VictorJuiz/thesis huggingface dataset:
Molecular mechanisms underlying haplotypespecific regulation of gene expression at the microtubule associated protein tau locus
Keywords: single nucleotide polymorphisms
microtubule associated protein tau
allele specific splicing
parkinson's disease
gene expression

Genome wide association studies (GWAS) have identified the H1 microtubule associated protein tau (MAPT) haplotype single nucleotide polymorphisms as leading common risk variants for Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Gene expression studies have demonstrated haplotype-specific increases in expression of MAPT exon 3-containing transcripts from the protective H2 allele compared to the H1. The difference in alternative splicing between the haplotypes likely contributes risk or protection in the absence of protein coding variants.
Here, we investigate the regulation of MAPT exon 3 alternative splicing by common, risk-associated, non-coding, haplotype-specific single nucleotide polymorphisms (SNPs) through a combination of in silico analysis of the MAPT locus, in vitro gene expression and biochemistry studies. Comparative sequence analysis of whole-locus genomic H1 and H2 MAPT (143 kb) vectors showed they capture over 86% of the MAPT sequence diversity. We generated and expressed haplotype-hybrid H1 and H2 MAPT vectors in a human neuroblastoma cell culture model and demonstrated that a functional SNP rs17651213 near the exon 3 5' splice site regulates exon 3 inclusion in a haplotype-specific manner. Using RNA-electrophoretic mobility shift assays (RNA-EMSA), we showed differential RNA-protein complex formation at the H1 and H2 sequence variants of SNP rs17651213. We further identified candidate trans-acting splicing factors interacting with functional SNP rs17651213 sequences by RNA-protein pull-down experiment and mass spectrometry. Finally, gene knockdown of candidate splice factors identified by mass spectrometry demonstrated a role for hnRNP F and hnRNP Q in the haplotype-specific regulation of exon 3 inclusion.
In this study, we have dissected the MAPT locus to identify sequences regulating the allele-specific alternative splicing of exon 3 and provided mechanistic insights into how common non-coding H1/H2 MAPT haplotype-specific SNPs may contribute to the risk/protection of neurodegeneration at a complex genetic locus.
Rare genetic variants and susceptibility to severe bacterial diseases
Keywords: Complex traits
Human genetics

Infectious diseases are a major cause of morbidity and mortality worldwide. Streptococcus pneumoniae
and Neisseria meningitidis are major causes of severe bacterial disease which can manifest as invasive disease such as bacteraemia and meningitis. Exposure to these pathogens is relatively widespread, yet only a minority of individuals develop invasive disease. A host genetic component to infectious disease susceptibility has been implied from twin and adoptee studies. A role for rare large effect genetic variants in predisposition to infection has been demonstrated through the study of individuals with primary immunodeficiencies. However, a majority of these studies have been undertaken in individuals with a history of recurrent disease or in multi-case families. The relative role of rare genetic variants of moderate to large effect at the population level has not been widely explored. This thesis presents effort made using next generation sequencing methods to identify rare genetic variants that lead to increased susceptibility to bacterial disease focussing on meningococcal disease, pleural infection(empyema), pneumococcal disease and sepsis phenotypes.
Using an exome sequencing approach in 13 cases with invasive meningococcal disease, a novel mutation leading to a complement deficiency and increased risk of meningococcal infection was identified and functionally validated in one individual. This mutation in the CFP gene was demonstrated as leading to impaired properdin secretion. Further analysis implicated loss of function mutations in CD4 and ZAP70 as novel loci for meningococcal disease susceptibility.
A case control association analysis for sepsis susceptibility highlighted the possible role for small Rho GTPases in sepsis pathology. By aggregating all rare predicted deleterious mutations in a gene, four genes in this pathway, (ROCK2, ARHGAP18, FYN and CDC42BPG) were implicated as having an excess of rare deleterious variants in sepsis samples compared to population controls.
A similar approach identified low frequency genetic variants in the CD109 gene as predisposing to empyema susceptibility in children.
Finally, preliminary evidence from adult individuals with invasive pneumococcal disease points to a potential role of the RNASE7 gene in invasive pneumococcal disease susceptibility. This association was primarily due to a predicted deleterious missense mutation present in cases and absent in controls.
Taken together, these results have identified a number of potential loci with rare variants associated with susceptibility to severe phenotypes of bacterial diseases.
Thin-walled structures for energy absorption
Keywords: energy absorption
structures
origami

