VictorJuiz/thesis huggingface dataset:
Asymmetric synthesis of α-alkylated aldehydes using chiral enamines

Direct generation of enantioenriched mono-α-alkylated aldehydes by intermolecular nucleophilic substitution is a general and long-standing problem in synthesis, and is of importance due to the diverse reactions such aldehydes undergo for introducing asymmetry into molecules.
The work described in this thesis initially details the development of the first lithium amide capable of efficiently converting terminal epoxide into enamine functionality, where the latter also demonstrates effective C-alkylation activity. Not only addition to Michael acceptors, but more notably substitution using activated organohalides (α-bromoacetates, benzyl, allyl and propargyl bromide) gave the corresponding α-substituted aldehydes in good to excellent yields. Alkylation with propargyl bromide yielded only the propargyl-substituted aldehyde with none of the corresponding allene observed; this result shows that N-alkylation followed by [3,3] sigmatropic rearrangement is not occuring. Importantly, a range of short-, longer-chain and secondary unactivated alkyl iodides also proved viable.
Significantly, with chiral lithium amides, the corresponding chiral enamines could be alkylated with strongly electrophilic benzyl, allyl and propargyl (no allene seen) bromides in very good yields, and with short chain alkyl iodides – MeI and EtI in satisfactory yields, to provide the first direct access to α-alkylated aldehydes with high asymmetric induction by intermolecular nucleophilic substitution.

Keywords: terminal epoxides
aldehydes
asymmetric synthesis
alkylation
enamines
Advisor: Hodgson, D
Regulation of the human RNA nucleotidyl transferase ZCCHC11

Terminal uridylation of RNA 3ꞌ ends has recently been recognised as an important biological regulatory mechanism. The human terminal uridyl transferase ZCCHC11 was shown previously to uridylate and thereby regulate replication-dependent histone mRNAs and several miRNA precursors and mature miRNAs. Studies in cancer cell lines, mouse models and patient samples suggest that ZCCHC11 is a potential oncogene. However, very little is known about regulation of its expression and subcellular localisation. In this study, the regulation of the expression of ZCCHC11 was investigated, especially in relation to the roles played by the untranslated regions of its mRNA. The second aim of this study was to investigate the subcellular localisation of ZCCHC11, both under physiological conditions and under cellular stress. The results presented show that ZCCHC11 expression is regulated negatively through its 5ꞌ and 3ꞌUTRs. Upstream open reading frames in the 5ꞌUTR decrease its translation, while regulation through the 3ꞌUTR involves the combined activity of positive and negative factors. In this study it was shown that HuR positively regulates ZCCHC11 expression, whereas TTP contributes to its negative regulation. An homologous enzyme, ZCCHC6, negatively regulates ZCCHC11 expression. Regulation through the 3ꞌUTR of ZCCHC11 is particularly marked following S-phase arrest. ZCCHC11 expression increases under cellular stress and both UTRs take part in this regulation. Regulation under cellular stress also involves an alteration in sub-cellular localisation. ZCCHC11 is predominantly cytoplasmic in unstressed cells, but re-localises to p-bodies and stress granules under cellular stress. Mutating one of three zinc knuckle motifs within ZCCHC11 significantly decreased differential co-localisation with stress granule marker TIA-1 under oxidative stress. Taken together, the data presented provide insights into the post-transcriptional regulation of this post-transcriptional regulatory protein and its subcellular localisation, especially under cellular stress.

