VictorJuiz/thesis huggingface dataset:
Unraveling the Molecular Mechanisms of Munc18 and Munc13 in Mast Cell Exocytosis

Exocytosis is a fundamental cellular process in which contents stored in vesicles are released out of cells via fusion of membranes. Exocytosis of secretory granules from immune cells such as cytotoxic T-lymphocytes, natural killer cells and mast cells play crucial physiological roles in protecting individuals from pathogens. The exocytosis is known to be mediated by Soluble N-ethylmaleimide sensitive factor Attachment protein REceptor (SNARE) complex where intertwined helix bundles provide energy to fuse lipid membranes. Furthermore, this process is regulated by indispensable proteins such as Munc18 and Munc13 through physically interacting with SNARE proteins. Disruption of proteins that are involved in the secretory granule exocytosis causes serious immune disorders including familial hemophagocytic lymphohistiocytosis. However, compared to vastly investigated mechanisms of neuronal exocytosis, natures of proteins and their precise molecular mechanisms involved in immune cell exocytosis remain elusive. It has been revealed that the immune cells employ Ca2+-triggered SNARE-mediated exocytosis, but how such processes are being regulated in the immune cells needs to be investigated thoroughly. Using Rat Basophilic Leukemia-2H3 (RBL-2H3) mast cells, the structure and interactive properties of Munc18 and Munc13 in respect to mast cell exocytosis were examined. Through knockdown and rescue approaches, results indicate that Munc18 protein is crucial for exocytosis of mast cells partly through regulating its cognate syntaxin partners such as syntaxin-3 and -11 for their protein level and trafficking. Independent knockdowns of syntaxin-3 and -11 demonstrate that syntaxin-3 is the key cognate syntaxin whose level and intracellular localization are regulated by Munc18. In addition, our data demonstrate that Munc13-4 plays an essential role in mast cell degranulation; mutational studies revealed that point mutations in C2 domains of Munc13-4 dramatically alter Ca2+-sensitivity of degranulation, whereas absence of Munc13-4 or multiple mutations in C2 domains result in almost complete loss of exocytosis from mast cells. Moreover, Munc13-4 mediates Ca2+-dependent regulation of fusion pore opening of single granule fusion events. Taken together, we postulate that both Munc18 and Munc13-4 are essential for mast cell exocytosis albeit their functions, therefore molecular mechanisms, are exerted in different stages of exocytosis.

Keywords: Exocytosis
Mast cell
Munc13
Munc18
SNARE
Advisor: Sugita, Shuzo
Functional Characterization and Molecular Evolutionary Analyses of Rhodopsin in Fishes and other Vertebrates

The visual perception of light is complex, achieved through sophisticated biological systems ranging from the molecular interactions of visual system proteins, to computational processing within retinal neuronal circuits, to the higher cortical synthesis of visual inputs. Photon absorption by the rod visual pigment rhodopsin forms the first step in the visual transduction cascade, ultimately mediating all dim-light organismal visual sensitivity. Natural selection has moulded vertebrate rhodopsin into a remarkable molecular machine, with a stunning sensitivity to single photons and an ultra-fast, femtosecond photoproduct formation. These evolutionary innovations are underpinned by the elegant structural and functional features of rhodopsin, serving as the basis for our understandings of other class A G protein-coupled receptors. Much remains to be discovered of the precise molecular mechanisms which govern rhodopsin structure and function, with mutational epistasis and other features of protein science presenting a formidable analytical barrier against progress. Comparative evolutionary approaches investigating protein adaptation are a powerful yet underexplored means by which novel features of protein science can be elucidated. In this thesis, an interdisciplinary approach involving computational models of molecular evolution combined with protein modelling and in vitro experimental tests of function were employed towards unravelling how natural variation in rhodopsin can reflect evolutionary adaptations that can ultimately illuminate and predict novel features of rhodopsin structure and function. Following a general introduction, Chapter II presents the first evidence for the cold-adaptation of rhodopsin, using high altitude Andean catfishes (Siluriformes) as a model system. Molecular targets under selection at high altitudes are shown to be highly similar between high altitude Tibetan Plateau and Andean catfish rhodopsins, with evidence in Chapter III suggesting possible phenotypic convergence of rhodopsin kinetics at high altitudes. In Chapter IV a new functional feature of rhodopsin was discovered, comprising a compensatory structural unit which modulates both rhodopsin spectral sensitivity and light-activated kinetics. This thesis identifies several novel features of rhodopsin structure and function while presenting case studies of protein adaptation. This multidimensional explication reflects and contributes to the emerging understanding that protein structure and function is inextricably linked to shifts in ecology, environment and the dynamics of molecular evolution.

