VictorJuiz/thesis huggingface dataset:
Integrative approaches in fragment-based drug discovery

Keywords: Structural Biology
Computational chemistry
Biophysics
Fragment-Based Drug Discovery
Pleckstrin-homology domain interacting protein

This thesis combines experimental and computational methods to investigate aspects of fragment identification and elaboration in fragment-based ligand design, a promising approach for identifying small molecule drugs, to target the pharmacologically relevant bromodomain PHIP(2). The research covers various aspects of the process, from initial crystallographic fragment screening to validation of follow-up compounds.
Chapters 1 and 2 provide an overview of relevant perspectives and methodologies in fragment-based drug discovery. Chapter 3 reports a crystallographic fragment screening against PHIP(2), resolving 47 fragments at the acetylated-lysine binding site, and evaluates the abilities of crowdsourced computational methods to replicate fragment binding and crystallographic poses. This chapter highlights the challenges associated with using computational methods for reproducing crystallographic fragment screening results with submissions performing relatively weakly. Chapter 4 demonstrates the advantages of X-ray crystallographic screening of crude reaction mixtures generated robotically, showcasing reduced time, solvent, and hardware requirements. Soaking crude reaction mixtures maintains crystal integrity which led to the identification of 22 binders, 3 with an alternate pose caused by a single methyl addition to the core fragment and 1 hit in assays. It demonstrates how affordable methods can generate large amounts of crystallographic data of fragment elaborations. Chapter 5 develops an algorithmic approach to extract features associated with crystallographic binding, deriving simple binding scores using data from Chapter 4. The method identifies 26 false negatives with binding scores enriching binders over non-binders. Employing these scores prospectively in a virtual screening demonstrated how binding features can be exploited to select further follow-up compounds leading to low micromolar potencies. Chapter 6 attempts to integrate more computationally intensive methods to identify fragment follow-up compounds with increased potency through virtual screening enhanced with free energy calculations. Only two out of six synthesised follow-up compounds showed weak binding in assays, and none were resolved in crystal structures.
This thesis tackles critical challenges in follow-up design, synthesis, and dataset analysis, underlining the limitations of existing methods in advancing fragment-based drug discovery. It emphasises the necessity of integrative approaches for an optimised “design, make, test” cycle in fragment-based drug discovery.
Theoretical and practical continuity in the making of Ottoman/Turkish literary history: a metahistoriographical analysis
Keywords: metahistoriographical analysis
Ottoman/Turkish literary historiography
theoretical and practical continuity

The practice of literary historiography in the Ottoman Empire and Turkey is considered to be a relatively recent phenomenon, the emergence of which is thought to take place in the early twentieth century. Mehmed Fuad Köprülü (1890-1966) is widely acknowledged as a pioneer of the discipline. Neither the period preceding Köprülü’s input, nor the aftermath of his impact have yet come under the spotlight of rigorous scholarly research. There have been no comprehensive analytical surveys of the corpus, with a comparative perspective that evaluates the works in and of themselves as well as their similarities and differences, which could reveal the evolution of the theoretical and practical aspects of the making of Ottoman/Turkish literary history.
The purpose of this study is to tell the untold story of the intellectual journey taken by the literary historians of the Ottoman Empire and Turkey employing a novel, analytical and systematic approach to the original texts. In this project, the focus is on the historiography of literary production in Turkish, both in Perso-Arabic script and Latin, and of the Ottoman Empire and of the Turkish Republic, although there might be historiographical practices carried out in other languages, by other peoples of the Empire. The study features an extensive analysis of the corpus, commencing with early forms of literary historiography seen in the second half of the nineteenth century and encompassing the forty-five works written in the following period until the present day. It continues with an argument that challenges the prevalent viewpoint posited by contemporary criticism, featuring the idea of an epistemological rupture attributed to the transformations in the late nineteenth and early twentieth century, and particularly to the formation of the Republic. Here is demonstrated that the idea of continuity dominates the course of historiographical practice, both in the theoretical and practical sense.
Constraining the CO2 and non-CO2 contributions to the rate of warming and implications for the Paris Agreement
Keywords: carbon budget
climate change
radiative forcing

