VictorJuiz/thesis huggingface dataset:
Symplectic and Subriemannian Geometry of Optimal Transport
Keywords: Symplectic Geometry
Subriemannian Geometry
Optimal Transportation

This thesis is devoted to subriemannian optimal transportation problems. In the first part of the thesis, we consider cost functions arising from very general optimal control costs. We prove the existence and uniqueness of an optimal map between two given measures under certain regularity and growth assumptions on the Lagrangian, absolute continuity of the measures with respect to the Lebesgue class, and, most importantly, the absence of sharp abnormal minimizers. In particular, this result is applicable in the case where the cost function is square of the subriemannian distance on a subriemannian manifold with a 2-generating distribution. This unifies and generalizes the corresponding Riemannian and subriemannian results of Brenier, McCann, Ambrosio-Rigot and Bernard-Buffoni. We also establish various properties of the optimal plan when abnormal minimizers are present. The second part of the thesis is devoted to the infinite-dimensional geometry of optimal transportation on a subriemannian manifold. We start by proving the following nonholonomic version of the classical Moser theorem: given a bracket-generating distribution on a connected compact manifold (possibly with boundary), two volume forms of equal total volume can be isotoped by the flow of a vector field tangent to this distribution. Next, we describe formal solutions of the corresponding subriemannian optimal transportation problem and present the Hamiltonian framework for both the Otto calculus and its subriemannian counterpart as infinite-dimensional Hamiltonian reductions on diffeomorphism groups. Finally, we define a subriemannian analog of the Wasserstein metric on the space of densities and prove that the subriemannian heat equation defines a gradient flow on the subriemannian Wasserstein space with the potential given by the Boltzmann relative entropy functional. Measure contraction property is one of the possible generalizations of Ricci curvature bound to more general metric measure spaces. In the third part of the thesis, we discuss when a three dimensional contact subriemannian manifold satisfies such property.
Carcinoembryonic Antigen-related Cellular Adhesion Molecule 1-Dependent Inhibition of T cell Responses
Keywords: CEACAM1
T cells
Neisseria
Opa

Neisseria gonorrhoeae infections are of major concern in areas of low socioeconomic status in both developed and developing nations. N. gonorrhoeae colonizes the genital tract by adhering to mucosal tissues through a number of adhesins, including the colony opacity-associated (Opa) proteins. Despite the random phase-variable expression of Opa proteins, 95% of clinical isolates express Opa variants that bind to the carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), suggesting an essential role in vivo. Interestingly, even though gonorrhea is characterized by an intense inflammatory response, the organism is capable of evading the adaptive immune response. In previous studies by the Gray-Owen group, it has been established that certain gonococcal Opa variants bind CEACAM1 expressed by CD4+ T helper lymphocytes and, thereby, reduce their activation and proliferation. Since T cells are essential in establishing immune memory, inhibition of T cell function could explain the deficit in immune memory following gonococcal infection. In this thesis, I describe my studies to elucidate how CEACAM1 inhibits T cell activation on a molecular level. In Chapter 2, I demonstrate that outer membrane vesicles (OMVs) naturally shed by OpaCEA-expressing Neisseria sp. effectively inhibit CD4+ T cell activation, implicating a role for OMVs during infection and establishing that the Opa proteins do not have to be expressed in the context of the bacterium in order to elicit an inhibitory effect. In Chapter 3, I describe early steps in the CEACAM1-dependent inhibitory signaling cascade elicited when N. gonorrhoeae binds to CD4+ T cells. Finally, in Chapter 4, I show that a dynamic monomer-dimer equilibrium controls CEACAM1 function in epithelial cells and lymphocytes. Combined, the results presented in this thesis allow the derivation of a model to explain how CEACAM1 controls CD4+ T cell function at a molecular level.
Geometric Structures on Spaces of Weighted Submanifolds
Keywords: weighted
Lagrangian
symplectic
infinite

