VictorJuiz/thesis huggingface dataset:
Machine learning methods for next generation sequencing data: applications to MLL-AF4 leukemia and demographic inference
Keywords: sequential monte carlo
ATAC-seq
upper paleolithic
topic modelling
directional migration
machine learning
MLL-AF4 leukemia
functional genomics
enhancer biology
latent Dirichlet Allocation
demographic inference

As next generation sequencing technologies continue to mature and find applications across genomics, it has become clear that the scale and scope of generated data far exceeds our ability for manual interpretation. Machine learning has shown remarkable success in finding patterns in this data and generating biologically testable hypotheses. In this thesis, I develop and apply machine learning methods which use NGS data to answer outstanding questions in population and functional genomics.
An understanding of the genetic history of global populations has been hindered by a lack of methods capable of inferring directional migration over time. I use a sequential Monte Carlo approach (a particle filter) to sample from the posterior distribution of ancestral recombination graphs and infer likely population size and migration histories from whole genome sequencing data. I apply this particle filter to global sequencing biobanks and uncover an abundance of migration from the ancestors of non-Africans into Africa between 40 and 70 thousand years ago. I show that latent directional migration has broader implications for the inference of population size in gold-standard approaches and explore this migration in the context of African pre-history.
On a cellular rather than population scale, I apply latent Dirichlet allocation to NGS-based chromatin accessibility assays in order to model shared and distinct regulatory pathways between different cell types. I demonstrate the method's utility by recovering known regulatory biology in erythroblast development. I apply this topic modelling approach to understand cis-regulatory element usage in a treatment-resistant leukemia caused by the MLL-AF4 oncoprotein. The results highlight a previously uncharacterized class of enhancer elements depleted in DOT1L-deposited H3 lysine 79 methylation and enriched for PAF1c binding.
In this thesis, I have developed and applied machine learning approaches to identify patterns in large genomics databases and answer biological questions on both population and cellular levels.
Philosophical foundations of norms of legal method
Keywords: secondary norms
legal norms
legal validity
legal systems
legal method

Legal method is about identifying and applying the law in a particular legal system. Norms of legal method regulate that activity. They are about, among other things, sources of law, legal interpretation and conflicts of law. The thesis asks questions regarding their philosophical foundations, that is questions that are not limited to any particular legal system but concern law in general. The questions are, firstly, about the norms themselves: What do they do? How many norms can there be? Are any of them necessary? Of what kind are they? What is their normative character? What is their function? Then the thesis addresses questions about the norms’ significance for some central issues in jurisprudence, namely legal validity and legal systems. It is claimed that understanding norms of legal method together philosophically is important to elucidate them as well as some questions or problems in jurisprudence.
What are the answers? Very briefly speaking, the norms have diverse roles and can be categorised accordingly. Norms of recognition and change address the issue of existence. Norms of interpretation address the issue of content. Norms of applicability address the issue of applicability. Norms of subsumption address the issue of application and norms of institutional decision-making address issues of institutional considerations and powers. The norms are united by sharing the overall role of identifying and applying the law. While there can be many (ultimate) norms in each category in a legal system, there must be at least one norm of recognition. Some of the norms are legal norms but others are so-called interpretive norms. While some norms are duty-imposing, permission-granting and power-conferring, others are so-called qualifying norms. The norms partly constitute the law. The norms are also important for legal validity and the structure and foundations of a legal system.
Exploration of time-warped cortical spike time patterns
Keywords: Time-warp
Precise spike timing
Neural population dynamics
State-dependent coding
Neural coding
Neuroscience
Cortex
Time-warp spike timing
Noise correlations

The thesis explores the nature of information representation by patterns of action potentials in the cortex. The thesis combines analysis of sensory-evoked in vivo cortical spiking activity, large scale biophysical cortical network simulations, phenomenological modelling of representation learning through spike-time-dependent plasticity and the development of a spiking neural network simulator. Together, these approaches engendered novel findings and hypotheses regarding the nature of cortical processing.
The thesis focuses on patterns of spikes in which each neuron spikes once (`multi-neuron single spike patterns') as a possible fundamental form of cortical information encoding. The thesis characterises the temporal structure of stimulus-evoked multi-neuron single spike patterns in response to single whisker deflections in the barrel cortex of the anaesthetised rat. Spike time patterns are found to be stretched and compressed in time (i.e. time-warped) depending on the excitability of the barrel cortex on a single trial. This partly explains why precise spike time patterns are rarely reported in vivo. It is proposed that downstream neurons may decode such representations in an excitability-dependent manner, thus increasing spike time coding capacity.
The characterised form of spike time variability is tested for in a detailed biophysical model of a column of rat somatosensory cortex. It was hoped that the model could be used to understand the phenomena's underlying mechanisms and to make further predictions. A framework was developed for comparing in vivo and in silico spiking activity. Key differences between in vivo and in silico spiking activity were found, however. These differences have been used to guide further model refinement.
Hypotheses of how time-warped multi-neuron patterns of single spikes may facilitate the brain's solution to the Feature Binding Problem are presented, as well as attempts to test these hypotheses in a phenomenological spiking neural network. The latter made up the initial work of the DPhil, which aimed to explore the emergence of spike time continua. Towards this a GPU spiking neural network simulator was co-created, and was demonstrated (by collaborators) to be the fastest of its class.
Towards the detection of anisotropic magnetic field effects in flavin-based systems
Keywords: radical pairs
microscopy
cryptochromes
fluorescence
magnetoreception

