VictorJuiz/thesis huggingface dataset:
The Role of dmbx1 and pcdh15 in Zebrafish Retinal Development and Disease

The retina is organized into layers of different retinal cells, including photoreceptors, which are responsible for vision. Precise development of the retina requires (1) the coordinated expression of genetic networks to promote the differentiation of different retinal cells from multipotent retinal progenitor cells (RPCs), and (2) the adaptation of structural features to elaborate unique cell morphologies necessary for their function. Improper development or maintenance of retinal cells are responsible for many retinal dystrophies including blinding diseases, Retinitis Pigmentosa (RP) and Usher syndrome (USH). In this thesis, I explore two genes that exemplify these processes including the homeobox transcription factor, dmbx1, and putative adhesion molecule and USH gene, pcdh15, in the retina. Using CRISPR genome editing technology, I created the first zebrafish mutants for the paralogs dmbx1a/b and pcdh15b that display retinopathic features. Despite previous accounts that suggest dmbx1 is required for RPC cell cycle exit, I find that although there are some early defects in RPC proliferation and cell death, the retina initially forms normally in the mutant context. However, specifically in dmbx1a mutants, I find novel phenotypes showing greater amounts of retinal cell death, failure of post-embryonic retinal growth, and progressive development of dystrophic photoreceptors. RNA-seq analysis indicates that these phenotypes can be attributed to dysregulation of a small subset of genes associated with retinal disease and ciliogenesis. Although reports of Pcdh15 mice mutants fail to mimic retinopathy, I show that zebrafish pcdh15b mutants display defects in the outer segment (OS) regions of photoreceptors, and the synapse. Zebrafish pcdh15b mutants show abnormal photoreceptor integrity, including detachment of OS from the cell body, and abnormal growth of OS discs, which are both exacerbated under bright light conditions, as well as disorganization of synaptic elements. Furthermore, the current model of USH-associated retinal disease suggests that USH is a degenerative issue, however, the detection of these defects in early developing photoreceptor cells indicates a progressive developmental pathology. Together, my work highlights new finding of these genes using zebrafish models, and the importance of establishing proper transcriptional gene networks, as well as maintaining structural molecules in the prevention of retinal dystrophies.

Keywords: Homeobox
Photoreceptor
Protocadherin
Retina
Usher syndrome
Zebrafish
Advisor: Tropepe, Vincent
Fatigue and Fracture Behavior of Graphene-based Nanomaterials

Mechanical durability is an important factor for a reliable design and commercialization of nanostructured products, where the components are susceptible to mechanical failure induced by static and cyclic loads. Known as "wonder material" graphene has demonstrated a great potential to be used in multifunctional nanostructures and nanodevices. However, after more than a decade of research, studies have reported the mechanical performance of graphene-based nanomaterials is far from the initial hype. The key issues are that graphene suffers from an intrinsically brittle behavior and an interfacially weak interaction in contact with adjacent constituents. The present thesis studies both issues under static and cyclic loads. Initially, atomistic simulations were performed to understand the underlying mechanisms and required kinetic conditions for the fatigue failure of graphene. While the failure was a thermally activated process, an extreme defect sensitivity was captured for graphene in which the fatigue life was completely dominated by the first covalent bond dissociation. Considering the inevitability of defects, such a drawback stressed a need for modifying the lattice structure of graphene such as by using chemical functionalization. Using extensive atomistic simulations coupled with AFM-based nanoindentation tests, we systematically studied the fatigue behavior of graphene oxide and presented the tailoring of functional groups as a tool to tune the intrinsic fatigue resistance and lifetime of graphene. It was demonstrated how a controlled chemical functionalization of graphene oxide can indeed enhance the defect tolerance and maximize the fatigue lifetime of graphene, up to five-fold at a low degree of functionalization (5\%) with higher content of epoxy groups. Using a similar approach, the possibility of tailoring functional groups was evaluated on enhancing the interfacial properties of graphene/polymer nanocomposites. From an atomistic insight, an enhanced load transfer was observed at the interface of functionalized graphene/polymer owing to the creation of mechanical entanglements and hydrogen-bond networks. We also reported that by a selective degree of functionalization (approximately 10\%), a superior fracture resistance can be achieved for the graphene-based polymer nanocomposites. This was attributed to a transition in the failure mode from interfacial slippage (for graphene/polymer) to an interfacial crack arresting (for graphene oxide/polymer).

