7,635 research outputs found

    Neuromodulatory effects on early visual signal processing

    Get PDF
    Understanding how the brain processes information and generates simple to complex behavior constitutes one of the core objectives in systems neuroscience. However, when studying different neural circuits, their dynamics and interactions researchers often assume fixed connectivity, overlooking a crucial factor - the effect of neuromodulators. Neuromodulators can modulate circuit activity depending on several aspects, such as different brain states or sensory contexts. Therefore, considering the modulatory effects of neuromodulators on the functionality of neural circuits is an indispensable step towards a more complete picture of the brain’s ability to process information. Generally, this issue affects all neural systems; hence this thesis tries to address this with an experimental and computational approach to resolve neuromodulatory effects on cell type-level in a well-define system, the mouse retina. In the first study, we established and applied a machine-learning-based classification algorithm to identify individual functional retinal ganglion cell types, which enabled detailed cell type-resolved analyses. We applied the classifier to newly acquired data of light-evoked retinal ganglion cell responses and successfully identified their functional types. Here, the cell type-resolved analysis revealed that a particular principle of efficient coding applies to all types in a similar way. In a second study, we focused on the issue of inter-experimental variability that can occur during the process of pooling datasets. As a result, further downstream analyses may be complicated by the subtle variations between the individual datasets. To tackle this, we proposed a theoretical framework based on an adversarial autoencoder with the objective to remove inter-experimental variability from the pooled dataset, while preserving the underlying biological signal of interest. In the last study of this thesis, we investigated the functional effects of the neuromodulator nitric oxide on the retinal output signal. To this end, we used our previously developed retinal ganglion cell type classifier to unravel type-specific effects and established a paired recording protocol to account for type-specific time-dependent effects. We found that certain retinal ganglion cell types showed adaptational type-specific changes and that nitric oxide had a distinct modulation of a particular group of retinal ganglion cells. In summary, I first present several experimental and computational methods that allow to study functional neuromodulatory effects on the retinal output signal in a cell type-resolved manner and, second, use these tools to demonstrate their feasibility to study the neuromodulator nitric oxide

    Isotope reconstructions of East Asian Monsoon behaviour across Glacial Terminations I and II from Lake Suigetsu, Japan (IAP2−18−54)

