VictorJuiz/thesis huggingface dataset:
Reconstitution of the mechano-sensitive cadherin-catenin/F-actin complex [electronic resource]
Keywords: Biophysics.

Cell-cell adhesion is essential for tissue development and maintenance. In epithelial tissue, the cadherin-catenin complex establishes this adhesion and associates with the actin cytoskeleton to do so. A long-standing hypothesis is that the cadherin-catenin complex binds actin filaments directly, but work using purified proteins challenged this idea in 2005. Since then, studies have found that the cadherin-catenin complex is sensitive to mechanical tension. As a result, we hypothesized that the complex requires tension to bind actin filaments. Results from an optical-trap assay supported this idea, and we concluded that cadherin-catenin complexes and actin filaments form two-state catch bonds, which last longer at intermediate levels of tension. Work of others suggested that association of vinculin with the cadherin-catenin complex is the molecular basis of the longer-lived catch bond state. Our follow-up work using the vinculin head domain, which binds the cadherin-catenin complex in solution but not actin filaments, demonstrated that association of vinculin lengthens the duration of actin bonds. Full-length vinculin, however, is an autoinhibited molecule that binds the cadherin-catenin /actin complex weakly. Thus, based on other studies, further work sought to test whether or not actomyosin-generated tension and abl-mediated phosphorylation were sufficient to increase this binding. Experiments conducted using a microscopy-based filament-binding assay showed that while tension and phosphorylation were not required for association of vinculin, they had an additive effect on the amount of bound vinculin. Altogether, my thesis work provided mechanistic insights into how mechanical tension affects the kinetics and composition of the cadherin-catenin/F-actin complex.
Recovering a Kantian analytic/synthetic distinction through incompatibility [electronic resource]
Keywords: Philosophy.

This dissertation seeks to recover a viable analytic/synthetic distinction that retains a distinctly Kantian heritage. It is formulated with distinctly metametaphysical intent, to be part of another philosophical project that Kant initiated: the critique of metaphysics. In my view, to take or treat a claim as analytic is to, at least implicitly, to undertake a commitment to its being deducible merely from our commitments about object-general, non-localized incompatibility and entailments claims; to treat a claim as synthetic is, at least implicitly, to undertake an implicit commitment to its not being so deducible. The account of the analytic/synthetic divide I provide is cleaved in terms of alethically modal concepts which, traditionally, have been seen as metaphysically-loaded and hence problematic for my purposes. This is because the dominant philosophical tradition for understanding alethic modality rests its account on the metaphysically and epistemically fraught notion of a continuum of inter-accessible possible worlds. To avoid this, my account draws on resources found in Robert Brandom's incompatibility semantics, which offers an alternative account of necessity and possibility in terms of the less-problematic notion of incompatibility (Brandom 2008). My appropriation of Brandom's incompatibility semantics incorporates several changes. First, I reinterpret Brandom's semantics using an intensional notion of schematic generality, which helps me to clarify the semantic interdependence of general and particular therein and resolve several epistemological and methodological concerns. I also discuss the complicating factor of nonmonotonicity by reference to the Michael Thompson's work on "natural-historical judgments" (2008), showing how the generality and modality expressed in nonmonotonic, modally-sophisticated claims can fit within my revised understanding of incompatibility semantics and the analytic/synthetic divide. Next, I modify Brandom's incompatibility semantics by formally extending it to equal the expressive power of Kripke Semantics by incorporating an analog of accessibility relations therein, and thereby rectifying formal and intuitive impoverishments of Brandom's formalism. I also provide an interpretation of what accessibility relations, transposed into incompatibility semantics, can be taken to mean by invoking a logical notion of meta-compatibility, and I provide a pragmatic explication of what linguistic practitioners must do in order to take or treat matters as meta-compatible.
Recovery of resources and energy using methane-utilizing bacteria [electronic resource] : synthesis and regeneration of biodegradable, tailorable bioplastics and production of nitrous oxide
Keywords: Civil and Environmental Engineering.

