VictorJuiz/thesis huggingface dataset:
Timing- and pattern-dependent long-term depression during mouse barrel cortex development
Keywords: Plasticity
Synapse
NMDA receptors
Cortex
Electrophysiology

Long-term depression (LTD) plays an important role in the refinement of neocortical maps during early postnatal development. Synapse formation and refinement in the cortex during development rely on synaptic plasticity, the cellular mechanisms of which are poorly understood. The aim of this thesis was to investigate timing- and pattern-dependent LTD at excitatory synapses in the mouse barrel cortex during development.
This thesis first describes the developmental prole and N-methyl-D-aspartate (NMDA) receptor GluN2 subtype-dependence of timing-dependent plasticity at layer 4-to-layer 2/3 synapses. A developmental dissociation of timing-dependent plasticity was observed where timing-dependent LTD (t-LTD) was found during early development (postnatal day, P6-8) but disappeared after P25. In contrast, timing-dependent LTP (t-LTP) only appeared in the second postnatal week of development (P11-15) and persisted in the adult cortex. This bidirectional plasticity also showed a GluN2 subtype-dependent dissociation. Whereas t-LTP was dependent on GluN2A subunit-containing NMDA receptors, t-LTD was dependent on GluN2C/D subunit-containing NMDA receptors.
This thesis also reports a novel anti-Hebbian form of NMDA receptor-dependent plasticity, in which presynaptic layer 4 neurons drive their presynaptic long-term self-depression without the involvement of postsynaptic action potentials or calcium. This mechanism suggests that, during development, presynaptic self-depression occurs when specific spike patterns (presynaptic burst-spike) in the presynaptic neuron are unsuccessful in driving postsynaptic activity.
Finally, this thesis addresses how t-LTD induction rules differ in vertical intra-columnar layer 4-to-layer 2/3 and horizontal cross-columnar layer 2/3-to-layer 2/3 synapses in the barrel cortex. Distinct GluN2 subunit expression in vertical and horizontal synapses regulated the time-window of t-LTD induction. It is also shown that different excitatory intra- and cross-columnar synapses onto the same postsynaptic layer 2/3 neurons can have different molecular requirements for the induction of t-LTD, and that they also interact to induce heterosynaptic associative LTD. These findings may have important implications for understanding the cellular mechanisms of experience-dependent plasticity and its relevance to the computational principles of cortical circuit operation.
Is narcolepsy an antibody-mediated autoimmune disease
Keywords: orexin
hypocretin
vaccination
sleep
antibodies
narcolepsy
paeditric
post-H1N1

Narcolepsy is a lifelong sleep disorder of unknown cause. Patients experience excessive daytime sleepiness (EDS) in conjunction with the pathognomonic symptom of cataplexy, which is a sudden bilateral loss of motor tone triggered by positive emotion. Central to the pathology of narcolepsy-cataplexy is the loss of orexin-secreting neurons in the hypothalamus and the concomitant loss of orexin neuropeptide in the cerebrospinal fluid (CSF). The cause is thought to be autoimmune, mainly because of the tight association with HLA DQB1*0602. However, there is no direct evidence to support this hypothesis. Since 2010, a particular H1N1 vaccine has been implicated as a rare trigger of narcolepsy-cataplexy in children. Post-vaccination cases have a particularly abrupt onset, and may provide new insights into disease aetiology. This thesis explored the possibility of a humoral immune cause.
Tests for the presence of antibodies directed towards neuronal antigens were performed on 17 sera/CSF pairs from children with recent onset narcolepsy-cataplexy as well as unpaired samples and those from adults and controls. Methods included a cell-based candidate antigen approach, antibody-screening techniques using rat brain tissue and neuronal cultures, and testing for biomarkers of autoimmunity. There was no consistent evidence of autoantibodies to a specific antigen in a high proportion of patients, but immunoreactivity to neuronal antigens, including unidentified antigens on the surface of neurons in culture, was identified in some samples.
This large narcolepsy cohort included recent-onset and post-vaccination cases, patients in whom putative autoantibodies are most likely to be found. Immunoreactivity in some cases provides preliminary evidence for autoantibodies which needs to be followed up. Further strategies are required to investigate the aetiological mechanisms underpinning narcolepsy-cataplexy, including addressing the possibility of T cell-mediated damage.
Single-molecule fluorescence of internalised biomolecules in live bacteria
Keywords: electroporation
E.coli
single-molecule fluorescence
particle tracking
in vivo