Advisor: Singh, Chandra Veer CV
Sain, Mohini M
Legalize it? A Comparative Study of Cannabis Economies in St. Vincent and St. Lucia

This dissertation examines the historical origins, as well as the cultural, political and economic significance of the ganja industries of the Eastern Caribbean islands of St. Vincent and St. Lucia. The primary research question this dissertation sought to answer was, would the legalization of ganja in the Eastern Caribbean be an economically viable replacement for bananas? The additional two sub-questions were: What are the power dynamics of the illegal ganja trade? Furthermore, what is the current contribution of the ganja trade to the economies of St. Vincent and St. Lucia? The central argument of this dissertation is that the emergence, variation and importance of the ganja economies in St. Vincent and St. Lucia arise from their particular historical legacies of colonial underdevelopment and the failure of capitalism to generate a sustained, widespread improvement in living standards. The historical combination of outward-oriented economies that failed to meet the needs of the domestic majority, and weak states (themselves a product of capitalist underdevelopment) facilitated a pattern of resistance rooted in the use of illegal activities as a mode of survival employed by the rural and urban poor. This pattern of resistance has its origins in clandestine circuits of trade and production that arose during slavery. However, unlike past illegal economic activities, the ganja economy, in responding to widespread unemployment and catering to regional as well as local needs, represents a departure from the plantation model of the past. Despite data limitations, this project has established that ganja has become much more important to these economies than bananas or remittances, acting as an indispensable grassroots social safety net. However, given the power of international capitalist interests and the predisposition of domestic elites, the available evidence thus far suggests that the governments of these Eastern Caribbean countries will not pursue the policies necessary to ensure that the ganja industry develops in a way that benefits local populations and threatens to erase the lifeline that ganja has provided for so many in the region.

Keywords: Cannabis
Plantation
Politics
St. Lucia
St. Vincent
Advisor: Teichman, Judith
Universes of the Mind: the Jungian Archetype of the Self in the Works of Philip K. Dick and Valerio Evangelisti

This thesis examines the influence of Jungian’s analytical psychology on Philip K. Dick’s early narratives and Valerio Evangelisti’ Eymerich Saga by focusing on the central Jungian archetype of the Self. “Universes of the mind,” a concept that comes from Dick, refers to the visionary power of symbolic images, namely, what Dick and Evangelisti tried to discover and investigate through their writing. By focusing on Dick’s Ubik and Evangelisti’s Cherudek, this thesis explores how Jung’s archetype of the Self manifests within the context of physics, mythology, numerology, alchemy and the history of religions in their novels. In both novels—and select other works by Dick and Evangelisti—Jungian theories of the archetypes influence not only the narrative structures but also the character dynamics. By moreover following Campbell’s hero journey—a theoretical journey based on Jung’s process of individuation—these writers represent the inner struggle of the individual to achieve psychological integration. Despite significant variances between them, the two authors take inspiration from Jung’s concepts of synchronicity and schizophrenia in order to represent the condition of capitalist society. These similarities between Dick’s and Evangelisti’s SF make it possible to identify a shared tendency in their use of literature as a way to represent the psychological effects of capitalism in western society.

Keywords: archetypal studies
Italian science fiction
jungian studies
Philip K Dick
science fiction
Valerio Evangelisti
Advisor: Somigli , Luca SM
Gene Immunotherapy Against Amyloid Pathology in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease is characterized by progressive accumulation of amyloid-beta peptides (Aβ) in the brain and severe cognitive decline. Several anti-Aβ immunotherapies failed to efficiently slow disease progression and improve cognition in clinical trials. The blood-brain barrier (BBB) limits the bioavailability of intravenously administered antibodies to the brain, potentially contributing to reduce efficacy. I hypothesized that engineering neurons to continuously produce anti-Aβ antibodies in the brain will increase therapeutic efficacy. To evaluate this hypothesis, I developed a gene immunotherapy approach; delivering adeno-associated virus 6 (AAV6) that encoded for a recombinant anti-Aβ single-chain variable fragment (rSol), AAV6-rSol, into the brain of TgCRND8 mice, a preclinical model of amyloidosis. rSol was derived from Solanezumab, a human antibody against soluble Aβ. I tested my hypothesis by completing three objectives. Firstly, I designed, constructed, and purified rSol, and then I confirmed its high affinity for soluble Aβ. Secondly, I engineered rSol under the control of synapsin promoter into an AAV6 and demonstrated that the expression of rSol was neuronal-specific in vitro and in vivo. In TgCRND8 mice, I found that rSol had prolonged neuronal expression for over 14 months, efficiently preventing Aβ deposition into Aβ plaques, reducing associated dystrophic neurites and decreasing the activation of astrocytes and microglia at 6-month post-intracranial delivery in neonates. Thirdly, I delivered AAV6-rSol into the brain of adult TgCRND8 mice non-invasively and evaluated the impact of this treatment on mice behaviour. Focused ultrasound (FUS), guided by magnetic resonance imaging (MRIgFUS) was used to temporarily increase the permeability of the BBB, allowing AAV6-rSol to reach the brain. No amelioration was detected in nest building activity and locomotion of TgCRND8 mice. Low gene delivery in these experiments likely contributed to the lack of robust effect on behaviour. I suggest that MRIgFUS-mediated gene delivery can be optimized using higher AAV dosage or more efficient serotypes such as AAV9, guided by the methodological protocol outlined in this thesis. In conclusion, I developed a neuronal gene immunotherapy with therapeutic efficacy against Aβ deposition. Combined with promising non-invasive gene delivery to the brain, gene immunotherapy could lead to clinical benefits in the future.