Methane is a familiar and abundantly available gas with both natural and anthropogenic sources. Aerobic methanotrophs (methane-utilizing bacteria) use methane as their sole carbon and energy source. Use of methanotrophs for biotechnological applications to convert methane into value-added products is attractive since methane is cheap, abundant, and in the case of anaerobic digestion is a renewable carbon source. One such potential application is production of biodegradable bioplastic, polyhydroxyalkanoates (PHAs), a sustainable alternative to petroleum-based plastics. Previously, poly(3-hydroxybutyrate) (P3HB) was the only type of PHAs reported to be produced by methanotrophs. However, applications for P3HB are limited by its narrow melt processing windows and lack of flexibility. This research present a methodology to produce various PHAs having a wide range of thermophysical properties using methane as a primary feedstock and added co-substrates. This research also focuses on a recycling strategy to regenerate waste PHA products into new PHAs using "abiotic-biotic PHA recycling" that is rapid and efficient, and can avoid downcycling (i.e., it can avoid decrease of molecular weights each cycle). Methanotrophs can also be used to remove nitrogen from wastewater and generate nitrous oxide, a potential co-oxidant of biogas methane to increase energy production. Finally, this research demonstrates a novel methanotroph fermentation scheme, an emulsion-based fermentation, which enables enhanced mass transfer of insoluble methane substrates to methanotroph medium without the need for vigorous agitation.
Recurrent Point Mutations in the Kinetochore Gene KNSTRN in Cutaneous Squamous Cell Carcinoma
Keywords:  Department of Biology
Biology
cancer
KNSTRN
squamous cell carcinoma
SCC
genetics
sequencing
molecular genetics
Thesis

Cutaneous squamous cell carcinoma (SCC) is the second most common cancer, with an annual global incidence in excess of 1 million. To identify recurrent genomic aberrations that underlie the development of this malignancy, single nucleotide variant (SNV) determinations from whole-exome sequencing of 12 SCC-normal pairs was used to distill a list of 336 candidate genes that were then sequenced in 100 SCC-matched normal pairs with an average depth exceeding 1200X. KNSTRN ranked third behind CDKN2A and TP53 among recurrently mutated genes in SCC after normalizing for gene length. KNSTRN encodes a kinetochore protein that has not previously been implicated in cancer. Somatic mutations in KNSTRN were present in 2 of 12 (17%) and 19 of 100 (19%) SCCs analyzed by whole exome and targeted sequencing respectively, and most mutations occurred around a UV-signature hotspot serine to phenylalanine substitution present at codon 24 (S24F). KNSTRN S24F was detected in SCC precursors, consistent with an early event in tumorigenesis. Cancer-associated mutant KNSTRN disrupted chromatid cohesion in normal cells, and using whole-genome copy number analysis, SCCs with KNSTRN S24F were determined to be significantly associated with an increase in copy number aberrations. Mutant KNSTRN also enhanced Ras-driven tumorigenesis in vivo. Thus, we report the first cancer-associated missense mutations in the kinetochore gene KNSTRN with dominant, pro-tumorigenic consequences in cutaneous SCC.
Refashioning Napoletanità: Identity, Corporeality, and Value Creation in the Neapolitan Bespoke Tailoring Industry
Keywords:  Department of Anthropology
artisanship
cultural commodification
gift
geographical indication protection
Naples
value
Thesis

Despite Naples' gritty, dangerous image being incongruous with conventional bourgeois aesthetics of Italian luxury fashion, Neapolitan bespoke tailoring is regarded as one of the most prestigious sectors of global luxury menswear. Editorial attention on these tailoring firms (sartorie) fail to fully unpack the complex interplay between Neapolitanness (napoletanita') and commercial value. Drawing on two summers of fieldwork in Naples and Florence, I argue that the sartorie conceive of their work's value as deriving from their napoletanita', understanding Neapolitan cultural identity's multiplicity of meanings and contradictions in ways that cohere with their ascendancy in luxury fashion. I first consider how history, renegotiated, is a powerful modality through which sartorie experience and express their napoletanita'. Naples' storied Greek, Roman, and Enlightenment past resolves tensions between the sartoria's cultural prestige and contemporary Naples' lack thereof, while "traditional" Neapolitan narratives of labor and handcraftsmanship resolve the luxury industry's inherent tension between commerce and exclusivity. The Mafia's violent 20th century legacy is understood as testifying to the enduring spirit of Neapolitans for having survived. Second, I outline how for sartorie artisanship rests upon a productive tension between the eye's perfect judgment and the hand's imperfect unmechanicality. Artisanship breaks down the traditional dichotomy between Maussian gift and Marxian commodity, by incorporating inalienable napoletanita', creating producer-client social obligations, and obscuring certain social relations of production in the sartoria. After Douglas, I suggest that the sartorie's corporeal concerns about the lack of artisanal eye or handcraftsmanship i competing menswear sectors evince social concerns about the gift of napoletanita's susceptibility to being threatened by industrialization. The final section centers a value-based understanding of labor processes and cultural commodification in safeguarding the future of waning artisanal industries, suggesting how the EU might implement geographical indication protection schemes beyond agricultural produce and foodstuffs industries.
Regulation of lysosomes in myelination and microglia function [electronic resource]
Keywords: Developmental Biology.

