VictorJuiz/thesis huggingface dataset:
Investigating the role of D-alanine and D-serine in the gut and brain, an in vivo and in vitro study

D-alanine co-localization to corticotroph cells of the anterior pituitary inspired the research in this thesis, as this co-localization may imply a relationship. Investigations into effects that D-alanine have on the anterior pituitary, via AtT20 cells found that D-alanine does in fact have an inhibitory relationship on ACTH secretion in AtT20 cells, and this was robustly proven. Additionally, D-serine was investigated for comparison, and this D-amino acid had similar effects. To ascertain inhibitory hormone effects by D-amino acids, an in vivo study using CD1 mice found that animals treated with D-alanine or D-serine had lower levels of corticosterone in their plasma. This supported the finding that these Damino acids have an inhibitory effect on HPA axis hormones.
In order to manipulate this regulation for potential therapeutic benefits the mechanism behind this inhibition was sought, and I found that this may be via a combination of Asc-1 and ASCT2 amino acid transporters and the SGK-1-POMC system. NMDARs and GlyRs were explored but the data did not support the direct involvement of these receptors in inhibition of HPA axis hormones: ACTH and corticosterone. Asc-1 involvement was determined by transfecting AtT20 cells with Asc-1 and observing a more pronounced inhibition in cells overexpressed with this amino acid transporter and treated with Dalanine. To support the in vitro data, 2 in vivo studies were performed – a model that increased Dalanine by feeding it to CD1 mice and a germ free model, which would lack D-alanine due to the lack of gut microbiota, the source of mammalian D-alanine. However the ‘D-alanine knockout model’ of germ-free mice did not have opposing effects on SGK1 and POMC in the cortex – though this may be due to presence of D-serine in these animals, as D-serine and D-alanine was found to exert similar effects on HPA axis hormones and SGK1. Determining that D-amino acids may have a therapeutic benefit of HPA axis regulation, the effects these molecules exert on the site of entry, the gut, was investigated in colorectal Human carcinoma cells Caco-2, and it was found that D-serine had pro-inflammatory effects on these gut cells, but not D-alanine, however the mechanism behind this inflammation was not determined. However, this was an interesting find as it supports the use of D-alanine over D-serine as a potential stress axis regulator, as this D-amino acid does not promote gut inflammation.
The robust inhibition of ACTH in the anterior pituitary by D-alanine, and D-serine (Chapter 2), is not directly linked to NMDA receptor or GlyRs activity, but may involve the SGK1 system, which interacts with POMC, precursor to ACTH, and the amino acid transporter Asc-1 (Chapter 3). However, ingestion of D-serine supplements may have a pro-inflammatory effect in the gut, as observed in Caco-2 colorectal cells in Chapter 4. The inhibition of HPA axis hormones (Corticosterone) by D-alanine and D-serine was also observed in CD1 mice (Chapter 5).

Keywords: AtT20 cells
d-serine
caco-2 cells
asc-1
d-alanine
Advisor: Burnet, P
An investigation of regulatory T cell therapy in advanced human skin experimental transplantation models

Regulatory T cells (Tregs) are powerful suppressors of immune responses and help preserve immune homeostasis and self-tolerance. Specific Treg subsets—including those expressing the chemokine receptors CCR4 and CCR8—demonstrate high suppressive potency in certain clinical contexts. Several studies have revealed the promise of Treg cellular therapies in counteracting immune-mediated pathologies including transplant rejection. Clinical translation of Treg therapies must be supported by ongoing pre-clinical and clinical research to both evidence and enhance its safety and efficacy.
Humanised experimental mice provide a cost-effective and practical approach to create in vivo models for pre-clinical transplant research. However, issues including high technical demand and variable capacities to represent human biology can limit their use.
The two aims of this study were to develop an advanced humanised mouse model that could support multilineage human haematopoeisis and accurately represent human allotransplantation, and to investigate whether specific skin-homing human Treg subsets can provide effective anti-rejection therapy for skin allografts.
In the first part of this study, HSPC-NBSGW mice—non-irradiated NOD,B6.SCID IL-2rγ-/-KitW41/W41 (NBSGW) mice engrafted with human CD133+ hematopoietic stem and progenitor cells (HSPCs)—were assessed for function capability in the context of allotransplantation. In depth characterisation of durable human haematopoeitic cell engraftment was followed by quantitative transcriptomic and immunophenotypic analyses of complete skin allograft rejection, which this model can effect through functional human innate and adaptive immune cells.
In the second part, the suppressive capabilities of chemokine receptor-expressing Tregs were evaluated phenotypically and functionally. In addition to potent immune suppression mediated by CCR4-expressing Tregs, subcutaneous CCL22 administration in the presence of Treg therapy prevented skin allograft rejection.
As the potential of Treg therapy has become clearer, pre-clinical research is becoming an increasingly essential tool for uncovering features of Treg behaviour and function that may help optimise safety and efficacy. The findings presented in this thesis advance the in vivo research toolkit and describe an additional method by which Tregs may be manipulated to enhance their therapeutic application.

