Afin d’améliorer la stabilité plasmatique de peptides, nous avons développé une nouvelle stratégie basée sur l’introduction d’une chaîne fluorocarbonée dans la séquence d’un peptide natif. En appliquant le concept à l’apeline-17, un peptide présentant un intérêt potentiel pour le traitement de maladies cardiovasculaires, nous avons amélioré sa stabilité plasmatique de 4 min à plus de 24 h ainsi que son efficacité in vivo. L’étude du mécanisme de stabilisation a permis de mettre en évidence la liaison de la fluoroapeline à l’albumine, conduisant à la protection du peptide vis-à-vis de la protéolyse. Le concept a été appliqué à d’autres peptides tels que l’apeline-13, l’angiotensine II, l’ocytocine et la spexine, démontrant ainsi l’étendue et les limitations de la méthode. Enfin, nous avons également conçu des sondes fluorescentes « turn-on » originales capables de révéler leur fluorescence uniquement après liaison au récepteur ciblé. Ces sondes pourront nous servir, par la suite, pour l’étude in vivo de la biodistribution des fluoropeptides. / In order to improve the plasma stability of peptides, we have developed a new strategy based on the introduction of a fluorocarbon chain in the sequence of a native peptide. By applying this concept to apelin-17, a peptide showing a potential interest for the treatment of cardiovascular diseases, we have improved its plasma stability from 4.6 min to more than 24 h as well as its in vivo efficacy. The mechanism leading to the increase of plasma stability has been carefully investigated demonstrating the binding of the fluoroapeline to the albumin, leading to protection towards roteolysis. The concept has been applied to other peptides such as apelin-13, angiotensin II, oxytocin and spexine, showing the extension and the limitations of this method. Finally, we have designed original fluorescent fluorogenic probes which turn on their fluorescence only after binding to the targeted receptor. These probes could be used for in vivo biodistribution studies of fluoropeptides.

Ischemic injury occurs when the flow of blood is reduced or blocked to an area of the body and can cause significant tissue damage by generation of reactive oxygen species (ROS), activation of apoptotic pathways and through induction of the inflammatory response. Restoration of blood flow and reperfusion of the blocked site, while essential, can generate a second injury that itself needs to be controlled. Together the two injuries are termed ischemia/reperfusion (I/R) injury. This type of injury is frequently encountered in medicine and is a major medical problem. Therapeutic strategies to combat I/R injury include the introduction of compounds that can scavenge ROS or can induce metabolic pathways with the effect of inhibiting apoptosis. Caffeic Acid Phenethyl Ester (CAPE), a polyphenolic compound found in propolis, has been shown to protect a variety of cells types against ROS in vitro and has also been shown to induce a variety of genes including hemeoxygenase 1 (HMOX-1) , an enzyme that has been implicated in a cytoprotective pathway. Despite showing significant cytoprotection of cells against oxidant stress in vitro, CAPE is readily hydrolyzed in plasma and is also quickly removed from circulation. This result may explain the limited cytoprotective effects of CAPE in vivo. We have synthesized a series of CAPE amide derivatives, including Caffeic Acid Phenethyl Amide (CAPA), with the aim of improving CAPE’s stability properties while maintaining the cytoprotective effects of the parent compound. We found that CAPA, in addition to 2 other amide derivatives, were able to protect human umbilical vein endothelial cells (HUVEC) against ROS to a similar degree as CAPE. In addition, we have observed significant improvement in plasma stability of CAPA over CAPE at multiple temperatures. The elimination half-life of CAPA from the systemic circulation was also seen to be significantly improved over CAPE following intravenous administration to male Sprague-Dawley rats. The longer residence time of CAPA over CAPE in circulation may potentially result in greater cytoprotection in vivo. / text

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Physics, 1980. / Vita. / Includes bibliographical references. / by Alan Charles Janos. / Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Physics, 1980.

This thesis reports observations of kink and tearing modes in the High Beta Tokamak - ExtendedPulse (HBT-EP) experiment. When unstable, these modes could limit the operation of tokamaks used for fusion power by terminating the plasma discharge and causing rapid loss of plasma energy. The aim of this work is to characterize the sudden transition after a sawtooth crash of coupled 2/1-3/1 tearing-kink modes into a sustained and disruptive 2/1 tearing mode. The following diagnostic techniques are used. Kink and tearing modes in HBT-EP distort the plasma edge, measured by a large array of Mirnov sensors, and perturb the interior of the plasma, observed routinely with Extreme Ultraviolet (EUV) detector arrays. Two arrays, with different transmission filters, are located with tangential views to estimate the time evolution of the plasma temperature profile. Four EUV arrays, with 16 detectors each, are positioned with different poloidal views for poloidal Extreme Ultraviolet (pEUV) emission tomography. The 2D emissive structures producing the pEUV signals are reconstructed with tomographic inversion using a pixel basis and fixed weighting smoothness regularization. Spatial and temporal correlations across these independent diagnostics are used to measure the evolution and structure of coupled modes using a technique called multidiagostic Singular Value Decomposition (mdSVD). In mdSVD, orthogonal modes are identified within any fixed time window with their unique spatial and temporal characteristics. The technique uncovers: coherent behavior of coupled (𝑚/𝑛) = (2/1) and (3/1) tearing-kink modes and rapid changes in plasma structure associated with sawtooth crashes which trigger disruptive and nondisruptive tearing modes. HBT-EP’s unique radially movable wall is found to significantly influence sawtooth triggering of disruptive tearing modes. The onset of sawtooth-triggered modes depends both on the plasma-wall separation, or wall coupling, and on the value of edge safety factor qₐ. We confirm that the condition for sawtooth triggering of disruptive (𝑚/𝑛) = (2/1) tearing modes does not correspond to the mode’s single-helicity stability condition Δ′₂/₁. We identify a dependency of the sawtooth period 𝝉_𝑠𝑡 on the wall position and qa as a candidate to explain the onset of the saturated tearing mode. This thesis motivates future efforts to model the influence of a nearby resistive wall on sawtooth triggering of tearing modes.

Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at 80 C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA)-plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter-assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to rs = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations.