Calcium dynamics and related alterations in pulmonary hypertension associated with heart failure

Congestive heart failure (CHF) represents an important Canadian health problem. Most patients with CHF develop pulmonary hypertension (PH), which is an important marker that signals progression of the disease and its poor outcome. Significant advances have been made for the treatment of heart failure (HF). Nevertheless, the morbidity and mortality among patients with advanced heart HF, who have developed PH remains high. Increased pulmonary vascular pressure (PVP) observed in PH leads to increased vascular tone and vascular remodelling associated with altered vasodilatory responses. It is noteworthy that a decrease in vasodilatory responses has been observed in PH. At the core of vasodilatory alterations lies endothelial dysfunction. This hallmark of most cardiovascular diseases is associated with alterations in calcium (Ca2+) homeostasis. Although global Ca2+ plays a role in a wide range of cellular functions, this thesis work focused on the impact of local Ca2+ signalling in endothelial cells (ECs). Among the different types of local Ca2+ signals, Ca2+ pulsars were identified. Ca2+ pulsars are local endothelial Ca2+ signals whose activity is finely regulated by physiological agents that modulate intracellular levels of inositol 1,4,5-triphosphate (IP3) and Ca2+. Ca2+ pulsars have been shown to have an effect on several important cellular functions. In mesenteric arteries, Ca2+ pulsars induce endotheliuminduced relaxation of vascular smooth muscle cells. Up until now, the regulatory mechanisms of Ca2+ pulsars remain to be uncovered. The spatio-temporal characteristics of Ca2+ pulsars suggest that they could play a role in the control of pulmonary vascular tone, potentially involving more transmembrane ion channels, as well as regulatory proteins. Transient receptor potential vanilloid 4 (TRPV4) channels are non-selective mechanosensitive osmo-regulated cation channels broadly expressed in a number of tissues. Activation of TRPV4 channels allows Ca2+ entry into the cell. A number of studies have shown the implication of TRPV4 as well as other channels from the TRP family in PH. Endothelial Ca2+-related pathophysiological mechanisms modulating pulmonary vascular tone and leading to the development of group II PH are poorly defined. In addition, the scarcity of studies exploring the pathophysiology and therapies of group II PH resides in the lack of validated small animal models with an adequate determination of the presence and severity of PH. The work in this thesis identified and characterized for the first time intracellular Ca2+ pulsars in pulmonary endothelium and their alterations in a clinically relevant mouse model of group II PH that was developed. In addition, this work revealed the implication of endothelial TRPV4 channels in Ca2+ pulsars dysregulation in group II-PH.L'insuffisance cardiaque (IC) représente un problème de santé important au Canada. La plupart des patients atteints d'IC développent une hypertension pulmonaire (HP), qui est un marqueur de la progression de la maladie et de son mauvais pronostic. Des progrès significatifs ont été réalisés pour le traitement de l'IC. Néanmoins, la morbidité et la mortalité chez les patients atteints d'IC avancée, qui ont développé l’HP reste élevée. L'augmentation de la pression vasculaire pulmonaire (PVP) observée en HP entraîne une augmentation du tonus vasculaire et un remodelage vasculaire associés à des réponses vasodilatatrices altérées. En effet, une diminution des réponses vasodilatatrices a été observée dans l'HP. La dysfonction endothéliale est au coeur des altérations vasodilatatrices. Cette caractéristique de la plupart des maladies cardiovasculaires est associée à des altérations de l'homéostasie du calcium (Ca2+). Bien que le Ca2+ global joue un rôle dans un grand nombre de fonctions cellulaires, la présente thèse est concentrée sur l'impact de la signalisation calcique locale dans les cellules endothéliales (CE). Parmi les différents types de signaux calciques locaux, les pulsars ont été identifiés. Les pulsars calciques sont des évènements endothéliaux locaux dont l'activité est finement régulée par des agents physiologiques qui modulent les niveaux intracellulaires d'inositol 1,4,5-triphosphate (IP3) et de Ca2+. Les pulsars ont un effet sur plusieurs fonctions cellulaires importantes. Dans les artères mésentériques, les pulsars induisent une relaxation des cellules musculaires lisses vasculaires. Jusqu'à présent, les mécanismes de régulation des pulsars Ca2+ restent à découvrir. Les caractéristiques spatio-temporelles des pulsars suggèrent qu'ils pourraient jouer un rôle dans le contrôle du tonus vasculaire pulmonaire, impliquant potentiellement plus de canaux ioniques transmembranaires, ainsi que des protéines régulatrices. Les canaux TRP de la famille vanilloïde 4 (TRPV4) sont des canaux cationiques méchanosensitifs, non sélectifs, largement exprimés dans un nombre de tissus. L'activation des canaux TRPV4 permet l'entrée de Ca2+ dans la cellule. Des études ont montré l'implication de TRPV4 ainsi que d'autres canaux de la famille TRP dans l’HP. Les mécanismes physiopathologiques liés au Ca2+ endothélial modulant le tonus vasculaire pulmonaire et conduisant au développement de l’HP du groupe II sont mal définis. En outre, la rareté des études explorant la physiopathologie et les thérapies de l’HP du groupe II réside dans l'absence de modèles animaux validés pour l’étude de l’HP du groupe II, avec une détermination adéquate de la présence et de la sévérité de l'HP. Les travaux issus de cette thèse ont identifié et caractérisé pour la première fois des pulsars Ca2+ intracellulaires dans l'endothélium pulmonaire et leurs altérations dans un modèle de souris cliniquement significatif de l’HP de groupe II qui a été développé. En outre, ce travail a révélé l'implication des canaux TRPV4 endothéliaux dans la dérégulation des pulsars Ca2+ dans l’HP du groupe II

