Positive schizotypy : a proposed endophenotype for psychosis in neurological disorders

In the current thesis, a model whereby the fully dimensional expression of positive schizotypal (PS) personality traits represents a psychological and biological diathesis that would predict psychotic decompensation in states of neurological stress was theoretically conceptualised and empirically validated. To our knowledge, this is the first piece of work to fully reconcile a predispositional psychological and biological susceptibility within a diathesis stress model of neurological psychosis. Whilst previous studies have assessed psychological or biological vulnerabilities to the development of psychotic symptoms in neurodegenerative and functional models, to date no individual study has theoretically or experimentally combined these features.The predictive ability of PS for neurological psychosis was validated on interdependent neuroanatomical, psychological, emotional, cognitive and symptomatic levels. The validity of PS as an endophenotype for neurological psychosis was tested across several behavioural and neuroimaging studies. The most compelling cognitive evidence for the endophenotype‘s validity was the finding that PS is associated with a bias to make false positive confabulationary style memories for psychosis congruent words. This finding converges with behavioural and anatomical evidence for a relationship between confabulation and delusions in pathological populations and was supported by the neuroimaging study of the individual differences of PS traits in healthy young individuals undertaken for the current thesis. Individual differences in schizotypal traits in normal individuals were found to be reflected endophenotypically in the structure of the brain in the bilateral but predominantly right frontal regions that have been anatomically and behaviourally related to psychosis in previous studies. The endophenotype was also validated as predicting psychosis in single case studies of patients with various diagnoses and was behaviourally and anatomically associated with the psychotic reactions of patients with Parkinson‘s disease to Levodopa medication. The validation studies suggest that, independent of aetiology, psychosis appears to be supported by bilateral but predominantly right sided frontal and limbic regions. The majority of individuals with this non-standard but dimensional trait will not decompensate into psychosis. However, the clinical data suggests that when individuals with high PS traits are under the duress of a significant affective, neurodegenerative or neuropharmacological stressor, the prominent symptom will be psychosis

Novel chemical sensors based on Boronic acids for glucose detection

Boronic acid (BA) derivatives have been exploited for their strong and reversible interactions with diol-containing compounds for the recognition of saccharides, such as glucose. Combining BA groups and fluorescent moieties can allow for sugar concentrations to be monitored by changes in fluorescence. In this thesis, two approaches based on BA sensing capabilities are investigated. In a direct sensing approach, the BA group is covalently attached to the fluorescent reporter group. Conversely, in an indirect sensing approach, a two-component system is created when the BA group and fluorophore are incorporated in to separate molecules. A direct sensing approach is described in Chapter 2, where the BA derivatives employed contain a quinoline-5-carboxylic acid functionality. These BA fluorescent sensors were investigated for their glucose sensing capabilities in solutions of various pH and when immobilised on to a ‘lens-like’ platform. An indirect sensing approach is described in Chapter 3, where a BA-cationic pyrimidinium molecule, induced fluorescence quenching in an anionic fluorophore (7-hydroxycoumarin). On introducing glucose, the fluorescence was recovered. This sensing system was investigated in solutions of various pH. Chapter 4 details the synthesis of a new family of BA-monomers. These monomers were characterised by 11B NMR and fluorescence in the absence and presence of glucose. In Chapter 5, the BA-monomers described in Chapter 4 were investigated for indirect sensing with the anionic fluorophore pyranine in solution and in hydrogels. Finally, in Chapter 6, additional strategies for the integration of a two-component sensing in to hydrogel matrices are investigated. The aim of this research is the development of novel sensing systems that could be integrated in to a continuous glucose-monitoring device. Such a platform could offer diabetics personal control over monitoring their glucose levels, to aid the prevention of the side effects associated with the disease