Advisor: Chang, Belinda SW
Horticultural Hybrids: Plants, Women, and Rhetoric in Early Modern England

This dissertation examines the rhetorical transformation of female bodies into plants and the gendering of plants in early modern English literature and science. Bringing gardening manuals and obstetrical treatises into conversation with a wide range of literary texts, such as Isabella Whitney’s A Sweet Nosgay, Mary Wroth’s The Countess of Montgomery’s Urania, John Milton’s Paradise Lost, and William Shakespeare’s The Winter’s Tale and Titus Andronicus, I argue that these horticultural metamorphoses occur when the generative potential of the female body threatens to elude patriarchal containment. Yet, I contend that the plant-women resist objectification by defying the conflation entirely, by wielding authority to metamorphose themselves into female-horticultural hybridity, or by discovering the surprising opportunity to embody new forms of discourse. Early modern ecocriticism and history of science typically detail the relationship between humans and nature, but my research reconceives that link by examining what happens when these two categories are rhetorically conflated. The resulting breakdown of boundaries reveals how early modern women and nature might evade patriarchal restrictions by becoming newly hybrid vegetal bodies capable of speaking from a dual subject position. The intermingling of horticulture and language in early modern England – where books could be gardens, forests, and posies, flowers could be powerful rhetoric, and grafting could be a graphic act of writing – creates room for this evasion to occur. I structure the project thematically, with an opening chapter on books as gardens, and subsequent chapters focusing on the female body as an enclosed garden, a flower, a fruit tree, and a forest tree. Metaphorical language creates these hybrid vegetal-female bodies, but this dissertation argues that the blurring of horticultural generation and literary or linguistic generation allows these feminized plant objects to regain authority over language and to remake themselves as subjects.

Keywords: ecocriticism
gender
horticulture
literature
Advisor: Harvey, Elizabeth D
Legal Gaps in Times of New Wars

War is a ubiquitous and dynamic social phenomenon subject of many international legal rules. International Humanitarian Law (IHL), the purpose of which is to regulate the conduct of war, was developed for interstate traditional wars rather than new wars, conflicts with particular features such as the presence of armed non-state actors, transboundary territorial scope and unlawful methods of war. This thesis will address the (in)adequacy of current IHL rules to deal with new wars. The core principles of IHL, combined with norms found outside of IHL’s legal body, such as International Criminal Law and the Responsibility to Protect (both of which revolved around violations of IHL that amount to war crimes) can aid IHL’s implementation and enforcement to new wars. The principle of humanity, applied through the Martens Clause, is still the most relevant mechanism to update IHL and fulfill its gaps without requiring the creation of new provisions.

Advisor: Brunnee, Jutta
Employing Gas Challenges and Breathing Manoeuvres to Assess Microvascular Functional Dynamics