Bond Valence Sum Analysis on Compounds Prepared by Topochemical Manipulation

The Bond Valence theory of Brown (1978) has been extensively used to correlate metal oxidation state to coordination environment in solids. Although the bond valence sum (BVS) appears to be extremely useful to coordination chemists, it has not often been applied as an alternative measure of refinement quality. In this work, previously reported six layered perovskite compounds including, RbLaNb2O7, Rb2LaNb2O7, Rb2SxLaNb2O7 (x ≤ 0.8), NaLaNb2O7, (Cs2Cl)LaNb2O7, and (FeCl)LaNb2O7, that have been prepared by topochemical manipulation and their structures have been determined by Rietveld refinements were analyzed. Our focus was to explore whether the determination of oxidation state using the bond distances derived from the Rietveld refinement method could be used to validate structure determination along with the reported goodness of fit values, χ2 , in the published structure. Good agreement between the calculated and the expected oxidation states would provide support for the chemical formula and the accuracy of a crystal structure determination. We applied the concept of the BVS method for selective metal ions including, niobium (Nb), lanthanum (La), rubidium (Rb), sodium (Na), cesium (Cs), sulfur (S), and iron (Fe). For all these metal ions, the final values resulted from BVS calculations for the six compounds overall showed good agreement between the calculated and the expected oxidation. Although this method is empirical, it can nevertheless help us to identify important trends when a series of related and similarly prepared samples are prepared

Engineering Heteromaterials to Control Lithium Ion Transport Pathways.

Safe and efficient operation of lithium ion batteries requires precisely directed flow of lithium ions and electrons to control the first directional volume changes in anode and cathode materials. Understanding and controlling the lithium ion transport in battery electrodes becomes crucial to the design of high performance and durable batteries. Recent work revealed that the chemical potential barriers encountered at the surfaces of heteromaterials play an important role in directing lithium ion transport at nanoscale. Here, we utilize in situ transmission electron microscopy to demonstrate that we can switch lithiation pathways from radial to axial to grain-by-grain lithiation through the systematic creation of heteromaterial combinations in the Si-Ge nanowire system. Our systematic studies show that engineered materials at nanoscale can overcome the intrinsic orientation-dependent lithiation, and open new pathways to aid in the development of compact, safe, and efficient batteries

The Human Pancreatic Islet Methylome and Its Role in Type 2 Diabetes

Islet dysfunction is central to the development and progression of type 2 diabetes (T2D). Epigenetic modifications are essential for establishing and maintaining cell identity and function in normal circumstances. Exposure to adverse environmental factors may alter the epigenome, and result in changes of gene expression and the resulting phenotype. The aim of this thesis was to analyze DNA methylation levels of specific genes, as well as genome-wide DNA methylation, in order to determine whether epigenetic dysregulation of pancreatic islets contributes to islet dysfunction in subjects with T2D. We also assessed the relationship between genetic variation and DNA methylation. We further examined the potential use of DNA methylation in blood DNA to predict future T2D. At the specific gene level, we found that DNA methylation of INS and PDX-1 was increased in pancreatic islets from subjects with T2D (Studies I and II). Conversely, their mRNA expression, insulin content and glucose-stimulated insulin secretion (GSIS) were decreased in the same islets. We next analyzed genome-wide DNA methylation in human pancreatic islets from both T2D and non-diabetic donors (Study III). Nearly 1,500 CpG sites (853 genes) were differentially methylated in T2D islets, with the majority showing decreased DNA methylation. 102 genes showed both altered DNA methylation and mRNA expression in T2D islets, including CDKN1A, PDE7B, SEPT9 and EXOC3L2. Our functional experiments provided further evidence that altering the expression of these genes, by modeling the situation in T2D, results in impaired insulin and glucagon secretion in cell line models. Furthermore, we showed that nearly half of the single nucleotide polymorphisms (SNPs) associated with T2D are CpG-SNPs, which can introduce or remove a CpG site (Study IV). Accordingly, we found that the degree of DNA methylation at CpG-SNP sites varied between individuals with different genotypes, and that some of the CpG-SNPs were associated with differential gene expression, alternative splicing and hormonal secretion. In Study V, we showed that altered DNA methylation at two CpG sites in the ABCG1 and PHOSPHO1 genes in blood from non-diabetic individuals was associated with a higher risk of future T2D. Subsequently, we found that CpG sites annotated to these genes were differentially methylated in T2D target tissues. Taken together, our findings suggest that epigenetic dysregulation of pancreatic islets play a role in islet dysfunction in subjects with T2D, and can be influenced by genetic variation and the environment