    Get PDF
    Understanding the response of the East Asian Monsoon to rising temperatures is crucial in light of recent anthropogenic climate change and the vulnerability of East Asia to future climatic hazards. However, East Asian Monsoon dynamics during warming periods in the late Quaternary are poorly understood, particularly on decadal to millennial timescales. Significant sources of this uncertainty are the spatially and temporally heterogeneous responses of the East Asian Monsoon to submillennial temperature fluctuations. The conflicting patterns observed in available reconstructions of East Asian Monsoon strength suggest that the teleconnections acting during these intervals were complex. Understanding the behaviours of the East Asian Monsoon by accounting for links to remote climatic perturbations allows for a more holistic understanding of deglacial climate changes. A means of tackling this ambiguity is by contributing well−dated, high−resolution records of East Asian Monsoon evolution spanning Glacial Terminations I and II (which typify accessible, contrasting examples of rapid global warming) to the growing network of reconstructions from across the region. The aim of this thesis is to deconvolve East Asian Monsoon evolution during the last two glacial terminations by utilising the unique hydrological distribution of East Asian Monsoon precipitation over Japan to reconstruct both seasonal modes of the system (i.e., the East Asian Winter Monsoon and East Asian Summer Monsoon). This aim is met by the construction of isotope−based, season−specific East Asian Monsoon records across Glacial Terminations I and II using materials from the Lake Suigetsu sediment cores. This thesis is comprised of four interconnected research papers, preceded by an introduction and succeeded by a summary of findings, discussion of relevance, suggestions for future work and conclusions. In the first research paper, we utilise extended contemporary monitoring of the stable isotope composition of precipitation, river water and lake water in the Lake Suigetsu catchment to understand the factors affecting these variables and aid robust interpretation of isotope−based proxy reconstructions from the Lake Suigetsu sediment cores. Our results show that the composition of precipitation was influenced by the dual East Asian Monsoon system, and that these signals were then transferred to the lake system where they were combined with secondary local influences on lake water composition. Based on our knowledge of late Quaternary catchment dynamics, these observations suggest that the palaeo−isotope composition of Lake Suigetsu was closely related to the East Asian Monsoon. In the second research paper, we examine the influence of remote climatic processes on the East Asian Winter Monsoon and East Asian Summer Monsoon in Japan during Glacial Termination I by reconstructing trends in the strength of each seasonal mode. This is achieved using oxygen isotope analysis of diatom silica and compound−specific hydrogen isotope analysis of n−alkanoic acids from the Lake Suigetsu sediment cores. Our results support distinctive seasonal behaviours of the East Asian Monsoon during Glacial Termination I, with evidence for East Asian Winter Monsoon weakening and East Asian Summer Monsoon strengthening. The East Asian Summer Monsoon also exhibited variations in strength which were synchronous with Antarctic temperature fluctuations after 16,000 years ago, which supports a temporally restricted climatic link between Japan and the Southern Hemisphere at this time. In the third research paper, we reconstruct the East Asian Summer Monsoon in Japan during Glacial Termination II, and contrast the findings to those from Glacial Termination I. The reconstruction presented in this chapter, which is based on compound−specific hydrogen isotope analysis of n−alkanoic acids, provides evidence for early East Asian Summer Monsoon strengthening followed by a gradual weakening phase with submillennial−scale variability. Comparison of this record to others derived from mainland China supports the assertion that East Asian Summer Monsoon behaviours during Glacial Termination II were spatially heterogenous. Additionally, the different evolutions of the East Asian Summer Monsoon during Glacial Terminations I and II indicate that the system operated distinctively under contrasting boundary conditions, although the new reconstructions from Japan were consistently more closely linked with Southern Hemisphere (Antarctic) temperatures than Northern Hemisphere (Greenlandic) temperatures during both intervals. The fourth research paper was motivated by a lack of an absolute chronology for the oldest (pre−50,000 years ago) parts of the Lake Suigetsu sediment cores (which includes Glacial Termination II). In this paper, we appraise the luminescence characteristics of the cores using rapid profiling techniques. These are employed across four key time periods in order to assess the application of these methods for the detection of local and environmental shifts, and to assess the suitability of the core materials for luminescence dating. We show that the luminescence characteristics of the cores were susceptible to a range of environmental perturbations, best illustrating local changes by using high−resolution contiguous sampling. The feasibility of future luminescence dating is supported by quantifiable luminescence signals, and first order approximate ages suggest that blue light optically stimulated luminescence dating of feldspar provides the most accurate and most practical assessment of burial age. This technique should be the subject of dating efforts in pursuit of refinements to the Suigetsu core chronology before 50,000 years ago. The findings of this thesis contribute to our collective knowledge of East Asian Monsoon behaviours during glacial terminations. Critically, they represent a geographical expansion of the regional high−resolution record network to include Japan. The value of this process is demonstrated by the decoupled evolutions of each seasonal mode during Glacial Termination I, and a remote link between Antarctic temperatures and East Asian Summer Monsoon evolution in Japan during Glacial Terminations I and II, which were hitherto unconstrained by high resolution analysis. These findings acknowledge and begin to rationalise spatial and temporal heterogeneities in East Asian Monsoon behaviours by comparison to other records. This work highlights the complexity of the East Asian Monsoon, and the value of long records from contrasting deglacial periods for a better comprehension of this system in the context of anthropogenic climate change

    Choreographing tragedy into the twenty-first century

    Get PDF
    What makes a tragedy? In the fifth century BCE this question found an answer through the conjoined forms of song and dance. Since the mid-twentieth century, and the work of the Tanztheater Wuppertal Pina Bausch, tragedy has been variously articulated as form coming apart at the seams. This thesis approaches tragedy through the work of five major choreographers and a director who each, in some way, turn back to Bausch. After exploring the Tanztheater Wuppertal’s techniques for choreographing tragedy in chapter one, I dedicate a chapter each to Dimitris Papaioannou, Akram Khan, Trajal Harrell, Ivo van Hove with Wim Vandekeybus, and Gisùle Vienne. Bringing together work in Queer and Trans* studies, Performance studies, Classics, Dance, and Classical Reception studies I work towards an understanding of the ways in which these choreographers articulate tragedy through embodiment and relation. I consider how tragedy transforms into the twenty-first century, how it shapes what it might mean to live and die with(out) one another. This includes tragic acts of mythic construction, attempts to describe a sense of the world as it collapses, colonial claims to ownership over the earth, and decolonial moves to enact new ways of being human. By developing an expanded sense of both choreography and the tragic one of my main contributions is a re-theorisation of tragedy that brings together two major pre-existing schools, to understand tragedy not as an event, but as a process. Under these conditions, and the shifting conditions of the world around us, I argue that the choreography of tragedy has and might continue to allow us to think about, name, and embody ourselves outside of the ongoing catastrophes we face

    Cultures of Citizenship in the Twenty-First Century: Literary and Cultural Perspectives on a Legal Concept

    Get PDF
    In the early twenty-first century, the concept of citizenship is more contested than ever. As refugees set out to cross the Mediterranean, European nation-states refer to "cultural integrity" and "immigrant inassimilability," revealing citizenship to be much more than a legal concept. The contributors to this volume take an interdisciplinary approach to considering how cultures of citizenship are being envisioned and interrogated in literary and cultural (con)texts. Through this framework, they attend to the tension between the citizen and its spectral others - a tension determined by how a country defines difference at a given moment

    Contribution of Relatedness and Genetic Factors to the Clinical Picture of Coeliac Disease

    Get PDF
    Keliakia on yleinen autoimmuunisairaus, jossa tÀrkein altistava ympÀristötekijÀ on ravinnon sisÀltÀmÀ gluteeni. Keliakiaa esiintyy maailmanlaajuisesti, mutta sen esiintyvyys Suomessa on erityisen korkea, vaikkakin laajalti alidiagnosoitu. Osasyy tÀlle on keliakian kirjava taudinkuva. Ruuansulatuskanavan oireet muodostivat pitkÀÀn keliakialle tyypillisen oirekuvan, mutta se on vÀhitellen korvautunut lievemmillÀ, usein ruuansulatuskanavan ulkopuolisilla oireilla. NykyÀÀn keliakia voi ilmentyÀ myös tÀysin oireettomana. Oireiden lisÀksi niiden puhkeamisessa, voimakkuudessa sekÀ kehittymisessÀ on paljon yksilöllisiÀ eroja. Myös keliakiapotilaiden vaste gluteenittomaan ruokavaliohoitoon vaihtelee. SyitÀ tai tekijöitÀ tÀmÀn potilaskohtaisesti vaihtelevan taudinkuvan taustalla ei kuitenkaan vielÀ tunneta. Nykyisin moni keliaakikko on osannut aiemmin epÀillÀ kohdallaan keliakiaa ja hakeutunut lÀÀkÀriin, koska sairaus on ollut tuttu keliakiaa sairastavien sukulaisten tai perheenjÀsenten kautta. NÀmÀ ns. familiaaliset keliaakikot ovat enemmistö, mutta keliakiaa esiintyy myös ns. sporadisesti, jolloin potilaalla ei ole tiedettyÀ sukutaustaa keliakialle. Tunnetuin keliakialle altistava perintötekijÀ on HLA-DQ2.5-haplotyyppi, mutta muidenkin, HLA-alueen ulkopuolisten, geenialueiden on todettu assosioituvan keliakiaan. TÀssÀ vÀitöskirjatutkimuksessa selvitettiin familiaalisen ja sporadisen keliakian eroavaisuuksia perintötekijöiden ja taudinkuvan suhteen. LisÀksi tutkittiin, onko HLA-DQ2.5-kuormalla (eli sillÀ, onko potilas HLA-DQ2.5-negatiivinen, - heterotsygootti vai -homotsygootti) ja HLA:n ulkopuolisilla geneettisillÀ varianteilla, mukaan lukien variantit kandidaattigeeneissÀ CCR9 ja CCL25, vaikutusta keliakian kliiniseen taudinkuvaan. TÀmÀn vÀitöskirjan tulokset paljastivat, ettÀ sporadinen keliakia omana erillisenÀ tautimuotonaan eroaa HLA-DQ-genotyypiltÀÀn familiaalisesta tautimuodosta, vaikka useita eroavaisuuksia kliinisen taudinkuvan suhteen ei löydettykÀÀn. Sporadisten potilaiden taudinkuva diagnoosihetkellÀ oli kuitenkin vakavampi ja yleinen terveydentila seurantahetkellÀ, gluteenittomalla dieetillÀ, huonompi kuin familiaalisilla potilailla. Tutkimukset myös osoittivat, ettÀ HLA-DQ2.5-negatiivisia potilaita leimasi HLA-DQ2.5-heterotsygootteja ja -homotsygootteja useammin klassinen oirekuva diagnoosihetkellÀ sekÀ pitkittyneet oireet seurantahetkellÀ. NÀmÀ tutkimuslöydökset toivottavasti rohkaisevat lÀÀkÀreitÀ sekÀ muuta hoitohenkilökuntaa kiinnittÀmÀÀn erityistÀ huomiota edellÀ mainittuihin potilasryhmiin. LisÀksi vÀitöstutkimuksen geneettisten analyysien tulokset osoittivat neljÀn HLA-alueen ulkopuolisen variantin assosioituvan familiaaliseen keliakiaan. NÀiden assosiaatioiden merkitys tulee kuitenkin vahvistaa jatkotutkimuksilla. HLA- DQ2.5-kuorman tai CCR9- ja CCL25-kandidaattigeenialueiden varianttien vaikutus keliakian taudinkuvaan oli tÀmÀn vÀitöskirjatutkimuksen perusteella vÀhÀinen.Coeliac disease, a systemic autoimmune disorder induced by dietary gluten, is widespread globally, but in Finland even particularly prevalent although still heavily underdiagnosed. One reason contributing to this is the remarkably multifaceted clinical picture of coeliac disease. The originally typical gastrointestinal symptoms are currently being increasingly replaced by a milder presentation with extraintestinal symptoms and even totally asymptomatic presentation is no longer abnormal. Nevertheless, coeliac disease patients do not differ from each other only in terms of symptoms. There is a wide individual variation concerning the onset, severity and progression of symptoms as well as response to dietary treatment i.e., gluten-free diet (GFD). The reasons and contributary factors underlying this wide clinical heterogeneity remain obscure. For many people nowadays, suspicion of coeliac disease is closely connected to known familial history of the disease. These familial cases are in the majority, but not every patient has affected relatives and such patients are considered sporadic. Where coeliac disease heredity is concerned, HLA-DQ2.5 is the best-known genetic component. However, numerous loci outside the HLA region have also been associated with the disease. The studies presented in this dissertation focused in investigating whether there are genetic and/or phenotypic differences between familial and sporadic coeliac disease and whether the dose of HLA-DQ2.5 or the presence of genetic variants outside HLA region, including the ones within candidate genes CCR9 and CCL25, contributes to the clinical picture of the disease. The findings of this dissertation managed to describe sporadic coeliac disease as an independent entity with a distinct HLA-DQ genotype even though not many significant phenotypic differences were observed between familial and sporadic coeliac disease. Nevertheless, the sporadic cases had more severe clinical phenotype at diagnosis as well as poorer overall health even after dietary treatment. Moreover, HLA-DQ2.5-negative coeliac disease patients were observed to present with classical phenotype at diagnosis as well as with persistent symptoms after dietary treatment more often than patients heterozygous or homozygous for high-risk HLA- DQ2.5. These findings will hopefully encourage physicians to pay special attention to both these patient groups. Four distinct non-HLA variants were associated with increased risk for familial coeliac disease, but the associations need to be confirmed in future studies. The contribution of HLA-DQ2.5 dose as well as non-HLA single nucleotide polymorphisms (SNPs) within CCR9 and CCL25 to the clinical picture of coeliac disease was found to be only modest