This thesis considered three types of new and improved high-performance energy absorbing devices for either compression or bending applications. These improvements were achieved by only altering their initial geometries for desired failure modes. Three types of proposed energy absorbing structures are as follows.
First, origami initiators were added to tubes with concave cross-sections. This new type of geometries, named as origami concave tubes, successfully triggered a reliable progressive buckling failure, which is uncommon for tubes with concave cross-sections. Origami concave tubes achieved ultra-high energy absorption and relatively low peak force. A comprehensive numerical, experimental, and theoretical analysis was conducted on the square, traditional concave, and origami concave tubes, which showed origami concave tubes achieved 3.3 times of specific energy absorption of square tubes. Additional to the huge improvement, it was illustrated that origami concave tubes can approach the theoretical limit of energy absorption through progressive buckling failure.
Second, thin-walled tubes with corrugated cross-section instead of traditional circular tubes were proposed for inversion. Comparing to circular tubes, the introduction of corrugation not only increased specific buckling force and reduced imperfection-sensitivity of tubes, but also decreased load needed for inversion process. In consequence, thin corrugated tubes could be inverted significantly more reliably, and even allowed practical frictional contact and geometric imperfection, which was not achieved or claimed before for tube inversion. A comprehensive numerical, experimental, and theoretical analysis was carried out on thin circular and corrugated tubes inversion, and validated the effectiveness of the new design. Thin corrugated tube inversion also reaches the theoretical limit of energy absorption.
Third, a series of novel bending devices of beams, panels, arches, and shells using origami technique were developed. These bending devices can provide more constant bending resistance and overall higher energy absorption than conventional open-section beams. Numerical simulations and experiments were used to validate these designs, which showed that properly designed origami bending devices can achieve 23.0%-40.0% increase of energy absorption and 12.7%-20.7% lower load uniformity than those of a conventional beam.
Nonlinear control of the Josephson plasma in superconducting cuprates
Keywords: Atomic and laser physics

Femtosecond optical laser pulses have been comprehensively applied in the past to control the material properties of high critical temperature superconductors. However, since the superconducting gap is of the order of several millielectronvolts, optical photons have the potential to deplete the condensate by breaking Cooper-pairs.
This thesis takes a novel direction as it reports on the non-dissipative control of the Josephson plasma in the layered cuprate superconductor La1:84Sr0:16CuO4 using terahertz electromagnetic waves. To achieve sufficiently intense sub-millimetre radiation, two complementary experimental approaches are taken. First, the table-top tilted pulse front technique is employed as a source of microjoule broadband terahertz pulses. Second, a large-scale free electron laser is operated to achieve multi-cycle pulses of less than two percent relative bandwidth.
Using the tilted pulse front technique, out-of-plane superconducting transport in La1:84Sr0:16CuO4 is gated bi-directionally on ultrafast timescales. The applied electric field modulates the interlayer coupling, leading to picosecond oscillations between superconducting and resistive states. Thereby, the modulation frequency is determined by the electric field strength in spirit of the a. c. Josephson effect. Throughout the oscillations, in-plane properties remain unperturbed, revealing an exotic state in which the dimensionality of the superconductivity is time-dependent.
Using a free electron laser, it is shown that resonant terahertz excitation of nonlinear Josephson plasma waves in La1:84Sr0:16CuO4 creates a metastable state that is transparent over a narrow spectral region. This finding is interpreted as the result of disruptive quantum interference between the linear plasma modes of the cuprate and an optically injected Josephson vortex lattice, which features the periodicity of the driving field, giving rise to three-level quantum interference optical transparency.
Both observations demonstrate the potential of layered superconductors for quantum nonlinear optics and are of relevance for applications in ultrafast nanoelectronics.
Room temperature caesium quantum memory for quantum information applications
Keywords: Quantum optics
Quantum computing
Spontaneous parameteric down-conversion
Atomic vapour
Alkali atoms
Four wave mixing
Single photons
Pulsed lasers
Quantum information
Raman transitions
Caesium
Quantum memory
Quantum process tomography
Nonlinear optics