Keywords: Treg
VCA
pre-clinical models
humanised mouse model
regulatory T cell
transplant rejection
adoptive cell therapy
vascularised composite allograft
skin transplantation
chemokine
Advisor: Hester, J
Issa, F
Characterising liquid electrolytes for lithium-ion and lithium metal batteries

Liquid electrolytes are crucial for the continuing development of lithium-ion (LIB) and lithium metal batteries (LMB). Improving the transport and thermodynamics of the electrolyte allows for higher energy and power densities, faster charging and longer cycle life, all of which are required for furthering advanced battery technologies. Specifically, the diffusion coefficient (Dapp) and transference number (tLi+) dictate to what extent a Li+ electrolyte concentration gradient forms across the cell, and the ionic conductivity (κ) and thermodynamic factor (χM) influence the ohmic, activation and concentration overpotentials.
In this work, a method for fully characterising Dapp, t+, κ, χM and the resistance of charge-transfer (Rct ) was described first, utilising operando Raman microspectroscopy in tandem with potentiostatic electrochemical impedance spectroscopy (PEIS). Using lithium bis(fluorosulfonylimide) in tetraglyme (LiFSI in G4) as a model system, the technique allowed for the characterisation of the electrolyte in one experimental setup. Furthermore, the study provided a method for visualising concentration gradients and a technique for correlating macroscopic transport and thermodynamic properties with microscopic intermolecular structure. Using the isolated properties, LIB and LMB simulations were conducted to understand how each property affected cell performance.
Next, tandem operando Raman microspectroscopy and PEIS were used to characterise a more complex system, namely ionic liquid electrolytes (ILEs), LiFSI in N-methyl-N-propylpyrrolidinium (Pyr1,3) FSI. This was the first time ILE concentration gradients have been analysed along with a full ILE characterisation of transport and thermodynamic properties. The asymmetric Li+ gradient provided evidence of large structures forming that settle to the bottom of the cell.
Finally, the plating morphology of lithium metal was studied using LiFSI in G4 and LiFSI in Pyr1,3FSI electrolytes. Using the transport properties from previous chapters and surface analysis via X-ray photoelectron spectroscopy (XPS), reasons were presented as to how the electrolyte influenced the nucleation of non-uniform growth.
Overall, these studies provided a basis for full transport and thermodynamic electrolyte characterisation to allow for the furthering of LIB and LMB technologies.

Keywords: transport thermodynamics of electrolytes
Li metal batteries
electrolyte
Li-ion batteries
Advisor: Pasta, M
Novel approaches to assess the prevalence of palaeoparasites in European archaeological sites

Palaeoparasitology is the study of parasites, in this case helminths, in archaeological contexts such as well-preserved human remains or sedimentary samples. The robust nature of helminth eggs, along with the distinct life cycle of different species has meant that the study of these organisms have provided insight into aspects such as hygiene and subsistence patterns in archaeological sites. However, discussion and research on the health impact of these parasitic organisms in historical populations is lacking from the published literature despite the significance of these organisms for health today. History is a resource to explore the resilience and spread of helminths, nevertheless, to be useful for informing modern practices the analysis of helminths in archaeological sites needs to be robust, quantified and comparable between sites. There were two methodological changes to palaeoparasitology which were investigated in this thesis to address this problem. The first was to produce a proxy for the prevalence rates of helminths in past societies. Most published studies are either undertaken on communal samples, where it is difficult to associate the quantity of helminth to the number of human hosts, or small scale studies of individual burials within a site. In this thesis, a large scale analysis of helminths from single burials in a number of archaeological sites was undertaken, and concordance between prevalence and risk factors in past and present populations was identified. These results were used to explore the effectiveness of different interventions utilised by modern health practitioners. Currently most studies utilise ancient DNA analysis in palaeoparasitology to confirm species identification so, the second goal was to develop genetic methods to produce data that could be used to study population dynamics and dispersal of helminths. This thesis explores the strength and weaknesses of different genetic approaches to palaeoparasitology, which provide a valuable foundation for future studies to identify the most appropriate techniques for their research questions. This thesis shows methods for making robust conclusions on the incidence and factors that control the spread of helminths in historical populations. This is vital if the work is to be of use for informing modern practices.