Keywords: Molecular Pathology
Advisor: Norbury, C
Lydia

A date-chart of significant periods and events from the third millennium BC to the seventh century AD prefaces the work. The text's chronological span runs from the heyday of the Mermnad kingdom to that of the Roman Empire, and the primary emphasis is on giving a narrative of the country's development under Greek influence: a wide range of literary and archaeological material is employed to this end.
The thesis is divided into six parts: the first deals with geographical notices in such authors as Strabo and Pliny; the second chronicles the Mermnad period, between the seventh and sixth centuries, with particular reference to contacts with the Ionian Greeks; the third describes Lydian experiences during the ensuing period of Persian hegemony, between the sixth and fourth centuries; the fourth, covering the sequel to Alexander's takeover, focusses on the culminating stages of Hellenization, discussing Sardis' Hellenistic period and the Seleukid and Attalid foundations in the countryside. The fifth part discusses the village communities, over an extended period as the topic warrants: inscriptions of the Roman period predominate, and are incorporated on the grounds that a broader panorama is thereby achieved, and that the patterns delineated will have changed only slowly and are anyway of relevance for the Hellenized country's continuing history. The sixth part, on religion native and foreign, deals with the relevant inscriptions and literature, charting the progressive influence of Persian and Greek cult but also the surviving Anatolian elements.
Appendices follow on the evidence for the process of change in language use from Lydian to Greek, on Maionia and the Heraklidai, and on Mycenaean contacts, together with a catalogue of the numismatic sources for religious history. Maps and sketch-plans accompany the text at appropriate points.
Free curves on varieties

In this thesis we study various ways in which every two general points on a variety can be connected by curves of a fixed genus, thus mimicking the notion of a rationally connected variety but for arbitrary genus. We assume the existence of a covering family of curves which dominates the product of a variety with itself either by allowing the curves in the family to vary in moduli, or by assuming the family is trivial for some fixed curve of genus g. A suitably free curve will be one with a large unobstructed deformation space, the images of whose deformations can join any number of points on a variety. We prove that, at least in characteristic zero, the existence of such a free curve of higher genus is equivalent to the variety being rationally connected. If one restricts to the case of genus one, similar results can be obtained even allowing the curves in the family to vary in moduli. In later chapters we study algebraic properties of such varieties and discuss attempts to prove the same rational connectedness result in positive characteristic.

Keywords: vector bundles on curves
etale fundamental groups
rationally connected varieties
free curves
Advisor: Flynn, EV
The body through the lens: anatomy and medical microscopy during the enlightenment

This thesis examines the role of microscope technology in informing medical and anatomical knowledge during the Enlightenment. Past historians have claimed that microscopy generally stagnated until the popularisation of achromatic microscopes and cell theory in the middle of the nineteenth century. As evidence for this decline, historians have pointed to the poor quality and slow development of microscope designs until the popularisation of achromatic microscopes in the 1820s. In contrast, this thesis highlights the role of specific Enlightenment-era microscopes in answering medical and anatomical questions. It suggests that medical microscopy was far more advanced than previous scholarship has ascertained. Thus far, instrument historians have focused more attention on competing instrument makers as opposed to rival instrument users. This thesis presents several case studies which explore both makers and users. These concern the histories of Enlightenment-era epidemiology, reproduction theory, anatomy, and physiology as well as the different types of microscopes which influenced these fields.
In terms of methodology, this thesis neither follows nor casts doubt on any particular theory of historical development; rather, it attempts to shed further light on available primary sources and their contexts. Presenting key case studies illustrates the difficulties that early microscope users faced in acquiring and publishing new observations. To explore the practice of early microscopy further, this thesis presents re-enactments of these case studies using Enlightenment-era microscopes and modern tissue samples. Thus, this thesis is a call to broaden the scope of primary sources available to historians of science and medicine to include instruments and re-enactments.
This thesis finds that technological advances did not correlate to microscopical discovery in medicine or anatomy. Both simple and complex microscope designs aided anatomical and medical research. Broader advances in anatomy, physiology, and medical etiology dictated the utility of medical microscopy. Although various groups, such as the French clinicians, saw little need for microscopy towards the end of the eighteenth century, microscope-based evidence continued to play a diagnostic role among lesser-known practitioners despite its lack of visibility in medical literature.

