How to Increase the Safety and Efficacy of Compounds against Neurodegeneration? A Multifunctional Approach

Successful drug design requires not only the detailed knowledge of the pharmacokinetic and pharmacodynamic profiles of the drug candidate portfolio but also a thorough documentation of the possible toxic effects on humans and the environment. Thus, experimental and computational strategies able to measure or predict specific profiles of designed compounds related to their potential toxicity are highly desired. Moreover, a strategy to avoid toxic effects thus enhancing the potential efficacy of drug candidates is of great interest. To fulfil this aim, the pharmacochemistry research unit at the EPGL has recently developed and improved methodologies that detect the potential human health and environmental hazards of compounds active against neurodegeneration at an early stage. A three-step strategy is presented herein. In particular, i) an alternative index to model the bioconcentration of chemicals in the environment was determined; ii) the antioxidant activity of chemical species against free radicals was evaluated. Moreover, since antioxidants play a key role in both toxicity prevention and neuroprotection, iii) the potential interaction of such compounds with enzymatic targets involved in the neurodegenerative cascade was investigated in silico

Improving the Estimation of the Wavenumber Spectra From Altimeter Observations

Satellite altimeters provide sea-level measurements along satellite track. A mean profile based on the measurements averaged over a time period is then subtracted to estimate the sea-level anomaly (SLA). In the spectral domain, SLA is characterized by a power spectral density (PSD) whose slope in a log–log scale is a parameter of great interest for ocean monitoring. Estimation of this spectral slope is usually done through a cumulated periodogram using a large number of signal samples. The location and dates of the data induce the spatial and temporal resolution of the slope estimates. To improve this resolution, this article studies a new parametric method based on an autoregressive model combined with a warping of the frequency scale (denoted as ARWARP). This ARWARP model provides a PSD estimate, with a lower variance than the classical Fourier-based ones and is reliable in the case of a small sample number. To give a reference in the performance of the SLA slope estimation, the corresponding Cramér–Rao bound is derived. Then, rather than performing linear regression on the spectral estimates, a new estimator of the slope is suggested, based on a model fitting of the PSD. A statistical validation is proposed on simulated SLA signals, showing the performance of slope estimation using this ARWARP spectral estimator, compared to classical Fourier-based methods. Application to Sentinel-3 real data highlights the main advantage of the ARWARP model, making possible SLA slope estimation on a short signal segment, i.e., with a high spatial and/or temporal resolution

Development of experimental methods to determine high lipophilicity of new chemical compounds : applications to cyclosporin A and bioconcentration

Cette thèse s'intéresse aux composés très lipophiles. En effet, bien qu'ils soient de plus en plus présents dans notre vie quotidienne, aucune méthode analytique ne peut mesurer leur lipophilie. La première partie de cette thèse est donc consacrée au développement des méthodes HPLC et UHPLC. Divers co solvants, phases stationnaires et modes d'élution ont été testés permettant ainsi de mesurer des lipophilies allant jusqu'à log Poct = 10. La deuxième partie de ce travail est dédiée à deux applications différentes de ces méthodes. Tout d'abord, la lipophilie de la cyclosporine A a été mesurée à l'aide de trois méthodes développées précédemment dans ce travail. En effet, malgré sa faible solubilité, et des premiers résultats expérimentaux laissant supposer une lipophilie importante, seules de faibles valeurs de log P ont été reportées dans la littérature. Finalement, la colonne permettant l'analyse la plus rapide a été choisie afin de prédire la bioconcentration en utilisant directement les facteurs de rétention

Ice Sheet Topography from a New CryoSat-2 SARIn Processing Chain, and Assessment by Comparison to ICESat-2 over Antarctica

In this study, we present a new level-2 processing chain dedicated to the CryoSat-2 Synthetic Aperture Radar Interferometric (SARIn) measurements acquired over ice sheets. Compared to the ESA ground segment processor, it includes revised methods to detect waveform leading edges and perform retracking at the Point of Closest Approach (POCA). CryoSat-2 SARIn mode surface height measurements retrieved from the newly developed processing chain are compared to ICESat-2 surface height measurements extracted from the ATL06 product. About 250,000 space–time nearly coincident observations are identified and examined over the Antarctic ice sheet, and over a one-year period. On average, the median elevation bias between both missions is about −18 cm, with CryoSat-2 underestimating the surface topography compared to ICESat-2. The Median Absolute Deviation (MAD) between CryoSat-2 and ICESat-2 elevation estimates is 46.5 cm. These performances were compared to those obtained with CryoSat-2 SARIn mode elevations from the ESA PDGS level-2 products (ICE Baseline-D processor). The MAD between CryoSat-2 and ICESat-2 elevation estimates is significantly reduced with the new processing developed, by about 42%. The improvement is more substantial over areas closer to the coast, where the topography is more complex and surface slope increases. In terms of perspectives, the impacts of surface roughness and volume scattering on the SARIn mode waveforms have to be further investigated. This is crucial to understand geographical variations of the elevation bias between CryoSat-2 and ICESat-2 and continue enhancing the SARIn mode level-2 processing