Keywords: Adeno-associated virus (AAV)
Alzheimer's disease
Gene therapy
MRI-guided focused ultrasound
Single chain variable fragment (scFv)
TgCRND8 mice
Advisor: Aubert, Isabelle
Hynynen, Kullervo
Patterns of Selection in Osmoregulatory and Visual Protein Coding Genes in Beloniform and Clupeiform Fishes as an Evolutionary Response to Major Ecological Transitions

Ecological transitions arise due to opportunities that present themselves facilitating species transitions to novel habitats, diets, behaviours, and other ecological adaptations that can be marked in their molecular blueprints. Studies have explored variation in species genetics in the context of evolution by implementing methods that estimate patterns of selection acting in genes likely involved with ecological transitions. In my thesis, I implement these methods to determine them overall patterns of selection on candidate genes that are likely influenced by ecological transitions using teleost fishes as my model system. To test hypotheses of transitions between marine and freshwater habitats as a major evolutionary event overcoming salinity barriers, I analyze osmoregulatory related (OR) and non-osmoregulatory related (NOR) genes using marine and freshwater Beloniformes (chapter 2). I find that evidence of positive selection was prevalent in OR genes for marine species based on random-sites models, but clade model analyses which estimates selection patterns between partitions in a phylogeny (i.e. between marine and freshwater) revealed an overall purifying selective force on OR genes across beloniforms, with stronger purifying selection in marine beloniforms. The results suggest that stronger selective forces may be prevalent in marine beloniforms in order to maintain protein integrity which may be important in these species that occupy diverse marine habitats (i.e. coastal, pelagic, lagoonal) where salinities can differ. I also find evidence for genome-wide influence due to similar patterns of selection acting on NOR genes, suggesting that transitioning to freshwater can impact other genes not directly associated with osmoregulation. In chapters 3 and 4, I further explore the influence of ecological transitions, but focusing on photic regime shifts between marine and freshwater habitats as well as transitions to different diets to elucidate if one ecological transition had a stronger impact on vision (i.e. opsin) evolution. I analyzed Beloniformes (chapter 3) and Clupeiformes (chapter 4) opsins and find that, interestingly, diet played a more prominent role in opsin evolution than habitat. Diet explained significant shifts in selection in six out of nine beloniform opsins and for all six clupeiform opsins analyzed.

Advisor: Lovejoy, Nathan R
Tell el-Yahudiyeh Ware at Tell el-Maskhuta – Evolution, Character, and Function during the Middle Bronze Age/Second Intermediate Period

Tell el-Maskhuta was a major settlement in Wadi Tumilat located in eastern Nile Delta with Western Asiatic population dating to the Second Intermediate Period. It was excavated by the Wadi Tumilat Project under the direction of John S. Holladay in the late 1970s and early 80s, and despite its remote location, showed great potential in understanding of the 15th Dynasty presence in the periphery of the eastern Nile Delta. Unfortunately, after the initial excavation and land survey were completed, the site was never fully analyzed or published. This study aims to re-examine the archival material and conduct a re-evaluation of the data collected during the excavation of the site. The typological and petrographic analysis of Tell el-Yahudiyeh ware found at Tell el-Maskhuta allowed to confirm the dating of the site and provided evidence of local adaptation and evolution of this vessel type. A pattern of changes in the fabric use attested for those highly specialized and standardized vessels was a sign of evolution of their sequence of production in order to accommodate locally available raw materials. It also signalled the emergence of a local ceramic tradition incorporating both Egyptian and Levantine traits. The analysis of available data showed that, contrary to previously accepted theories, Wadi Tumilat could have been involved in the long-distance, over-land trade with both southern and northern Levant. The results of this work present a better understanding of the site’s function and development during the Middle Bronze Age (MBA), its place in the Hyksos trade network, and role in the local settlement system. Consequently, Wadi Tumilat was considered as a significant southern corridor leading in and out of Egypt, and a part of the southern desert route traversing the Sinai Peninsula towards the Negev Desert and the Jordan Valley. Tell el-Maskhuta, due to its size and location, could have functioned as a “gateway city” into the Wadi, and consequently into the Nile Delta. As a part of the Hyksos trade network, Tell el-Maskhuta provides invaluable clues to the logistics of the 15th Dynasty economy and its contacts with neighbouring areas beyond the reach of the maritime trade.