Proper blood vessel function entails the transport of blood and modulation of perfusion in response to stimuli. This serves to maintain adequate blood pressure and nutrient delivery. The ability of blood vessels to modulate perfusion in response to demand is a key feature of microvascular integrity (MI). Loss of MI is a characteristic feature of endothelial dysfunction (ED) and is found in several conditions, including hypertension, chronic kidney disease (CKD) and diabetes. To date, most of the research on ED diagnosis has focused on the brain and although there is a clear link between cerebrovascular dysfunction and microvascular pathologies, little work has been done to diagnose extra-cranial ED. Assessment of MI necessitates two steps: a vasoactive stimulus to generate a response (i.e. vasoconstriction/ vasodilatation) and an imaging method to continuously monitor the response. The works presented in this thesis aim to further our understanding of microvascular reactivity with the aim of creating a non-invasive Magnetic Resonance Imaging (MRI) based technique to diagnose extra-cranial MD with the aid of a vasoactive gas challenge stimuli. To achieve this aim, we used a series of hypercapnic and hypoxic gas challenges to induce maximal hemodynamic responses so as navigate the spectrum of vessel calibre. We also employed a long life blood pool agent (Gadofosveset) to allow us to track the changes in vessel calibre. Using this agent, we could navigate the spectrum of vessel calibre in the high perfusion organs such as the kidney and low perfusion skeletal muscle. Furthermore, by employing a specific sequence of vasoactive gases we were able to assess the degree of ED in a hind limb ischemic rat model. Though still its infancy the works presented in this thesis offer us an introduction to the utility of using a gas challenge algorithm in conjunction with MRI to be used for the assessment of vessel health in a number of pathologies.

Keywords: Gas Challenge
Ischemic- Reperfusion Injury
Magnetic Resonance Imaging
Microvasculature
Vasomodulation
Vasoreactivity
Advisor: Cheng, Hai-Ling M
Macgregor, Robert B
Search and Join Algorithms for Tables in Data Lakes

Data lakes are repositories of data sets stored in their raw formats. Data lakes can be dumping grounds if users cannot find and utilize the data in them. In this thesis, we describe two problems in managing data lakes: searching for tables that can be joined, and auto-generating syntactic transformations for joining tables with join values of different formats. Given a query table and a join column, the first problem is defined as searching for tables that can be joined with the query table on the join column. Our contributions toward solving this problem are twofold: 1) an approximate search index (based on locality sensitive hashing) to support threshold-based search queries -- find tables that can join with more than a threshold percentage of the distinct join values in the query table; and 2) an exact search index that supports top-k search queries -- find the best k tables that cover the largest number of distinct join values. Both approaches use new data-aware optimizations to provide interactive query performance over real data lakes with millions of tables including many large tables (e.g., millions of rows). Ours is the first approach for searching for joinable tables and we show that it greatly outperforms previous approaches for computing set intersection (used for keyword search and other applications). We also published open source implementations of the joinable table search algorithms and benchmarks created using real data lakes. For the second problem, we propose a technique that generates transformations, without human input, for joining tables with different formats on the join columns. The technique uses a novel approach to pinpoint highly promising joinable row pairs, before using the pairs as input/output examples to perform a greedy search to find a good transformation. The technique scales to tables as large as 10K rows while still maintaining interactive speed. The solutions presented in this thesis make data lakes more searchable and usable, and allow data scientists to be efficient. These experimentally-validated solutions also create an avenue for new data science discoveries that are important in business and government decision-making.

Keywords: data discovery
data lakes
data management
data science
query processing
search algorithms
Advisor: Miller, Renée J
Optimized PN Junctions and Three-dimensional Integration for Carrier-depletion Silicon Optical Modulators

