Doctor of Philosophy

dissertationThe blood-brain barrier (BBB) limits entry of most molecules into the brain and complicates the development of brain-targeting compounds, necessitating novel BBB models. This dissertation describes the first microfluidic BBB model allowing the study of BBB properties in relation to various chemical compounds by enabling tunable wall shear stress (WSS) via dynamic fluid flow, cell-cell interaction through a thin co-culture membrane, time-dependent delivery of test compounds, and integration of sensors into the system, resulting in significant reduction of reagents and cells required and shorter cell seeding time. Use of parallel channels first enabled simultaneous monitoring of multiple cell populations under a wide range (~x15) of WSS. The microfluidic model formed the BBB by incorporating brain endothelial (b.End3) and glial (C6/C8D1A) cells at the intersection of two crossing microchannels, respectively representing luminal and abluminal sides, fabricated in a transparent polydimethylsiloxane (PDMS) substrate utilizing high-precision soft lithography techniques. The utilized cells were adopted from immortalized cells for high consistency over repeated passages and pure and proliferative culture. The developed microfluidic BBB model was validated by (1) expression of tight junction protein ZO-1 and glial protein GFAP by fluorescence imaging, and P-gp activity by Calcein AM, confirming key BBB proteins; (2) high trans-endothelial electrical resistance (TEER) of co-cultures exceeding 250Ωcm2 confirming sufficiently contiguous cell layer formation; (3) chemically-induced barrier modulation, with transient TEER loss by 150μM histamine (~50% for 8-15min), and increase in permeability at elevated pH (10.0); (4) size-dependent (668-70,000Da) compound permeability mimicking in vivo trends; and (5) highly linear correlation (R2>0.85) of clearance rates of seven selected neural drugs with in vivo brain/plasma ratios. We demonstrated the effects of WSS (0-86dyn/cm2) on bEnd.3 properties under increasing WSS, including increase in (6) TEER, (7) cell re-alignment toward flow direction, and (8) protein expression of ZO-1/P-gp, and (9) decrease in tracer permeability. The developed in vitro microfluidic BBB model provides distinct advantages for monitoring and modulating barrier functions and prediction of compound permeability. Thus, it would provide an innovative platform to study mechanisms and pathology of barrier function as well as to assess novel pharmaceuticals early in development for their BBB clearance capabilities

Prospects for the determination of the top-quark Yukawa coupling at future e+e−e^+e^- colliders

We estimate the sensitivity to the top-quark Yukawa coupling $y_t$ at future $e^+e^-$ colliders. We go beyond the standard approach that focuses on $t\bar t h$ production and consider final states with a Higgs boson but not top quarks. The sensitivity to $y_t$ in such processes comes from the coupling of the Higgs boson to top quarks in loops. Such final states can be produced in significant numbers at center-of-mass energies that will be accessible by all proposed $e^+e^-$ colliders. In a simplified theoretical framework to parametrise deviations from the Standard Model, we find that at FCC-$ee$ and CEPC operating at $\sqrt{s}=240$ GeV, $y_t$ could potentially be measured with precision better than $1\%$. For CLIC and ILC the extraction of $y_t$ could be improved by a factor of about 2 and 7 respectively, compared to its extraction from just $t\bar t h$ final states.Comment: 14 pages, 2 figures. v2 (published version): added references, extended discussio

A COMPARATIVE THREE-DIMENSIONAL ANALYSIS OF BREATHING AND NON-BREATHING IN FRONT-CRAWL SWIMMING

Only a few studies have examined the effects of breathing in the kinematics of front crawl swimming (e.g. Payton et al., 1999). Important limitations of previous studies were that they were conducted (totally or partly) with the use of two-dimensional (2D) analysis techniques, and that body roll was calculated based on the assumption that the trunk moves as a rigid part. However, Cappaert et al. (1995) reported not only different range of motions but also different timing of shoulder and hip roll. This indicated that the rigid trunk assumption is not tenable. Therefore, the purpose of this study was to examine the effect of breathing on the kinematics of the whole body centre of mass (CM) and roll of the shoulders and hips using three-dimensional (3D) analysis methods applied to a full body model

