VictorJuiz/thesis huggingface dataset:
Relational norms
Keywords: relationships
relational norms
partiality

The thesis is a study of relational norms-those norms that regulate how we behave in our valuable relationships. I argue that the presence of relational norms in the law reflects its capacities and limitations as an instrument for the guidance of conduct. I make three arguments to support of this claim. First, I argue that we have norms that are constitutive of our practically significant relationships. Second, I argue that the content and justification of these relationships is not necessarily reflected in their legal forms. Third, I argue that we can have relationships that are justified by their instrumental value. There are three Parts to this thesis, each of which is devoted to one of these claims. Part I discusses relational norms in practical reasoning. I identify relational norms as norms that constitute a relationship of value. I then argue that we can owe obligations to one another in what I call the ‘relationship sense’. These obligations are neither necessarily enforceable, nor necessarily correlate with the rights of others. Part II discusses relational norms in law. I consider various constraints on the incorporation of relational norms in law, as well as the various relationships of correlativity that are sometimes said to define private law. I also consider the nature of legal rights to perform certain relational duties. I argue that although the duties are burdensome, these rights promote our interests, or at least are claimed to do so by legal officials. Part III considers the significance of relational norms to the general character of law. First I argue that we can have instrumental relationships—relationships that possess their value in virtue of some end that they serve. I then argue that any authoritative relationship that exists between legal officials and their subjects must be instrumentally justified.
"I sometimes question myself" The learning trajectories of four senior managers as they confronted changing demands at work
Keywords: Adult development
Alasdair MacIntyre
sociocultural theory
Identity work
Learning at the workplace

This study explores the learning trajectories of four senior managers at the Royal Mail as they confronted new demands at work. e four managers worked at the Royal Mail during the years prior to, and during its privatisation, when it was also undergoing an intense modernisation.
Theoretically, I took a sociocultural approach, drawing on Vygotsky (1998), Edwards (2010), Holland et al. (1998), and Sfard and Prusak (2005), among others. I was also provoked by Alasdair MacIntyre’s characterisation of the manager and his understanding of practice, which emphasises human ourishing.
Data was collected through iterative unstructured and semi-structured interviews, and by work shadowing the managers. Methodologically, I developed a useful interview protocol to capture stories about work and a more nuanced understanding of what mattered to participants. I also built a conceptual framework that draws theoretically from a sociocultural understanding of learning and development, as well as from MacIntyre (2013) and Taylor (1989). e model emerged from the dialectics of theory and empirical data.
The research shows that as the Royal Mail underwent organisational change, the managers had to navigate situations of misalignment between what mattered to them and what mattered to other members of the organisation. Such situations of misalignment brought about new demands. As they confronted the demands, the managers realised the need to close a gap between who they were and who they were expected to become. Gap-closing efforts were characterised as a process of learning and development that involved intense identity work. In the process, the managers had to work through a series of contradictions, which can be expressed in the form of questions: Who am I really? Who should I no longer be? Who do I resist becoming? And, who do I struggle to become? Gap-closing was given by a dialectic between the managers’ commitments and identi cations, and the stories of what was good in the gured world of managing at the Royal Mail.
Contrary to some of MacIntyre’s suggestions, I found that the four managers in the study, Linda, Eric, Margaret and Julian did question themselves about some of the ends they pursued. ey also exhibited varying degrees of agency, and did establish a distance with the impositions of their institutional realities. In the eld, I found instances of moral debate, the exercising of virtues and the managers’ very human efforts to live a worthy life and to ourish. Yet, I also found empirical grounds for some of MacIntyre’s claims. As the managers navigated misalignment, they used an array of strategies intended to persuade others in a manipulative way, sometimes treating ends as given, and sometimes eluding moral debate.
The study contributes to the literature of learning and development through its original theoretical approach that draws from both sociocultural and MacIntyrean ideas.
University-firm collaboration for innovation in Chile
Keywords: Chile
university-firm collaboration
innovation policy

University-firm collaboration has been regarded as central to the innovation performance of firms and, at aggregate level, of countries. These linkages have been widely promoted as part of innovation policy in many countries. However, there are no conclusive studies of the dynamics of these interactions in developing countries and most of the research on the topic has focused on one side of a two-sided interaction. This gap in our understanding is particularly relevant in the case of developing countries since their innovation systems are 'immature.'
This thesis attempts to explain how multi-level factors shape the incentives for agents to engage in collaboration. The analysis reveals conflicting incentives on both sides of university-firm interactions. The productive and institutional environment, as well as the public policy under which academics, universities, and firms operate, create, often unintended, incentives both for and against collaboration. Increasing understanding of these interactions helps to align policy design.
By studying university-firm collaboration in Chile, this thesis aims at advancing scholarship in four key ways: (i) by studying university-firm linkages in a developing country that possesses comparative advantages in natural resources; (ii) by incorporating management and innovation theories in the study of innovation incentives, which, until recently, have only been studied using market failure analysis in developing country settings; (iii) by using a novel analytical approach that combines the analysis of the supply and demand sides of these linkages, while also incorporating the multi-level factors influencing them; and (iv) by assessing the impact of university-firm collaboration on the innovation performance of a sample of Chilean firms using a novel dataset specially prepared for this thesis. This quantitative analysis provides valuable insight about the type of firms that benefit from collaboration with universities and about the type of innovations activities that produce these benefits.
Targeting PFKFB4 in mitotically vulnerable ovarian cancer cells
Keywords: PFKFB4 PFKFB3 paclitaxel ovarian cancer AKT

