Experimental assessment of the speed of light perturbation in free-fall absolute gravimeters

Precision absolute gravity measurements are growing in importance, especially in the context of the new definition of the kilogram. For the case of free-fall absolute gravimeters with a Michelson-type interferometer tracking the position of a free falling body, one of the effects that needs to be taken into account is the speed of light perturbation due to the finite speed of propagation of light. This effect has been extensively discussed in the past, and there is at present a disagreement between different studies. In this work, we present the analysis of new data and confirm the result expected from the theoretical analysis applied nowadays in free-fall gravimeters. We also review the standard derivations of this effect (by using phase shift or Doppler effect arguments) and show their equivalence

Etude des terroirs viticoles vaudois 3. Modélisation des paramètres climatiques

Study of wine-growing land ("terroirs") characteristics in the canton de Vaud (Switzerland): modelization of the climatical parameters. As part of the study on the viticultural terroirs of "canton de Vaud", a climatic model integrating temperature, relief, radiation and pluviometry was built

Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.

Anti-angiogenic treatments targeting the vascular endothelial growth factor or its receptors have shown clinical benefits. However, impact on long-term survival remains limited. Solid tumors display an acidic microenvironment that profoundly influences their biology. Consequences of acidity on endothelial cells and anti-angiogenic therapies remain poorly characterized and hence are the focus of this study. We found that exposing endothelial cells to acidic extracellular pH resulted in reduced cell proliferation and migration. Also, whereas VEGF increased endothelial cell proliferation and survival at pH 7.4, it had no effect at pH 6.4. Furthermore, in acidic conditions, stimulation of endothelial cells with VEGF did not result in activation of downstream signaling pathways such as AKT. At a molecular level, acidity significantly decreased the expression of VEGFR-2 by endothelial cells. Consequently, anti-angiogenic therapies that target VEGFR-2 such as sunitinib and sorafenib failed to block endothelial cell proliferation in acidic conditions. In vivo, neutralizing tumor acidity with sodium bicarbonate increased the percentage of endothelial cells expressing VEGFR-2 in tumor xenografts. Furthermore, combining sodium bicarbonate with sunitinib provided stronger anti-cancer activity than either treatment alone. Histological analysis showed that sunitinib had a stronger anti-angiogenic effect when combined with sodium bicarbonate. Overall, our results show that endothelial cells prosper independently of VEGF in acidic conditions partly as a consequence of decreased VEGFR-2 expression. They further suggest that strategies aiming to raise intratumoral pH can improve the efficacy of anti-VEGF treatments

Scalable Production of AAV Vectors in Orbitally Shaken HEK293 Cells.

Adeno-associated virus (AAV) vectors are currently among the most commonly applied for in vivo gene therapy approaches. The evaluation of vectors during clinical development requires the production of considerable amounts of highly pure and potent vectors. Here, we set up a scalable process for AAV production, using orbitally shaken bioreactors and a fully characterized suspension-adapted cell line, HEKExpress. We conducted a proof-of-concept production of AAV2/8 and AAV2/9 vectors using HEKExpress cells. Furthermore, we compared the production of AAV2/9 vectors using this suspension cell line to classical protocols based on adherent HEK293 cells to demonstrate bioequivalence in vitro and in vivo. Following upstream processing, we purified vectors via gradient centrifugation and immunoaffinity chromatography. The in vitro characterization revealed differences due to the purification method, as well as the transfection protocol and the corresponding HEK293 cell line. The purification method and cell line used also affected in vivo transduction efficiency after bilateral injection of AAV2/9 vectors expressing a GFP reporter fused with a nuclear localization signal (AAV2/9-CBA-nlsGFP) into the striatum of adult mice. These results show that AAV vectors deriving from suspension HEKExpress cells are bioequivalent and may exhibit higher potency than vectors produced with adherent HEK293 cells

Creating an Interactive Network for Wine-cultivation

This paper presents an ongoing project in the Swiss Canton de Vaud - the development of an interactive network for wine-cultivation. The goal of the project is to develop an interactive application where winegrowers and other actors involved in wine-cultivation can input and share data (both spatial and non-spatial) and information related to wine-cultivation

Development of Efficient AAV2/DJ-Based Viral Vectors to Selectively Downregulate the Expression of Neuronal or Astrocytic Target Proteins in the Rat Central Nervous System.

Viral vectors have become very popular to overexpress or downregulate proteins of interest in different cell types. They conveniently allow the precise targeting of well-defined tissue areas, which is particularly useful in complex organs like the brain. In theory, each vector should have its own cell specificity that can be obtained by using different strategies (e.g., using a cell-specific promoter). For the moment, there is few vectors that have been developed to alternatively target, using the same capsid, neurons and astrocytes in the central nervous system. There is even fewer examples of adeno-associated viral vectors able to efficiently transduce cells both in vitro and in vivo. The development of viral vectors allowing the cell-specific downregulation of a protein in cultured cells of the central nervous system as well as in vivo within a large brain area would be highly desirable to address several important questions in neurobiology. Here we report that the use of the AAV2/DJ viral vector associated to an hybrid CMV/chicken β-actin promoter (CBA) or to a modified form of the glial fibrillary acidic protein promoter (G1B3) allows a specific transduction of neurons or astrocytes in more than half of the barrel field within the rat somatosensory cortex. Moreover, the use of the miR30E-shRNA technology led to an efficient downregulation of two proteins of interest related to metabolism both in vitro and in vivo. Our results demonstrate that it is possible to downregulate the expression of different protein isoforms in a cell-specific manner using a common serotype. It is proposed that such an approach could be extended to other cell types and used to target several proteins of interest within the same brain area