In this thesis we use a diffeo-geometric framework based on manifolds hat are locally modeled on ``convenient'' vector spaces to study the geometry of some infinite dimensional spaces. Given a finite dimensional symplectic manifold M, we construct a weak symplectic structure on each leaf I_w of a foliation of the space of compact oriented isotropic submanifolds in M equipped with top degree forms of total measure 1. These forms are called weightings and such manifolds are said to be weighted. We show that this symplectic structure on the particular leaves consisting of weighted Lagrangians is equivalent to a heuristic weak symplectic structure of Weinstein. When the weightings are positive, these symplectic spaces are symplectomorphic to reductions of a weak symplectic structure of Donaldson on the space of embeddings of a fixed compact oriented manifold into M. When M is compact, by generalizing a moment map of Weinstein we construct a symplectomorphism of each leaf I_w consisting of positive weighted isotropics onto a coadjoint orbit of the group of Hamiltonian symplectomorphisms of M equipped with the Kirillov-Kostant-Souriau symplectic structure. After defining notions of Poisson algebras and Poisson manifolds, we prove that each space I_w can also be identified with a symplectic leaf of a Poisson structure. Finally, we discuss a kinematic description of spaces of weighted submanifolds.
Patients' Narratives of Open-heart Surgery: Emplotting the Technological
Keywords: Narrative
Technology
Heart surgery
Narrative emplotment
Patients' experiences
Narrative inquiry
Poetry
Humanistic

The steady increase of technology has become particularly ubiquitous in environments of heart surgery. Patients in these environments come into close contact with technology in its many guises. Often, practitioners may be deterred from engaging with patients because technology and the associated routines of care become the focus. As a result, it is important to understand how patients make sense of the technological situations encountered during treatment and recovery with attention to the constitution of identity and emerging moral issues. A narrative methodology was employed to examine patients’ experiential accounts of the technological in open-heart surgery and recovery. Sixteen patients were interviewed 3-4 days after surgery and 4-6 weeks after discharge, in addition participant journals were employed. Study results pointed to the technological as the dominant discourse in heart surgery and recovery, strongly organizing health care practices and patients’ recovery. These discursive influences shaped participants’ stories resulting in two temporal shifts of authorial voice. Authorial voice reflects the dominant discourse and structured how stories unfolded. The first temporal shift exhibited how technology acted as the authorial voice, structuring stories of the preoperative and early postoperative period. Although participants were the narrators of their own stories, they were strongly influenced by the dominant discourse of the technological and its associated dimensions of care. Participants’ stories revealed how patients were at the centre of activity, but passive, universal and undifferentiated. Although technology continued to influence stories of the later postoperative period and recovery at home, there was a shift of authorial voice to participants. Narratives reflected how the technological was incorporated into participants’ daily lives, but their stories included more personal elements rooted in their own particularities. Study implications involve a critical uptake of technology that emphasizes the balance between technologically- and humanistically-focused practices in heart surgery and recovery. A key implication is the critical need to encompass affective and social dimensions of patients within the technologically-driven practices of heart surgery. Of great significance is how practitioners, particularly nurses, can act as supporting characters in helping with transitions of authorial voice from the technological back to the participant.
Fatty Acid Ethyl Esters (FAEE), A Biomarker of Alcohol Exposure: Hope for a Silent Epidemic of Fetal Alcohol Affected Children
Keywords: Alcohol
Biomarker
FAEE
FASD

One percent of children in North America may be affected by fetal alcohol spectrum disorder (FASD). FASD remains difficult to diagnose because confirmation of maternal alcohol use is a diagnostic criterion, and women consuming alcohol during pregnancy are reluctant to divulge this information for fear of stigmatization and losing custody of the child. Consequently, using a biomarker to assess alcohol exposure would provide a tremendous advantage. Recently, the measurement of fatty acid ethyl ester (FAEE) in hair has provided a powerful tool for assessing alcohol exposure. My thesis fills a translational gap of research between the development of the FAEE hair test and its application in the context of FASD. The guinea pig has been a critical model for FASD research, in which FAEE hair analysis has previously distinguished ethanol-exposed dams/offspring from controls. My first study, reports a positive dose-concentration relationship between alcohol exposure and hair FAEE, in the human, and the guinea pig. Humans also displayed over an order of magnitude higher FAEE incorporation per equivalent alcohol exporsure, suggesting that the test will be a sensitive clinical marker of fetal alcohol exposure. My second study utilized multi-coloured rats to investigate the potential of a hair-colour bias, as has been reported for other clinical hair assays; no evidence of bias is reported here. My third study is the first to examine the clinical use of the FAEE hair test in parents at high risk of having children with FASD. Over one third of parents tested positive for excessive alcohol use. Parents were investigated by social workers working for child protection services, and my fourth study reports that hair FAEE results agree with social worker reports. Individuals highly suspected of abusing alcohol were at a significantly greater risk of testing positive, whereas individuals tested based on other reasons (such as to cover all bases) were negatively associated with testing positive. The last study of my thesis, confirmed an association between alcohol and drug use by parents at high risk for having children with FASD, posing an added risk to children. This work helps bridge a gap in translational research, suggesting that the FAEE hair test has potential for use in FASD diagnosis and research.
Priority Setting in Community Care Access Centres
Keywords: priority setting
resource allocation
health care rationing
home care

In Ontario, access to publicly funded home care services is managed by Community Care Access Centres (CCACs). CCAC case managers are responsible for assessing all potential clients and prioritizing the allocation of services. The objectives of this thesis were to: 1) describe the types of decisions made by CCAC organizations and by individual case managers concerning the allocation of nursing, personal support and homemaking services to long-term adult clients with no mental health issues; and 2) to describe and assess the factors and values that influence these decisions. We conducted two case studies in which qualitative data were collected through 39 semi-structured interviews and a review of relevant documents from an urban and a rural area CCAC. A modified thematic analysis was used to identify themes related to the types of priority setting decisions and the associated factors and values. An internet-based survey was then designed based on these results and answered by 177 case managers from 8 of the 14 CCACs. The survey contained discrete choice experiments to examine the relative importance of client attributes and values to prioritization choices related to personal support and homemaking services, as well as questions that examined case managers’ attitudes towards priority setting. We found that both the rural and the urban CCACs utilized similar forms of priority setting and that case managers made the majority of these decisions during their daily interactions with clients. Numerous client, CCAC, and external factors related to the values of safety, independence and client-focused care were considered by case managers during needs assessment and service plan development. The relative importance of the selected client attributes in defining need for personal support and homemaking services was tested and found to be significantly affected by the location of the case manager (rural or urban area), years of experience in home care, and recent experience providing informal care. Case managers allocated services in the spirit of equal service for equal need and in consideration of operational efficiency. We also identified a number of case manager-related, client-related and external factors that interfered with the achievement of horizontal equity.
Functional Organization of Central and Peripheral Circadian Oscillators
Keywords: Circadian Rhythms
Suprachiasmatic Nucleus
Oscillators
Molecular Clock
Tissue-autonomous rhythms
Tetracycline Inducible System
PER2::Luciferase
Bioluminescence