Poetry as Social Justice in The English Review

Undergraduate Textual or Investigativ

Phantom dosimetry and image quality of Galileos Comfort Plus cone beam computed tomography

Introduction: Increasing use of CBCT in many aspects of dental treatment has been associated with an elevated concern for the long-term risks of x-ray exposure, especially in adolescent patients. An industry response to this has been to offer lower-exposure and collimated field scanning options. Methods: Effective doses resulting from various combinations of field size/location (FOV), number of image frames, and mAs settings were calculated for ATOM child and adult anthropomorphic phantom exposures using the Galileos Comfort Plus CBCT unit. Optical Stimulated Dosimetry was used with a previously validated protocol. Image quality data was acquired with the Quart DVT CBCT phantom. Results: For the same exposures, child doses averaged 32% greater than adult (p=0.0004). Full field doses were greater than mandibular followed by maxillary (p=0.0002). Dose increased with increasing mAs (p>0.0001). Increasing Contrast Noise Ratio (CNR) was associated with increasing mAs (p=0.0106) and frames (p=0.0423), while Modulation Transfer Function (MTF) was not (p>0.05). Conclusions: An average of 66% reduction in dose can be achieved when using standard exposure parameters in comparison with high-definition exposures. CNR was correlated with increasing dose; however, the clinical implication of this requires further study.Master of Scienc

Encoding and estimation of first-and second-order binocular disparity in natural images

Research supported by BBSRC Grant Nos. BB/G004803/1 (RG) and BB/K018973/1 (PH/DH).The first stage of processing of binocular information in the visual cortex is performed by mechanisms that are bandpass-tuned for spatial frequency and orientation. Psychophysical and physiological evidence have also demonstrated the existence of second-order mechanisms in binocular processing, which can encode disparities that are not directly accessible to first-order mechanisms. We compared the responses of first- and second-order binocular filters to natural images. We found that the responses of the second-order mechanisms are to some extent correlated with the responses of the first-order mechanisms, and that they can contribute to increasing both the accuracy, and depth range, of binocular stereopsis.Publisher PDFPeer reviewe

Stressor-Induced Increase in Muscle Fatigability of Young Men and Women is Predicted by Strength but Not Voluntary Activation

This study investigated mechanisms for the stressor-induced changes in muscle fatigability in men and women. Participants performed an isometric-fatiguing contraction at 20% maximal voluntary contraction (MVC) until failure with the elbow flexor muscles. Study one (n = 55; 29 women) involved two experimental sessions: 1) a high-stressor session that required a difficult mental-math task before and during a fatiguing contraction and 2) a control session with no mental math. For some participants (n = 28; 14 women), cortical stimulation was used to examine mechanisms that contributed to muscle fatigability during the high-stressor and control sessions. Study two (n = 23; nine women) determined the influence of a low stressor, i.e., a simple mental-math task, on muscle fatigability. In study one, the time-to-task failure was less for the high-stressor session than control (P \u3c 0.05) for women (19.4%) and men (9.5%): the sex difference response disappeared when covaried for initial strength (MVC). MVC force, voluntary activation, and peak-twitch amplitude decreased similarly for the control and high-stressor sessions (P \u3c 0.05). In study two, the time-to-task failure of men or women was not influenced by the low stressor (P \u3e 0.05). The greater fatigability, when exposed to a high stressor during a low-force task, was not exclusive to women but involved a strength-related mechanism in both weaker men and women that accelerated declines in voluntary activation and slowing of contractile properties

Stressor-Induced Increase in Muscle Fatigability of Young Men and Women is Predicted by Strength but Not Voluntary Activation