Many animals, and in particular migratory birds, have the ability to use the geomagnetic field to navigate. The leading hypothesis to explain the origin of their compass sense is based on magnetosensitive radical pairs (RPs) formed in cryptochrome flavoproteins.
Numerous studies have demonstrated that the reactivity of light-induced RPs within flavin-based model systems and cryptochromes could be influenced by the magnitude of a magnetic field, giving rise to magnetic field effects (MFEs). Yet, many questions remain unanswered, especially regarding the ability of these systems to detect the direction of the field, which has been shown to provide critical information for navigation.
This work examines different chemical and spectroscopic approaches for their poten- tial to yield or elucidate directionally sensitive magnetic field responses in flavin-based RPs. Chapter 1 explores whether selectively manipulating the magnetic properties of cryptochromes in vivo could disturb the bird’s migratory behaviour. If it did, it would demonstrate that cryptochromes are i) sensitive to the field direction and ii) the primary magnetic sensor for avian magnetoreception. The potential of this ambitious experiment is assessed by examining the impact of isotopic substitution (which changes the hyperfine interaction driving the RPs’ magnetosensitivity) on the MFE of model systems.
In vitro, the directionally dependent response of RPs to a field (anisotropic MFEs) can only be detected if the radicals are immobilised and oriented. In Chapters 2-3, several matrices are investigated as potential immobilisation media and the unexpected behaviour of flavins in glycerol solutions is further examined. Chapter 4 explores direct molecular alignment via protein crystallisation and introduces confocal microscopy as a powerful technique for the study of MFEs in crystals. By exploiting the capabilities of this technique, the MFEs of several cryptochromes, including avian cryptochromes, are investigated and contrasted, leading up to the examination of anisotropic MFEs in cryptochrome crystals (Chapter 5).
How elite professional service firms recruit graduates in China
Keywords: Higher education
Professional service firms
Elites
China
Hiring

China has been experiencing a series of socio-economic transitions since the market reform was explicitly accentuated in the 1990s. On the one hand, China has grown to be the second largest economy and is now producing one of the largest groups of university-educated workers in the world. On the other hand, as a newly emergent player, the professional service sector has contributed to assimilating highly-educated graduates and accelerating the trends of financialisaton, internationalisation and knowledge-based expansion of Chinese society and economy. However, how the growing professional service sector intersects with Chinese transitions is underexplored. In particular, regardless of its theoretical and empirical significance, how professional service firms recruit graduates has long been neglected by existing literature. In this sense, this thesis aims to remedy this gap through a qualitative investigation into the campus recruitment of professional service firms in China. In Chapter 1, I begin by describing key background and context of this thesis as well as its theoretical framework and methodology. In light of a theoretical framework of symbolic boundaries and positional conflict, it attempts to provide the insights into a site of elite hiring and explore its theoretical potential. Drawing on 73 semi-structured interviews with recruiters in elite financial and consulting firms, contents of job advertisements and an array of on-site observations to campus fairs and a day of job interviews, this study is structured as four empirical chapters that chronologically analyse the process of graduate recruitment. Chapter 2 surveys what kinds of talents recruiters were looking for before the formal selection started. Chapter 3 and 4 focus on how recruiters screened and selected résumés. Chapter 5 probs into how recruiters assessed interview performances. Overall, this thesis argues that graduate hiring was a culturally ‘scripted’ project of elite professional service firms in China and shaped by recruiters’ cultural belief and wider organisational and institutional circumstances. In this context, recruiters tended to use various information in order to select graduates akin to or preferred by them or resonant to their ideals for the purpose of maintaining the order of professional workplaces.
'Women in an extraordinary time': the transnational network and educational spaces of the Canadian Eiwa Girls' mission schools in 1920s and 1930s Japan
Keywords: mission schools
Japanese history
women's history
Japan
transnational history
history of education

