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GLUT9/SLC2A9 is a urate transporter and takes a fundamental role in the maintenance of normal serum urate levels. GLUT9 is the sole transporter of reabsorbed urate from renal epithelial cells to blood, thus making it an ideal pharmacological target for the development of urate-lowering drugs. None of the three currently available assays for studying GLUT9 pharmacological inhibition can support a high throughput drug discovery screening campaign. In this manuscript we present two novel assay technologies which can be used in a drug discovery screening cascade for GLUT9: a GLUT9 membrane potential assay for primary screening; and a solid-supported membrane (SSM)-based supported electrophysiological assay for secondary screening.

Acoustic droplet ejection mass spectrometry (ADE-MS) has recently emerged as a promising label-free, MS-based readout method for high throughput screening (HTS) campaigns in early pharmaceutical drug discovery, since it enables high-speed analysis directly from 384- or 1536-well plates. In this manuscript we describe our characterization of an ADE-MS based high sample content enzymatic assay for mutant isocitrate dehydrogenase 1 (IDH1) R132H with a strong focus on assay development. IDH1 R132H has become a very attractive therapeutic target in the field of antitumor drug discovery, and several pharmaceutical companies have attempted to develop novel small molecule inhibitors against mutant IDH1. With the development of an mIDH1 ADE-MS based HTS assay and a detailed comparison of this new readout technique to the commonly used fluorescence intensity mIDH1 assay, we demonstrated good correlation of both methods and were able to identify new potent inhibitors of mIDH1.

The introduction of selective area growth (SAG) in a mature semi‐insulating buried heterostructure (SIBH) platform for the realization of photonic integrated circuits on monolithic InP has been demonstrated. A thorough determination of the relations between quantum well thickness, transition energies, and mask geometries is performed on dedicated wafers by means of extensive micro‐X‐Ray diffraction and microphotoluminescence measurements. Based on those results, SAG is used to grow, with a single epitaxy step, AlGaInAs multiple quantum wells heterostructures, to tailor the active regions of Fabry–Pérot and distributed feedback (DFB) lasers emitting in the O‐Band. SIBH DFB lasers are realized, exhibiting threshold currents < 7.2 mA (at 25 °C), and emitting over 100‐nm spectral range in the O‐Band. A novel process flow for the production of distributed feedback lasers for datacenter applications has been demonstrated based on selective area growth. The method has allowed for the coverage of the whole O‐Band at different operating points on uncooled operation and on a short production cycle. This approach is presented as a stepping stone toward the next generation of photonic integrated circuits.

Classical high-throughput screening (HTS) technologies for the analysis of ionic currents across biological membranes can be performed using fluorescence-based, radioactive, and mass spectrometry (MS)-based uptake assays. These assays provide rapid results for pharmacological HTS, but the underlying, indirect analytical character of these assays can be linked to high false-positive hit rates. Thus, orthogonal and secondary assays using more biological target-based technologies are indispensable for further compound validation and optimization. Direct assay technologies for transporter proteins are electrophysiology-based, but are also complex, time-consuming, and not well applicable for automated profiling purposes. In contrast to conventional patch clamp systems, solid supported membrane (SSM)-based electrophysiology is a sensitive, membrane-based method for transporter analysis, and current technical developments target the demand for automated, accelerated, and sensitive assays for transporter-directed compound screening. In this study, the suitability of the SSM-based technique for pharmacological compound identification and optimization was evaluated performing cell-free SSM-based measurements with the electrogenic amino acid transporter B0AT1 (SLC6A19). Electrophysiological characterization of leucine-induced currents demonstrated that the observed signals were specific to B0AT1. Moreover, B0AT1-dependent responses were successfully inhibited using an established in-house tool compound. Evaluation of current stability and data reproducibility verified the robustness and reliability of the applied assay. Active compounds from primary screens of large compound libraries were validated, and false-positive hits were identified. These results clearly demonstrate the suitability of the SSM-based technique as a direct electrophysiological method for rapid and automated identification of small molecules that can inhibit B0AT1 activity.

Classical high-throughput screening (HTS) technologies for the analysis of ionic currents across biological membranes can be performed using fluorescence-based, radioactive, and mass spectrometry (MS)-based uptake assays. These assays provide rapid results for pharmacological HTS, but the underlying, indirect analytical character of these assays can be linked to high false-positive hit rates. Thus, orthogonal and secondary assays using more biological target-based technologies are indispensable for further compound validation and optimization. Direct assay technologies for transporter proteins are electrophysiology-based, but are also complex, time-consuming, and not well applicable for automated profiling purposes. In contrast to conventional patch clamp systems, solid supported membrane (SSM)-based electrophysiology is a sensitive, membrane-based method for transporter analysis, and current technical developments target the demand for automated, accelerated, and sensitive assays for transporter-directed compound screening. In this study, the suitability of the SSM-based technique for pharmacological compound identification and optimization was evaluated performing cell-free SSM-based measurements with the electrogenic amino acid transporter B0AT1 (SLC6A19). Electrophysiological characterization of leucine-induced currents demonstrated that the observed signals were specific to B0AT1. Moreover, B0AT1-dependent responses were successfully inhibited using an established in-house tool compound. Evaluation of current stability and data reproducibility verified the robustness and reliability of the applied assay. Active compounds from primary screens of large compound libraries were validated, and false-positive hits were identified. These results clearly demonstrate the suitability of the SSM-based technique as a direct electrophysiological method for rapid and automated identification of small molecules that can inhibit B0AT1 activity.

The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed.

We demonstrate a hybrid silicon tunable laser with wide tunability and rapid switching speed for applications in sensing and optical networks. By implementing an optimized carrier injection phase shifter design, the filters of the silicon laser cavity may be efficiently controlled, enabling both fine and broad wavelength tuning across a 56 nm range, in addition to a rapid 10 ns switching time. The laser emits up to 10 dBm output power, and the linewidth is near 200 kHz. The fast wavelength switching demonstrated here may be employed in data center and access networks, while the potential for rapid wavelength sweeping is attractive for optical sensing and imaging applications.

In order to better understand the water vapor (WV) intrusion into the tropical stratosphere, a mesoscale simulation of the tropical tropopause layer using the BRAMS (Brazilian version of Regional Atmospheric Modeling System (RAMS)) model is evaluated for a wet season. This simulation with a horizontal grid point resolution of 20 km × 20 km cannot resolve the stratospheric overshooting convection (SOC). Its ability to reproduce other key parameters playing a role in the stratospheric WV abundance is investigated using the balloon-borne TRO-Pico campaign measurements, the upper-air soundings over Brazil, and the satellite observations by Aura Microwave Limb Sounder, Microwave Humidity Sounder, and Geostationary Operational Environmental Satellite 12. The BRAMS exhibits a good ability in simulating temperature, cold-point, WV variability around the tropopause. However, the simulation is typically observed to be warmer by ~2.0°C and wetter by ~0.4 ppmv at the hygropause, which can be partly affiliated with the grid boundary nudging of the model by European Centre for Medium-Range Weather Forecasts operational analyses. The modeled cloud tops show a good correlation (maximum cross-correlation of ~0.7) with Geostationary Operational Environmental Satellite 12. Furthermore, the overshooting cells detected by Microwave Humidity Sounder are observed at the locations, where 75% of the modeled cloud tops are higher than 11 km. Finally, the modeled inertia-gravity wave periodicity and wavelength are comparable with those deduced from the radio sounding measurements during TRO-Pico campaign. The good behavior of BRAMS confirms the SOC contribution in the WV abundance, and variability is of lesser importance than the large-scale processes. This simulation can be used as a reference run for upscaling the impact of SOC at a continental scale for future studies. The model depicts the typical variability of temperature and water vapor in the tropical tropopause layer, and the gravity wave propertiesHigh modeled cloud tops are observed at the overshooting locations detected by MHS, showing similar variability as GOES-12 measurementsImpact of stratospheric sudden warming occurring in the Arctic is detected in the tropical tropopause layer over South America

Abstract: The results of measurements of water-vapor vertical profiles in the upper troposphere and stratosphere on board a meteorological balloon with a FLASH-B optical fluorescent hygrometer (Russia) are presented. These data were obtained during two international field campaigns in West Africa (August 2006) and Central America (August 2007). Eleven high-resolution water-vapor vertical profiles measured in the course of these works make it possible to characterize the processes controlling humidity in the tropical tropopause region. Layers with increased humidity are detected in the lower stratosphere over West Africa to the level of the potential temperature 450 K. An analysis of satellite maps of the brightness temperature, balloon ozone measurements, and aerosol scattering, as well as trajectory modeling, display the relation between the observed layers with increased humidity and the phenomena of convective overshooting of the tropopause, as a result of which cold and ozone-depleted air penetrates into the lower stratosphere together with ice particles, which, rapidly sublimating, locally increase the water-vapor concentration. A comparison of the humidity data obtained in West Africa in 2006 and in Central America in 2007 reveals substantial distinctions in values and vertical structures of water vapor, both in the tropopause region and in the middle stratosphere.

