VictorJuiz/thesis huggingface dataset:
Total asymmetric syntheses of iminosugars
Keywords: organic chemistry
natural products
total synthesis

This thesis is concerned with the development of ring-closing iodoamination and ringexpansion methodology and its subsequent application to the asymmetric syntheses of pyrrolidine and piperidine iminosugars.
Chapter 1 highlights the remarkable biological properties displayed by iminosugars and introduces methods for the formation of the pyrrolidine and piperidine sub-classes.
Chapter 2 describes investigations into the ring-closing iodoamination of bishomoallylic amines which occurs with concomitant N-debenzylation to give an iodomethyl pyrrolidine scaffold. Conversion to the corresponding aziridinium species followed by its regioselective intermolecular ring-opening by H2O enabled the synthesis of (+)-2,5-dideoxy-2,5-imino-Dglucitol (DGDP). A protocol for the preparation of its 1-deoxy-1-amino analogue (+)-ADGDP was also developed.
Chapter 3 details studies into the ring-expansion of iodomethyl pyrrolidine scaffolds via the trapping of CO2 (from NaHCO3) to produce cyclic carbonates as single diastereoisomers. Subsequent deprotection of these piperidines allowed the syntheses of (−)-1-deoxymannojirimycin (DMJ) and (+)-1-deoxyallonojirimycin (DANJ) to be completed.
Chapter 4 delineates investigations into the trapping of alternative “X=C=Y” electrophiles, via the ring-expansion methodology developed in Chapter 3, initially utilising a model system. These studies culminated in the development of the trapping of p-TsNCO and the application of this methodology in the total asymmetric syntheses of (−)-ADMJ and (+)-ADANJ, the 2-deoxy-2-amino analogues of (−)-DMJ and (+)-DANJ, respectively.
Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.
The behaviour of jacked concrete pipes during site installation
Keywords: pipe jacking

While much money and effort has been spent by manufacturers and users of pipe jacking equipment to develop suitable techniques, this work appears to be the first to study the method at full scale, in a scientific research programme. It has involved monitoring a series of five pipe jacks during construction. In each case a heavily instrumented pipe was incorporated into the pipe string to measure pipe joint stresses, pipe and joint compressions and contact stresses between pipe and ground. Total jacking loads and movements of the pipe string were also measured and all results correlated with a detailed site log, full tunnel alignment surveys, and observed ground conditions. The success of the site monitoring has been highly dependent upon the development of a suitable instrumentation and data acquisition system in conjunction with appropriate site procedures for working in the restricted and physically demanding pipe jack environment without undue disruption to normal site operations. The build up of total jacking force is the result of highly complex soil-pipe interaction. The local interface stresses are essentially frictional in most ground conditions, and can be related to the shear strength of the ground. The problem is in determining the effective radial stresses which are affected by soil insitu stresses, stiffness and strength; groundwater conditions; rate of progress; pipeline misalignment and use of lubricants. Relations between pressure distributions at pipe joints and measured tunnel alignments are presented. That small angular deviations between successive pipes cause severe localisation of stresses on their ends is clearly demonstrated. Careful back analysis shows that the linear stress approach of the Concrete Pipe Association of Australia can adequately match the measured stresses and could be used by pipe manufacturers to provide design data on allowable jacking forces for pipes on the basis of pipe size, packer properties, concrete strength and angular alignment. It is also clear from the small pipe barrel stresses that improved packing materials would allow more of the potential strength of pipes to be achieved. Since relative angular than absolute deviations control transfer mechanisms between pipes, uncritical adherence to specifications based on absolute line and level is counter-productive.
Feedback in dwarf galaxies
Keywords: numerical astrophysics
galaxies
astrophysics

Stellar feedback processes have been suggested as a mechanism for explaining various properties of galaxies, especially dwarf galaxies, which have weaker potentials and thus lower escape velocities for galactic winds. In this thesis, I present work done during my DPhil to better understand these processes. I begin by discussing the techniques used to simulate galaxies as collections of astrophysical fluids in a cosmolog- ical context, and present some methods for interpreting the results of such simulations. I then present two projects aimed at furthering our understanding of feedback in dwarf galaxies.
The first project is the investigation of a suite of simulations of satellites of a Milky Way-class halo. We discuss the formation of high-redshift dwarf galaxies and the effect that supernova feedback and reionisation have on the gas content and star formation history of these objects. We find that neither process has a dramatic effect on the star formation rates in high redshift dwarf galaxies that have already begun forming stars prior to reionisation. We do find, however, that the population of satellites is dramatically altered by the presence of cooled gas in the host halo, which increases the tidal stripping of satellites that pass close to the host. The second project concerns detailed simulations of a 15 solar mass star throughout its evolution, studying photoionisation, wind and supernova feedback from this star in various environments. Preliminary results are given for these simulations, which are compared to the results of previous authors.
Competitive identity formation in the Turkish diaspora
Keywords: Armenian genocide
Turkish-American
diasporic identity