Silicon (Si) optical modulators are used for high speed electrical-to-optical conversion in transceivers for data communications. However, since the plasma dispersion effect in Si is weak, efficient Si modulators remain an outstanding challenge. Typical Si Mach-Zehnder modulators (MZMs) with lateral PN junctions have VpiL values around 2.5 V*cm and require a drive signal swing of 4-5 V peak-to-peak (Vpp). This leads to large device footprint, high power consumption, and a drive signal swing that is not usually complementary metal oxide semiconductor (CMOS) compatible. This thesis studies two approaches to advance the state of the art of Si optical modulators: vertically-engineered PN junctions to improve the modulation efficiency and three-dimensional (3D) integration to reduce the parasitics in photonic-electronic integration. For the first approach, we study the efficiency, loss, and bandwidth trade-off of different vertically-engineered junction profiles. Simulations show that the modulation efficiency is improved by folding the junction line in Si waveguide at the cost of a higher junction capacitance. Experimentally, a novel U-shaped PN junction is demonstrated to have a VpiL of 0.26 V*cm at -0.5 V bias, which is about 10 times more efficient compared to the typical lateral PN junction. The measured optical insertion loss is similar to that of a lateral junction. The designed U-shaped junction has been implemented in Si MZMs and Si microring modulators (MRMs). On-off keying and pulse amplitude modulation formats have been tested using Si MRMs with the designed U-shaped junction. For the second approach, a flip-chip bonded transmitter consisting of a CMOS driver and a Si MZM is demonstrated. The designed Si MZM, based on lateral PN junctions, has an electro-optic bandwidth of 26 GHz. The drive signal used to drive the 3D transmitter is no higher than 1 Vpp. High-speed operation of the transmitter at up to 50 Gb/s with a record-high extinction ratio of 8 dB is demonstrated with a power consumption of 553 mW. Overall, this thesis shows lumped electrode, high bandwidth, micron-scale Si MZMs can be realized. This development can lead to power efficient Si photonic transmitters with energy consumption around 140 fJ/bit supporting >100 Gb/s per channel.

Keywords: Flip-chip integration
Integrated optics
Modulators
Silicon photonics
Waveguide junctions
Advisor: Poon, Joyce K.S.
Structural Investigations of Saposin/Hydrolase Systems

The degradation of sphingolipids (SLs) in mammals relies on the interplay between a set of lysosomal hydrolases and their cofactor proteins, the saposins. The saposins are a group of small, non-enzymatic proteins that possesses strong lipid binding/solubilizing properties. They function as biological detergents that assist the soluble acid hydrolases in accessing to their membrane-bound lipidic substrates by two proposed modes of action. In the “solubilizer” model, saposins extract SLs into soluble saposin-lipid complexes that act as the substrates for the corresponding enzymes, and in the “liftase” model, the saposins remodel bilayer surfaces to enhance the activity of membrane-associated hydrolases. In this thesis, I first present the crystal structure of human acid sphingomyelinase, the enzyme responsible for the lysosomal degradation of sphingomyelin. This enzyme has a built-in saposin domain that is crucial for its membrane-binding ability, and the elucidation of this crystal structure provides valuable molecular details of a “liftase” system. Next, I described crystal structures of acid ceramidase (AC), a lysosomal enzyme that facilitates the degradation of ceramide at the water-membrane interface. This enzyme enters the lysosome as an immature precursor protein and undergoes a self-cleavage process to yield the catalytically active mature form. A comparison of the crystal structures of immature and mature AC reveals a dramatic structural rearrangement resulting in the exposure of a large hydrophobic surface for membrane binding. Finally, I place the work described in this thesis in the context of previously described saposin/hydrolase systems, leading to novel insights into the modes of action of these protein complexes on different types of target SLs. Collectively, these findings advance our understanding of the molecular mechanisms of lysosomal saposin/hydrolase systems in the degradation of SLs.

Keywords: acid ceramdiase
acid sphingomyelinase
interfcial catalysis
lipid storage disorder
saposin
sphingolipids degradation
Advisor: Privé, Gilbert
Data-aware Computational Imaging Acceleration