Quantum memories are key components in photonics-based quantum information processing networks. Their ability to store and retrieve information on demand makes repeat-until-success strategies scalable. Warm alkali-metal vapours are interesting candidates for the implementation of such memories, thanks to their very long storage times as well as their experimental simplicity and versatility. Operation with the Raman memory protocol enables high time-bandwidth products, which denote the number of possible storage trials within the memory lifetime. Since large time-bandwidth products enable multiple synchronisation trials of probabilistically operating quantum gates via memory-based temporal multiplexing, the Raman memory is a promising tool for such tasks. Particularly, the broad spectral bandwidth allows for direct and technologically simple interfacing with other photonic primitives, such as heralded single photon sources. Here, this kind of light-matter interface is implemented using a warm caesium vapour Raman memory. Firstly, we study the storage of polarisation-encoded quantum information, a common standard in quantum information processing. High quality polarisation preservation for bright coherent state input signals can be achieved, when operating the Raman memory in a dual-rail configuration inside a polarisation interferometer. Secondly, heralded single photons are stored in the memory. To this end, the memory is operated on-demand by feed-forward of source heralding events, which constitutes a key technological capability for applications in temporal multiplexing. Prior to storage, single photons are produced in a waveguide-based spontaneous parametric down conversion source, whose bespoke design spectrally tailors the heralded photons to the memory acceptance bandwidth. The faithful retrieval of stored single photons is found to be currently limited by noise in the memory, with a signal-to-noise ratio of approximately 0.3 in the memory output. Nevertheless, a clear influence of the quantum nature of an input photon is observed in the retrieved light by measuring the read-out signal's photon statistics via the g(2)-autocorrelation function. Here, we find a drop in g(2) by more than three standard deviations, from g(2) &Tilde; 1.69 to g(2) &Tilde; 1.59 upon changing the input signal from coherent states to heralded single photons. Finally, the memory noise processes and their scalings with the experimental parameters are examined in detail. Four-wave-mixing noise is determined as the sole important noise source for the Raman memory. These experimental results and their theoretical description point towards practical solutions for noise-free operation.
Behold your mother: the Virgin Mary in English monasticism, c. 1050-c. 1200
Keywords: Virgin Mary
Anglo-Norman England
Medieval Monasticism

This thesis examines the place of the Virgin Mary in the intellectual culture of Benedictine and Cistercian monasticism in medieval England, between c. 1050 and c. 1200. Drawing high profile thinkers, including Anselm of Canterbury (d. 1109), into dialogue with lesser known figures, it reveals the richness of monastic contributions to Marian doctrine and devotion, in many cases for the first time. The shape of the analysis is provided by five key 'moments' from Mary’s life, unfolded consecutively across six chapters. Chapters 1 and 2, on Mary's conception, reveal a confident and pioneering monastic culture which drove the evolution of an obscure Anglo-Saxon feast into a theological doctrine, despite fierce opposition at home and abroad. Chapter 3 explains how Mary's virginity was adopted as a blueprint for the monastic life by Ælred of Rievaulx (d. 1167) and Baldwin of Forde (d. 1190), both of whom were inspired by its fruitfulness in the Incarnation of Christ. Chapter 4 brings to light the contributions made to exegesis of the Song of Songs as a poem about Mary’s humility by the mysterious Honorius Augustodunensis (d. 1140) and John of Forde (d. 1214). Chapter 5, on the divine maternity, demonstrates how English monastic theologians gave new life to understanding of Mary as Theotokos ('God-bearer') by drawing out its significance for their own spiritual maternity as leaders of religious communities. Chapter 6 shows how Mary was believed to have entered into the pain of the Crucifixion through her own spiritual martyrdom, and how monks sought to share the experience with her by a communion of charity. These and other insights offer a compelling glimpse into the culture of English monasticism between the demise of the Anglo-Saxons and the advent of the friars. Inspired by a desire to understand and ultimately to know Mary, Benedictine and Cistercian monks produced theological and spiritual works which were imaginative, often intimate and occasionally pioneering. Most of all, they were profoundly pastoral, composed in the belief that Mary could inspire and support those who had embarked upon the monastic via perfectionis.
Innovation hubs in Africa: assemblers of technology entrepreneurs
Keywords: organization of entrepreneurship
assembly
entrepreneurial communities
Africa
innovation hubs

Innovation hub organizations—or 'hubs'—have become a prevalent form of support for technology entrepreneurship in Africa. About 170 African hubs have been established, most since 2010. Practitioners have argued either that hubs are transformative network infra-structures for Africa's fledgling digital economy or that they are ineffective business incubators. This thesis steps back from this debate about whether hubs work. Instead, it asks how African hubs work, specifically how they shape relationships of technology entrepreneurs. Literature on intermediation and incubation is reviewed to establish a theoretical framework. The thesis then tests and extends the framework based on an extensive, grounded empirical inquiry. In-depth case study data (including 119 interviews with 133 participants) on six hubs were collected during field studies in Kigali, Harare, and Accra from September-December 2014. The thesis finds that the analyzed hub organizations were defined by nested, fluidly bounded entrepreneurial communities. Communities varied by their level of activation: mem-bers of active communities had concern for each other and recognized communities as social entities, while inactive community members only shared a loose purpose. The six hubs followed two distinct organizational patterns: the technology hub (depending on active core communities) and the entrepreneurship hub (relying on active peripheral communities). Based on these results, the thesis theorizes hubs as assemblers of technology entrepreneurs: hubs assemble previously distant and different actors into entrepreneurial communities. Assembly is unique to hubs: it is related to but different from incubation and most forms of intermediation. Assembly theory addresses important meso-level analytical gaps in prior research on the coordination and organization of entrepreneurship. The thesis underscores limitations in African technology entrepreneurship environments, advising hub practitioners to acknowledge that 'only what is there can be assembled.' Ultimately, it highlights that hubs have been critically misunderstood, and clarifies what hubs can and cannot do for technology entrepreneurs
Molecular determinants of chromatin accessibility at CpG islands in mouse embryonic stem cells
Keywords: genomics
chromatin accessibility
transcription
epigenetics