Ice Sheet Topography from a New CryoSat-2 SARIn Processing Chain, and Assessment by Comparison to ICESat-2 over Antarctica

In this study, we present a new level-2 processing chain dedicated to the CryoSat-2 Synthetic Aperture Radar Interferometric (SARIn) measurements acquired over ice sheets. Compared to the ESA ground segment processor, it includes revised methods to detect waveform leading edges and perform retracking at the Point of Closest Approach (POCA). CryoSat-2 SARIn mode surface height measurements retrieved from the newly developed processing chain are compared to ICESat-2 surface height measurements extracted from the ATL06 product. About 250,000 space–time nearly coincident observations are identified and examined over the Antarctic ice sheet, and over a one-year period. On average, the median elevation bias between both missions is about −18 cm, with CryoSat-2 underestimating the surface topography compared to ICESat-2. The Median Absolute Deviation (MAD) between CryoSat-2 and ICESat-2 elevation estimates is 46.5 cm. These performances were compared to those obtained with CryoSat-2 SARIn mode elevations from the ESA PDGS level-2 products (ICE Baseline-D processor). The MAD between CryoSat-2 and ICESat-2 elevation estimates is significantly reduced with the new processing developed, by about 42%. The improvement is more substantial over areas closer to the coast, where the topography is more complex and surface slope increases. In terms of perspectives, the impacts of surface roughness and volume scattering on the SARIn mode waveforms have to be further investigated. This is crucial to understand geographical variations of the elevation bias between CryoSat-2 and ICESat-2 and continue enhancing the SARIn mode level-2 processing

A metallo pro-drug to target Cu(II) in the context of Alzheimer's disease

International audienceAlzheimer's disease and oxidative stress are connected. In the present communication, we report the use of a Mn(II)-based superoxide dismutase mimic ([MnII(L)]+, 1+) as a pro-drug candidate to target Cu(II) associated events, i.e. Cu(II)-induced formation of reactive oxygen species (ROS) and modulation of the amyloid-beta (Aβ) peptide aggregation. Complex 1+ is able to remove Cu(II) from Aβ, stop ROS and prevent alteration of Aβ aggregation as would do the corresponding free ligand LH. Using 1+ instead of LH in further biological applications would have the double advantage to avoid the cell toxicity of LH and to benefit from its proved SOD-like activity

SARAL/AltiKa Absolute Calibration from the Multi-Mission Corsica Facilities,

International audienceThe geodetic Corsica site was set up in 1998 in order to perform altimeter calibration of the TOPEX/Poseidon (T/P) mission and subsequently, Jason-1 and OSTM/Jason-2. The scope of the site was widened in 2005 in order to undertake the calibration of the Envisat mission and most recently of SARAL/AltiKa. Here we present the first results from the latter mission using both indirect and direct calibration/validation approaches. The indirect approach utilizes a coastal tide gauge and, as a consequence, the altimeter derived sea surface height (SSH) needs to be corrected for the geoid slope. The direct approach utilizes a novel GPS-based system deployed offshore under the satellite ground track that permits a direct comparison with the altimeter derived SSH. The advantages and disadvantages of both systems (GPS-based and tide gauges) and methods (direct or indirect) will be described and discussed. Our results for O/IGD-R data show a very good consistency for these three kinds of products: their derived absolute SSH biases are consistent within 17 mm and their associated standard deviation ranges from 31 to 35 mm. The AltiKa absolute SSH bias derived from GPS-zodiac measurement using the direct method is −54 ±10 mm based on the first 13 cycles

Lipophilicity determination of highly lipophilic compounds by liquid chromatography

Different experimental strategies using short columns in both conventional liquid chromatography (HPLC) and ultra-high pressure liquid chromatography (UHPLC) were evaluated to allow, for the first time with these techniques, the lipophilicity determination of compounds with log P>5. Various organic modifiers, stationary phases, and elution modes were tested on 14 rigid compounds with a CLogP between 5 and 8, and 38 compounds with log P(oct) from 0 to 5. The best results in HPLC were obtained with the 20-mm Discovery RP Amide C16 stationary phase in isocratic mode using MeOH as organic modifier. To improve analysis time, the UHPLC approach was then evaluated. Consequently, a generic method was developed with a 30-mm Acquity BEH Shield RP18 column in gradient mode using MeOH as organic modifier, allowing a fourfold gain of time compared to the HPLC method, for the highly lipophilic compounds tested. Finally, the most rapid and accurate results were obtained with a 10-mm Hypersil GOLD Javelin HTS stationary phase in UHPLC, enabling an eightfold gain of time compared to the HPLC method