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus has long been considered a master circadian pacemaker that drives rhythms in physiology and behavior in mammals. The recent discovery of self-sustained and cell-autonomous circadian oscillators in peripheral tissues has challenged this position. This dissertation tested the general hypothesis that the SCN has properties that distinguish it from other oscillators, thereby positioning it atop a circadian hierarchy. The general approach was to compare the consequences of altering the molecular circadian clock on tissue-autonomous rhythmicity in mice. In the first experiments, the role of the SCN as a master clock was tested by manipulating the expression of a circadian gene in the brain. Specifically, the expression of the short period tau mutation of casein kinase-1-epsilon (CK1ε) was controlled in an anatomically- and a temporally-specific manner via a tetracycline transactivator regulatory system. This inducible expression of CK1εtau affected the period of activity rhythms when expressed in the SCN, but did not affect the tissue-autonomous rhythmic properties in the peripheral tissues. Second, real-time bioluminescence imaging of tissues from PER2::LUCIFERASE mice revealed that period and phase of different circadian oscillators were tissue specific. Various circadian gene mutations (Cry1-/-, Cry2-/-, Cry1-/-;Cry2-/-, Clock∆19/∆19) produced little difference in rhythmic properties between the SCN and peripheral oscillators, although Cry1-/- SCN had more robust and persistent rhythms compared with the periphery. Third, the loss of Bmal1, which produces behavioral arrhythmicity, eliminated rhythms in the peripheral tissues, but not in the SCN. Bmal1-/- SCN rhythms were highly variable in period and amplitude, fitting a stochastic, but not a deterministic model of rhythm generation. Unlike mutations in other circadian genes, rhythmicity was completely abolished in single SCN neurons in Bmal1-/- mice, indicating that rhythms in Bmal1-/- SCN tissue are a property of the tissue organization rather than an averaging of single-cell autonomous rhythms. The SCN, therefore, has a unique anatomical organization that contributes to long-term stability and temporal organization of the circadian hierarchy.
Supraspinatus Musculotendinous Architecture: A Cadaveric and In Vivo Ultrasound Investigation of the Normal and Pathological Muscle
Keywords: muscle architecture, supraspinatus, utrasound, three-dimensional modeling, rehabilitation, anatomy, rotator cuff tendon tear

The purpose of the study was to investigate the static and dynamic architecture of supraspinatus throughout its volume in the normal and pathological state. The architecture was first investigated in cadaveric specimens free of any tendon pathology. Using a serial dissection and digitization method tailored for supraspinatus, the musculotendinous architecture was modeled in situ. The 3D model reconstructed in Autodesk MayaTM allowed for visualization and quantification of the fiber bundle architecture i.e. fiber bundle length (FBL), pennation angle (PA), muscle volume (MV) and tendon dimensions. Based on attachment sites and architectural parameters, the supraspinatus was found to have two architecturally distinct regions, anterior and posterior, each with three subdivisions. The findings from the cadaveric investigation served as a map and platform for the development of an ultrasound (US) protocol that allowed for the dynamic fiber bundle architecture to be quantified in vivo in normal subjects and subjects with a full-thickness supraspinatus tendon tear. The architecture was studied in the relaxed state and in three contracted states (60º abduction with either neutral rotation, 80º external rotation, or 80º internal rotation). The dynamic changes in the architecture within the distinct regions of the muscle were not uniform and varied as a function of joint position. Mean FBL in the anterior region shortened significantly with contraction (p<0.05) but not in the posterior. In the anterior region, mean PA was significantly smaller in the middle part compared to the deep (p<0.05). Comparison of the normal and pathological muscle found large differences in the percentage change of FBL and PA with contraction. The architectural parameter that showed the largest changes with tendon pathology was PA. In sum, the results showed that the static and dynamic fiber bundle architecture of supraspinatus is heterogeneous throughout the muscle volume and may influence tendon stresses. The architectural data collected in this study and the 3D muscle model can be used to develop future contractile models. The US protocol may serve as an assessment tool to predict the functional outcome of rehabilitative exercises and surgery.
MEMS-based Mechanical Characterization of Micrometer-sized Biomaterials
Keywords: MEMS force sensor
Microgripper
Micro-scale compression test
Drug delivery microcapsule
Young's modulus
Viscoelastic parameters

