VictorJuiz/thesis huggingface dataset:
Tropical-extratropical teleconnections and atmospheric drivers of European drought events
Keywords: Teleconnections

Atmospheric dynamics are important in tropical-extratropical teleconnections. Using maximum covariance analysis (MCA), we investigate the leading modes of covariability between the tropical outgoing longwave radiation and the extratropical geopotential height. Using observed data, the leading mode of covariability on the seasonal timescale is associated with the El-Ni~no Southern Oscillation. Using a Met Office climate model (GC3) control run, although the leading tropical mode is still ENSO, the extratropical pattern shows large differences in the North Pacific-American region.
GC3 has a large North Pacific jet bias, which according to ray tracing can affect wave propagations from the tropics. Using a barotropic model with the same ENSO tropical forcing but linearized upon the different basic states of reanalysis and GC3, the largest differences in the response are in the North Pacific-American region and agree with the MCA differences. The result is also supported by baroclinic experiments. Our finding may contribute to resolving the signal-tonoise paradox in some climate predictions.
Next, we test the mechanism of influence from the tropics to European droughts, to find potential tropical drivers of Rossby waves that are consistent between observations and the idealized models. We identify a northward shift in the tropical Atlantic precipitation and a weakening of the tropical eastern Pacific precipitation, which significantly influence about 60% of European drought events.
Investigation of nanoscopic dynamics and potentials by interferometric scattering microscopy
Keywords: single-molecule microscopy
interferometric microscopy
myosin 5a
label-free detection
single particle tracking

The advent of single-particle tracking and super-resolution imaging techniques have brought forth a revolution in the field of single-molecule optical microscopy. This thesis details the development and subsequent implementation of the technique known as interferometric scattering microscopy as a novel single-molecule tool to study nanoscopic dynamics and their underlying potentials. Specifically, Chapter 2 lays out the theoretical framework and draws comparisons between this technique and other state-of-the-art single-molecule optical approaches. Chapter 3 provides a detailed description for the design and implementation of an interferometric scattering microscope including alignment, instrumentation, hardware interfacing, image processing and respective characterisation to achieve the highest levels of performance. The following two chapters use model systems, namely the diffusion of receptor GM1 in a supported lipid bilayer and the movement of molecular motor myosin 5a, to demonstrate the intrinsic shot-noise limited nature of the technique, its ability to decouple the temporal resolution from localisation precision, and highlight the importance of taking both parameters into consideration when drawing conclusions about the dynamics of each model system. Chapter 6 provides a proof-of-concept study on the limits of sensitivity and demonstrates for the first time the all-optical label-free imaging, detection and tracking of a single protein. In the last chapter, interferometric scattering microscopy is used to quantitatively study dynamic heterogeneous systems in situ at the single particle level and thus serves as a proof of principle for future label-free studies beyond the realms of biophysics.
Graphene tunnel junctions for nanoelectronics and biosensing: intrinsic electronic noise and response to environmental factors
Keywords: Graphene nanodevices

This thesis is concerned with the investigation of Graphene Tunnel Junctions (GTJs) and their applications. GTJs are fabricated by feedback-controlled electroburning, which results in the controllable formation of nanometric tunnelling gaps. Tunnelling currents have been widely used to study electron transport through single molecules, however the scope of their practical applications remains limited.
The main aim of this thesis is to assess the feasibility of the use of GTJs for biosensing. The first research chapter summarises the results demonstrating that GTJs are highly sensitive to their local electrostatic environment. Under cryogenic conditions with reduced perturbations from the environment, the devices are used to study the dynamics of nearby charge traps. Measurements show features of Two Level Fluctuation and Lorentzian Noise. This verifies that in optimum situation the junctions are capable of detecting single electron dynamics.
The second research chapter describes the emergence of 1=f noise resulting from the superposition of fluctuators upon the increase of temperature. This chapter also presents the impact of noise on the measurement sensitivity and resulting limits of detectable sensing signals on the order of 1-10 nA. In the next chapter the impact of a liquid environment is studied. Water polarisation effects at graphene-water interface lead to decreased current levels due to electrostatic screening, and to increased noise due to molecular fluctuations.
Next, the viability of biosensing using GTJs is demonstrated by the detection of single nucleotides at nM concentrations in water solutions. The detection of deoxy-guanine and thymine triphosphates moving around junctions due to Brownian motion is demonstrated, with specifc tunnelling current spikes in the range of 1-100 nA.
Finally, I present an outlook on the development of GTJ sensing devices, including the fabrication protocol and device geometry of suspended GTJs capable of sequencing linear DNA strands. Furthermore local side-gate devices with enhanced sensing performance are proposed.
Use of patient-derived cellular models to investigate the mechanistic basis of circadian dysfunctions and chronomodulatory drugs in bipolar disorder
Keywords: circadian rhythms
fibroblasts
lithium
bipolar disorder
chronomodulation