Novel chemical sensors based on Boronic acids for glucose detection

Boronic acid (BA) derivatives have been exploited for their strong and reversible interactions with diol-containing compounds for the recognition of saccharides, such as glucose. Combining BA groups and fluorescent moieties can allow for sugar concentrations to be monitored by changes in fluorescence. In this thesis, two approaches based on BA sensing capabilities are investigated. In a direct sensing approach, the BA group is covalently attached to the fluorescent reporter group. Conversely, in an indirect sensing approach, a two-component system is created when the BA group and fluorophore are incorporated in to separate molecules. A direct sensing approach is described in Chapter 2, where the BA derivatives employed contain a quinoline-5-carboxylic acid functionality. These BA fluorescent sensors were investigated for their glucose sensing capabilities in solutions of various pH and when immobilised on to a ‘lens-like’ platform. An indirect sensing approach is described in Chapter 3, where a BA-cationic pyrimidinium molecule, induced fluorescence quenching in an anionic fluorophore (7-hydroxycoumarin). On introducing glucose, the fluorescence was recovered. This sensing system was investigated in solutions of various pH. Chapter 4 details the synthesis of a new family of BA-monomers. These monomers were characterised by 11B NMR and fluorescence in the absence and presence of glucose. In Chapter 5, the BA-monomers described in Chapter 4 were investigated for indirect sensing with the anionic fluorophore pyranine in solution and in hydrogels. Finally, in Chapter 6, additional strategies for the integration of a two-component sensing in to hydrogel matrices are investigated. The aim of this research is the development of novel sensing systems that could be integrated in to a continuous glucose-monitoring device. Such a platform could offer diabetics personal control over monitoring their glucose levels, to aid the prevention of the side effects associated with the disease

Fabrication of non-enzymatic optical glucose sensors based on boronic acid derivatives

Diabetes is an incurable disease known to have severe acute and chronic side effects, namely blindness, heart disease or kidney failure, among others[1-3]. While monitoring the disease marker glucose in blood prolongs life expectancy, non-invasive continuous monitoring systems currently aren’t available[1-3]. The blood-glucose range for a healthy person is ~3-8mM, increasing to up to 40mM for people with diabetes[3], where the related glucose levels in the ocular fluid are 0.05-0.5mM increasing to up to 5mM for diabetics[3]. Consequently, there is considerable interested in using ocular fluid as a sample medium for tracking the disease marker. In this context, boronic acid (BA) sugar sensors have been investigated for potential use in sensing devices, like smart contact lenses[1-3]. The Lewis acidic BA moiety of the sensor is known for its strong interaction with diols[1-3]. On interaction with diols e.g. sugars, the anionic boronate form is produced leading to a decrease in the fluorescence intensity of the BA sensor with increasing sugar concentrations[1-3]. In this abstract, the synthesis and fluorescence studies of novel BA derivatives for colorimetric sugar sensing are presented. These BA sensors have been synthesised via a one-step nucleophilic substitution reaction[1-2]. The newly synthesised BA sensors were compared in terms of their fluorescence, sensitivity to glucose and their sensing range with the BA sensor - m-[N-[(3-boronobenzyl)-6-methoxyquinolinium bromide]] which has been studied previously for its sugar sensing capabilities at physiological pH[1-2]