The mechanical properties of biomaterials play important roles in performing their specialized functions: synthesizing, storing, and transporting biomolecules; maintaining internal structures; and responding to external environments. Besides biological cells, there are also many other biomaterials that are highly deformable and have a diameter between 1μm and 100μm, comparable to that of most biological cells. For example, many polymeric microcapsules for drug delivery use are spherical particles of micrometers size. In order to mechanically characterize individual micrometer-sized biomaterials, the capability of capturing high-resolution and low-magnitude force feedback is required. This research focuses on the development of micro devices and experimental techniques for quantifying the mechanical properties of alginate-chitosan microcapsules. The micro devices include microelectromechanical systems (MEMS) capacitive force sensors and force-feedback microgrippers, capable of measuring sub-μN forces. Employing the MEMS devices, systems were constructed to perform the micro-scale compression testing of microcapsules. The force sensors are capable of resolving forces up to 110μN with a resolution of 33.2nN along two independent axes. The force sensors were applied to characterizing the mechanical properties of hydrogel microparticles without assembling additional end-effectors. The microcapsules were immobilized by a PDMS holding device and compressed between the sensor probe and holding device. Young's modulus values of individual microcapsules with 1%, 2%, and 3% chitosan coating were determined through the micro-scale compression testing in both distilled deionized (DDI) water and pH 7.4 phosphate buffered saline (PBS). The Young's modulus values were also correlated to protein release rates. Instead of compressing the microcapsule against the wall of the holding device, a force-feedback MEMS microgripper with the capability of directly compressing the microcapsule between two gripping arms has been used for characterizing both the elastic and viscoelastic properties of the microcapsules during micromanipulation. The single-chip microgripper integrates an electrothermal microactuator and two capacitive force sensors, one for contact detection (force resolution: 38.5nN) and the other for gripping force measurements (force resolution: 19.9nN). Through nanoNewton force measurements, closed-loop force control, and visual tracking, the system quantified the Young's modulus values and viscoelastic parameters of alginate microcapsules, demonstrating an easy-to-operate, accurate compression testing technique for characterizing soft, micrometer-sized biomaterials.
Enhancing the Intracellular Delivery of Engineered Nanoparticles for Cancer Imaging and Therapeutics
Keywords: 0794
0541
0379
0307

Recent advances in the field of bionanotechnology have enabled researchers to design a variety of tools to detect, image and monitor biological process in cells. Despite this progress, the limited understanding of nanomaterial-cellular interactions has hindered the widespread use of these nanomaterials in biological systems. In this thesis, we examined the potential effects of metallic nanoparticle geometry on important cellular processes such as membrane trafficking, intracellular transport and subcellular signalling. We found that the size of nanoparticles plays an important role on their ability to interact with the cell surface receptors thus dictating their subsequent ability to activate intracellular signalling cascades. Interestingly, trafficking of these nanoparticles was dependent on their size due to biochemical and thermodynamical constraints. These findings suggest that nanomaterials actively interact with biological systems, thus, directly modulating vital cellular processes. In addition, by utilizing various physical and chemical properties of nanomaterials, we developed a novel class of hybrid nanoscaled carrier systems capable of delivering semiconductor quantum dots (QDs) into live cells without inducing membrane damage. Using biodegradable polymeric nanoparticles, bioconjugated QDs were encapsulated and delivered into trafficking vesicles of live cells. The environmentally sensitive surface charge of the polymeric nanoparticles exhibited positive zeta potential inside acidic endo-lysosomes, thus enabling their escape from the vesicular sequestration into the cytosol. Hydrolytic-induced degradation then releases the bioconjugate QDs for active labelling of subcellular structures for real-time studies. Unlike previously described intracellular QD delivery methods, the proposed system offers an efficient way to non-invasively deliver bioconjugated QDs without inducing cell damage, enabling researchers to accurately monitor cellular processes in real-time. The understanding of both physical and chemical properties of nanomaterials is crucial to the design of biocompatible nanosystems to study fundamental processes in biological systems. Here, we demonstrated that both the size and surface chemistry of nanoparticles can be modified to obtain desired biological responses. Future experimental efforts to study other physical and chemical properties could allow the development of more sophisticated and effective platforms for biological applications.