In the last two decades emerging single-molecule fluorescence tools have been developed and adapted to study individual molecules in vitro under various conditions and to reveal biochemical and cellular processes in live cells with high precision. Single-molecule investigations in vivo rely mainly on fluorescent protein (FP) fusions with low quantum yield and photostability. Methods to introduce organic-labelled fluorescent molecules into cells have been achieved for mammalian cells via microinjection (not possible with bacteria) and are limited in throughput. We have developed a physical transfection method for delivering organic-fluorophore labelled biomolecules into live bacteria for single-molecule studies. We internalised labelled dsDNA and proteins (up to 100kDa) with high efficiency whilst maintain- ing cell viability. I was able to count the number of internalised molecules through photobleaching analysis. From this analysis, I was able to tune the concentration of internalised material from high concentrations compatible with localisation-based super-resolution imaging to lower concentrations compatible with single-molecule observation. Using localisation and tracking algorithms I followed the diffusion of individual molecules for up to 10 s and monitored the tracking paths within the cellular cytoplasm. This method allows us to observe molecules for up to 10 minutes (FPs ~ 5 s) under continuous illumination opening a new time regime to study biological processes. Our approaches are general and widely applicable to different microorganisms using biomolecules labelled with organic fluorophores already available for in vitro experiments.
Towards a computer model of the historical phonology and morphology of Latin
Keywords: Python
historical linguistics
computational linguistics
optimality theory
phonology
morphology
Latin

Research projects in Optimality Theory tend to take a synchronic view of a particular generalisation, and set their standards for rigour in typological terms (see for example Suzuki 1998 on dissimilation, Crosswhite 2001 on vowel reduction). The goal of this thesis is to use Stratal OT to take a diachronic view of multiple generalisations within the morpho-phonology of one language, namely Latin, with the principal empirical aim of producing an analysis that is demonstrably true to all the attested facts of the generalisations in question.
To that end, I have written PyOT, a computer program implementing the OT calculus and a theory of phonological representations, which I use in this work to model the histories of Lachmann’s Law, rhotacism and the phonologically conditioned allomorphy of the -alis/aris- suffix as active generalisations within the phonological component of the grammar. Appendix A gives the results of the computer model applied to a dataset consisting of 185 attested Latin forms, which suffice to illustrate the exact conditions of the generalisations in question.
I show that producing a complete analysis of the three generalisations I have chosen to model entails analysis of other generalisations that interact with them, including the treatment of the Indo-European voiced aspirates in Latin (which interacts with rhotacism), and reduplication in forming perfect stems (which interacts with Lachmann’s Law). Constraint rankings sufficient to model these interactions, and consistent with the general conditions of the interacting generalisations have been included in the model.
The intention is for this work to illustrate both the utility of formal phonological theory in advancing hypotheses within historical-comparative linguistics, and the potential of PyOT as a tool for producing Optimality-Theoretic models of (eventually) a language’s entire phonology.
Age-related white matter changes in patients with TIA and stroke: population-based study on aetiological and prognostic significance
Keywords: Computed Tomography
Stroke
TIA
Magnetic Resonance Imaging
leukoaraiosis
Age-related white matter changes
Ageing
white matter changes

White matter changes (WMC) seen on CT and MRI brain scans of healthy subjects and of vascular or dementia patients are strongly associated with age. Their pathogenesis is still under debate, and associations with vascular risk factors have varied according to studies. Their prognostic meaning, both in the general population and in stroke patients, is also not completely established.
I systematically reviewed the literature on prevalence and associations of WMC and then evaluated CT and MRI scans of the first 8 years of a population-based study of all strokes and TIA in Oxfordshire (OXVASC). In this population I researched sex and age-specific associations between WMC and different types of strokes (TOAST), different components of blood pressure, and possible vascular risk factors. I also looked into their prognostic meaning for stroke recurrence and outcome, cognitive performance and mortality.
1840 patients were assessed by MRI (520) and/or CT (1717). White matter changes were independently associated with the lacunar type of stroke. The association with hypertension was confirmed (using 10 years of pre-morbid blood pressure readings), and it was particularly strong in the younger patients, mainly for diastolic hypertension. There was no association with blood pressure variability and peripheral pulse pressure. Hypercholesterolaemia, diabetes, smoking, ischaemic heart disease, carotid stenosis and atrial fibrillation were not associated with white matter changes. There was also no association with gender. Severe WMC posed a higher risk of disability and cognitive impairment at one year from the stroke, and of death in the following 10 years.
This is the first study on white matter changes associations and on their prognostic meaning, to be set in a large population-based cohort of stroke and TIA. I confirmed the association between white matter changes and higher blood pressure, in particular diastolic hypertension. I also showed the association with lacunar type of stroke to be independent from vascular risk factors, and WMC to reduce life expectancy and functional and cognitive outcome of patients with stroke.
Consequences and mechanisms of leadership in pigeon flocks
Keywords: Social learning
Computational biology
Swarm Intelligence
Homing pigeons
Animal Behaviour