The central nervous system, composed of the brain and the spinal cord, is made up of two broad classes of cell types: neurons and glia. The interaction between glial cells and neurons is crucial for proper development and function of the nervous system. The first type of glial cells, macroglia, includes astrocytes and oligodendrocytes. Oligodendrocytes are the cells that form myelin, an evolutionary adaptation that allows rapid and efficient propagation of action potentials along axons. Diseases of myelin include multiple sclerosis, in which damage to the myelin sheath in the central nervous system disrupts flow of information between the brain and the body, often leading to debilitating symptoms. The second glia cell type, microglia, performs a variety of roles in the CNS including phagocytic clearance of dead neurons and debris. Microglia have been implicated in neurodegenerative diseases such as Alzheimer's Disease, which is characterized by memory loss, neuronal death and accumulation of abnormal amyloid plaques. By understanding the pathways that control microglia and oligodendrocyte development and function, novel therapies for CNS diseases may be developed by harnessing the capabilities of these cell types. In this dissertation, I focus on the roles of the Rag-Ragulator complex and other lysosomal-associated proteins in microglia and oligodendrocytes. In Chapter 2, I describe the identification of mutations that disrupt the Rag-Ragulator complex in a screen for myelin mutants. In mutants lacking RagA and Lamtor4, components of the Rag-Ragulator complex, myelinated axons are reduced compared to wildtype siblings, despite the presence of oligodendrocytes. The absence of Rag-Ragulator function prevents oligodendrocytes from maturing and ensheathing exons. These results point toward a key function of lysosomes in myelination. In Chapter 3, I describe the microglial function of the Rag-Ragulator complex. RagA and Lamtor4 mutants have a reduced number of microglia. The few microglia that are present have an expanded lysosomal compartment - yet are unable to properly clear debris that they have engulfed. In Chapter 4, I characterize Tcirg1b mutants, which exhibit a similar microglia phenotype to RagA mutants. Tcirg1b encodes a component of the vacuolar proton pump that acidifies the lysosome. Tcirg1b mutants have microglia that are engorged with undigested apoptotic neuronal debris. Together, this work defines new roles of lysosomal genes in oligodendrocytes and microglia, thereby highlighting the importance of lysosome function in different glial cell types.
Regulation of the ARL6 GTPase cycle within the primary cilium [electronic resource]
Keywords: Biochemistry.

Primary cilia organize cellular signaling cascades by dynamically concentrating signaling receptors in response to extracellular cues. In particular, the removal of signaling molecules from cilia tunes the sensitivity of major signaling pathways but remains a poorly understood process. A major sorting complex for the cilium is the BBSome, a coat-like complex of eight Bardet-Biedl Syndrome (BBS) proteins, which directly recognizes signal receptors and co-moves with the intraflagellar transport (IFT) machinery within cilia. Importantly, recruitment of the BBSome to membranes relies on GTP loading onto the ARF-like GTPase ARL6/BBS3, but no regulators for the nucleotide state of ARL6 have been identified so far. Identification of the guanine nucleotide exchange factor (GEF) and GTPase-activating protein (GAP) for ARL6 is key to pinpointing the locations where BBSome coats assemble and disassemble, respectively, and will further shed light on the pathomechanisms of BBS. Because mutations in the Rab-like GTPase and IFT-B subunit IFT27/RABL4 were recently identified in a BBS family, we sought to characterize the function of IFT27 in BBSome-mediated trafficking. Strikingly, ARL6, BBSome and the candidate BBSome cargo GPR161 accumulated in IFT27-deficient cilia, and photokinetic assays on stable cell lines expressing fluorescently tagged BBSome revealed that IFT27 perturbation reduces BBSome exit rates ~3-fold while leaving BBSome entry rates unaffected. At the molecular level, IFT27 disengages from the rest of IFT-B to directly associate with and stabilize the nucleotide-free form of ARL6 against aggregation. Thus, we propose that within cilia, IFT27 dissociates from IFT-B to directly participate in GTP loading onto ARL6, promoting the assembly of exit-bound and cargo-laden BBSome coats. Additional mechanisms for the regulation of IFT27 and ARL6 within cilia are discussed.
Religious redirection [electronic resource] : Muslim-Christian market interaction in early islamic Syria-Palestine
Keywords: Anthropology.