Several applications are pushing the development of high performance modelocked lasers: generation of short pulses for extremely high bit rate transmission at 100 Gbs and beyond, alloptical clock recovery at 40 Gbs and beyond, generation of millimeter wave signals through modebeating on a high speed photodiode, optical sampling for analogtodigital conversion, and generation of wavelengthdivisionmultiplexing channels. This paper will report on new advances in InPbased quantum dash modelocked lasers, which largely surpass the performance of their bulk or quantum well counterparts in terms of the modebeating spectral purity and the bandwidth of optical spectrum. In particular, we will describe the quantum dash nanostructures used for the modelocked lasers and the dependence of the modelocking properties on detailed quantum dash structures. We will demonstrate that these quantum dash lasers can be actively modelocked, generating subpicosecond or picosecond pulses at different repetition frequencies with extremely low timing jitter. They can also be used to achieve alloptical clock recovery, with timing jitter compliant with International Telecommunication Union ITU standards even for highly degraded input optical signaltonoise ratio. Finally, we demonstrate that, owing to the very wide and flat optical spectrum and the low relativeintensity noise level of the modelocked laser, errorfree transmission over 50 km single mode fiber has been achieved for eight wavelength division multiplexing ITU channels at 10 Gbs with a channel spacing of 100 GHz. © 2009 AlcatelLucent.

Abstract: In this paper, we define a class of Petri nets, called Petri nets with counters, that can be seen as place/transition Petri nets enriched with a vector of integer variables on which linear operations may be applied. Their semantics usually leads to huge or infinite reachability graphs. Then, a more compact representation for this semantics is defined as a symbolic state graph whose nodes possibly encode infinitely many values for the variables. Both representations are shown behaviourally equivalent. [Copyright &y& Elsevier]

Several applications are pushing the development of high performance mode-locked lasers: generation of short pulses for extremely high bit rate transmission at 100 Gb/s and beyond, all-optical clock recovery at 40 Gb/s and beyond, generation of millimeter wave signals through mode-beating on a high speed photodiode, optical sampling for analog-to-digital conversion, and generation of wavelength-division-multiplexing channels. This paper will report on new advances in InP-based quantum dash mode-locked lasers, which largely surpass the performance of their bulk or quantum well counterparts in terms of the mode-beating spectral purity and the bandwidth of optical spectrum. In particular, we will describe the quantum dash nanostructures used for the mode-locked lasers and the dependence of the mode-locking properties on detailed quantum dash structures. We will demonstrate that these quantum dash lasers can be actively mode-locked, generating sub-picosecond or picosecond pulses at different repetition frequencies with extremely low timing jitter. They can also be used to achieve all-optical clock recovery, with timing jitter compliant with International Telecommunication Union (ITU) standards even for highly degraded input optical signal-to-noise ratio. Finally, we demonstrate that, owing to the very wide and flat optical spectrum and the low relative-intensity noise level of the mode-locked laser, error-free transmission over 50 km single mode fiber has been achieved for eight wavelength division multiplexing ITU channels at 10 Gb/s with a channel spacing of 100 GHz.

Après avoir rappelé et illustré l’impact de la tentative de suicide d’un adolescent sur ses proches, l’auteur montre que l’hospitalisation même brève du jeune peut être l’occasion de reconnaître la détresse des familles et de les associer à la prise en charge proposée.

The Innovative Medicines Initiative Consortium RESOLUTE has started to develop tools and produce data sets to de-orphanize transporters in the solute carrier protein (SLC) superfamily, thereby lowering the barrier for the scientific community to explore SLCs as an attractive drug target class.

An innovative balloonborne microjoule lidar (MULID) has been developed within the framework of the HIBISCUS project to provide nighttime measurements of visible and subvisible cirrus and aerosols. MULID has been designed to be a low-cost and an ultralow consumption instrument, due to the remote possibilities of payload recovery and the necessity of a low-weight battery power supply. Ground tests have been performed at the Observatory of Haute Provence (France), and the first technical flight has been made from Trapani, Italy, on a stratospheric balloon; finally, the instrument has been scientifically deployed during the pre-HIBISCUS and HIBISCUS tropical campaigns in Bauru, Brazil, in February 2003 and February 2004, respectively. A description of the instrument is provided together with the results of the ground-based and flight tests as well as an overview and discussion of the first results.