The Tōyō Eiwa Jogakkō, Shizuoka Eiwa Jogakkō, and Yamanashi Eiwa Jogakkō girls’ mission schools were founded by the Woman’s Missionary Society of the Methodist Church of Canada (from 1925 the United Church of Canada) in the 1880s in Tokyo, Shizuoka, and Kōfu, Japan respectively. The students, graduates, missionaries, and Japanese educators of these three institutions were physically and intellectually part of a transnational network of Christian women and organizations in 1920s and 1930s Japan. The community these inter-generational and non-diplomatic Eiwa actors built, the communication and exchange students undertook, and the mobility of graduates transcended state boundaries of Japan, Canada, and beyond. By exploring individuals and activities of these three girls’ schools and the network they constructed in the pre-WWII period, this thesis expands our understanding of educational and intellectual life in 1930s Japan. Through network development, physical and intellectual spatial construction, and curriculum and activity design, these historical actors reached outside their institutions to actively connect themselves and their peers with the wider world. In the 1930s, this appears to have been conducted with a sense of urgency. Ultimately, these schools survived a tense and nationalistic period of world history to operate into the present day. By shifting the lens from male educators to little-known women including students, and from missionaries to include Japanese actors, this study shows within these spaces mutual exchange and communication across national borders, international education, and discussions on and activities related to world peace took place throughout the 1930s. These actors envisioned Christianity, women, youth, education, and mutual exchange across state and East-West divides as able to foster understanding between individuals of different nations. This thesis thus looks to Eiwa women and youth in their roles as graduates, educators, and students to demonstrate a dynamic understanding of 1930s Japanese educational and intellectual life.
Tissue scale electrophysiological-mechanical continuum modelling for white matter transcranial ultrasound neuromodulation
Keywords: homogenised continuum flexoelectricity
ultrasound neuromodulation
electromechanical coupling

Neurological disorders are a substantial health and economic burden worldwide. Low-intensity transcranial ultrasound stimulation (TUS) is now considered as one of the most promising treatments for neurological disorders due to its high spatial resolution compared to other non-invasive neuromodulation methods. While for many decades now, ultrasound has been known to be able to influence or modulate neuronal activities in the brain, its underlying mechanisms are still poorly understood. Maybe not fully unrelated, while nerve impulses have traditionally been considered to be a purely electrical phenomenon, a growing body of evidence is now pointing towards additional thermodynamic changes occurring alongside the action potential. Numerous models have been proposed to study this electromechanical coupling phenomenon. Among these, the flexoelectric theory is postulating that a temporal variation of strain gradient in the membrane leads to current creation. Whether or not this hypothesis is fully accurate microscopically in the context of TUS, it offers a phenomenological framework that could be used at the organ scale to quantify electrical induction in the presence of minute mechanical vibrations. However, the flexoelectric theory relies on formulations directly built on the microstructural description of the underlying dielectric polarisation. In membranes, this constrains the flexoelectricity modelling to simple membrane morphologies and prevents the simulation of flexoelectricity in large scale assemblies of multiple biological cells. To this end, this work proposes a homogenised bulk flexoelectric model focussing on the continuum level formulations of bundles of flexoelectric cylinders. This model was calibrated against a microscale formulation to ensure multiscale compatibility, but it can be directly used at the macroscale for the description of strain-gradient induced electromechanical coupling without the need to account for the microstructural polarisation. A 1D proof of concept is first proposed, followed by 2D and 3D formulations of the homogenised bulk flexoelectric model. The homogenised model is used for brain white matter tracts in the context of TUS, where ultrasound induced electrical activity arising within the tracts is simulated in a human head model in 2D and a monkey head model in 3D. In the latter case, a direct comparison against experimental models is proposed. In particular, this study proposes a way to predict the loss of brain region correlation during TUS. To conclude, the framework proposed here has the potential to fully capture multiphysics phenomena such as in TUS. The results from this study provide a theoretical building block to identify the desirable ultrasound parameters for clinical and/or experimental applications that can be used for the successful treatment of neurological disorders.
A signal through the noise: accurate determination of hydrogen atom positions in crystal structures and optimisation of Laue neutron diffraction methods
Keywords: neutron diffraction
crystallographic modelling