Ocular glucose biosensing using boronic acid fluorophores

Boronic acids (BAs) are well-known for their interactions with diol-containing compounds like glucose. Fluorescent moieties are commonly incorporated into a BA derivative’s framework to monitor the effect of varying glucose concentrations in a given environment. Hence, a novel carboxylic acid fluorescent BA derivative, o-COOHBA, has been investigated for glucose sensing, in solution and when immobilised onto a polydimethylsiloxane (PDMS) “lens”-like surface. This approach aims to develop smart-contact lenses that will allow people suffering from diabetes to track their condition continuously and non-invasively in real-time. 1. Introduction Diabetes is a worldwide incurable disease known to have acute and chronic health effects1-2. This disease affects the cardiovascular and peripheral nervous systems, kidneys, and can also be fatal in some cases1-2. Blindness, heart or kidney failures are among the most common life-threatening effects of diabetes2. Monitoring physiological blood-glucose concentrations is a means of managing the disease, however few non-invasive continuous monitoring methods currently exist1-2. Consequently, there is considerable interested in using aqueous ocular fluid as a sample medium for tracking the disease marker glucose. 2. Sensing Mechanism The Lewis acidic BA moiety of the sensor is known for its strong interaction with electron-rich diols, like sugars1-2. On interaction with sugars, e.g. glucose, the fluorescent BA form is transformed into the anionic boronate form, which is non-fluorescent, leading to a decrease in the fluorescence intensity with increasing sugar concentrations1-2. Scheme 1: Sensing mechanism for BA derivatives. 3. Synthesis of o-COOHBA Sensor A novel BA sensor, o-COOHBA, was synthesized via a one-step nucleophilic substitution reaction that required equimolar quantities of BA and quinoline derivatives, as seen in Scheme 2. The successful formation of o-COOHBA was confirmed by 1H NMR. Scheme 2: Synthesis of o-COOHBA; (i) anhydrous dimethylsulfoxide, N2, 70 0C for 48h. 4. Fluorescence of o-COOHBA Fluorescence measurements were performed on a Jasco FP-8300 Spectrophotometer using a precision cell made from quartz with 10 mm path length. The excitation wavelength required was 380 nm with a corresponding emission wavelength of 485 nm. On increased glucose concentrations, a decrease in fluorescence intensity was observed in the range of 0-10 mM in solution and similarly, in the range of 0-5 mM when anchored to a PDMS surface, corresponding to the ocular-glucose concentrations for diabetics, ~50 μM – 5 mM2. All tests were carried out at an ambient temperature using a pH 7.4 phosphate buffer. 5. Conclusion In both solution studies and when anchored on to the PDMS surface, a decrease in fluorescence intensity was observed on increased glucose concentrations. The excitation wavelength of 380 nm is also advantageous, as it lies close to the visible-region of the electromagnetic spectrum, which allows for the use of cheap, readily available LEDs as excitation sources. The carboxylic acid substituent was desirable for immobilizing the BA sensor onto a wide variety of polymeric substrates

Boronic acid derivatives for sugar sensing

Several boronic acid (BA) derivatives, suitable for sugar sensing (see Figure), have been synthesised via a one-step nucleophilic substitution reaction from the appropriate quinoline starting materials and the benzylboronic acid derivative1. The quinoline moiety confers the fluorescent behaviour of these sensors through its associated conjugated framework. The BA moiety of the sensor is known for its strong interaction with diols and hence, the sugar sensing application1,2. On interacting with sugars (e.g. glucose, fructose and lactose) the fluorescence emission decreases with increasing sugar concentration1. The BA sensors reported previously in the literature (compounds 1, 2, 5 and 6, see Figure), have been found to be suitable for glucose sensing, in the ocular aqueous humour, in which the glucose range for a healthy person is 300-800 μM, increasing to 200-4000 μM for people with diabetes1. As a result, BA sensors have been investigated for glucose sensing when incorporated into platforms, such as smart contact lenses1,2. In this present work, novel BA sensors synthesized for the first time by us (compounds 3, 4, 7 and 8, see Figure), will be compared to BA sensor 1 in terms of their fluorescence, sensitivity to sugars and glucose sensing range

Novel chemical sensors using boronic acids for glucose detection

Boronic acids (BAs) are well-­known for their interactions with diol-­containing compounds like glucose. Fluorescent moieties are commonly considered to enable monitoring of this interaction by changes in fluorescence. Incorporation of a BA component into charged molecules, can be used to induce quenching in the emission of a fluorescent molecule, thereby creating a two-­component sensing system1-­2. Hence, a novel cationic pyrimidine BA derivative, PBA, has been investigated for its indirect glucose sensing capabilities. In this approach, the fluorescence of 7-­hydroxycoumarin (7HC) is monitored. Increasing concentrations of our novel PBA sensor, quenches the fluorescence of 7HC by 98% (Fig. 1A). The decrease in fluorescence intensity of the system is achieved through electrostatic and p-­p stacking interactions between the fluorophore and PBA-­quencher1-­2. In the presence of saccharides, the Lewis acidic BA moiety of the sensor is known to form strong, reversible interactions2. This leads to the formation of an anionic boronate diester2, resulting in the dissociation of the BA-­quencher and fluorophore complex, causing a sequential recovery of fluorescence in 7HC1-­2 by 16% (Fig. 1B). This glucose-­sensing switch can be used to indirectly quantify glucose concentrations. Moreover, the inclusion of anchoring moieties in to the PBA-­quencher shows potential for the incorporation of this molecule into soft hydrogel platforms