Strong Morita Equivalence and Imprimitivity Theorems

The purpose of this thesis is to give an exposition of two topics, mostly following the books \cite{R & W} and \cite{Wil}. First, we wish to investigate crossed product $C^*$-algebras in its most general form. Crossed product $C^*$-algebras are $C^*$-algebras which encode information about the action of a locally compact Hausdorff group $G$ as automorphisms on a $C^*$-algebra $A$. One of the prettiest example of such a dynamical system that I have observed in the wild arises in the gauge-invariant uniqueness theorem \cite{Rae}, which assigns to every $C^*$-algebra $C^*(E)$ associated with a graph $E$ a \emph{gauge action} of the unit circle \T to automorphisms on $C^*(E)$. Group $C^*$-algebras also arise as a crossed product of a dynamical system. I found crossed products in its most general form very abstract and much of its constructions motivated by phenomena in a simpler case. Because of this, much of the initial portion of this exposition is dedicated to the action of a discrete group on a unital $C^*$-algebra, where most of the examples are given. I must admit that I find calculations of crossed products when one has an indiscrete group $G$ acting on our $C^*$-algebra daunting except under very simple cases. This leads to our second topic, on imprimitivity theorems of crossed product $C^*$-algebras. Imprimitivity theorems are machines that output (strong) Morita equivalences between crossed products. Morita equivalence is an invariant on $C^*$-algebras which preserve properties like the ideal structure and the associated $K$-groups. For example, no two commutative $C^*$-algebras are Morita equivalent, but $C(X) \otimes M_n$ is Morita equivalent to $C(X)$ whenever $n$ is a positive integer and $X$ is a compact Hausdorff space. Notice that Morita equivalence can be used to prove that a given $C^*$-algebra is simple. All this leads to our concluding application: Takai duality. The set-up is as follows: we have an action $\alpha$ of an abelian group $G$ on a $C^*$-algebra $A$. On the associated crossed product $A \rtimes_\alpha G$, there is a dual action \Hat{\alpha} from the Pontryagin dual \Hat{G}. Takai duality states that the iterated crossed product (A \rtimes_\alpha G) \rtimes \Hat{G} is isomorphic to A \otimes \calK(L^2(G)) in a canonical way. This theorem is used to show for example that all graph $C^*$-algebras are nuclear or to establish theorems on the $K$-theory on crossed product $C^*$-algebras

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.

Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study. Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis. Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment. Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy

Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors.

The inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) by chemical inhibitors, such as rapamycin, has demonstrated anti-cancer activity in preclinical and clinical trials. Their efficacy is, however, limited and tumors eventually relapse through resistance formation. In this study, using two different cancer mouse models, we identify tumor hypoxia as a novel mechanism of resistance of cancer cells against mTORC1 inhibitors. Indeed, we show that the activity of mTORC1 is mainly restricted to the non-hypoxic tumor compartment, as evidenced by a mutually exclusive staining pattern of the mTORC1 activity marker pS6 and the hypoxia marker pimonidazole. Consequently, whereas rapamycin reduces cancer cell proliferation in non-hypoxic regions, it has no effect in hypoxic areas, suggesting that cancer cells proliferate independently of mTORC1 under hypoxia. Targeting the hypoxic tumor compartment by knockdown of carbonic anhydrase IX (CAIX) using short hairpin RNA or by chemical inhibition of CAIX with acetazolamide potentiates the anti-cancer activity of rapamycin. Taken together, these data emphasize that hypoxia impairs the anti-cancer efficacy of rapalogs. Therapeutic strategies targeting the hypoxic tumor compartment, such as the inhibition of CAIX, potentiate the efficacy of rapamycin and warrant further clinical evaluation

Simultaneous determination of wave speed and arrival time of reflected waves using the pressure-velocity loop

This is the post print version of the article. The official published version can be found at the link below.In a previous paper we demonstrated that the linear portion of the pressure–velocity loop (PU-loop) corresponding to early systole could be used to calculate the local wave speed. In this paper we extend this work to show that determination of the time at which the PU-loop first deviates from linearity provides a convenient way to determine the arrival time of reflected waves (Tr). We also present a new technique using the PU-loop that allows for the determination of wave speed and Tr simultaneously. We measured pressure and flow in elastic tubes of different diameters, where a strong reflection site existed at known distances away form the measurement site. We also measured pressure and flow in the ascending aorta of 11 anaesthetised dogs where a strong reflection site was produced through total arterial occlusion at four different sites. Wave speed was determined from the initial slope of the PU-loop and Tr was determined using a new algorithm that detects the sampling point at which the initial linear part of the PU-loop deviates from linearity. The results of the new technique for detecting Tr were comparable to those determined using the foot-to-foot and wave intensity analysis methods. In elastic tubes Tr detected using the new algorithm was almost identical to that detected using wave intensity analysis and foot-to-foot methods with a maximum difference of 2%. Tr detected using the PU-loop in vivo highly correlated with that detected using wave intensity analysis (r 2 = 0.83, P < 0.001). We conclude that the new technique described in this paper offers a convenient and objective method for detecting Tr, and allows for the dynamic determination of wave speed and Tr, simultaneously