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

    Get PDF
    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (ÎČ2 = 0.18, p-value = 0.07; ÎČ3 = −0.10, p-value = 0.02). SHS exposure at home (ÎČ2 = 0.10, p-value = 0.09; ÎČ3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (ÎČ2 = 0.03, p-value = 0.10; ÎČ3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK

    Spatial Distribution of Meso- and Microplastics in Floodplain Soilscapes: Novel Insights from Rural to Urban Floodplains in Central Germany

    Get PDF
    Plastics and especially microplastics have become an emerging threat to global ecosystems. Despite the manifold benefits and applications of the human-made material plastic, the uncontrolled release of plastics into the environment has led to a “global plastic crisis”. During the last decades it becomes apparent that this crisis leads to the presence of plastics within different environments including marine, aquatic and terrestrial systems under worldwide evidence. Furthermore, environmental plastic research was able to reveal that although plastic often ends up in oceans, the majority of plastics in the environment are transported as part of a “global plastic cycle” from the land to sea via river systems. Those river systems are not isolated in the landscape, but rather a part of an “aquatic-terrestrial interface” which also encompasses floodplains and their soilscapes. The present thesis focuses on the spatial distribution and spatio-temporal accumulation of meso- and microplastics in floodplain soilscapes following the overall objective to unravel the role of floodplain soilscapes as depositional areas of plastics within the global plastic cycle. In this context, a number of individual contributions have been published, reaching from conceptual spatial research approaches, over case studies conducted within two different floodplain soilscapes, to further opinions on the scientific benefit of plastic residues in floodplain soils. The individual contributions are linked by the major hypothesis that floodplain soilscapes act as temporal accumulation sites for plastics, driven by flood-related processes and land use over the last 70 years. To proof this major hypothesis and to overcome the lack of spatial reference in microplastics research, a geospatial sampling approach was conducted. Initial spatial data on meso- and microplastics in floodplain soils were obtained by a holistic analysis approach including the analysis of basic soil feature and metal analysis, the quantification of meso- and microplastics as well as sediment dating. Within both studied river floodplains geospatial sampling enables a detection of meso- and microplastics over the entire floodplain area and within the entire soil column reaching depths of two meters. Additionally, a frequent accumulation of plastics was found within the upper 50 cm of floodplain soils. In combination with dating of near-channel floodplain sites, it could be demonstrated that those plastic accumulations are related to recent sedimentary deposits since the 1960s. However, evidence of plastic from deeper soil layers suggests that vertical displacements in floodplain soils occur and that plastics become mobilized. Furthermore, the presence of plastics in upstream areas suggests that plastics are released to river systems and deposited via flood dynamics already in rural areas. Additionally it appears that anthropogenic impacts, such as tillage or floodplain restoration influence plastic distributions. The findings of this thesis clarify that floodplain soilscapes are part of the global plastic cycle as temporally depositional areas of plastics, but raising further questions on the mobility of plastics in soils and about the exact contribution of different environmental drivers towards plastic deposition. Finally, the present thesis indicates that the spatial reference of environmental plastic research should be rethought, in order to understand the spatial dynamics of plastics within the aquatic-terrestrial interface

    Phosphate-based glass microspheres for bone repair and localised chemotherapy and radiotherapy treatment of bone cancers

    Get PDF
    Phosphate-based glasses (PBGs) are hugely promising materials for bone repair and regeneration as they can be formulated to be compositionally similar to the inorganic component of bone. Alterations to PBG formulations can be made to tailor their degradation rates and subsequent release of biotherapeutic ions to induce cellular responses, such as osteogenesis. In this work, novel invert-PBGs in the series xP2O5·(56-x)CaO·24MgO·20Na2O (mol%), where x is 40, 35, 32.5 and 30, were formulated to contain pyro (Q1) and orthophosphate (Q0) species. These PBGs were then processed into highly porous microspheres (PMS) via a flame spheroidisation process developed within the research group. Compositional and structural analysis using EDX and 31P-MAS NMR analysis revealed significant depolymerisation had occurred with reducing phosphate content, which increased further when PBGs were processed into PMS. A decrease from 50% to 0% of Q2 species and increase from 6% to 35% of Q0 species was observed for the PMS when the phosphate content decreased from 40 to 30 mol%. Ion