Bipolar disorder is a highly incapacitating neuropsychiatric disorder, where patients exhibit cycling episodes of mania and depression. In addition to these characteristics, sleep and circadian rhythm disruptions are frequently observed through changes in physiology and behaviour. Lithium treatment remains effective in inducing acute and long-term mood stabilisation, yet there is ambiguity as to how it exerts its therapeutic benefits. As lithium induces significant chronomodulatory effects, one possible mechanism may be via the alteration of circadian rhythms. Using virally transduced bipolar patient-derived fibroblasts, we investigated basal circadian rhythms, as well as the cellular responses to chronomodulatory agents in order to identify any aberrancies. We then went on to investigate the mechanism via which lithium induces its chronomodulatory effects.
The use of patient-derived fibroblasts revealed the presence of circadian abnormalities, manifesting as a broad distribution of period lengths. Further, patients with a longer period phenotype exhibited muted chronomodulatory changes following lithium treatment. These changes were not restricted to lithium and were also observed with two novel chronomodulators. Remarkably, these compounds also exhibited changes to circadian rhythms and displayed lithium-like behaviours in vivo, highlighting their translational potential. We subsequently went on to confirm that lithium inhibited two major receptor coupled systems: inositol monophosphatase and adenylate cyclase. Using immortalised cell lines, we showed that lithium induces period lengthening predominantly via perturbing the phosphoinositide pathway, which elevates expression of the transcription factor C/EBPα. Whilst we found that adenylate cyclase signalling plays a contributory but subordinate role in mediating period effects, such information may be vital in informing future drug discovery processes, as it could enable the identification of mechanistically novel mood- stabilisers with fewer undesirable side effects. Thus, in this DPhil thesis, we present data highlighting that patient-derived fibroblasts could be instrumental tools which could perpetuate the drug discovery process, and suggest that C/EBPα may be responsible for lithium-induced circadian period lengthening.
The resurrection of Durga: Indira Gandhi's spectacular politics in the 1980s
Keywords: state spectacle
middle class
political performance
consumption
liberalisation
Indira Gandhi

The cult of personality around Prime Minister Indira Gandhi has traditionally been explained with reference to her role in the Bangladesh War, the Emergency, and Operation Blue Star. Moreover, historiographical narratives woven around these episodes largely portray her as a champion of ‘socialism’ and the poor. Going beyond these characterisations, this thesis is organised around four ‘state spectacles’ that captured Indian middle class imagination in the early 1980s – the Asian Games in New Delhi (1982), the launch of the Maruti-Suzuki ‘family car’ (1983), the Festival of India in Britain (1982), and the Non-Aligned Movement Summit in New Delhi (1983). The production and reception of these spectacles is analysed against the context of the Emergency imposed by Mrs Gandhi in 1975. During this period, public opinion swayed against the incumbent Congress Party and Mrs Gandhi, who was consequently ousted in the 1977 elections.
In certain ways, Mrs Gandhi’s ‘political resurrection’ in January 1980 reaffirmed her position as a popular national leader. However, she was conscious of the fragility of her dominance, and her dented image in public and the media. The primary objective of this thesis is to examine how Mrs Gandhi, through the visual medium of the ‘spectacle’, sought to remake her image from a ‘dictator’ of the Emergency days to a symbol of stability, aspirations, and national pride upon re-election. Additionally, it questions the success of this political project by turning its gaze toward the spectator-consumer – in this case a pre-liberalisation, urban middle class in India.
Consulting a range of textual and visual archives, the thesis argues that the above ‘mega-media-events’ and their carefully constructed associations with consumption, leisure, and entertainment enabled Mrs Gandhi to secure legitimacy amongst established and emerging categories of the middle class in India. In doing so, it seeks to portray another dimension of Mrs Gandhi’s constructed image as a leader of this influential demographic in ‘the long 1980s’, a period which brought enduring shifts in the Indian socio-economic landscape a full decade before the era of liberalisation.
Understanding the disease mechanisms of cerebellar ataxia through induced pluripotent stem cell models
Keywords: protein kinase C gamma
PKCg
Purkinje cells
cerebellum
SCA14
neurodegeneration
induced pluripotent stem cells
cerebellar ataxia
postmortem brain