This study investigated mechanisms for the stressor-induced changes in muscle fatigability in men and women. Participants performed an isometric-fatiguing contraction at 20% maximal voluntary contraction (MVC) until failure with the elbow flexor muscles. Study one (n = 55; 29 women) involved two experimental sessions: 1) a high-stressor session that required a difficult mental-math task before and during a fatiguing contraction and 2) a control session with no mental math. For some participants (n = 28; 14 women), cortical stimulation was used to examine mechanisms that contributed to muscle fatigability during the high-stressor and control sessions. Study two (n = 23; nine women) determined the influence of a low stressor, i.e., a simple mental-math task, on muscle fatigability. In study one, the time-to-task failure was less for the high-stressor session than control (P \u3c 0.05) for women (19.4%) and men (9.5%): the sex difference response disappeared when covaried for initial strength (MVC). MVC force, voluntary activation, and peak-twitch amplitude decreased similarly for the control and high-stressor sessions (P \u3c 0.05). In study two, the time-to-task failure of men or women was not influenced by the low stressor (P \u3e 0.05). The greater fatigability, when exposed to a high stressor during a low-force task, was not exclusive to women but involved a strength-related mechanism in both weaker men and women that accelerated declines in voluntary activation and slowing of contractile properties

Catheter ablation of fractionated electrograms for atrial fibrillation: does it improve outcomes and can it be refined based on electrogram morphology or knowledge of the remodelling process?.

PhDCatheter ablation complex or fractionated atrial electrograms (CFAE) may improve outcomes for persistent AF. However, it is unclear whether CFAE are important in maintaining AF or whether targeting of CFAE can be refined based on electrogram morphology or knowledge of the remodelling process. A detailed classification of CFAE was described. Assessment of 100 CFAE by visual inspection in real time correlated well with detailed offline measurement. Targeting of different CFAE morphologies in 20 patients with persistent AF caused cycle length prolongation only with ablation of certain CFAE morphologies. Therefore, targeting CFAE is not simply atrial de-bulking, certain CFAE morphologies are more important for maintaining AF. A computer model was established to simulate LA wall stress using a 3D reconstruction of the chamber from CT imaging. Electrophysiologic data was acquired in 19 patients in persistent AF and compared to simulated wall stress data. Peaks in wall stress were associated with areas of low voltage suggestive of focal remodelling. CFAE were not associated with peaks in wall stress or areas of remodelling. Wall stress did not determine whether ablation of CFAE caused cycle length prolongation. Long term outcome of catheter ablation for AF was good with little late recurrence. Outcome for persistent AF was improved by targeting CFAE in addition to pulmonary vein isolation and may reduce late recurrenceBritish Heart Foundatio

Precise measurements of the W boson's mass and lepton flavour universality, and trigger development with the LHCb experiment at CERN

In the electroweak sector of the Standard Model (SM), comparing precise measurements with predictions built on the SM's assumptions offers one of the principal avenues for indirect discoveries of new physics. The W boson mass, mW, is a key SM parameter that is notoriously difficult to measure at hadron colliders, and the lack of high-precision measurements of it limits the sector's discovery power. Meanwhile, the SM's fundamental property of lepton flavour universality (LFU) has been questioned by hints of discrepancy in recent measurements of rare B-meson decays and legacy tests of W-boson decays. This thesis presents two measurements using LHCb's 2016 data that address these important issues: first, a proof-of-principle extraction of mW that paves the way for a competitive legacy measurement; and second, a test of the W boson's LFU in decays to tau leptons and muons that, when completed, will validate and complement other recent measurements shedding light on previous LFU anomalies. The value of mW was measured to be mW = 80354 _ 23stat _ 10exp _ 17theory _ 9PDF MeV; which is consistent with previous direct measurements and indirect SM predictions. It is not consistent with the very-recent CDF measurement, and therefore places LHCb in prime position to address this high-profile disagreement with a future measurement using all available data. LHCb is currently undergoing commissioning for a fresh period of data-taking, which features a brand-new detector, a factor of five more collisions and a fully redesigned trigger system. The development of the trigger validation tool HltEfficiencyChecker is also presented, which plays a crucial role in facilitating trigger optimization that fully exploits the new detector, whilst also conforming to its constraints. This tool helped the collaboration decide that the new first-level trigger should be implemented with GPUs, and is now widely used in LHCb, as exemplified in the development of trigger selections for electroweak processes in Run 3 presented here