetic data is the only available information about how reproductive isolation has arisen. We have a poor understanding of how evolutionary forces and genomic features contribute to reproductive isolation, primarily due to the difficulty of inferring barriers to gene flow. In particular, it is unclear what role genes that are sex-biased in expression and/or sex-linked play in speciation. In my thesis, I aim to infer the locations of putative barriers to gene flow to understand to what extent different genomic features, in particular fast-evolving sex-biased genes, contribute to reproductive isolation between a sister species pair of scarce swallowtail (Iphiclides) butterflies. In my first research project, I estimate core population genetic parameters across all sister species pairs of European butterflies and fit simple models of divergence to ask how well classic phylogeographic hypotheses fit recent diversification events in this taxonomic group. In my second research project, I infer explicit models of the speciation process and model effective migration rates along the genome to locate putative barriers to gene flow. I ask whether these barriers to long-term gene flow are associated with areas of the genome that show a reduction in recent introgression across a hybrid zone. In my third and final research project, I extend the demographic modeling of speciation in the Iphiclides species pair to the Z chromosome and ask whether barrier regions are associated with sex-biased genes, as a result of their faster rate of evolution. In summary, my findings suggest that fast-evolving male-biased genes likely contribute to extensive sex-linked reproductive isolation, as well as paving the way for future research on the population genetics of European butterflies and the evolutionary genomics of speciation
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