In eukaryotic cells, transcription factors and polymerases must access DNA in the context of nucleosomes and chromatin. The accessibility of DNA sequences to such trans-acting factors is an important feature of gene regulatory elements, including promoters. In vertebrates, the majority of gene promoters coincide with CpG islands (CGIs), which remain free from DNA methylation and exhibit elevated CpG densities. This hypomethylated and CpG-rich state at CGI promoters is associated not only with transcriptional activity, but also with high levels of chromatin accessibility. However, the causes and consequences of such chromatin accessibility remain unclear. To address this, I have profiled chromatin accessibility in mouse embryonic stem cells (ESCs). In addition to confirming that CGI accessibility is independent of transcriptional activity, I was able to demonstrate that the loss of DNA methylation in ESCs resulted in increased chromatin accessibility at a subset of CpG-rich repetitive elements, suggesting that non-methylated CpG-rich sequences may, at least partially, facilitate open chromatin states. This was supported by preliminary work targeting bacterial CpG-rich sequences into the mouse genome, where they were sufficient to establish novel regions of chromatin accessibility. To examine potential mechanisms by which hypomethylated DNA could serve to promote chromatin accessibility, I profiled chromatin accessibility in mouse ESCs lacking various chromatin-modifying proteins which are normally enriched at CGIs, with the histone demethylases KDM2A/B linked to maintaining open chromatin at CGIs. As an alternative approach to understanding the causes of chromatin accessibility in mouse ESCs, I examined the mechanism by which the pioneer transcription factor OCT4 is able to access previously inaccessible chromatin, and reveal that it requires the chromatin remodeller BRG1 to remodel chromatin and facilitate transcription factor binding at distal regulatory elements. Ultimately, this work provides an insight into some of the molecular determinants of chromatin accessibility in mouse ESCs, although many of the consequences of such chromatin states remain unclear.
Easing information extraction on the web through automated rules discovery
Keywords: List Segmentation
Semantic Annotations
Web Data Extraction
Data Repair
Knoweldge Base
Data Cleaning
Named Entity Recognition

The advent of the era of big data on the Web has made automatic web information extraction an essential tool in data acquisition processes. Unfortunately, automated solutions are in most cases more error prone than those created by humans, resulting in dirty and erroneous data. Automatic repair and cleaning of the extracted data is thus a necessary complement to information extraction on the Web.
This thesis investigates the problem of inducing cleaning rules on web extracted data in order to (i) repair and align the data w.r.t. an original target schema, (ii) produce repairs that are as generic as possible such that different instances can benefit from them. The problem is addressed from three different angles: replace cross-site redundancy with an ensemble of entity recognisers; produce general repairs that can be encoded in the extraction process; and exploit entity-wide relations to infer common knowledge on extracted data.
First, we present ROSeAnn, an unsupervised approach to integrate semantic annotators and produce a unied and consistent annotation layer on top of them. Both the diversity in vocabulary and widely varying accuracy justify the need for middleware that reconciles different annotator opinions. Considering annotators as "black-boxes" that do not require per-domain supervision allows us to recognise semantically related content in web extracted data in a scalable way.
Second, we show in WADaR how annotators can be used to discover rules to repair web extracted data. We study the problem of computing joint repairs for web data extraction programs and their extracted data, providing an approximate solution that requires no per-source supervision and proves effective across a wide variety of domains and sources. The proposed solution is effective not only in repairing the extracted data, but also in encoding such repairs in the original extraction process.
Third, we investigate how relationships among entities can be exploited to discover inconsistencies and additional information. We present RuDiK, a disk-based scalable solution to discover first-order logic rules over RDF knowledge bases built from web sources. We present an approach that does not limit its search space to rules that rely on "positive" relationships between entities, as in the case with traditional mining of constraints. On the contrary, it extends the search space to also discover negative rules, i.e., patterns that lead to contradictions in the data.