Anthropogenic climate change is well established, with historical emissions of greenhouse gases and aerosols causing 1.1C warming today, and rising at +0.2C/decade. At this rate the Paris Agreement’s 1.5C warming threshold is reached within two decades. For policymakers this proximity means that the anthropogenic warming rate is one of the most important variables to constrain today. Several methodologies exist to determine warming contributions utilizing Earth observations and climate models of varying complexity. However, many of these approaches do not establish the impact of recent emissions trends in short-lived aerosol pollutants, and consequently may underestimate the present-day rate of warming. This thesis begins by investigating the CO2, non-CO2 greenhouse gas, and aerosol contributions to anthropogenic global warming today, focusing on evidence presented by trends in satellite and in-situ observations. These trends are attributed to anthropogenic and natural sources using simplified climate models, informed by full-complexity general circulation models, to assess the observational evidence for an aerosol-induced warming acceleration. The simplified modelling approach is then pursued to evaluate physical constraints on future policy. For CO2, the use of a ‘remaining carbon budget’ — the emissions compatible with a warming threshold — simplifies policy objectives until net zero. However, the combined physical requirements of CO2 and non-CO2 mitigation ‘budgets’ is complicated by the varied lifetimes and efficacies displayed by non-CO2 pollutants, resulting in a non-trivial relationship between emissions and warming. In this thesis, I show how the forcing-equivalent metric can produce physically-coherent estimates of individual pollutants’ contribution to the remaining budget. Finally, I explore the physical conditions required for warming stabilisation, based on a mathematical framework describing the long-term properties of the carbon and thermal cycles. As a whole, my work demonstrates how models and observational constraints can be combined to provide the physical guide rails over which climate policy can be optimised.
How does autonomy in curricular design impact on teacher agency? 
Keywords: MLT
MLT 2017

For my part 3 MSc project, I have conducted scale practitioner research in regards to the impact of autonomy in curriculum design on teacher agency; this study has been exploratory, aiming to understand why and with what means teachers make decisions regarding curriculum. Studies show that teacher’s autonomy are often constricted by pressures of accountability and performativity measures. My current school, however, offers a curriculum framework that is school-based and teacher driven. Given a ‘blank slate,’ what decision do teachers make regarding curriculum design and why? Based on the premise that agency deals with action, I decided to use Mische and Emirbayer’s three-dimensional model of agency to guide my methodology, data collection and coding. Accordingly, I deployed a mixed-methods qualitative approach, including both structured and semi-structured interviews, along with observational methods (of each teacher planning a new unit) to explore my research question. I chose to use selective sampling, with six participants, half of whom have had more than five years’ experience teaching in the current Middle Years model, and half in their first.
The findings suggest that previous experience and specific contextual factors have a greater influence on teacher decision making than autonomy. Whilst many of the participants perceived autonomy in curriculum design as ‘freedom’ during their initial interview, observations during planning revealed that a teacher planned in accordance with how he or she had been trained and took few risks in regards to innovating for a different future. This suggests that the iterative dimension of agency strongly influences the practical-evaluative (contextual). Also, whilst teachers articulated educational aims, the majority of teacher talk during planning dealt with the practicalities of the classroom and of specific students; thus, whilst the projective element featured during the initial interviews, these aspirations were not articulated during the planning process. As the literature suggested, autonomy cannot be viewed as an independent variable. Educational leaders should not assume that giving teachers autonomy will empower them to take risks and imagine alternative futures. My study revealed that each school must carefully consider the opportunities that teachers have to engage with the intellectual theories and debates involved in curriculum development and provide the time and support for teachers to develop strong horizontal relationships with their colleagues.
To what extent are students from Mainland China able to access enquiry based learning (EBL) in Geography in the UK?
Keywords: MLT 2018
MLT

Enquiry based learning (EBL) is an influential style of teaching and learning. An increasing number of students from Mainland China are enrolling at independent schools in England. These students are unfamiliar with the creative and open approach of EBL and there is currently little recognition that Chinese students may find it challenging to learn through EBL. The focus of my research was ‘to what extent are students from Mainland China able to access EBL in a geography classroom in England?’
The investigation was conducted over twelve weeks and involved collaboration with a specialist English as an addition language (EAL) teacher. The methods used were teacher led student interviews, action research cycles and finally classroom observations of my teaching practice by the specialist EAL teacher.
Findings indicated that numerous barriers to learning were present. These included lexical, reading speed, confidence, reluctance to ask questions, understanding of spoken language, comprehension of tasks, lack of creativity, unmanageable tasks within allocated time periods and tasks with no prescribed answers. Differentiation strategies were developed and implemented to reduce these barriers. These included key word sheets with images, multiple choice answers, differentiated writing frames which incorporated images, image analysis and sorting activities, anonymous post-it’s, flipped learning tasks, partially completed and model answers. A combination of these strategies helped reduce the learning barriers.
Enhancing independent learning in physics by developing study skills
Keywords: MLT
MLT 2020