The assessment of changes induced by human activities on Earth atmospheric composition and thus on global climate requires a long-term and regular survey of the stratospheric and tropospheric atmospheric layers. The objective of this paper is to describe the atmospheric observations performed continuously at Reunion Island (55.5° east, 20.8° south) for 15 years. The various instruments contributing to the systematic observations are described as well as the measured parameters, the accuracy and the database. The LiDAR systems give profiles of temperature, aerosols and ozone in the troposphere and stratosphere, probes give profiles of temperature, ozone and relative humidity, radiometers and spectrometers give stratospheric and tropospheric integrated columns of a variety of atmospheric trace gases. Data are included in international networks, and used for satellite validation. Moreover, some scientific activities for which this station offers exceptional opportunities are highlighted, especially air mass exchanges nearby dynamical barriers: (1) On the vertical scale through the tropical tropopause layer (stratosphere–troposphere exchange). (2) On the quasi-horizontal scale across the southern subtropical barrier separating the tropical stratospheric reservoir from mid- and high latitudes.

In this study, the authors have compared the performance of 2 high-throughput screening assays for a serin/threonine kinase: a microplate-based, bioluminescent assay that uses the luciferin/luciferase system to monitor ATP consumption, and a microfluidic assay that measures the change in mobility in an electric field of a fluorescently labeled peptide upon phosphorylation. Both assays are homogeneous, nonradioactive, antibody independent and could be miniaturized to a reaction volume of 4 μl. The robustness of both formats was demonstrated by Z′ values > 0.8. Screening of a small library (2133 compounds) showed that the results obtained with both technologies correlate very well. Although the threshold for hits was set to a comparably low value—22.2% and 13.7% inhibition for the ATP consumption and microfluidic assay, respectively, corresponding to mean plus 3 standard deviations—the overlap of active compounds identified with the 2 assay formats was greater than 94%. Thus, both assays allow the identification of even low potency inhibitors with a high level of confidence.

In this study, the authors have compared the performance of 2 high-throughput screening assays for a serin/threonine kinase: a microplate-based, bioluminescent assay that uses the luciferin/luciferase system to monitor ATP consumption, and a microfluidic assay that measures the change in mobility in an electric field of a fluorescently labeled peptide upon phosphorylation. Both assays are homogeneous, nonradioactive, antibody independent and could be miniaturized to a reaction volume of 4 μl. The robustness of both formats was demonstrated by Z' values > 0.8. Screening of a small library (2133 compounds) showed that the results obtained with both technologies correlate very well. Although the threshold for hits was set to a comparably low value—22.2% and 13.7% inhibition for the ATP consumption and microfluidic assay, respectively, corresponding to mean plus 3 standard deviations—the overlap of active compounds identified with the 2 assay formats was greater than 94%. Thus, both assays allow the identification of even low potency inhibitors with a high level of confidence. (Journal of Biomolecular Screening2004:409-416)

We present a new approach to the modelling of time constrained systems. It is based on untimed high-level Petri nets using the concept of causal time. With this concept, the progression of time is modelled in the system by the occurrence of a distinguished tick, event, which serves as a reference to the rest of the system. In order to validate this approach as suitable for automated verification, a case study is provided and the results obtained using a model-checker on high-level Petri nets are compared with those obtained for timed automata using prominent tools. The comparison is encouraging and shows that the causal time approach is intuitive and modular. It also potentially allows for efficient verification. [Copyright &y& Elsevier]

A new, light balloonborne UV–visible spectrometer, called SALOMON, is designed to perform nighttime measurements of stratospheric trace-gas species by using the Moon as a light source. The first flight, performed on 31 October 1998 at mid-latitude with a float altitude of 26.7 km, allowed the performance of the pointing system to be checked and vertical profiles of ozone, NO_2, NO_3, and possibly OBrO to be obtained. First the instrument and then the performance of the pointing system and the detector are described. Finally the vertical profiles are compared with other profiles obtained at the same location five years before with the heavier balloonborne spectrometer AMON, which uses a star as the light source.

The Stratospheric Regular Sounding project was planned to measure regularly the vertical profiles of several tracers like ozone, water vapor, NOx, ClOx and BrOx radicals, aerosol, pressure and temperature, at three latitudes, to discriminate between the transport and photochemical terms which control their distribution. As part of this project, the “Istituto di Fisica dell’Atmosfera” launched nine laser backscattersondes (LABS) on board stratospheric balloons to make observations of background aerosol and PSCs. LABS was launched with an optical particle counter operated by the University of Wyoming. Observations have been performed in the arctic, mid-latitudes and tropical regions in different seasons. Polar stratospheric clouds have been observed in areas inside and outside the polar vortex edge. A background aerosol was observed both in mid-latitudes and in arctic regions with a backscattering ratio of 1.2 at 692 nm. Very stratified aerosol layers, possibly transported into the lower stratosphere by deep convective systems, have been observed in the lower stratosphere between 20 and 29 km in the tropics in the Southern Hemisphere.