This thesis investigates how collective decisions in bird flocks arise from simple rules, the factors that give some birds more influence over a flock's direction, and how travelling as a flock affects spatial learning. I used GPS loggers to track pigeons homing alone and in flocks, and applied mathematical modelling to explore the mechanisms underlying group decisions. Across several experiments, the key results were as follows:
Flying home with a more experienced individual not only gave a pigeon an immediate advantage in terms of taking a more direct route, but the followers also learned homing routes just as accurately as pigeons flying alone. This shows that using social cues did not interfere with learning about the landscape during a series of paired flights.
Pigeons that were faster during solo homing flights also tended to fly at the front of flocks, where they had more influence over the direction taken. Analysis of momentary interactions during paired flights and simulations of pair trajectories support the conclusion that speed increases the likelihood of leading.
A pigeon's solo homing efficiency before flock flights did not correlate with leadership in flocks of ten, but leaders did have more efficient solo tracks when tested after a series of flock flights. A possible explanation is that leaders attended more to the landscape and therefore learned faster.
Flocks took straighter routes than pigeons flying alone, as would be expected if they effectively pooled information. In addition, pigeons responded more strongly to the direction of several neighbours, during flock flights, than to a single neighbour during paired flights. This behaviour makes sense adaptively because social information will be more reliable when following several conspecifics compared to one.
Through a combination of high-resolution tracking and mathematical modelling, this thesis sheds light on the mechanisms of flocking and its navigational consequences.
From 'exporting the revolution' to 'postmodern Pan-Islamism': a discourse analysis of the Islamic Republic of Iran's ideology, 1979-2009
Keywords: Pan-Islamism
Mahmoud Ahmadinejad
Mohammad Khatami
Ali Khamenei
discourse analysis
Ali Akbar Hashemi Rafsanjani
Iranian politics 1979-
Ruhollah Khomeini
corpus linguistics

Since the early days of 1979, the Islamic Revolution of Iran has been seen as a phenomenon unique in history, one which must be viewed as somehow separate from other political Islamic movements in the 20th century.
In chapter 1, this thesis problematizes this interpretation of the Revolution by analyzing it through the lens of an earlier ideological movement, pan-Islamism, and applying methods from the study of conceptual history to draw linkages between this movement and the Islamic Revolution, rooting it more deeply in the region’s political and intellectual history, and casting light on the poorly-understood pan-Islamic aspects of Iran’s Revolutionary ideology.
In chapter 2, it applies methodological innovations from the digital humanities, more specifically corpus linguistics, in carrying out a series of five case studies to examine the transformation of Iranian ideology over time, by analyzing a set of five text corpora comprised of individual leaders’ writings and speeches. It further illustrates how theoretical advances in discourse analysis and history seem to be moving towards the same point, and how the application of corpus linguistic methods advances these bodies of theory.
Chapters 3 through 7 comprise the case studies, which are, in order: Ruhollah Khomeini and Ali Khamenei, the two Supreme Leaders; Ali Akbar Hashemi Rasfanjani, Mohammad Khatami, and Mahmoud Ahmadinejad, the three Presidents since 1989. These chapters illustrate through analysis of the textual data how each political leader has adapted the received political discourse to the exigencies of their times, and how pan-Islamism itself has remained a consistent, albeit dynamic, linking thread running through the period 1979-2009.
By studying pan-Islamism in the Iranian context, we can explain several features of Iranian political discourse which otherwise seem incomprehensible, and better situate the Islamic Republic within the political and discursive transformations taking place at the regional level of the Middle East, and the global level of the Muslim umma.
Evolvability: a formal approach
Keywords: alife
evo-devo
neutralnetworks
development
rna
evolvability
artificiallife
speciation
network
modularity
complexity