Bio-inspired active fluidic systems based on stimuli-responsive materials

The 1980s vision of low-cost autonomous chem/bio-sensing devices that can function reliably for years as components of implanted artificial organs, or as building blocks of widely distributed environmental sensor networks remains unrealised, despite huge investments in research effort and resources. In the 1990s, it was expected that microfluidics would provide a solution, by enabling advanced functions like calibration and sample processing to be integrated into a small, potentially mass produced chip [1]. However, microfluidics essentially emerged from semiconductor fabrication technologies, and was based on principles largely borrowed from the hugely successful microelectronics industry. Today, the dominant use model for chem/bio-sensors is ‘use once and discard’, and while this can be relatively reliable, it normally involves manual sampling and is not a scalable model [2]. In recent years, the area of stimuli-responsive materials has grown rapidly, and many different modes of action have been demosntrated. In this paper, I will focus mainly, but not exclusively, on photo-responisve soft gels and micro-vehicles based on hydrophobic droplets and show how they could be incorporated into microfluidic systems to replicate (albeit in a primitive way) some functions of our own biological circulation systems [3]. Through such concpets, it may be possible to create futuristic analytical devices in which the fluidic system is much more than a means to transport samples and reagents to a detector. Rather, it becomes an active component in the device, capable of performing advanced functions like system status checking, leak/damage detection and self-repair/maintenance. In this manner, it may be possible to dramatically extend the functional lifetime of anaytical devices far beyond the current state of the art, and make progress towards relaising the 1980s vision for chem/bio-sensors

Biomimetic microfluidics

Through developments in 3D fabrication technologies in recent years, we can now build and characterize much more sophisticated 3D platforms than was previously possible. We can create regions of differing polarity and hydrophobicity, mix passive and binding behaviours, and regions of differing flexibility/rigidity, hardness/softness. In addition, we can integrate materials that can switch between these characteristics, enabling the creation of biomimetic microfluidic building blocks that exhibit switchable characteristics such as programmed microvehicle movement (chemotaxis), switchable binding and release, switchable soft polymer actuation (e.g. valving), and detection. These building blocks can be in turn integrated into microfluidic systems with hitherto unsurpassed functionalities that can contribute to bridging the gap between what is required for many applications, and what we can currently deliver [1]. The emerging transition from existing engineering-inspired 2D to bioinspired 3D fluidic concepts represents a major turning point in the evolution of microfluidics. Implementation of these disruptive concepts may open the way to realise biochemical sensing systems with performance characteristics far beyond those of current devices. A key development will be the integration of biomimetic functions like self-awareness/self-diagnosis of condition and self-repair capabilities to extend their useful lifetime [2]. In this contribution, I will present ideas and demonstrations of practical ways to begin building a biomimetic function toolbox that could form the basis of futuristic microfluidic systems. Examples will include chemotactic microvehicles that can collaborate to perform sophisticated functions at specific locations [3] and precision control of flow behaviour in channels using light [4]. Strategies for creating high resolution (sub-200 nm) 3D soft-polymer responsive structures will be discussed. References [1] F. Benito-Lopez, R. Byrne, A.M. Răduţă, N.E. Vrana, G. McGuinness, D. Diamond, Ionogel-based light-actuated valves for controlling liquid flow in micro-fluidic manifolds, Lab Chip. 10 (2010) 195–201. doi:10.1039/B914709H. [2] L. Florea, K. Wagner, P. Wagner, G.G. Wallace, F. Benito-Lopez, D.L. Officer, D. Diamond, Photo-Chemopropulsion - Light-Stimulated Movement of Microdroplets, Advanced Materials. 26 (2014) 7339–7345. doi:10.1002/adma.201403007. [3] W. Francis, C. Fay, L. Florea, D. Diamond, Self-propelled chemotactic ionic liquid droplets, Chem. Commun. 51 (2015) 2342–2344. doi:10.1039/C4CC09214G. [4] C. Delaney, P. McCluskey, S. Coleman, J. Whyte, N. Kent, D. Diamond, Precision control of flow rate in microfluidic channels using photoresponsive soft polymer actuators, Lab Chip. 17 (2017) 2013–2021. doi:10.1039/C7LC00368D