Taxanes represent some of the most common chemotherapeutic agents for ovarian cancer treatment. However, they are only effective in approximately 40% of patients. As such, novel therapeutic strategies are required to potentiate their effect in ovarian cancer to improve patient outcome and prevent chemotherapy resistance.
A hallmark of many cancers is the constitutive activation of the PI3K/AKT pathway, which drives cell survival and metabolism. In this thesis, I identified a potential vulnerability in ovarian cancer cell lines during paclitaxel-induced mitotic arrest, comprising of a striking decrease in AKT activity coupled with a significant reduction in glucose 6-phosphate and ATP levels. The reanalysis of a high content siRNA screen to discover metabolic enzymes important for ovarian cancer cell survival during paclitaxel-induced mitotic arrest, identified the metabolic enzyme PFKFB4. PFKFB4 depletion followed by paclitaxel treatment resulted in a significant decrease in mitotically arrested cells. This was accompanied by a significant increase in caspase-3/7 activity and the levels of reactive oxygen species only in mitotically arrested cells, and a significant enhancement in mitotic cell death and mitotic slippage. Depletion of the related family member, PFKFB3, demonstrated a similar phenotype.
The exogenous expression of constitutively active AKT or siRNA-resistant PFKFB4 did not confer resistance to PFKFB4 depletion and paclitaxel treatment, indicating that the mechanism of mitotic cell reduction is complex. Nonetheless, the observation that some ovarian cancer cells lose AKT activity during mitotic arrest and could become vulnerable to metabolic targeting is a new concept in cancer therapy. In addition, I have identified previously unrecognised roles of PFKFB3 and PFKFB4 in mitotically arrested ovarian cancer cells. This work supports the notion that combining mitotic-targeted therapies with metabolic inhibitors may act to potentiate the effects of antimitotics in ovarian cancer cells.
The Lachish letters: a reappraisal of the Ostraca discovered in 1935 and 1938 at Tell ed-Duweir
Keywords: Archaeology of Ancient Israel
British Mandate of Palestine
Book of Jeremiah
Lachish (Tell ed-Duweir)
Lachish Letters
Ostraca
Classical Hebrew
North-west Semitic Epigraphy

The 21 inscribed ceramic sherds (or ostraca) known as the "Lachish Letters", which were discovered during the British Mandate Period excavations of Tell ed-Duweir (Lachish), underwent eighty years of scholarship that improved our understanding of at least some of these inscriptions. The archive is terse and fragmentary, and the least well-preserved and faded ostraca from this collection have been seriously overlooked, ironically when the "Lachish Letters" have more or less been regarded as a homogenous group of documents written during the final decades of the Judahite kingdom. Some of the ostraca were discovered in different stratigraphic contexts and pertaining to different settings, if not timeframes.
The principal aim of this study is to produce an updated edition of these ostraca by objectively and systematically reassessing and understanding these artefacts, the inscriptions they bear, and their respective stratigraphic layers and archaeological contexts. This is carried out by integrating past studies and modern-day developments on the ostraca (and the site itself) from different perspectives: archaeology, palaeography, philology, the Hebrew Bible, and Classical Hebrew studies. This interdisciplinary approach enables a revision of outstanding controversial issues and a dismissal of outdated proposals on the readings, interpretation, and import of these ostraca in their contemporary world. Despite the illegibility of some inscriptions, this study pays attention to all 21 ostraca via physical examination under the lens, to confirm or deny any dubious readings as far as the naked eye can tell us. A crucial criterion is the integration of photographic data and written documentation gathered from unpublished and archived material of the Mandate Period that were accessible to the author at the time of writing.
The study concludes that this surviving group of ostraca is far from homogeneous, and there still exist lacunae in their historico-archaeological contexts and interpretations. Our understanding of the source and function of the ostraca (especially the few legible messages and lists of names) remains riddled with controversies, which derive from the fragmentary nature of the corpus and the limitations in the documentation and preservation of these artefacts.
Mobilising stone: investigating relations of materiality, movement and corporality in Holocene Saharan rock-art
Keywords: African Rock Art
Rock Art
Sahara
Relational Ontologies
Ethnoarchaeology
Saharan Rock Art
African Pastoralism