Keywords: Egypt
Hyksos
Middle Bronze Age
Second Intermediate Period
Tell el-Yahudiyeh ware
Wadi Tumilat
Advisor: Pouls-Wegner, Mary Ann
Unthinkable Subjects: Postmortem Poetics in Modernity

“Unthinkable Subjects: Postmortem Poetics in Modernity” investigates the status of the dead in theory and the avant-garde at the limits of race and sex. Bringing together queer theory, critical race studies, psychoanalysis, and contemporary experimental writing, this thesis suggests that the dead animate these fields as a site for ethical and political inquiry. If oppressive rhetoric murders by castigating nonnormative others beyond the sphere of the common—as sick, infected, contagion, dying, or already dead—this thesis examines the risks of reclaiming such murdered and murderous bodies. Since fatality invigorates queer theory and critical race studies, the first part of the thesis considers the murderous subjectivities that compose these fields. In this section, the thesis critiques the “murderous jouissance” of the antisocial thesis in queer theory, which offers the most extreme version of self-annihilating fantasy as an ethos of being in the world. Given that the antisocial thesis is most often articulated through psychoanalysis, the thesis goes on to historicize questions of psychoanalysis and race in Frantz Fanon, arguing that for racialized subjects a condition of murderousness registers the violent logic of racism as a psychotic aberration. The rest of the thesis offers readings of contemporary experimental texts working along axes of race and sex, troubling both queer theory’s self-assured fantasy and the apparent inescapability of racialization as a psychically damaging prison. The writers in this study—Wilson Harris, Gail Scott, and Renee Gladman—paradoxically respond to the murderous language of oppressive rhetoric with texts that demonstrate how language not only murders but is itself murdered. Murdered language is registered by the experimental poetics that claim unbecoming, decay, attrition, severance, and violence as their form, resulting in narratives of “in-existence”—texts that formally dwell in and meditate on ambivalence, refuse narrative wholeness, solicit poetic enigma, and traverse the antagonisms of language. Each author’s investment in murder, self-murder, self-annihilation, or self-removal paradoxically offers nonaggressive forms of undoing, ravishment, and coming undone as that which occasions novel ways to claim ontological murder at the scintillating and ecstatic limit of fatal language.

Keywords: contemporary poetry and poetics
critical race studies
experimental writing
literature and death
psychoanalysis
queer theory
Advisor: Ruti, Mari
Cobb, Michael
Nuclear Export of Proteasomes in Yeast

Ubiquitin proteasome system (UPS) is responsible for ~90% of regulated protein turnover in eukaryotes to sustain protein homeostasis. The proteasome is the key protease of the UPS. It is composed of the catalytic core particle (CP) and regulatory particle (RP) that consists of a base and a lid. Regulation of the proteasome’s abundance, activity and localization is critical for cell survival with implications in cancer and neurodegeneration. Proteasome localization is a dynamic process prone to changes dictated by its environment. In proliferating yeast cells growing in nutrient-rich conditions proteasomes are localized primarily in the nucleus throughout the cell cycle and are involved in proteolysis. Upon carbon depletion yeast cells enter quiescence, a reversible phase characterized by cell cycle arrest and low ATP reserves. Proteasomes are then exported from the nucleus to the cytoplasm by a mechanism that seemingly is not the canonical nuclear export pathway where a nuclear export receptor (exportin) fuelled by the GTPase Ran (RanGTP) shuttles its cargo from the nucleus through the nuclear pore complex (NPC) into the cytoplasm and subsequent GTP hydrolysis dissociates the export complex. Previously, Ran (Gsp1 in yeast) but no known exportins were shown to co-purify with the proteasome. This led to the hypothesis that the proteasome could drive its own export by interacting with GTP-bound Gsp1 (Gsp1GTP) and the NPC mediated by its RP base subunits Rpn1 and/or Rpn2. Homologous Rpn1 and Rpn2 show structural similarity to transport receptors. To that end, this work demonstrates that proteasomes are exported as fully assembled holoenzymes in a Gsp1-dependent manner through the NPC. Yeast proteasome mutant strain rpn2ΔN with N-terminally truncated Rpn2 is deficient in proteasome nuclear export. Furthermore, unlike wild type, rpn2ΔN-proteasomes do not bind Gsp1 due to their structural instability. Incorporation of Rpn2 constructs into rpn2ΔN-proteasomes improves stability, rescues export and restores Gsp1 binding, resulting from the stable inclusion of Rpn2’s C-terminus within the proteasome. Gsp1GTP interacts with the RP base, likely through Rpn1 and Rpt1, also an RP base subunit. In conclusion, the proteasome’s RP base serves as the adapter for the holoenzyme’s export by promoting interactions with Gsp1GTP and the NPC.

Keywords: Nuclear export
Nuclear import
Nucleocytoplasmic transport
Proteasome
Yeast
Advisor: Enenkel, Cordula