This thesis examines the politics of narrative control, and how it relates to the formation of diasporic consciousness among Turkish migrants in the United States. It asks how Turkish diasporic identity is formed and shaped by discourses that frame Turks, and that interrogate who or what a ‘Turk’ is? This thesis suggests that this process of continual construction and re-construction of diasporic consciousness should be investigated as a matter of competitive identity formation, meaning that there is competition between multiple actors to impose a definition or label on a diasporic group and to achieve broad-based support for that label or definition. This also implies the attribution of specific values, ideas, and political agendas to that group.
The thesis examines the roots, motivations and activities of Turkish American activists in Washington DC. Based on an analysis of their political orientations and internal fissures, it focuses on the current political debate over official recognition of the deportations and massacres of Armenians by Ottoman forces as a genocide. It argues that Turkish American activists have coalesced on the defensive around this issue, framing it as a matter critical to the identity of Turks. Their manifold activities to prevent the further institutionalisation of the ‘genocide’ label in American political discourse do not, however, always resonate with the passive majority of Turkish Americans.
Molecular Genetics of Language Impairment
Keywords: Communication Disorders
Genetics,Behavioral
Neurosciences
Genetics,Medical
Genetics

Developmental language impairments are neurodevelopmental disorders in which the acquisition of language, a task which children typically perform with ease, is hindered or fraught with difficulty. This work focuses on specific language impairment (SLI), a common and highly heritable language impairment in which language development is abnormal while other developmental domains are normal. Additionally, a case-study of a child with a broader linguistic and behavioural phenotype is also presented. The work described in this thesis includes both genetic and functional investigations which were aimed at identifying candidate genes for language impairment and provide insight into the genetic mechanisms that underlie language development.
I performed a genome-wide association study of SLI which included child genotype effects, maternal genotype effects, parent-of-origin effects, and maternal-foetal interaction effects. This study found significant paternal parent-of-origin effects with the gene NOP9 on chromosome 14, and suggestive maternal parent-of-origin effects with a region on chromosome 5 which had previously been implicated in autism and ADHD. Case-control and quantitative association analyses of HLA genes and SLI identified several risk alleles and protective alleles. A case-control association analysis for related individuals which used an isolated population affected by SLI identified a non-synonymous coding variant in the gene NFXL1 which was significantly more frequent in affected individuals than in unaffected individuals. High-throughput sequencing of the coding regions of NFXL1 and LD blocks surrounding associated variants in ATP2C2, CMIP and CNTNAP2 (as reported in previous studies) identified novel or rare non-synonymous coding variants in NFXL1 and ATP2C2 in SLI families as well as intronic variants in all four genes that were significantly more frequent in SLI probands than in population controls.
I describe a functional study of NFXL1 examining its expression in various brain regions, the presence of different splice variants across several tissues, its effect on genes it potentially interacts with, and the subcellular localisation of the protein.
Finally, I present the case-study of a child with language impairment who had chromosomal rearrangements which spanned the location of FOXP2. I examine the potential influence the chromosomal rearrangements had on FOXP2 expression and describe a lincRNA gene which was disrupted by the chromosomal inversion.
In conclusion, this work identified new candidate genes for language impairment, provided further support for the involvement of previously-identified candidate genes in SLI and contributed to the understanding of the molecular function of a newly-identified candidate gene for SLI.
Constituting the settler colony and reconstituting the indigene:- the native administration and constitutionalism of Sir George Grey K. C. B. during his two New Zealand governorships (1845-1853, 1861-68) until the outbreak of the Waikato War in 1863
Keywords: Harringtonianism
James Harrington (1611-1677)
South African history
British Imperial racial policy and administration
New Zealand history
Australian history
history of the British Empire
Sir George Grey K. C. B (1812-1898)