The cerebellar ataxias are a heterogeneous group of incurable disorders that are characterised by progressive dysfunction and degeneration of Purkinje cells. Although numerous causative genes have been identified, the underlying pathogenic mechanisms remain incompletely understood, due to the limited availability of human brain tissue and the lack of reliable disease models. Accumulating evidence has suggested that subtypes of autosomal dominant ataxias (SCAs) are likely to be caused by shared pathogenic pathways. Focused on spinocerebellar ataxia type 14 (SCA14), a subtype of SCAs, this work aimed to understand the aetiology of SCA14 and related SCAs using novel disease models derived from human induced pluripotent stem cells (iPSCs). SCA14 is caused by mutations in protein kinase C gamma (PKCγ), a central molecule in signalling pathways that are important for Purkinje cell development and function. Using iPSCs derived from patients carrying two distinct SCA14 mutations (H36R and H101Q), this work has revealed three novel interconnected disease mechanisms. (1) SCA14 mutations promoted formation of PKCγ foci, which accumulate in the cytoplasm. (2) Mutant PKCγ showed increased kinase activity resulting in increased phosphorylation of substrates. (3) The mislocalisation of hyperactive mutant PKCγ is likely to affect the phosphorylation of its targets at the membrane and the cytoplasm. Importantly, results obtained in SCA14 iPSCs faithfully recapitulated the pathological findings observed in the patient post-mortem cerebellum. Finally, to determine the developmental changes in Purkinje cells, human Purkinje cells were generated from control and SCA14 iPSCs using a novel simplified protocol. Notably, the dendritic development and survival of human SCA14 Purkinje cells were significantly compromised in long-term culture. CRISPR/Cas9-mediated genome editing was also employed to correct the mutations and produce isogenic controls of SCA14 iPSCs. Together, this work highlighted the importance of a faithful disease model and the value of a patient material-driven approach for understanding the aetiology of neurological disorders. In the future, these patient iPSCs would be an ideal platform for further investigation of molecular pathways and therapeutic development for SCA14 and other cerebellar ataxias.
Insights from primary immunodeficiencies: investigating the role of GIMAP6 in the immune system
Keywords: Primary immunodeficiencies
GIMAP6

While molecular, cellular, and animal models play a vital role in immunological research, the study of patients with inborn errors of immunity provides a unique opportunity to elucidate the direct importance of specific genes in the human immune system. In this thesis, I have investigated the disease etiology of four sets of patients believed to have novel primary immunodeficiencies (PIDs) using whole exome sequencing coupled with in vitro and in vivo assays of both patient cells and model systems. In one patient, I confirmed a mutation in DNMT3B, a DNA methyltransferase known to cause a previously identified PID. I next investigated whether a homozygous missense mutation in TICAM2, a toll-like receptor signaling adaptor, might underlie the disease of a patient with recurrent pneumonia. In collaborative project, I then examined the potential role of a newly described PID-associated gene, GTPase of the immunity-associated protein 5 (GIMAP5), in autophagy and metabolism. GIMAP5 is a member of a family of conserved GTPases with a poorly understood role in leukocyte development and survival. Stemming from the work on the GIMAP5 cohort, I identified a patient presenting with splenomegaly and autoimmunity who has a novel homozygous missense mutation in GIMAP6. The majority of this thesis focuses on verification of GIMAP6 as a PID-associated gene and investigation of its molecular function. Using both patient cells and knockout mouse models, I demonstrated an autophagic defect in GIMAP6-deficient T cells, implicating GIMAP6 as a regulator of autophagy. Furthermore, I determined that Gimap6 knockout mice have early mortality due to microangiopathic kidney disease. I demonstrated that this renal disease was not immune-mediated therefore implying that GIMAP6 has a novel role in endothelial cell function. The work presented in this thesis thus highlights both the challenges of studying PIDs and the promise of these diseases to help elucidate the mechanisms of human immunity and therapies for PID patients.
Establishing a detailed tephrochronological framework for Japan to aid the synchronisation of palaeoenvironmental records across the Asian/Pacific region
Keywords: Cryptotephra
Tephrostratigraphy
B-Tm tephra
Japan
Quaternary Science
Changbaishan volcano
Lake Suigetsu
Age-modelling
Lake Sediments
East Asia
Tephrochronology
Varve Sediments
Ulleungdo volcano
Tephra framework