In this piece of practitioner action research I aimed to help students of Advanced Level Physics to become better at learning independently through teaching study skills in prescriptive homework assignments. This focus is of personal importance, having taught A level Physics for four years my in lesson or face to face teaching has improved, I’ve come to realise that a major limiting factor in my students success is their activities outside of classrooms, either entirely independently or as students working together without the presence and guidance of their teacher. This is relevant to the wider school context as there is drive to improve students metacognition, their thinking about thinking, learning about learning, to maximise students’ success in their A-level studies and in learning later in life. Teachers are dedicated to encouraging our students to become lifelong learners, helping them to develop as independent learners while studying is key to achieving this. As practitioner action research the approach taken was to investigate the specific focus, ‘how to encourage students to learn independently’ through cycles of intervention, observation, reflection and conclusion. During these research cycles the environment in which the research took place changed significantly, the school was partially closed down due to the coronavirus pandemic, and students were asked to work independently from home, communicating with their teacher and other students digitally. This gave unique opportunity for students to be observed working independently, but did mean that the intervention was put on hiatus. The intervention continues into the next academic year, and this document outlines how the research to date has influenced myself and my school’s thinking on independent learning, and how the research will continue with two new classes of year 12 Advanced level Physics students.
High porosity cooling features for turbine blade applications
Keywords: transpiration cooling
turbine blade cooling

Improving the cooling effectiveness of turbine blades is one of the key drivers in gas turbine engine performance. Transpiration cooling describes an ideal arrangement that maximises this cool-ing effectiveness through the use of porous structures. High internal surface area and uniform cool-ant distribution are some of its main benefits. However, physical limitations in manufacturing and materials mean that this arrangement is impractical to implement.
This research identifies some of the key properties that makes transpiration cooling success-ful and recreate them with geometric features already within the bounds of existing manufacturing capabilities. The use of simple, small round film cooling holes, in tight staggered arrays at varying locations around the blade profile was found to generate exceptional levels of film effectiveness. A series of experimental campaigns were carried out to quantify the effects of different parameters in driving this high film effectiveness. Features placed on the early suction surface of the blade running at low blowing ratios were seen to be perform particularly well, with film effectiveness levels above 90% being maintained to the trailing edge.
Analytical modelling of the results demonstrated that the overall array of film holes generates films that behave similarly to tangential injection slots. A saturated film core was identified, which remained effectively separate from the turbulent boundary layer. Further analysis suggested that the performance of the suction surface films could be explained by these operating in a laminar-like regime, contradicting many commonly held assumptions used for suction surface film modelling.
Investigations into the nature of the interactions between the individual film cooling jets were also carried out using numerical simulations. These illustrated some of the beneficial outcomes of positioning film holes in close proximity to each other. The effects of counter rotating vortex pairs and boundary layer velocity profiles were identified as key mechanisms driving these interactions. Crucially, the magnitude of these interactions was found to outweigh any effect of individual film hole geometry.
The present work culminated in a series of metal effectiveness tests on turbine blade geometries. These were used to obtain a complete measure of the performance of high porosity cooling arrays within a double walled cooling scheme. The aim of these experiments was to showcase the potential breakthrough in film cooling that had been unlocked by the high porosity array approach. Results in this experiment demonstrated that metal effectiveness values for the proposed systems already exceeded those of mature state of the art cooling arrangements.
Granting member state nationality to third country nationals : naturalisation issue in the EU
Keywords: third
EU
naturalisation
country
citizenship
naturalization
European Union
Union
nationals
nationality