This project investigates Saharan pastoralist rock-art (7500–3000BP), with a particular focus on the engravings of the Messak Plateau in southwest Libya. Taking an anthropological approach, the art is examined within the context of the lives of its creators – transhumant cattle-herders who occupied the plateau seasonally. Drawing from fieldwork in Libya together with data from multiple expeditions in the Sahara, the study addresses a major lacuna in Saharan research by focusing on materially constituted, as-lived dimensions at the micro scale. A fundamental but archaeologically elusive aspect of lived experience is a consideration of ‘movement’, both physical and esoteric. Its incorporation is central to this project, forming a multi-aspected theoretical framework and a methodological tool. Augmented by input from specialists in geomorphology, pastoralism, stone sculpting and animal behaviour, this movement-driven focus has produced a more developed picture of the Messak herder lives, advancing our understanding of these particular non-text, somatic societies.
A singular contribution is the creation of a hypothetical model for small-scale, quotidian pastoralist practices, which expands upon the archaeological evidence, fleshing out details of a well-systematised form of dairy pastoralism involving controlled breeding and the processing of milk products. At the same time it is proposed that the herders’ relationship with their cattle was one of partnership rather than ownership, involving trans-species empathy and a valuation of animal personhood. This viewpoint is part of a broader set of animal-human relations reflecting a cosmological order that diverges from modern, Western ontological constructs.
Other significant findings include detailed information on the role and identity of the image-maker, revisionist data on the amount of effort and skill expended in carving processes, and an examination of the ways in which rock-art was used to manifest social emotional concerns. These were expressed via animal emotions portrayed in the rock-art, and also through performative, gestural markings associated with the imagery. Such expressions include apotropaic, supplicatory or other interactions involving communication with unseen powers.
Modulation of ageing characteristics with an anti-ageing compound
Keywords: C. elegans
Ageing
Adipocytes

Investigating the cellular processes anti-ageing compounds interact with can identify genes and pathways involved in ageing. The macrolide lactone FK506 was identified in a phenotypic screen as extending lifespan in yeast and C. elegans through an unknown mechanism. FK506 also ameliorates neurodegeneration and age-related weight gain in rodents. Here, the mechanism of action of FK506 has been investigated in two experimental systems: C. elegans and 3T3-L1 mouse adipocytes.
As the general mechanisms of ageing are well conserved between C. elegans and mammals, C. elegans has been used to understand how FK506 acts at an organismal level. Firstly, the result of the phenotypic screen was confirmed. FK506 treatment induced lifespan extension in C. elegans in the presence of population crowding stress, but not in the absence of crowding. FK506 treatment inhibited neither E. coli OP50 growth nor C. elegans pharyngeal pumping, demonstrating that FK506 did not induce dietary restriction to extend lifespan. FK506 treatment increased C. elegans thrashing and pharynx pumping rates in early adulthood and delayed accumulation of gut bacteria, showing that FK506 extended healthspan. A transcriptome analysis of FK506-treated C. elegans allowed the identification of transcripts whose levels change and potential pathways by which FK506 manifests its effect. To explore this and to identify potential targets of FK506, the cellular functions required for FK506 to extend C. elegans lifespan and healthspan were investigated using RNA-seq, RNAi, genetic mutation and co-treatment with small molecule inhibitors and inducers. Interestingly, FK506 was found to have different mechanisms of action on lifespan and healthspan. The mechanism of FK506 on C. elegans thrashing rate was DAF-16 dependent, did not require population crowding stress, had a partial interaction with FUdR and autophagy, and may involve Ca2+ flux. The mechanism of FK506-induced C. elegans lifespan extension overlapped with dietary restriction and was dependent on calcineurin, TOR-independent regulation of autophagy and the presence of population crowding stress.
FK506 may modulate body weight by influencing metabolism and/or acting on adipocytes directly. FK506-treated aged 3T3-L1 adipocytes accumulated significantly less lipid, indicating that FK506 acts directly on adipocytes. RNA-seq of FK506-treated adipocytes found that translation-associated RNAs were upregulated whilst RNAs associated with lipid metabolism were downregulated. An ER-localised FK506-binding protein was up regulated in both C. elegans and 3T3-L1 adipocytes, fkb-4 and Fkbp2 respectively.
In conclusion, FK506 has been confirmed as a potential anti-ageing treatment, through its ability to extend lifespan and healthspan in C. C. elegans. In addition, FK506 has also been shown to act directly on mouse adipocytes, resulting in a reduction in lipid accumulation. This action could explain how FK506 caused weight loss in obese aged rats, restoring body mass to a healthy adult weight.
Structural insights into human SNF2/SWI2 chromatin remodeler SMARCAD1 and its role in DNA repair
Keywords: Protein Structure
Ubiquitin
SMARCAD1
nuclear magnetic resonance
SUMO Interacting Motif
Chromatin Remodelling
SUMO
CUE Domain