Keywords: microscope history
history of medical microscopy
eighteenth-century microscopes
Advisor: Corsi, P
Bennett, J
Making sense of affirmative action

This thesis examines organizational programmes designed to manage racial identities in the South African workplace. It focuses on race-based affirmative action (AA) programmes.
The AA debate has become a proxy for a more fundamental contest over the political boundaries of legitimate action and discourse. Notwithstanding pockets of resistance, there is consensus (amongst business leaders) on the need for AA policies. This is explained, in part, by post-1994 shifts in the boundaries of legitimacy. Rejection of AA is no longer a legitimate course of action.
The AA controversy seems to be serving as a litmus test for the state of race relations in SA. The political transition has been accompanied by attempts to reconstitute political identities. It is suggested that the language of Africanism is providing the conceptual grammar with which to understand these processes. Race has become the primary axis through which an African identity, apposite to the 1990s, is being theorized. In the face of economic uncertainty and inequality the temptation is to naturalize identities. Hence the appeal of strictly defined race-based AA programmes.
Despite the moral lexicon which has sprung up around AA, many companies are arguing that AA makes good business sense. It is needed to meet changes in the demographic profile of the consumer and supplier markets. The political and legislative imperative to implement AA means that companies need to make sense of it economically. This is not to suggest that managers are simply having to make a leap of faith with regards to AA. The issue is more complex: whilst many are making a virtue out of necessity, this necessity may prove to have its virtues.
AA programmes cannot be understood in isolation from the economic 'realities' that enable, shape and constrain them. Given these adverse economic conditions, AA will, in all likelihood, have limited individual impact. At most, its gains will be modest. It will not eliminate the apartheid legacy of racial and gender inequalities, nor can it alone overcome the effects of other economic forces. AA needs to be located within a broader policy agenda aimed at promoting economic equity. It is in this respect that it has the potential to be an effective policy tool.
The Grand Condé in exile

This thesis looks at the career of the Grand Condé - Louis II de Bourbon, Prince de Condé - between 1652 and 1660. During this period the prince was in exile in the Spanish Netherlands. As a consequence of his power and status in France the prince's exile had a decisive impact not just upon the politics of the captaingeneral's court in Brussels, but more widely, upon the foreign policy of Cromwell's Protectorate, Philip IV's government in Madrid, the regime of Cardinal Mazarin in Paris and the Franco-Spanish war.
International relations between France and Spain during the 1650's have been largely ignored by historians, so too has French political history in this period. Yet, the 1650's were a vital decade for France and Spain both historically and historiographically. The period saw the final stage of the costly and attritional conflict between the two 'great' crowns, whilst in France the regime of Cardinal Mazarin was the last ten years of government by a cardinal-minister before Louis XIV's declaration of personal rule in 1661. This has assumed enormous significance for historians many of whom see it as an important period of transition.
Ten major European archives have been consulted to build a detailed picture of the impact of Condé's exile upon politics within France and the war being fought in the Flanders theatre. The cardinal's regime existed throughout the 1650's in an environment of acute uncertainty and instability whilst it was by no means clear that the war with Spain was a demonstration of an 'ascendant' France dealing the death blows to a 'declining' Spain. By raising questions about France's 'rise' to European supremacy and the internal stability of Mazarin's regime the thesis rejects the straightforward terms in which this period has been treated. In particular, using the example of Condé and placing his exile and Mazarin's regime in the context of aristocratic politics, it demonstrates that there were no indications that grandee power was in decline. Indeed, the thesis argues that the power of the grands as a crucial element in the power structure of Ancien Regime France, was set to continue into the next century.
Knowledge of God in Philo of Alexandria with special reference to the Allegorical Commentary