Keywords: aDNA
microscopy
Palaeoparasitology
Advisor: Larson, G
Smith, A
Technological change and work

This doctoral thesis examines the impact of innovation on jobs using the first historical index of job quality and international comparative case studies of sectors in Great Britain and the United States. It makes four principal contributions. First, it constructs a new indicator of living standards that measures work-related wellbeing in the past. Second, it shows that macroinventions increased the division of labor and thereby raised the inequality of work-related wellbeing. Third, it demonstrates that firms’ push to reduce unit labor costs produced a race between job quality and productivity. Managers adopted microinventions that could have reduced work intensity or improved safety, but to raise productivity they demanded higher effort levels and increased throughput, which mitigated improvements to safety and conditions. Fourth, it shows that some instances of technological change produced widespread unemployment and provided opportunities to reorganize the workforce. Higher-status workers used the dislocation of innovation to claim or retain the best jobs. These findings contribute to historical scholarship on the development of living standards and provide perspective for debates about job polarization and the future of work.

Keywords: technological change
wellbeing
textile history
Industrial Revolution
transportation
living standards
railroads
inequality
innovation
Advisor: Humphries, K
Broadberry, S
Them against us: dynamics of intergroup conflict during the European refugee crisis

This thesis focuses on the expansion of conflict between natives and refugees during the European refugee crisis in Germany. While connected by the common theme, each chapter explores a different manifestation of conflict in the form of a stand- alone article. The first article investigates the spatial and temporal clustering of anti-refugee attacks to illustrate why some places and some moments in time are more prone to violence than others. Results underline the role that threatening events play in reshaping the ecologies of intergroup conflict. Events that are seen as particularly threatening, such as the New Year’s Eve sexual assaults, can increase the amount and change the distribution of subsequent attacks—mobilising new, previously peaceful communities to behave aggressively towards local refugee populations. The second article also explores the corrosive impact of threatening events, but focuses instead on how such events shape the everyday lives of majority and minority groups. Studying attitudinal changes among both the German and the resident refugee population, the article finds that exposure to terrorism exacerbates anti-refugee sentiment among German respondents, while increasing experiences of discrimination and mental distress among refugees. These results highlight a crucial but often overlooked aspect of intergroup conflict: how the lives of blamed minority groups—against which much of the increase in vitriol, discrimination, and violence is directed—are impacted by threatening events. The third article examines what happens when refugees and Germans live side-by-side, sharing the same neighbourhood. The study combines real-estate listings with information on when new refugee shelters opened throughout Munich—a city disproportionately exposed to the refugee crisis—to scrutinise whether the arrival of refugees affects a hosting neighbourhood’s perceived desirability. Results from the difference-in- difference design find no evidence that a refugee shelter opening decreases the prices of nearby properties. Although most Germans, when asked, prefer not to have a refugee as their neighbour, such attitudes do not seem strong enough to affect actual decisions over where to live. The process of occupying the same space and thus encountering refugees on an daily basis may even sensitise residents to the precarious situation of refugees and therefore reduce anti-refugee sentiment.

Keywords: refugee
threatening events
violence
attitudes
group conflict
immigration
Advisor: Biggs, M
Lebanese sectarianism: understanding and mitigating bias

Intergroup biases are correlated with an erosion of civil society, uneven distribution of public goods, sub-optimal economic outcomes, political corruption, and intergroup conflict. These negative consequences have inspired generations of researchers to devise theories to understand the nature of bias and to develop methods to mitigate such bias. The objective of this book is to apply these theories to the Lebanese context to understand the extent and nature of biases among Lebanese sectarian groups. Specifically, this book explores intergroup relations among Lebanese Christians, Shias and Sunnis. The book then tests whether bias mitigation strategies that were developed in Western contexts may ameliorate intergroup biases in Lebanon.
This book uses two studies to make five principal contributions to the literature. The first study administers conjoint and lab-in-the-field investment experiments to students in four Lebanese universities. The second study uses similar experimental instruments and captures a broader swath of the Lebanese population in towns and village dispersed throughout the country. The evidence from these studies shows that bias exists among sectarian, partisan, and religious groups. Furthermore, bias along partisan lines is substantially stronger than bias along sectarian lines. This finding is in line with a growing literature on the primacy of affective polarization in Western context. The book then assesses three possible ways to mitigate intergroup bias. First, this book tests the contact hypothesis in Lebanese universities, finding limited evidence that intergroup contact in the university context has a positive effect on students' attitudes and behaviors. Second, the book assesses whether variation in social geography creates opportunities for intergroup reconciliation or triggers intergroup threat perceptions. Finally, this book tests whether an episode of a unifying national narrative that transcends partisan and sectarian divisions is capable of diminishing intergroup bias. Results for the positive effects of a unifying national narrative are suggestive, but muted.