ATP-dependent chromatin remodelers have been proposed to act sequentially, and to a certain extent non-redundantly, in the priming stages of the DNA Damage Response pathways by establishing chromatin in lesion sites ready to act as a scaffold for repair factors or to be displaced in order to allow DNA repair. Among remodeling factors proposed to play a role in DNA repair is SMARCAD1, a poorly characterized, non-canonical member of the SWR1-like family of SNF2/SWI2 superfamily of ATPases, which has recently been identified as a potential target for ATM/ATR phosphorylation at canonical and non-canonical sites upon DNA damage.
The actual mechanism for SMARCAD1 recruitment and involvement in DNA remodeling is still unknown, and unlike most other chromatin remodelers, SMARCAD1 does not contain DNA- or histone-binding domains frequently accompanying such proteins. Instead, in addition to the core ATPase domain, only two CUE domains (a type of helical ubiquitin-binding domain) have been identified.
This thesis presents the findings of an investigation intended to structurally characterize SMARCAD1 by dissecting and identifying its domain architecture, and examining the activity and ligand selectivity of its binding domains in the functional context of DNA damage repair. The solution NMR structure of the CUE1 domain is presented, describing a triple helix bundle consistent with other members of the family. Furthermore, a novel SUMO interacting motif was identified and through a combination of NMR titrations and phospho-proteomics analysis, shown to be constitutively phosphorylated which excludes the possibility of DNA damage dependent ATM targeting as the recruitment mechanism for DNA repair.
Additionally, it is demonstrated that both CUE domains are poor binders of mono-ubiquitin, however CUE1 specifically mediates the high affinity binary interaction with the transcriptionally repressive master regulator KAP1. This interaction was shown to be independent of post-translational ubiquitylation but rather sustained through direct interaction with the dimeric RBCC domain of KAP1. Finally, mass spectrometry profiling of domain-dependent interactions (based on differential abundance relative to changes due to chemically induced DNA damage) suggests SMARCAD1 may be involved in p53 transcriptional regulation through interactions maintained with CUE1 prior to DNA damage, whereas the SIM domain selectively targets protein interactions upon DNA damage that simultaneously activate p53 transcriptional control and recruit SMARCAD1 to DNA damage repair pathways.
Development of a camera for tera–electronVolt gamma–ray astronomy
Keywords: Axion like particle
Cherenkov Telescope Array (CTA)
High energy gamma ray
Active Galactic Nuclei
Gamma ray Cherenkov Telescope (GCT)

In this thesis I describe the development of a compact camera for ground-based multi TeV gamma-ray astronomy, using the Imaging Atmospheric Cherenkov Telescope (IACT) technique.
The camera is based on multi-anode photomultipliers (MAPM) and is designed for use on the Gamma Cherenkov Telescope (GCT), which is proposed to be part of the Small Size Telescope (SST) array of the Cherenkov Telescope Array (CTA). GCT achieves high performance with a compact and cost efficient design via a Schwarzschild-Couder (SC) dual-mirror optical system.
The GCT optical design allows the use of a compact camera of diameter roughly 0.5 m. The curved focal plane is equipped with 32 tiles of 64-pixels MAPM for a total of 2048 pixels of ∼0.2◦ angular size, resulting in a field of view of ∼9◦. The GCT camera is designed to record the flashes of Cherenkov light from electromagnetic cascades, which last only a few tens of nanoseconds. I give a detailed description of the design, the challenges encountered during testing in the lab, and the performance of the most critical components.
I give details on the custom front-end electronics modules that provide the required fast electronics, facilitating sampling and digitization, as well as first level of triggering. The camera-level triggering system is a custom backplane, developed to reject spurious triggers on the night sky background, which typically is of the order of few tens of millions of photons per pixel per second. This is to be compared with the rate of the astrophysical signal, which is of the order of few hundreds of events per second at the relevant energies. Additionally I provide a detailed description of all the software needed for the data acquisition and control of the camera, from the very low level drivers to high level and user friendly processes.
I follow the commissioning of the camera, from the individual core components to the integration of the system. I then describe the integration of the camera on the GCT prototype telescope structure, and the achievement of "first light", validating for the first time the full proof-of-concept of an IACT with SC optics.
I also report a study I performed on expectations for an extragalactic survey for blazars with CTA. The cumulative source count distribution of blazars is presented, including implications from two different phenomena: axion-like particle (ALP) to gamma-ray oscillations in the intergalactic magnetic field, and secondary gamma rays from hadronic origins. I conclude that a shallow and wide survey will provide the best science return for CTA, that the impact of ALP is modest and that the secondary mechanism of gamma-ray production would allow detection of blazars up to redshift of 1 in the multi-TeV energy band.