release studies also revealed up to a 4-fold decrease in cations and an 8-fold decrease in phosphate anions released with decreasing phosphate content. In vitro bioactivity studies revealed that the orthophosphate rich PMS had favourable bioactivity responses after 28 days of immersion in SBF. Indirect and direct cell culture studies confirmed that the PMS were cytocompatible and supported cell growth and proliferation over 7 days of culture. The P30 PMS with ~65% pyro and ~35% ortho phosphate content revealed the most favourable properties and was proposed to be highly suitable for bone repair and regeneration, especially for orthobiologic applications owing to their highly porous morphology. Doxorubicin (DOX) was used as a model drug to assess its loading and release kinetics from porous phosphate-based glass microspheres to ascertain their suitability for localised drug delivery for the treatment of bone cancers. P40 PMS revealed a DOX loading efficiency of 55%, which was significantly greater than P30 PMS at 29.1%. Both P40 and P30 PMS released more DOX in phosphate buffered saline (PBS) at pH 5 as compared to release at pH 7.4. P40 PMS released 57% of DOX at pH 5 over a 48-hour period, whereas P30 PMS only released 15% of DOX. A pH-responsive DOX release in a more acidic environment suggests that the chemotherapeutic delivery and efficacy properties may lead to increased drug release within tumour tissues. Internal radiotherapy has been shown to be an effective treatment modality to destroy cancerous tissues and is usually achieved by the placement of radioactive sources at the tumour site. In this work, a novel processing method was established to combine yttrium oxide (Y2O3) with P40 phosphate glass particles to form uniform, solid microspheres containing very high yttrium levels via our flame spheroidisation process. The 30Y (~15 mol% Y2O3) and 50Y microspheres (~39 mol% Y2O3) had equivalent and superior yttrium content in comparison to clinically available microspheres used for internal radiotherapy (i.e., TherasphereÂź). The yttrium-containing microspheres formed were shown to be glass-ceramics, with crystalline phases present but with all elements homogenously distributed throughout the microspheres. Increasing yttrium addition resulted in increased durability of the microspheres, with 50Y microspheres revealing a 10-fold decrease in the release rate of some ions compared to P40 solid microspheres. Indirect and direct cell culture studies confirmed that the 30Y and 50Y microspheres were cytocompatible and supported cell growth and proliferation over 7 days of culture. No significant difference was observed in the metabolic and ALP activity for MG63s for both 30Y and 50Y microspheres from both indirect and direct cell culture studies. Yttrium was incorporated into the phosphate-based microspheres at a level that had not previously been achieved or observed from the literature studies and were shown to support bone cell attachment and growth. A high yttrium content could enable more radiation to be delivered per dose of microspheres, resulting in shorter neutron activation times which could prove beneficial for logistical issues associated with transportation of the biomaterials following nuclear activation. The radionuclide holmium-166 (166Ho) which is comparable to yttrium-90 (90Y) in that it emits ÎČ-radiation with a similar tissue penetration range and a significantly reduced half-life of 26.8 hours, was also investigated. The beneficial paramagnetic properties and density of 166Ho indicates that 166Ho-doped materials could be visualised through clinical imaging techniques, whilst simultaneously delivering a therapeutic dose of radiation. In this work, solid holmium-containing microspheres were similarly produced via the flame spheroidisation process using holmium oxide (Ho2O3) and P40 phosphate glass particles. The glass-ceramic microspheres produced had equivalent (30H: ~17mol% Ho2O3) and superior (50H: ~30mol% Ho2O3) holmium content in comparison to clinically used yttrium-doped microspheres (i.e. TherasphereÂź). Analogous to yttrium containing microspheres, elevated holmium content resulted in topographically unique features on the surface of some 50H microspheres. This increased holmium content resulted in significantly reduced ion release rates for all the ions and the holmium-microspheres did not show evidence of bioactivity. However, in vitro indirect and direct cell culture studies demonstrated their cytocompatibility. No significant difference was observed in the metabolic and ALP activity of MG63 cells for 30H and 50H microspheres in both the indirect and direct cell culture methods. This study appears to be the first to demonstrate microspheres containing high levels of holmium content that can also facilitate direct cell growth and proliferation of human osteoblast-like cells. The microspheres developed are therefore hugely promising biomaterials for both drug delivery and internal radiotherapy applications, as well as for promoting bone repair and regeneration at damaged sites. High holmium content could also result in higher specific activity per microsphere to increase radiotherapy delivery whilst also promoting higher visibility via imaging modalities