Tephra (volcanic ash) layers have the potential to synchronise palaeoenvironmental archives across regional to hemispheric scales. Highly productive arc regions, like those in East Asia, offer a considerable number of widespread isochrons, but before records can be confidently correlated using these layers, a refined and integrated tephrochronological framework is required. The Lake Suigetsu sequence, obtained from a small tectonic lake in central Honshu, is the most precisely dated sedimentary record for Japan. Here, the sediments are examined for the presence of thin (sub-millimetre in thickness) and ‘non-visible’ (cryptotephra) layers in order to provide a comprehensive record of East Asian volcanism, and a linchpin site for correlating sequences.
On average, cryptotephra layers are identified four times more frequently than visible markers in the studied sediments of Lake Suigetsu, providing an unprecedented record of ash fall events that reached the densely populated regions of central Honshu. Major and trace element glass geochemistry obtained from these tephra layers is compared to new and published datasets to pinpoint their volcanic source. The cryptotephra were erupted from sources that span the length of Japan, and volcanoes further west, including Ulleungdo (South Korea) and Changbaishan (North Korea/China).
Constrained eruption ages are modelled for the tephra layers identified in the sequence, which can be transferred into other sedimentary records that contain these markers. Cryptotephra identifications show that many eruptions dispersed ash more widely than previously anticipated, and are able to synchronise palaeoclimate records over hemispheric scales. For example, the archive provides the most southerly tephra occurrence of the B-Tm tephra, synchronising this mid-latitude record to the Greenland ice cores. The augmented Lake Suigetsu eruption archive is established as a key node within the tephrostratigraphic framework for Japan, and provides an important resource for volcanological research, with constraints on the frequency, reoccurrence intervals and dispersal of numerous eruption events.
Malaria transmission in Cambodia: Are plantations a hotspot?
Keywords: malaria transmission
plantation
Cambodia
malaria modelling
migrant workers
rubber plantation
south east Asia
hotspot
Malaria

Background: Malaria is a leading cause of morbidity in Cambodia with an estimated 55,000 cases in 2014. Malaria prevalence is highest in forested rural areas, where a large proportion of the population live and work. Plantations are hypothesised to be “hotspots” for malaria transmission due to their proximity to forests and the vectors therein.
Methods: An analysis of malaria incidence data collected on plantations and in surrounding local villages in north-eastern Cambodia, as well as epidemiological analysis of risk factors for malaria prevalence on plantations. A deterministic compartmental model was developed to simulate malaria transmission dynamics on plantations.
Findings and conclusions: Malaria incidence in both villages and plantations follows a seasonal pattern with a peak in cases toward the end of the wet season in October to November. There was no statistical difference in incidence between settings. Mondulkiri province has a second peak at the start of the wet season which may be attributed to the type of work conducted on the plantations at that time or population migration. Permanent non-vector permeable housing in the wet season (OR 0.30; 95% CI: 0.11–0.86, p <0.05) and use of bed nets in the dry season (OR 0.15; 95% CI: 0.03–0.62, p <0.001) were the only factors found to have a significantly reduced odds of malaria prevalence. The plantation malaria model demonstrates that importation of cases by migrant workers is currently not a factor in malaria transmission on plantations. Plantation workers with immunity and asymptomatic malaria act as a reservoir enhancing malaria transmission and need to be targeted in elimination efforts. The malaria model also shows that as the plantations approach elimination, the transmission pattern will shift from a stable endemic to unstable epidemic pattern due to declining immunity which is likely to result in more clinical and severe malaria.
Development and characterisation of human monoclonal antibodies against the Ebola virus glycoprotein
Keywords: antibodies
Ebola virus
human monoclonal antibodies
monoclonal
immunotherapy
therapeutic antibodies
Ebola virus glycoprotein

The current Ebola virus outbreak in West Africa has infected over 27,000 people and claimed over 11,000 lives, making it the deadliest and most widespread Ebola epidemic in history. The high caseload and rapid geographic spread has been due in part to crumbling healthcare infrastructure, critical shortages of healthcare workers, paucity of resources, and local traditional practices. In addition, although supportive care is available at treatment centres, there are no effective therapies available in the affected countries. A number of potential Ebola virus therapeutic agents are currently being tested in accelerated clinical trials, but there is still no drug with proven efficacy in humans.
In this dissertation I describe the isolation of the first fully human Ebola-specific monoclonal antibodies (mAb) from vaccinees during phase 1 of the Oxford Ebola vaccine trial. This was achieved through single cell sorting of antibody secreting cells (ASC) at day seven post boost, isolation of the immunoglobulin (Ig) heavy and light chain genes, expression vector cloning and transfection of human cell lines to produce mAbs. I also attempt to characterise the Ebola-specific mAb’s binding affinity, binding site, and cross-reactivity with other historic Ebola virus strains by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assays (IFA). I have also tested their neutralising ability with an in vitro pseudotyped influenza microneutralisation (MN) assay. I present a diverse panel of twelve mAbs with a range of binding characteristics and neutralising abilities, four of which are cross-reactive with both the Zaire and Sudan Ebola viruses. Once fully characterised, these antibodies may potentially be used as part of a mAb cocktail for pre- or post-exposure prophylaxis and cure for Ebola virus disease.