This thesis is a context-sensitive study of key epistemological commitments and concerns presented in Philo’s two series of exegetical writings. The major conclusion advanced in this thesis is that two theological epistemologies, distinct yet related, can be detected among these writings. The first epistemology is specific to the Allegorical Commentary. The second epistemology is specific to the ‘Exposition of the Law.’
The epistemology of the Allegorical Commentary reflects a threefold conviction: the sovereignty of God, the creaturely contingency of the human mind and its inescapable limitations. In conversation with key epistemological notions of his day, Philo develops this threefold conviction in exegetical discourses that are grounded in Pentateuchal texts portraying the God of Moses as both possessing epistemic authority and aiding the aspiring mind to gain purification and perfection in the knowledge of God. Guided by this threefold conviction, Philo enlists key metaphors of his day – initiation into divine mysteries and divine inspiration, among others –in order to capture something of the essence of Moses’ twofold way of ascending to the divine, an approach which requires at times the enhancement of human reason and at other times the eviction of human reason.
The epistemology of the ‘Exposition’ reflects Philo’s understanding of the Pentateuch as a perfect whole partitioned into three distinct yet inseverable parts. Philo’s knowledge discourses in the ‘creation’ part of the ‘Exposition’ reflect two primary movements of thought. The first is heavily invested with a Platonic reading of Genesis 1.27 while the second invests Genesis 2.7 with a mixture of Platonic and Stoic notions of human transformation and well-being. Philo’s discourses in the ‘patriarchs’ segment reflect an interest in portraying the three great patriarchs as exemplars of the virtues of instruction (Abraham), nature (Isaac), and practice (Jacob) which featured prominently in Greek models of education. In the ‘Moses’ segment of the ‘Exposition,’ many of Philo’s discourses on knowledge are marked by an interest in presenting Moses as the ideal king, lawgiver, prophet and priest who surpasses Plato’s paradigm of the philosopher-king. In keeping with this view, Philo insists that the written laws of Moses represent the perfect counterpart to the unwritten law of nature. The life and laws of Moses serve as the paradigm for Philo to understand his own experiences of noetic ascent and exhort readers to cultivate similar aspirational notions and practices.

Keywords: law of nature
divine incomprehensibility
divine beneficence
Exposition of the Law
exegesis
laws of Moses
Allegorical Commentary
human rationality
Plato
Aristotle
Protagoras of Abdera
epistemology
philosopher-king
mystery initiation
Philo of Alexandria
post-Hellenistic philosophy
divine inspiration
Advisor: Bockmuehl, M
Studies towards the total synthesis of tetrodecamycin

Tetrodecamycin (1) is a novel α-(𝛾-hydroxyacyl) tetronic acid based polyketide antibiotic isolated from the culture broth of Streptomyces nashvillensis MJ885-mF8 by Takeuchi et al. in 1994. Compound 1 shows potent inhibitory activity against Gram-positive bacteria including Bacillus anthracis and methicillin resistant Staphylococcus aureus (MRSA).
It was proposed that an Aldol reaction of trans-decalin core 2 and tetronic acid derivative 3 followed by a face selective epoxidation and a subsequent epoxide-opening reaction would deliver the 6,6,7,5-skeleton of tetrodecamycm (1). To investigate this proposal, the silyl enol ether 5 was prepared from cycloheptene 4 in 7 steps. An unusual domino silyl enol ether reaction sequence was observed when the silyl enol ether 5 was submitted to a Diels-Alder reaction. It afforded cycloadduct 6, which was converted to the key intermediate 2 after another 3 steps (Scheme 1).
Concurrently, double functionalisation of simple cyclic silyl enol ethers was investigated. Because of some difficulties in reproducing good overall yields to the cycloadduct 6, a second synthetic route was proposed. It was envisaged that a palladium-catalysed oxidative cyclisation or an organoselenium-mediated cyclisation reaction of compound 8 would construct the 6,6,7,5- skeleton 7, which would be converted to tetrodecamycin (1) via dihydroxylation followed by an introduction of the exo-methylene group. The intramolecular Diels-Alder reaction of trienal 11 afforded trans-decalin 10, which was converted to β-keto ester 9 in 2 steps. A Dieckmann-type cyclisation of 9 afforded compound 8 in good yield. However, so far transformation to compound 7 has not been achieved (Scheme 2).