Sir George Grey (1812-1898) served as Governor of South Australia, of New Zealand twice, and of the Cape Colony. This thesis explains his policy for the first time for a history of the political ideas of colonization. Grey introduced the policy of racial amalgamation to settler colonies after the 1837 Report of the Select Committee into Aboriginal Affairs, that had advised the policy of segregation as had been North American policy under Sir William Johnson. This thesis demonstrates that Grey was a Liberal Anglican who had adopted neo-Harringtonian thought, and who introduced Jeffersonian native policy into British native policy. He practised the strategic theory of Antoine-Henri Jomini, applying it to native policy. Grey captured the monarchical constitution of the empire for what had been a settler policy of dissent to the segregation of indigenes that dated back to Tudor Ireland and early Viginia. Grey's distinctive intellectual practices were ethnograpical research and speculation, for which he enjoyed an international reputation, and the constitutional design of settler colonies, an activity he came to totally identify with. The thesis concentrates on his first New Zealand governorship (1845-53) and upon the resumption of his second New Zealand governorship (1861-68) because it was in that colony he first fully practised his native policy and participated in constitutional design, and into which he brought about a crisis of indigenous amalgamation on the eve of the Waikato War in 1863, having introduced full responsible government.
Avian malaria in the montane tropics
Keywords: parasite
community diversity
eccological uniqueness
avian malaria
host
phylogenetic uniqueness

Understanding the unequal distribution of life on earth is a fundamental goal of ecology and evolutionary biology. Past efforts to explain large-scale patterns in diversity have tended to focus on two broad classes of explanation, one invoking the importance of abiotic factors (i.e. climate and vegetation) and the other biotic (i.e. competition); but neither has proven entirely adequate. Parasites are a major but poorly understood component of life that may offer some answers. Yet despite widespread theoretical support and some empirical evidence, the role of parasites in explaining patterns in the diversity, distribution, and abundance of species remains largely untested in natural communities. In this thesis I use a mega-diverse elevation gradient of birds as a model system to study the role of avian malaria in explaining these macroecological patterns.
In the first data chapter I tested the extent to which patterns of infection across species is predictable. I found that the effects of host ecology and environment were weakly related to infection prevalence and were not consistent across different malaria lineages. Instead, I show that hosts coexisting with many close phylogenetic relatives consistently experience higher infection than evolutionarily distinct host species. In the second chapter I tested if parasite sharing may help explain these observed relationships and show that parasite sharing among host pairs declines with the time since divergence. Spatial contiguity between host pairs was also positively associated with parasite sharing. In the third chapter I tested how infection prevalence varies across species ranges in accordance with expected variation in host abundance. I show that birds are more likely to be infected at the centre of their elevation range, where host abundance is expected to be highest. Intriguingly, I also found that the incidence of host infection is unrelated to the position within the geographic range of the parasite. In the fourth data chapter, I tested whether parasites may regulate diversity by limiting geographic ranges of their hosts through ‘apparent competition’ in which a non-lethal parasite in a primary host, may be lethal in a secondary host. In support of this, I found that more observed bird ranges end at parasite infection zones than would be expected by chance.
Taken together, my results suggest that parasites may play a major role in shaping patterns in the distribution and diversity of species, over both ecological and evolutionary scales. This is likely to arise and be maintained by host parasite interactions in which distantly related hosts are less likely to be infected by local parasites than close relatives, thus promoting the build up of diversity locally. On the basis of my analyses, I conclude that across montane elevation gradients in birds, and across diversity gradients more generally, parasites are likely to play a crucial role in the origin and maintenance of high biological diversity
.
Characterisation of a novel group B oncolytic adenovirus, ColoAd1
Keywords: group B
adenovirus
oncolysis
oncolytic viruses

Developing high potent oncolytic virus with multimodal antitumour capabilities is crucial for realizing the full potential of oncolytic virotherapy in cancer treatment. ColoAd1 is a novel replicating chimeric group B adenovirus recently bioselected from a large library of recombinant viruse. This thesis aims at evaluating the oncolysis ability of ColoAd1, characterization of its cellular activities and the corresponding responses from host tumour cells, elucidating the killing mechanism as well as exploring its potential applications in the advanced cancer therapy.
Among all oncolytic adenoviruses tested, ColoAd1 elicited the strongest cytotoxicity with a rapid killing kinetics in tumour cells. The virus displayed high infection efficiency, enhanced genome replication (compared to other adenoviruses) and strict selectively in tumour cells.The viral oncolysis also induced a bystander killing effect.
Investigation of the host cells responses during ColoAd1 oncolysis showed the virus mediated cell killing is not classic apoptosis but rather necrosis-like. The dying cells displayed the early cytoplasmic membrane leakage, falling intracellular ATP with a rise in calcium, disruption of the cell cycle and cellular DNA damage, with rapid release of progeny virions from the cell; on the other hand, ColoAd1-killing lacked the characteristic hallmarks of apoptosis. Autophagy may play a role in final execution of oncolysis but is not the main death mechanism. The cellular pathway involved in ColoAd1 oncolysis was further studied by using a panel of specific inhibitors. The results indicated the ColoAd1 mediated cell death is PARP- and RIP1- dependent and necroptosis could be the major death mechanism.
The highly oncolytic potency and special killing mechanism of ColoAd1 may have beneficial implication for advanced cancer therapies, including the possibility of circumventing drug resistance and invoking cancer immunotherapy.
The data in this thesis supported ColoAd1 as a novel potent oncolytic virus candidate. It promises to overcome the major drawbacks of Ad5 and therefore could have enhanced therapeutic efficacy in future clinical trial.
Elucidating the role of GBA in the pathology of Parkinson's disease using patient derived dopaminergic neurons differentiated from induced pluripotent stem cells.
Keywords: Parkinson's disease
heterozygous GBA-N370S
iPSC
dopaminergic neuron