In this thesis, Laue neutron diffraction methods are applied to determine the positions of hydrogen atoms in crystal structures accurately and with confidence, as well as informing the optimisation and development of these methods. This has allowed a variety of chemically and crystallographically interesting studies to be performed, specifically:
Determining the novel geometry around transition-metal hydride centers, where the signal due to the hydrides can be more confidently distinguished than in an X-ray diffraction experiment; using Laue neutron derived difference Fourier maps to demonstrate that proton disorder can be mistakenly assigned in X-ray derived crystallographic models; performing variable temperature Laue neutron diffraction to identify proton migratory behaviour across short-strong hydrogen bonds; reassigning the space group of a previously reported cobalt(III) coordination complex, in which the lack of inversion symmetry becomes apparent upon accurate determination of the hydrogen atom positions; using Laue neutron diffraction data to more confidently classify systems as co-crystals or salts.
Following this, the optimisation and development of the Laue neutron diffraction methods used is described. This focuses on:
Recommendations for the efficient collection of Laue neutron data, in order to optimise the data set completeness and awarded beam-time; strategic considerations for how to best answer the scientific question(s) at hand in a Laue neutron experiment, whilst planning against future contingencies; improving methods for crystal packing and shipping, particularly for air and moisture sensitive materials; discussing issues arising from ice forming on the crystal during a Laue neutron diffraction experiment, and methods for minimising this problem; more effectively modelling disorder using ring shapes, in the crystallographic refinement package CRYSTALS; providing rationale for Laue neutron specific checkCIF comments.
Alongside the aforementioned research projects, the relevant history and theory contextualising the crystallographic methods used is presented.
Translation in context: a descriptive account of Romeo and Juliet in versions by Konstantin Bal’mont and Anna Radlova
Keywords: Translation
Konstantin Balmont
Anna Radlova
Theatre
English
Romeo and Juliet
Shakespeare
Sergei Radlov
Russian
Tairov

This thesis will analyse two translations of Romeo and Juliet completed in the early years of the Soviet Union: one produced by Konstantin Bal’mont in 1919, the other by Anna Radlova in 1934. The research will use the Descriptive Translation Studies framework, particularly Gideon Toury’s idea of translation norms, in order to try to account for some of the choices made in both translations, as well as for the reception of these translations.
Indefinite causal orders in thermodynamics and from time superpositions
Keywords: quantum refrigeration
indefinite causal orders
quantum thermodynamics
superpositions in time

This thesis is concerned with the use of indefinite causal orders (ICOs) for thermodynamic tasks, and a new context in which these exotic causal structures might arise — from superpositions in time. I propose a thermodynamic refrigeration cycle which uses indefinite causal orders to achieve non-classical cooling. The cycle cools a cold reservoir while consuming purity in a control qubit. I first show that the application to an input state of two identical thermalising channels of temperature T in an indefinite causal order can result in an output state with a temperature not equal to T. This result allows the construction of the refrigeration cycle. I investigate its properties and show that thermodynamically, the result is compatible with unitary quantum mechanics in the circuit model, but could not be achieved classically. This result suggests the development of a new class of thermodynamic resource theories in which operations are allowed to be performed in an indefinite causal order. I proceed to detail a simulation of the protocol using the IBM cloud quantum computing service, which is open to all users of the internet. The simulation, which is itself a quantum refrigerator, shows that the refrigeration cycle is robust to noise and can be implemented on Noisy Intermediate-Scale Quantum (NISQ) devices. This represents the development of a promising new test-bed for ICO protocols. Finally, the possibility for ICOs to arise from superpositions in time is considered. A new formalism, developed to analyse such superpositions, is applied to the case of two events which have a quantum uncertainty associated with their times. It is shown that these events can be used as triggers which enable an ICO. The fact that such commonplace phenomena can give rise to indefinite causal orders suggests that they might be much more common in nature than is typically understood.
Civic honourability in Western Asia Minor from the late Attalid dynasty to the early Principate, 188 BCE to 98 CE
Keywords: Euergetism
epigraphy
Asia Minor
honorific culture

This is a study of the impact of Roman imperialism on the public honorific culture of the Greek cities of western Asia Minor, 188 BCE to 98 CE. It is concerned with the way that local civic languages of power, framed in the terms of reciprocal benefaction and gift- exchange, adapted to changing political structures, as Rome succeeded the earlier Seleukid and Attalid regimes. This entails relating a mass of archaeological realia for public civic discourse, as embodied in several hundred inscribed honorific decrees, statue-base inscriptions, and public dedicatory inscriptions, to known historical and political contexts, thereby composing a diachronic history of discursive and ideological change and continuity tied to specific chronological and regional boundaries. Of the five chapters, Chapters 1, 2, and 4 chart the influence of high political change. The post-Seleukid era, 188-29 BCE, witnesses an overarching Roman dominance conceived in terms of universal euergetism that affects both late Attalid euergetic self-presentation and the honorific status of local citizens, who become plenipotentiary intermediaries with Roman power. Under the principate the autocratic power of the emperor channels the ambitions of local citizens into the imperial cult, which becomes an arena for elite giving at the provincial and local levels, and encourages honorific hierarchisation and titularisation. Chapters 3 and 5 examine developments in internal political culture across these two periods. Euergetic activity in relation to gymnasia and local cults in the decades after 188 is traceable to anxieties over local identity and growing socio-economic imbalance between citizens and non-citizens; this is exacerbated in the 1st century by the presence of resident Romans, and deepening wealth inequalities, thereby giving prominence to wealth and familial descent as arguments for civic honourability. The result is a subtle change in ethos, as honorific monuments by the early empire emphasise the honorand’s memorability rather than exemplarity.