Advisor: Baldwin, J
Role of OX40-OX40L interactions in the immune response to solid organ allografts

Transplantation is the treatment of choice for end stage organ failure however current immunosuppressive therapies whilst effective at preventing acute allograft rejection, fail to prevent late graft loss due to chronic rejection and are associated with an increased risk of infection and malignancy. Therefore there is a clear unmet clinical need for improved strategies to prevent allograft rejection.
OX40 is a member of the TNFR superfamily that has potent costimulatory properties. Although the impact of blockade of the OX40-OX40L pathway has been well documented in models of autoimmune disease, its effect on the rejection of allografts is less well defined. Therefore the aim of this thesis was to determine the impact of OX40 blockade on conventional and regulatory T cell responses to allografts.
We found that activation of CD4+ and CD8+ naïve and memory T cells resulted in the induction of OX40 expression and that blockade of OX40-OX40L interactions partially inhibited the response of alloreactive T cells in vitro and prevented skin allograft rejection but did not result in the induction of tolerance. OX40 blockade was found to have no effect on the activation and proliferation of T cells but rather effector T cells failed to accumulate and migrate to skin allografts. This was shown to be the result of an enhanced degree of cell death amongst proliferating effector cells.
In addition, blockade of OX40-OX40L interactions at a time of exposure to alloantigen resulted in a pool of Treg with an enhanced ability to suppress T cell responses to alloantigen in vitro and in vivo. Counter-intuitively, OX40 blockade was found to increase the potency of alloreactive Treg by promoting survival following re-activation.
Finally, although OX40 blockade impacted both conventional and regulatory T cell responses, anti-OX40 administration did not promote skin or heart allograft survival in immunocompetent recipients and failed to synergise with blockade of other costimulatory molecules to prevent allograft rejection. In conclusion, these data demonstrate that blockade of OX40-OX40L interactions can attenuate naïve and memory T cell responses to alloantigen whilst promoting the survival of alloreactive Treg. Therefore, we propose that anti-OX40 would be a worthwhile adjunct to pre-existing strategies to induce tolerance.

Keywords: Treg
costimulation
OX40
T cells
mice
Advisor: Jones, N
Wood, K
The role of ephrinB2 in hematopoietic stem/progenitor cell differentiation from an arterial hemogenic endothelium

During development, hematopoiesis develops in temporally distinct waves in the yolk sac (YS) and embryo proper, culminating in the emergence of definitive hematopoietic stem cells (HSCs) from the hemogenic endothelium (HE) of the dorsal aorta. The close association of this aortic endothelium with definitive hematopoiesis suggests a functional relationship between arteriogenesis and blood development, but this association is not fully understood. To gain insight into this relationship, we have chosen to study the role of the “arterial” marker, EphrinB2 (EfnB2) in hematopoietic specification. EfnB2 is a transmembrane protein critical for the development of the arterial vascular system. We find that EfnB2 is expressed in the VE-Cadh+CD41- HE in Day 2 BL-CFC (blast-colony forming cell) culture and Day 6 EBs (embryoid bodies), and that EfnB2 expression in ES cell differentiation enriches for endothelial cells with greater hemogenic capacity. Knock-down experiments in ES cells showed that EfnB2 is not required for endothelial cell commitment and survival. It is also not required for early hematopoietic commitment and differentiation from EBs or BL-CFCs. However, we find that EfnB2 is required for the maturation of ES cells into CD41+/CD45+ hematopoietic cells in OP9 co-culture and for definitive hematopoietic colony formation in MethoCult3434 medium. This requirement for EfnB2 expression was confirmed by peptide-mediated blocking of EfnB2 binding to its cognate receptors and by forced expression of a phospho-tyrosine signaling-deficient EfnB2. These results provide evidence for an essential role of endothelial EfnB2 in hematopoiesis.

Keywords: EphrinB2
Advisor: Porcher, C
Tosato, G