VictorJuiz/thesis huggingface dataset:
The invention of an investment incentive for pharmaceutical invention

Pharmaceutical drugs are often hailed as the poster child for the proposition that patents foster accelerated rates of innovation. This sentiment stems, in large part, from the significantly high research and development (R&D;) costs endemic to the pharmaceutical sector. I argue that if the role of the patent regime is one of fostering higher amounts of investment in the R&D; process, it is better served by a direct investment protection regime, where the protection does not depend upon whether or not the underlying idea behind the drug is “new” and “inventive”, the two central tenets of patent law. Rather, any drug that successfully makes it past the regulatory filter ought to be entitled to protection, since its discovery and development entail significant investment and risk.
Owing to the inadequacy of the current patent regime in appropriately protecting intensive pharmaceutical R&D; investments from free-riders, I propose a comprehensive investment protection regime that protects all the investment costs incurred during the drug discovery and development process. Though similar to existing data protection regimes in some respects, it differs in others. Firstly, it enables a recovery of all R&D; costs, and not only costs associated with clinical trials. Secondly, unlike patents and data exclusivity which offer uniform periods of protection, it rewards investments in a proportionate manner, wherein drug originators are entitled to protection against free-riders only until such time as they recoup their specific investments and earn a rate of return on investment that is dependent on the health value of the drug.
Given that a pure market exclusivity based investment protection regime is likely to foster excessive pricing and subject the market to the dictates of a single firm, I advocate a compensatory liability model based on a novel cost sharing methodology, where follow-on entrants are free to manufacture the drug, but must pay a reasonable amount of compensation to the originator.

Keywords: drug regulation
R&amp;D
investment
prizes
investment protection
patents
international trade law
TRIPS
data exclusivity
public funding
pharmaceuticals
WTO
drugs
compulsory licensing
Human cleavage factor I (CFIm) and its role in alternative polyadenylation of pre-mRNA

For many human protein-coding genes, alternative cleavage and polyadenylation (APA) of pre-mRNA generates distinct 3' untranslated regions (3'UTRs) with differing regulatory potential. Widespread 3'UTR shortening via APA occurs in proliferative cell states, including cancer, where it can lead to oncogene overexpression. There has therefore been significant interest in identifying factors which influence poly(A) site choice in different physiological states. The multi-subunit human cleavage factor I complex (CFIm), a core component of the mammalian pre-mRNA cleavage machinery, has been identified as a potential master regulator of APA, as its depletion leads to widespread 3'UTR shortening. However, mechanistic understanding of how CFIm influences poly(A) site selection, and how its activity is regulated, is lacking. In this work, gene editing was used to generate cell lines with substantial, permanent depletion of the 25 kDa or 68 kDa subunits of CFIm (CFIm25 and CFIm68), which exhibited the expected 3'UTR shortening for representative transcripts. Reversal of this 3'UTR shortening by CFIm25 or CFIm68 re-expression provided the basis for a complementation assay, which allowed various aspects of CFIm25 and CFIm68 function to be investigated in vivo. The capacity of CFIm25 to recognise UGUA RNA sequences was shown to make an important contribution to poly(A) site selection transcriptome-wide, and a novel function for the C-terminal arginine/serine-rich (RS domain) of CFIm68 in poly(A) site selection was identified. The potential contribution of CFIm post-translational modification (PTM) to APA regulation was also explored. Novel acetylation sites on CFIm25 and CFIm68 were identified, as well as extensive serine phosphorylation in the CFIm68 RS domain. Complementation analysis revealed that phosphomimetic mutations in this RS domain inhibited distal poly(A) site selection, suggesting a potential role for CFIm68 phosphorylation in APA regulation. Taken together, the findings presented here provide insights into several important determinants of CFIm function, and the complementation assay developed provides a useful tool for future investigations.

Keywords: cleavage factor
mRNA
alternative polyadenylation
Advisor: Norbury, C
Enantioselective synthesis of chiral building blocks with non-stabilized nucleophiles