    Enecarbamates as platforms for the synthesis of diverse polycyclic scaffolds

    Get PDF
    The efficient and continued exploration of novel chemical space is vital for the discovery of new drugs, with the construction of sp3-rich scaffolds being of particular interest. This thesis describes the elaboration of a common intermediate, via a toolkit of techniques, to access structurally diverse, novel, and highly three-dimensional polycyclic scaffolds, based on pharmaceutically valuable N-heterocyclic cores. Chapter one discusses the importance of properties and structure at several stages in the drug discovery process, including those for leads and fragments. Common motifs are highlighted and associated modern synthetic approaches discussed. Chapter two describes the delivery of a library of enecarbamate and hemiaminal ether-based building blocks through a unified approach. A toolkit of α- and ÎČ-functionalisation methods are applied for their elaboration. Chapter three describes the development and use of the ÎČ-functionalisation toolkit for enecarbamates, through the photocatalysed construction of spirocyclic systems. Herein, five exemplary spirocyclic structures are accessed based on two scaffolds. Chapter four evaluates the versatility of the photoredox toolkit via its application in the synthesis of ten bicyclic amides and five bicyclic anilines, from enecarbamates, through a modular approach. The resulting structural distortion regarding N lone pair and π-system overlap is assessed, via their physical properties, including measured nonaqueous pKaH. The subsequent impact on reactivity and bioactivity is evaluated. Chapter five discusses the use of enecarbamates in annulative technologies for the preparation of a series of fused motifs including two bicyclic lactams, seven oxetanes and nine cyclic aminals. A fully diastereoselective, photochemical synthesis of oxetanes is described and cyclic aminals have been highlighted as structures bearing a potential novel warhead. Chapters six and seven present the thesis conclusion and all associated experimental details, including full characterisation of synthesised compounds
    • 

    corecore