This dissertation examines cultural and religious change in a context of interreligious interaction at Jarash city in Jordan during the early Islamic period (600-1000 CE). Through archaeological study of market street shops, an early congregational mosque in the centre of urban Jarash, and an array of material items and practices, it investigates how religion is lived out in everyday experience and changes gradually. In late antique Jarash—a predominantly Christian city with numerous churches—a congregational mosque is built, the urban marketplace expands, and new changes are seen in commercial and material culture. I explore these changes by considering the relationship between mosque and market in the urban environment, studies of macro-botanical, phytolith, faunal and human remains, writing tablets, and mass-produced religious commodities. This enables a description of the material bases of social and religious belonging, changes in farming, food and diet, commercial practices involving money and trust, and ideas of the sacred in material culture. The dissertation suggests that the early urban mosque in Jarash facilitated intermingling and interaction. Evidence indicates that a food suq (market) became closely associated with the mosque and that market streets were organised by trade occupation. The discussion of bio-environmental data provides an account of how people put religious ideas to use and are shaped by their relations with ecological things and market exchange. The dissertation also illustrates how personal texts inscribed on mass-produced lamps created a distinct, local form of spirituality that emerged in the fluid relations between Christians and early Muslims. Overall it offers an understanding of how religious communities reshape each other in grounded, material ways through social interaction. Comparing change at a political state-level with change in religiosity in everyday material culture related to individuals, I show how these processes differ in timing. The dissertation suggests early Islam to be cross-cutting of religious and social boundaries within the study setting.
The religious roots of inequality in Africa [electronic resource]
Keywords: Political Science.

Compared to Christians, Muslims in sub-Saharan Africa have fewer years of education, are less likely to be literate in any language, and their children are less likely to be in school. This project is the first to provide a quantitative and comparative documentation of this widespread inequality, and addresses two key questions. First, what are the origins of the Christian-Muslim education gap in Africa? Second, what explains variation in its persistence over time? I find that religious demographics play an important role in explaining the origins and persistence of the Christian-Muslim education gap in Africa. Employing case studies of colonial Nigeria and Uganda, I find that the distribution of the Muslim population and the degree of Islamization of political institutions in pre-colonial Africa affected demand for and investment in education in the colonial period through two channels: the religious marketplace and the structure of political power. Within Uganda, the percentage of an ethnic group that is Muslim is negatively correlated with Muslim educational attainment and positively correlated with the magnitude of the Christian-Muslim education gap in the colonial period. Further, Muslim educational attainment during the colonial period is predicted by exposure to missionary schools. There is considerable variation in persistence of educational inequality across countries over time. In some cases, the Christian-Muslim education gap has remained stable or declined, and in other cases the gap has grown. I suggest that part of the persistence of inequality is also related to religious demographics. Muslims in several African countries today continue to have worse educational outcomes, and the Christian-Muslim education gap is larger, where they comprise a local majority. The long-term effect of colonial investments, and particularly physical access to schools, likely explains some but not all of this relationship in the current period. In the case of Malawi, controlling for access, Muslims living as a majority continue to have lower educational attainment than Christians living in the same area and than Muslims living as minority. I conduct a household survey with embedded experiments to investigate a set of mechanisms that may underlie this relationship.
Renewable materials and chemicals from waste lignin [electronic resource]
Keywords: Chemistry.

Lignin is the second most abundant natural polymer, making up 30% of the total carbon in the biosphere. Industries that utilize the "woody" biomass of plants (e.g. papermaking and biofuel production) generate more than 130 million tons of lignin per year. There is intrinsic value in the aromatic components of lignin. Lignin is hence an inexpensive and only renewable feedstock for the production of aromatic chemicals that are currently derived almost exclusively from fossil resources. Despite the abundance of lignin and potential economic benefits of lignin utilization, challenges in lignin utilization has relegated its application to low-value ones. For instance, as a filler in concrete and animal feed, as a dispersant, and as fire-retardant. The challenges stem mainly from its poor physical properties as a material. Moreover, the complexity and high stability of lignin bonds make deconstruction of lignin to aromatic monomers profoundly challenging. Presented herein are efforts towards transforming lignin to functional materials in high-value applications -- as a bulk polymer and aromatic monomers -- by suitably harnessing some unique molecular features of lignin. These include (i) UV-performance arising from lignin's aromaticity; (ii) chemical recalcitrance due to strong stability of bonds; and (iii) the highly prevalent β-O-4 motif in lignin which we chose as a target for depolymerization chemistry. First, we developed a catalytic and solvent-free method to synthesis lignin--lactide copolymers. We used these copolymers as dispersion modifiers in "corn-derived" polylactic acid (PLA)-based materials to allow PLA to block UV radiation. Second, we took advantage of lignin's chemical stability and formulated an eco-friendly, 100% waste-derived wood adhesive. We demonstrated that the adhesive performs on par with formaldehyde-containing ones that are used in household wood-based furniture items. Last, we applied mild chemical methods to target the β-Ο-4 linkage in lignin, and characterized the stream of aromatic monomers produced. The depletion of fossil fuels and the environmental impact of petroleum-based plastics have driven a strong global interest in renewable polymers derived from non-food feedstocks. Our work with synthesis of functional lignin-based materials is an important step towards the complete utilization of lignocellulosic biomass, and serves to complement studies in cellulose and hemicellulose utilization.