This thesis describes the combination of non-stabilized nucleophiles and prochiral/racemic electrophiles in transition metal catalyzed asymmetric transformations. These enantioselective reactions have tremendous potential for the formation of chiral building blocks and new structural motifs that can be found in a variety of natural products and their derivatives.
The first part of the thesis focuses on the synthetic approach towards anti-cancer active diterpenoid structures. The two key steps involve a Cu-catalyzed asymmetric conjugate addition of alkylzirconocenes to enones and an intramolecular oxidative cyclisation. Particular investigations into the cyclisation are made with organocatalysis, transition metal catalysis and electrochemistry for the formation of these tricyclic scaffolds.
In the second part this work builds on the Rh-catalyzed asymmetric Suzuki–Miyaura coupling of benzeneboronic acids and cyclic allyl chlorides, which has been developed in our group. Here, the main point is to use more challenging coupling partners, such as heteroaromatic boronic acids, which are coupled to racemic cyclic allyl halides. The utility of this method is demonstrated by performing further transformations and an asymmetric synthesis of the natural product (+)- isoanabasine.
The last chapter describes the development of a new asymmetric Hiyama coupling of arylsiloxanes with racemic cyclic allyl chloride. Attempts are made to generate substrates that are not accessible via the asymmetric Suzuki–Miyaura reaction. After extensive optimisation a variety of arylsiloxanes is generated and tested with the best conditions to prove its utility in comparison to the asymmetric Suzuki–Miyaura coupling.

Keywords: Electrochemistry
Suzuki–Miyaura coupling
Boronic Acid
Siloxane
Enantioselective catalysis
Hiyama coupling
Organocatalysis
Advisor: Fletcher, S
Essays on the economics of information and education

This thesis consists of three self-contained chapters which study different topics in the economics of information and education.
The first chapter studies what families can infer about schools' relative quality from rankings, when schools' performance depends not only on their quality but also on their student intake. I develop a dynamic framework in which each cohort of families has access to the most recent ranking, but can neither observe application choices nor the allocation of past students. I study a steady-state Bayesian-Nash equilibrium, and find that a performance-based ranking is more informative about school quality if oversubscribed schools select a larger share of their intake based on ability. I also find that such a ranking is more informative if it is less costly for families to attend a non-local school.
The second chapter studies a decision maker (DM) who can consult an advisor before choosing whether or not to switch from the status quo. Both agree that switching is optimal if and only if a certain hypothesis is true. But the advisor may be biased in how he trades off falsely accepting against falsely rejecting the hypothesis. The advisor has access to a testing technology which generates noisy but informative binary signals. Over two periods, the advisor can sequentially carry out costly tests before reporting his findings to the DM. I contrast the setting in which the DM observes all test outcomes with a setting in which testing itself is hidden and the advisor verifiably discloses outcomes. I fully characterise the circumstances in which the DM is strictly better off with hidden testing than with observable testing. Finally, I study what my findings imply about the bias of the ideal advisor.
The third chapter studies the influence of peers on educational performance. I estimate a linear-in-means model of peer effects using a methodology adopted from [DeGiorgi2010]. For identification, I exploit the fact that students have different classmates in different subjects. As instruments for classmates' performance I use the characteristics of students who share common classmates with the individual but who are not themselves the individual's classmates. I find that students are significantly influenced by their classmates' average performance but not by their classmates' average characteristics: a student's average test score in maths and English increases by 0.677 of a standard deviation if the average performance of his peer group increases by one standard deviation.

Advisor: Meyer, M
Structural insights into innate immunity against African trypanosomes

The haptoglobin-haemoglobin receptor (HpHbR) is expressed by the African try- panosome, T. brucei, whilst in the bloodstream of the mammalian host. This allows ac- quisition of haem, but also results in uptake of trypanolytic factor 1, a mediator of in- nate immunity against non-human African trypanosomes. Here, the structure of HpHbR in complex with its ligand, haptoglobin-haemoglobin (HpHb), is presented, revealing an elongated binding site along the membrane-distal half of the receptor. A &Tilde;50° kink allows the simultaneous binding of two receptors to one dimeric HpHb, increasing the efficiency of ligand uptake whilst also increasing binding site exposure within the densely packed cell surface. The possibility of targeting this receptor with antibody-drug conjugates is ex- plored. The characterisation of the unexpected interaction between T. congolense HpHbR and its previously unknown ligand, haemoglobin, is also presented. This receptor is iden- tified as an epimastigote-specific protein expressed whilst the trypanosome occupies the mouthparts of the tsetse fly vector. An evolutionary pathway of the receptor is proposed, describing how the receptor has changed to adapt to a role as a bloodstream form-specific protein in T. brucei. Apolipoprotein L1 (ApoL1) is the pore-forming component of the trypanolytic factors. An expression and purification protocol for ApoL1 is presented here, and the functionality of the protein established. Initial attempts to characterise the pores and structure of ApoL1 are described.