Computational Imaging (CI) is an essential front-line building block for a wide range of applications including computer vision, advanced driver-assistance systems, medical imaging, photography and robotics. Such applications process large amounts of sensory data and need to do so either in real-time or within user-interactive setup constraints. In addition, these applications are typically run on cost- and energy-constrained devices with limited compute and memory resources. CI algorithms perform sophisticated processing of the noisy sensor output to compensate for the imperfections of the image acquisition hardware, to overcome challenging imaging conditions and to reveal new features of the captured image. This dissertation analyzes the performance of recent CI implementations on high-end commodity processors showing that practical deployment is beyond the reach of such architectures. Accordingly, the dissertation identifies unique characteristics of the data processed by these algorithms and exploits them to propose efficient data-aware CI accelerators. Specifically, this dissertation accelerates two CI implementation approaches: 1.Analytical solutions represented by Block-Matching and 3D filtering (BM3D), a state-of-the-art algorithm that is used in a wide set of core CI tasks including image denoising, sharpening, deblurring and super-resolution. We propose IDEAL, an image denoising/sharpening hardware accelerator. IDEAL incorporates Matches Reuse (MR), a novel software-hardware co-optimization that exploits typical image content to significantly reduce the computations needed without loss in output quality. IDEAL is orders of magnitude faster and more energy efficient compared to high-end CPUs and GPUs. 2.Machine learning-based implementations represented by a set of recent deep neural networks (DNNs) performing several CI tasks. We characterize strong spatiotemporal correlation between the adjacent values processed by these DNNs. Accordingly, we introduce Differential Convolution, a convolution processing technique that operates on the deltas of the values rather than on the absolute values. We propose Diffy, a novel DNN accelerator that incorporates Differential Convolution translating the characterized correlation into improved performance, reduced on- and off-chip storage and communication, and ultimately, improved energy efficiency. The proposed hardware accelerators enable practical deployment and achieve the performance needed for user-interactive, real-time and continuous vision applications. The designs are shown to outperform state-of-the-art accelerators and commodity architectures.

Keywords: Acceleration
Computational imaging
Computer Vision
Deep Learning
Machine Learning
Neural Networks
Advisor: Moshovos, Andreas
Ethical Leadership as a Double-edged Sword for Team Creativity: The Examination of Dual Mechanisms and a Leader’s Individualistic-collectivistic Orientation

In modern organizations, team leaders are often expected to meet two demands – creativity and ethicality. By looking at how ethical leadership relates to team creativity, the current research investigates whether the two demands can be achieved simultaneously or conflict with each other. A comprehensive review of this literature revealed equivocal past findings of the relationship between ethical leadership and creativity. Some researchers have found a positive relationship, while others have found a non-significant or even negative relationship. The central goal of this research is to provide a comprehensive understanding of the relationship between ethical leadership and team creativity by organizing the inconsistent past findings into two contradictory mechanisms: team psychological safety and team norm conformity. In addition, this research investigates when ethical leaders help their teams attend to either of the two mechanisms by examining a leader’s individualism-collectivism. A field study conducted in a chemical company where 357 employees in 105 R teams participated provided mixed support for my hypotheses. I found that despite some inconsistency, team psychological safety generally played a positive mediating role of the relationship between ethical leadership and team creativity, while team norm conformity negatively mediated the relationship. In addition, a leader’s individualism-collectivism moderated these relationships such that teams led by individualistic ethical leaders were more likely to attend to the team psychological safety mechanism, while teams led by collectivistic ethical leaders were more likely to attend to the team norm conformity mechanism.

Keywords: Collectivism
Ethical Leadership
Individualism
Norm Conformity
Psychological Safety
Team Creativity
Advisor: Zhong, Chen-Bo
A Meta-analysis of the Relationship between Study Abroad and Intercultural Competence

A growing body of research dating back to the early 1980’s has focused on the outcomes and impacts of college and university students participating in study abroad programs. A large proportion of this research has examined how intercultural competence is enhanced for students from participating in study abroad. Intercultural competence is valued as an interpersonal skill for personal and civic responsibilities, but it is also believed to enhance employability and effectiveness in the labour market. Despite decades of research, there have been few attempts to quantify the relationship between study abroad and intercultural competence and fewer still to investigate which student, study abroad program and research design characteristics are associated with this relationship. In this dissertation, studies that included a pre-test and post-test measure of intercultural competence in a study abroad program were reviewed and coded for a series of student, study abroad and research design characteristics aligned with Engle and Engle’s study abroad program framework and Astin’s Inputs-Environments-Output model. Ultimately, 72 studies with 85 unique results were used. A random-effects meta-analysis approach was used to combine the results of all these studies into an overall effect size of g = 0.38, df(84), 95% CI (0.32, 0.45), p

Keywords: college students
intercultural competence
meta-analysis
study abroad
Advisor: Seifert, Tricia A