This introductory chapter will deal with 1) the background to the nationality issue within the EU, 2) the purpose of this paper and how it is structured, 3) the review of relevant literature and the contribution this thesis hopes to make, 4) the theoretical frameworks to be used, and 5) the sources.
I. 1. The Background
The 1930 Hague Convention on Certain Questions Relating to the Conflict of Nationality Laws, Article 1, stipulates that ‘It is for each State to determine under its own law who are its nationals.’ This recognition that states have the autonomy in defining who are their nationals appears to have been directly transposed into the framework of the European Union. The 1992 Declaration on Nationality, which was annexed to the Treaty on European Union, more commonly known as the Maastricht Treaty (hereinafter referred to as the TEU), paragraph 2, says, '...the question whether an individual possesses the nationality of a Member State shall be settled solely by reference to the national law of the Member State concerned...’.
The recognition at the EU level of the Member States’ competence in defining their nationals, however, has increasingly been the target of criticisms. There has been a number of literature calling for the restriction of Member States' competence in this sphere.’ These criticisms are often based on the following line of argument: Given the fact that the term ‘nationality of a Member State’ or 'Member State nationals’ has increasingly been invoked in Community law, it is inconsistent and unjustifiable that this term has not yet acquired any Community definition while another term which is equally important within the legal framework of the Community, ‘worker’, has been repeatedly defined at the Community level.
Continued in thesis …
Controls on nickel isotope compositions of modern seawaters and marine sediments
Keywords: sulfides
phytoplankton
Ni isotopes
sediments
trace metal cycling

In this thesis, Ni isotope fractionation during marine phytoplankton uptake and amorphous Ni-sulfide formation are characterized, to improve the understanding of biogeochemistry of Ni and its isotopes in the ocean, from the surface to the bottom of the ocean. The first direct Ni isotope measurement in phytoplankton cells suggests that marine phytoplankton preferentially take up heavy Ni isotopes from the culturing medium with species-dependent isotope fractionation factors. This finding contrasts to previous hypothesis in the community that biological activity consumes isotopically light Ni in the surface ocean where the enrichment of isotopically heavy Ni is observed. The contradiction inspires a new framework of considering relative binding strength between biological metal acquisition mechanism and ambient ligands, which reconciles findings from culturing and the modern ocean. Coccolithophores show an enhancement of Fe, depletions of Co and Cu, and a decreasing isotopic pattern; with increasing Ni availability in the media, which are not seen in cultures of other species. The distinct Ni/Co efflux proteins for regulating excess cellular Ni shown in coccolithophores may cause their contrasting isotopic pattern. The Ni isotope fractionation during amorphous sulfide formation and the mineral transformation from amorphous to crystalline sulfides; suggest a potential benthic flux of isotopically heavy Ni from sulfide-containing sediments in euxinic ocean settings. This diagenetic remobilization of Ni is supported by the slightly lighter Ni isotope compositions found in nearshore euxinic sediments off Namibian margin; compared to the offshore sediments, which are anoxic but not euxinic according to the porewater chemistry. This thesis addresses important processes in the biogeochemical cycling of Ni and its isotopes in the modern ocean, demonstrating the potential and limitation of its application as a novel geochemical tracer.
"Breaking in" to Hollywood: an ethnography of women filmmakers
Keywords: women's careers
Hollywood
television
feature films
filmmaking
women filmmakers
gender inequality
ethnography

Although Hollywood filmmaking is brutally competitive, aspiring filmmakers try to “break in” and develop careers anyway, hoping to beat the nearly impossible odds. Research has shown that men are much more likely to succeed than women, who directed 5.4% of the top-grossing narrative films between 2007 and 2021 (Smith et al. 2022). Beyond largely statistical data, there is little research into women filmmakers’ experiences on the ground, and this thesis provides a distinctive, in-depth anthropological study of this significant and persistent gender gap in Hollywood. Exploring research materials collected during a critical period–the year preceding the emergence of the #Metoo movement–and drawing on interviews with 38 film and television workers from 2018, I examine production patterns, practices, and hierarchies to explain how “breaking in” to Hollywood is a highly gendered process. Focusing on women filmmakers at different times in their life course, the ethnographic chapters identify and analyze gender-based challenges at three key career stages–emerging, mid-career, and established–demonstrating that, and illuminating contextual reasons why, most women never truly “break in” to Hollywood as filmmakers. As their careers evolve, so too do reasons for not hiring them. Ultimately I argue that exclusion, precarity and risk are significant interwoven factors which have compounding effects on the lives of women filmmakers, impacting on, yet not deflecting them from, their continued efforts to break in.