Keywords: Human African Trypanosomiasis
Strucutral biology
Sleeping sickness
Advisor: Higgins, M
'The defence of contraries'

The aim of this thesis is to examine the meanings and functions of paradox in the late Renaissance. My understanding of Renaissance paradox, in contrast to that of most critics and historians, rests entirely on contemporary definitions of the term, rather than on its present-day meaning. Paradoxes as they are envisaged in this study begin to appear in the wake of the humanist rediscovery and dissemination of Cicero's Paradoxa Stoicorum. In this work, paradoxes are characterized as 'admirabilia contraque opinionem omnium', a definition that draws attention to two important traits of paradox, repeatedly invoked in the Renaissance: its association with wonder, and its opposition to common opinion. This thesis examines the history of classical paradox as it was revived, expanded beyond the narrow confines of Stoic ethics, and adapted to new purposes so successfully that it became a recognisable genre of polemical writing, with hundreds of works in Latin and the vernacular being described as paradoxes. Previous studies of Renaissance paradox have centred almost exclusively on its literary and vernacular manifestations, and on the paradoxical encomium in particular. My own work charts the rise to prominence and the ensuing transformations of paradox in a range of disciplines: rhetoric and ethics, theology, law, medicine, and natural philosophy. I compare the different associations that paradoxes acquire in all these areas, and the argumentative strategies that they deploy. My analysis of specific examples of paradox is informed by the methods of both literary analysis and intellectual history. Paradoxes, I argue, offered their authors the possibility of departing from established norms and of voicing novel views in a period of intellectual unrest. In their challenge to received and common opinion, they paved the way for more radical ideas in the following century, and they have much to tell us about dissident ways of thinking in the late Renaissance.

Keywords: sixteenth
disciplines
paradox
life
Renaissance
17th
seventeenth
Europe
16th
contraries
century
intellectuals
Advisor: Cave, T
Maclean, I
Supply services of English armed forces, 1509-50

This thesis attempts to trace the effect of the increased size and complexity of armies and navies in the early VIth Century on the English supply services, and also to analyse selected campaigns as a test of governmental efficiency.
The provision of ships, guns, gunpowder, and hand-weapons is first discussed, in relation to national self—sufficiency. Ship timber was occasionally imported, but England could, if necessary, have done without foreign supplies; the timber problem was not a pressing one at this period. Naval stores (pitch, cordage etc.) on the other hand, were almost always imported, and the Baltic had thus already acquired something of its later strategic importance. Equally important were the Netherlands. In 1509 all but the smallest artillery was obtained there. This was remedied by the beginning of large-scale bronze and cast-iron gun-manufacture in England; but England still depended on the Netherlands in 1550 for saltpetre (for gunpowder) and copper (for bronze).
Werner Sombart's contention that military requirements stimulated the growth of large-scale industry is discussed; shipbuilding and cannon-founding support his argument, provided that the small-scale of industry in general at this period is borne in mind.
[Continued in thesis ...]

Keywords: supply
forces
English
armed
services
Insights into the design of an improved PfRH5 malaria immunogen using vaccine-induced monoclonal antibodies

The causative agent of the most deadly form of malaria, P. falciparum, was identified over 130 years ago, yet this disease still causes 430,000 deaths each year. Although naturally-acquired immunity exists, it requires a heavy and sustained exposure to the parasite, with most succumbing as young children, before this immunity has fully developed. Effective treatments exist but with small-molecule drug resistance on the rise and little in the way of affordable alternatives, the need for an efficacious malaria vaccine is as great as ever. A successful malaria vaccine is likely to necessitate targeting each stage of the parasite's lifecycle. Immunity directed to the blood-stage, the stage which causes all the symptoms of malaria, is unique in that it would allow for a concomitant development of naturally-acquired immunity along with a reduction in morbidity and mortality. To date, antibody-mediated immunity to the blood stage requires intractably high levels of antibody and this problem is compounded by a paucity of viable candidates with which to effectively target different strains. Other fields of vaccinology, over the past decade, have been employing various structure-based strategies to increase the specific activity of the immune response thus lowering the antibody levels required for protection. However, very few detailed investigations of this kind have been conducted on a P. falciparum vaccine candidate, and certainly none as promising as PfRH5. In a world's first, fully-human antibodies raised in response to PfRH5 vaccination were isolated and extensively characterised, both functionally and structurally with the intention of elucidating the important features necessary to inform the design of an improved PfRH5-based vaccine. Synergistic and antagonistic effects of antibody combinations were noted and highlight new complexities of the immune response to PfRH5, opening the door to unanticipated potential for rational vaccine design.