Advisor: Duch, R
Eggers, A
Duality of responsibility in international law

Duality of responsibility in international law arises when the same conduct entails the international responsibility both of the state and of the individual through which the state acts. The thesis examines the origins of duality of responsibility and what this du-ality entails for the interpretation and application of the rules governing the interna-tional responsibility of states and individuals. In principle, state and individual respon-sibility exist in parallel and are independent from each other. This, however, does not mean that they do not overlap. First, duality of responsibility is the corollary of the du-ality of obligations. This means that the content of certain international obligations of the individual is materially identical to, or necessarily co-determined by, the international obligation of the state. Second, the state can only act through individuals (natural persons). When the same obligation is incumbent on both the state and the individual, both state and individual responsibility may be engaged when the individual’s conduct is attributable to the state. In parallel, the law of individual responsibility has developed its own rules of attribution of conduct. The unprincipled dissociation between the state and the individual acting as its organ or agent for the purposes of engagement of their respective responsibility would amount to a legal, if not logical, contradiction. Third, individual responsibility under international law is predominantly criminal, but not exclusively so. As both states and individuals can be responsible under international law for the same conduct, they must both incur secondary obligations to make reparation for the same injury in whole or in part. In this sense, duality of responsibility also leads to duality of consequences. The thesis argues that duality of responsibility reflects not only a feature, but also the general principle governing the international responsibility of multiple internationally responsible actors: the principle of independent responsibility. More importantly, duality of responsibility occasions, at a substantive level, the gradual merging of the rules and principles of state and individual responsibility into a common law of international responsibility.

Keywords: state responsibility
international humanitarian law
war reparation
use of force
attribution of conduct
international criminal law
Advisor: Tzanakopoulos, A
Mechanisms underlying rapid forgetting in health and Alzheimer’s disease

Working memory is known to allow retaining and manipulation of information over short periods of time. It forms an essential part of cognitive processes and over the years different researchers came up with models trying to explain the mechanisms underlying how we hold onto important information. From a clinical perspective, it is even more essential to explore what underlies forgetting over such short periods of time given that patients presenting in the clinic with memory problems can suffer from transient innocuous to severe neurodegenerative disease associated with forgetting.
In a first chapter, classical and modern models of working memory are explored and mechanisms of guiding attention in working memory are introduced. Their implications and relationship to anatomical structures are discussed in order to set the scene for the following chapters in which their relevance for the detection of significant impairment due to neurodegeneration is tested. In particular, one domain of working memory, rarely explored in the past, is examined: Though previous studies on working memory focused on encoding and maintenance, only few researchers have yet looked into retrieval the literature on which is in particular explored in the introduction.
The following three empirical chapters explore in a total of nine experiments how retrieval cues impact on retrieval from visuospatial working memory, how retrieval of information already in a privileged state is protected from interference and finally how information retrieved from working memory can be tested in the absence of a cue. This new uncued free full report allows for the distinction between errors that happen due to forgetting or confusion of one or several features of objects that are to be remembered.
In the second half of this thesis, essential findings in working memory come to be applied in patient populations. Firstly, the effects of rivastigmine on working memory performance and focussing attention are under investigation in people suffering from Parkinson’s disease dementia. Secondly, a new gamified tablet-based task for the use in people at risk of developing Alzheimer’s disease in the future is introduced and tested in different age groups
In conclusion, this thesis shows that retrieval cues themselves can impair retrieval from visuospatial short-term memory and that most recently presented information is protected from these detrimental effects. Moreover, one can test working memory in the absence of a probe which allows to assess the fate of all features bound into objects individually. Finally, rivastigmine is shown to improve working memory performance in patients suffering from Parkinson’s disease dementia and different age groups perform similar in a portable tablet task that is aimed at detecting pathologic but not age-related changes in working memory.

Keywords: Alzheimer's Disease
Parkinson's Disease Dementia
Preclinical Detection
Short-Term Memory
Advisor: Husain, M
Manohar, S