During the 1982 and 1983 Balloon Intercomparison Campaigns, the vertical profile of stratospheric NO2 was measured remotely by nine instruments and that of NO by two. Total overhead columns were measured by two more instruments. Between 30 and 35km, where measurements overlapped, agreement between NO profiles was within ±30%, which is better than the accuracies claimed by the experimenters. Between 35 and 40km there was similarly good agreement between NO2 profiles, but below 30km, differences of greater than a factor three were found. In the second Campaign, NO2 values from most instruments agreed within their quoted errors, except that the Oxford radiometer gave much lower values; but the first Campaign and the column measurements show a more uniform spread of results.

50 jugulo-subclavian venous junctions were removed to study the endovenous structures of the subclavian vein and of this junction. The diameter of the subclavian vein is always less than that of the internal jugular vein. Valvules were constantly found, whereas endovenous structures such as those found in the ilio-caval junctions were very rare. In view of these findings, these structures may be regarded as of embryologic origin.

AbstractThe method that has been used in the past to determine the position of superpressure balloons employed in long-term meteorological and technological experiments—projects GHOST (Global Horizontal Sounding Technique), EOLE (French, God of the Winds), SOMEX (Solar Monitoring Experiment), etc.—was to measure the solar elevation during the daylight hours and then compute the balloon position at local noon: latitude by the noon solar altitude and longitude by the time of balloon noon. This method has disadvantages: it requires a lengthy series of measurements during the day and has degraded accuracy when the maximum solar angle approaches 90°. Another method was therefore devised in which the solar angle data are complemented by data that indicate the local geomagnetic rigidity; the correlation of the two data yields an improved position determination algorithm. This method was applied to the trajectory determination of the SOMEX balloons with considerable success.

Two-dimensional photonic crystals (PCs) were fabricated in InP/GaInAsP waveguides by e-beam lithography and inductively coupled plasma etching. Transmission measurements through simple PC slabs, one-dimensional Fabry-Pe´rot cavities and PC-based waveguides are reported showing clear improvements of the PC optical properties with respect to the results obtained by other etch methods.

L'auteur rapporte comment nombre de situations familiales critiques sont aujourd'hui sous-tendues par l'incapacite´ des protagonistes a` se diffe´rencier, dans une socie´te´ du ≪ gommage > et du ≪ collage ≫. Il en de´duit deux principes the´rapeutiques essentiels : l'importance de la me´diation par un tiers et la ne´cessite´ de prises en charge plurifocales.

An optimised all-active Mach-Zehnder wavelength converter is presented. At 10 Gbit/s, a conversion penalty of 1 dB is reached at an input signal power of –10 dBm. The signal power dynamic range is at least 15 dB with on-chip signal preamplifier current control.

Clamped-gain SOA modules for 1.55 µm wavelength including DBR-gratings, tensile strained bulk material and mode size adaptors have been realised. Thanks to the stabilised gain over a large optical power range, amplification and routing of WDM signals at 16 × 10 Gbit/s has been achieved.

A four-channel wavelength selector with 200 GHz channel spacing monolithically integrated on InP is reported. Record low fibre-to-fibre insertion loss of 1.5 dB was obtained at a bias current of only 30 mA. BER performance at 2.5 Gbit/s has also been investigated.

An optical self-aligned flip-chip packaging technique for tilted semiconductor optical amplifier arrays is reported. It uses a Si motherboard with V-grooves for self-alignment between the tilted SOA array and angle polished fibre arrays. Fibre-to-fibre gain of 14 ± 1 dB and ripple ±0.1 dB without antireflection coating on the fibres have been achieved.

To improve the epidemiological study of suicide and attempted suicides in Aquitaine, France, we developed a comprehensive surveillance system based on the input of Sentinel General Practitioners (SGPs). From October 1986 to May 1988, for each case of suicide or attempted suicide, the SGPs reported epidemiological data to our system through a computer network of personal home terminals (Minitels). Data included age, sex, method and result of attempt and antecedents. In an analysis of the relationship between the suicidal method, antecedents and results of suicidal act, the principal findings were a high rate of antecedents of suicide attempts by drug overdoses, hangings and drownings; and no antecedents for attempts by the use of firearms. This may show that the increasing accessibility of firearms is making it more likely that impulsive suicide attempts will be lethal.