Keywords: Synergy
Malaria
Vaccine
Monoclonal antibody
Advisor: Draper, S
Higgins, M
Translational relevance of AIPL1 and NUB1 in cancer

Background: Aryl Hydrocarbon Receptor Interacting Protein-Like 1 (AIPL1) interacts with NUB1 and restricts the entry of NUB1 protein into the nucleus. The interferon-induced NEDD8 ultimate buster (NUB1) protein causes degradation of neddylated and FAT10ylated proteins through the ubiquitin proteasome system. We observed AIPL1 were frequently down-regulated in various cancers compared to normal tissues. The mechanistic roles of AIPL1 and NUB1 protein in cancer cell cycle regulation remain unexplored.
Results: Meta-analysis of cancer databases revealed that expression transcripts of chaperones, including AIPL1, were down-regulated in lung, pancreatic cancer and breast cancer relative to the adjacent normal tissues. Opposite levels of both AIPL1 and NUB1 transcripts were observed in the breast cancer. So it triggers the in vitro experiments using breast cancer cells. METABRIC breast cancer clinical cohort highlighted that patients with low NUB1 transcripts had poor survival in the ER-negative subgroup (but not in ER-positive) of breast cancer patients: hazard ratio (HR)=0.66, 95% confidence interval (CI)=0.5-0.87, p=0.003 and triple negative subgroup of breast cancer patients: HR=0.67, 95% CI=0.47-0.96, p=0.028. NUB1 silencing significantly inhibits in vitro cell growth in MDA-MB-231 and MCF7 under hypoxia. AIPL1 protein forms multimers in cancer cells. NUB1 protein moved into the nucleus in hypoxia (0.1% O2 48hrs) with final confluency at 80-90%. p21 (marker of senescence) & p27 (marker of cell cycle arrest) accumulated in NUB1-silent MDA-MB-231 and RCC4 cells. It suggested that low NUB1 nuclear localisation in hypoxia cause cancer cell cycle arrest. In MDA-MB-231 cell, upon hypoxia, neddylation inhibitor (MLN4924) treated and siNUB1 transfected cells showed decreased CUL1 and further accumulated p21 & p27. The evidence suggested lower neddylated CUL1 and reduced NUB1 cooperatively stabilise p21 and p27 as the substrate of CUL1-ubiquitin ligase. The neddylation inhibitor MLN4924 treated and NUB1 knockdown group exhibited more cells in sub-G1 stage as compared to the control group. In connection to higher p21/p27, it is associated with prolonged arrested cellular aging with depletion. After silencing of NUB1, the increases in cell death of cancer cells upon hypoxia happen through the neddylation-dependent CUL1-p27-p21 and CUL2-VHL axis. We then demonstrated that HIF1α protein could be both neddylated and FAT10ylated upon reoxygenation. In a tissue microarray study of breast cancer, lower cytoplasmic expression (n=57) had worse overall survival than higher cytoplasmic expression (n=57): HR=1.779, 95% CI=1.006-3.346, p=0.048.
Conclusions: AIPL1 and NUB1 proteins exert a role in cell cycle regulation in breast cancer. Low cytoplasmic NUB1 levels are observed in the G1-S transition of cancer cells. NUB1 depletion causes G0/G1 phase arrest due to CUL1 and CUL2 ubiquitin E3 ligase-dependent pathways.

Keywords: Neddylation
chaperone
ubiquitin
Advisor: Pezzella, F
Acuto, O
Octave flutes in England 1660-1800

The small recorders, the flageolet, the fife, and the piccolo are octave flutes, sounding at four-foot pitch. The bulk of the literature relating to the recorder in the late seventeenth- and eighteenth-century England focuses on the alto (treble), for this was the most commonly used member of the family, but octave recorders have never been the subject of detailed scrutiny. There is no comprehensive study of the flageolet or of the fife in England during this period, and virtually nothing has been written on the early use of the piccolo. The thesis examines the organology of the four instruments, with most attention being given to the recorder, the dominant octave flute of the era; the changes in the instrument from the sixteenth to the eighteenth century are described, and related to changes in assigned music. The reasons for the displacement of the flageolet by the recorder in the late seventeenth century and the recorder's substantial displacement by the German flute in the eighteenth are explored. Duct flutes have long been the particular province of amateur musicians, who often studied from a self-instructor, and examples of these tutors are examined, together with a representative repertoire. Particular note is made of the English 'small flute concerti' and the use of the sopranino recorder in the late eighteenth century. A chapter examines social, financial, and performance aspects (including performance venues); professional and amateur usage of the instruments and gender differences are discussed. A comparison is made of the usage of the instruments in Continental Europe and England, where differing practices are observed regarding tutors, repertoire, and, in particular, the usage of the piccolo. The introductory review of extant literature indicates thirteen matters in which I consider the literature on octave flutes 1660–1800 to be deficient. The thesis explores these lacunae.

Keywords: Flageolet
Recorder
Advisor: Aspden, S