Polytropic behavior in the structures of Interplanetary Coronal Mass Ejections

The polytropic process characterizes the thermodynamics of space plasma particle populations. The polytropic index, ${\gamma}$, is particularly important as it describes the thermodynamic behavior of the system by quantifying the changes in temperature as the system is compressed or expanded. Using Wind spacecraft plasma and magnetic field data during $01/1995 - 12/2018$, we investigate the thermodynamic evolution in 336 Interplanetary Coronal Mass Ejection (ICME) events. For each event, we derive the index ${\gamma}$ in the sheath and magnetic ejecta structures, along with the pre- and post- event regions. We then examine the distributions of all ${\gamma}$ indices in these four regions and derive the entropic gradient of each, which is indicative of the ambient heating. We find that in the ICME sheath region, where wave turbulence is expected to be highest, the thermodynamics takes longest to recover into the original quasi-adiabatic process, while it recovers faster in the quieter ejecta region. This pattern creates a thermodynamic cycle, featuring a near adiabatic value ${\gamma}$ ~ ${\gamma}$${_a}$ (=5/3) upstream of the ICMEs, ${\gamma}$${_a}$ - ${\gamma}$ ~ 0.26 in the sheaths, ${\gamma}$${_a}$ - ${\gamma}$ ~ 0.13 in the ICME ejecta, and recovers again to ${\gamma}$ ~ ${\gamma}$${_a}$ after the passage of the ICME. These results expose the turbulent heating rates in the ICME plasma: the lower the polytropic index from its adiabatic value and closer to its isothermal value, the larger the entropic gradient, and thus, the rate of turbulent heating that heats the ICME plasma.Comment: 9 pages, 3 figure

Spherical Harmonic Representation of Energetic Neutral Atom Flux Components Observed by IBEX

The Interstellar Boundary Explorer (IBEX) images the heliosphere by observing energetic neutral atoms (ENAs). The IBEX-Hi instrument onboard IBEX provides full-sky maps of ENA fluxes produced in the heliosphere and very local interstellar medium (VLISM) through charge exchange of suprathermal ions with interstellar neutral atoms. The first IBEX-Hi results showed that in addition to the anticipated globally distributed flux (GDF), a narrow and bright emission from a circular region in the sky, dubbed the IBEX ribbon, is visible in all energy steps. While the GDF is mainly produced in the inner heliosheath, ample evidence indicates that the ribbon forms outside the heliopause in the regions where the interstellar magnetic field is perpendicular to the lines of sight. The IBEX maps produced by the mission team distribute the observations into $6\deg\times6\deg$ rectangle pixels in ecliptic coordinates. The overlap of the GDF and ribbon components complicates qualitative analyses of each source. Here, we find the spherical harmonic representation of the IBEX maps, separating the GDF and ribbon components. This representation describes the ENA flux components in the sky without relying on any pixelization scheme. Using this separation, we discuss the temporal evolution of each component over the solar cycle. We find that the GDF is characterized by larger spatial scale structures than the ribbon. However, we identify two isolated, small-scale signals in the GDF region that require further study.Comment: 27 pages, 13 figures, v2 accepted for publication in ApJ

Lattice strain effects on the optical properties of MoS2 nanosheets.

"Strain engineering" in functional materials has been widely explored to tailor the physical properties of electronic materials and improve their electrical and/or optical properties. Here, we exploit both in plane and out of plane uniaxial tensile strains in MoS2 to modulate its band gap and engineer its optical properties. We utilize X-ray diffraction and cross-sectional transmission electron microscopy to quantify the strains in the as-synthesized MoS2 nanosheets and apply measured shifts of Raman-active modes to confirm lattice strain modification of both the out-of-plane and in-plane phonon vibrations of the MoS2 nanosheets. The induced band gap evolution due to in-plane and out-of-plane tensile stresses is validated by photoluminescence (PL) measurements, promising a potential route for unprecedented manipulation of the physical, electrical and optical properties of MoS2