This dissertation clarifies the concept of evolvability, the increased capacity of some organisms or systems to support evolution, especially the evolution of life-like complexity. I survey the literature, which is spread over the fields of population genetics, developmental biology, artificial life, and microbial and molecular evolution. Finding that researchers have often used the term vaguely and incompatibly I identify five distinct kinds or senses of evolvability. I also identify five key constituent ideas, which I discuss in the context of organismic evolvability, a sense of evolvability with deep roots in the traditional fields of animal development and macroevolution. In these fields research into evolvability has historically been hampered by an insuﬃciently detailed knowledge of development. Research in molecular evolution has produced a thorough knowledge of the folding of RNA into secondary structure, which can be regarded as a model of development. This has motivated new approaches to evolvability based on representing development via a single genotype-phenotype mapping function. I build on these approaches to invent new mathematical methods to formalise the traditional ideas. I create an exact model illustrating a classic example of evolvability, the capacity for repeated segmentation and simple modularity. I analyse this with two new formal approaches. First is the genospace algebra, a propositional calculus based on graph theory. It is a formal language for describing genotype-phenotype maps. It provides a system for making calculations, proofs, and diagrams about mutational structures in genotype space, and it is ﬂexible enough to allow description at arbitrary degrees of resolution. Second is a pair of concepts, the genetic leverage and the genetic fulcrum. The leverage provides a crude numerical measure of evolvability, and the fulcrum provides a heuristic for identifying the genomic and developmental causes of evolvability. Besides its specific relevance to diversification and development, evolvability is also crucial to the fundamental question of how evolution produces ordinary biological life. Simulation systems that implement only a conventional textbook model of evolution -– systems possessing only variation, inheritance, and selection –- fail to evolve anything resembling the complexity of the biological world. Research into evolvability is our best bet to illuminate the "missing ingredient" for life-like evolution.
Binary hypotheses for bipolar mass loss in transients
Keywords: Stellar
87A
Planetary Nebula
Common Envelope
Stellar Merger
Planetary Nebulae
SPH
Cassiopeia A
Bipolar
Napoleon's Hat
SN 1987A
Eta Carinae

We investigate binary hypotheses for the formation of bipolar nebulae using the smoothed particle hydrodynamics code Gadget-2. In the general case, we present a parameter study of mass loss from very simple common envelope models, which seems to show a strongly bipolar trend for sufficiently oblate envelopes and low enough spiral-in injection energy. The density profiles of the envelopes produce differing structure within the ejecta.
We also investigate 3 specific bipolar mass loss events. In the case of the outer nebula of SN 1987A, we study the effects of fast polar jets interacting with a pre- existing progenitor wind and find that these are consistent with the observed light echoes from the nebula, in particular for the feature known as ’Napoleon’s Hat’. In the case of Cas A, we briefly study the effects of close binarity on supernova ejecta and suggest the influence of a close, compact companion may lead to at least one jet-like disturbance that may be observable in a supernova remnant. Finally, we study whether a fast bipolar wind, similar to that of Eta Car’s present wind, may inflate ejecta similar to that produced in the common envelope models to a shape consistent with that of Eta Car’s Homunculus Nebula.
Theoretical advances in the modelling and interrogation of biochemical reaction systems: alternative formulations of the chemical Langevin equation and optimal experiment design for model discrimination
Keywords: diffusion processes
control theory
systems biology
chemical reaction kinetics
experiment design
chemical Langevin equation
model discrimination

This thesis is concerned with methodologies for the accurate quantitative modelling of molecular biological systems. The first part is devoted to the chemical Langevin equation (CLE), a stochastic differential equation driven by a multidimensional Wiener process. The CLE is an approximation to the standard discrete Markov jump process model of chemical reaction kinetics. It is valid in the regime where molecular populations are abundant enough to assume their concentrations change continuously, but stochastic fluctuations still play a major role. We observe that the CLE is not a single equation, but a family of equations with shared finite-dimensional distributions. On the theoretical side, we prove that as many Wiener processes are sufficient to formulate the CLE as there are independent variables in the equation, which is just the rank of the stoichiometric matrix. On the practical side, we show that in the case where there are m_1 pairs of reversible reactions and m_2 irreversible reactions, there is another, simple formulation of the CLE with only m_1+m_2 Wiener processes, whereas the standard approach uses 2m_1+m_2. Considerable computational savings are achieved with this latter formulation. A flaw of the CLE model is identified: trajectories may leave the nonnegative orthant with positive probability.
The second part addresses the challenge when alternative, structurally different ordinary differential equation models of similar complexity fit the available experimental data equally well. We review optimal experiment design methods for choosing the initial state and structural changes on the biological system to maximally discriminate between the outputs of rival models in terms of L_2-distance. We determine the optimal stimulus (input) profile for externally excitable systems. The numerical implementation relies on sum of squares decompositions and is demonstrated on two rival models of signal processing in starving Dictyostelium amoebae. Such experiments accelerate the perfection of our understanding of biochemical mechanisms.