Heterozygous mutations in the glucocerebrosidase (GBA) gene represent the most common risk factor for Parkinson’s disease (PD), a disease in which midbrain dopaminergic neurons are preferentially vulnerable. However, the mechanisms underlying this association are still unknown, mostly due to the lack of an appropriate model of study. In this thesis, we aimed at elucidating the role of heterozygous GBA mutations in PD using a specific human induced pluripotent stem cell (hiPSC)-based model of disease.
First we developed a protocol for the efficient differentiation of hiPSCs into dopaminergic cultures, and extensively characterized the derived dopaminergic neurons which expressed multiple midbrain relevant markers and produced dopamine. Next we screened a clinical cohort of PD patients to identify carriers of GBA mutations of interest. Using for the first time hiPSCs generated from PD patients heterozygous for a GBA mutation (together with idiopathic cases and control individuals) we were able to efficiently derive dopaminergic cultures and identify relevant disease mechanisms. Upon differentiation into dopaminergic neuronal cultures, we observed retention of mutant glucocerebrosidase (GCase) protein in the endoplasmic reticulum (ER) with no change in protein levels, leading to upregulation of ER stress machinery and resulting in increased autophagic demand. At the lysosomal level, we found a reduction of GCase activity in dopaminergic neuronal cultures, and the enlargement of the lysosomal compartment in identified dopaminergic neurons suggesting a decreased capacity for protein clearance.
Together, these perturbations of cellular homeostasis resulted in increased release of α-synuclein and could likely represent critical early cellular phenotypes of Parkinson's disease and explain the high risk of heterozygous GBA mutations for PD.
Unravelling the biological roles of charged carbohydrates
Keywords: PHOSPHATE
SULFATE
TREHALOSE
ORGANIC CHEMISTRY
TREHALOSE-6-PHOSPHATE
MALDI
CARBOHYDRATE CHEMISTRY
SnRK1
MANNOSE RECEPTOR

The phosphate and sulfate esters of carbohydrates are widespread in nature, where they partake in a variety of signalling roles. This thesis focuses on the involvement of trehalose-6-phosphate (Tre-6-P) in regulating plant growth, and the function of sulfated carbohydrates in the immune response.
In plants, Tre-6-P is a critical messenger that conveys environmental information for the control of metabolic state. Beneficial natural conditions lead to an increase in the in vivo concentration of Tre-6-P, which in turn triggers biosynthetic processes facilitating plant growth. However, the mechanism by which this effect is exerted is largely unknown. A thorough understanding of this fundamental signalling pathway could allow considerable improvements in agriculture. Recent evidence has found an interaction between Tre 6 P and a protein kinase system (SnRK1), mediated via an intermediary protein whose identity is unknown. Our efforts to identify this elusive protein are presented. Methodology is developed to allow the synthesis of Tre-6-P analogues for defining structure-activity relationships, with particular attention focused towards the desymmetrization of trehalose and the control of phosphate migrations. Tre-6-P is tethered to a solid phase resin allowing affinity extraction of putative intermediary factors. The 14-3-3 class of regulatory proteins is identified as a potential binding partner of Tre-6-P.
The mannose receptor (MR) is an essential element of the mammalian immune system. Expressed on macrophages, the protein can bind and internalize pathogens through their surface exposed carbohydrates. However, the receptor can also dimerize, upon which it is able to divalently bind to sulfated carbohydrates. The biological significance of this sulfate binding is poorly understood. Current hypotheses invoke a role for the sulfate mediated trafficking of MR dimers to areas of B-cell maturation for antigen presentation, thus linking the innate and adaptive defence mechanisms. In any case, the dimerization of the MR is an essential prerequisite for interaction with carbohydrate sulfates. Methodology is required to probe this dimerization on the surface of cells under their native conditions. In this thesis, we use fluorescence microscopy to study the binding of various probes to macrophage and endothelial liver derived cell lines. Results of our initial investigations are presented that show internalization of the probes. The use of FRET imaging to directly probe the presence of MR dimers is studied.