Laboratoire National de Métrologie et d'Essais

Precision frequency sources such as quartz oscillators, masers, and passive atomic frequency standards are affected by phase and frequency instabilities including both random and deterministic components. It is of prime importance to have a comprehensive characterization of these instabilities in order to be able to assess the potential utility of each source. For that purpose, many parameters have been proposed especially for dealing with random fluctuations. Some of them have been recommended by the IEEE Subcommittee on Frequency Stability and later by Study Group 7 on "Standard Frequencies and Time Signals" of the International Radio Consultative Committee (CCIR). Others are not so widely used but show interesting capabilities. This paper aims at giving a broad review of parameters proposed for phase and frequency instability characterization, including both classical widely used concepts and more recent less familiar approaches. Transfer functions that link frequency-domain and time-domain parameters are emphasized because they provide improved understanding of the properties of a given time-domain parameter or facilitate introducing of new parameters. As far as new approaches are concerned, an attempt has been made to demonstrate clearly their respective advantages. To this end, some developments that did not appear in the original references ate presented here, e.g, the modified three sample variance Σ <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">y</inf> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> (τ), the expressions of 〈δy <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-</sup> <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">T</inf> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> 〉, the intetpretation of structure functions of phase and its relations with Σ <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">y</inf> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> (τ) and the Hadamard variance. The effects of polynomial phase and frequency drifts on various parameters have also been pointed out in parallel with those of random processes modeled by power-law spectral densities.

The general theory of relativity predicts that a star passing close to a supermassive black hole should exhibit a relativistic redshift. In this study, we used observations of the Galactic Center star S0-2 to test this prediction. We combined existing spectroscopic and astrometric measurements from 1995-2017, which cover S0-2's 16-year orbit, with measurements from March to September 2018, which cover three events during S0-2's closest approach to the black hole. We detected a combination of special relativistic and gravitational redshift, quantified using the redshift parameter ϒ. Our result, ϒ = 0.88 ± 0.17, is consistent with general relativity (ϒ = 1) and excludes a Newtonian model (ϒ = 0) with a statistical significance of 5σ.

By the end of 2018, 42 years after the landing of the two Viking seismometers on Mars, InSight will deploy onto Mars' surface the SEIS (Seismic Experiment for Internal Structure) instrument; a six-axes seismometer equipped with both a long-period three-axes Very Broad Band (VBB) instrument and a three-axes short-period (SP) instrument. These six sensors will cover a broad range of the seismic bandwidth, from 0.01 Hz to 50 Hz, with possible extension to longer periods. Data will be transmitted in the form of three continuous VBB components at 2 sample per second (sps), an estimation of the short period energy content from the SP at 1 sps and a continuous compound VBB/SP vertical axis at 10 sps. The continuous streams will be augmented by requested event data with sample rates from 20 to 100 sps. SEIS will improve upon the existing resolution of Viking's Mars seismic monitoring by a factor of 2500 at 1 Hz and 200 000 at 0.1 Hz. An additional major improvement is that, contrary to Viking, the seismometers will be deployed via a robotic arm directly onto Mars' surface and will be protected against temperature and wind by highly efficient thermal and wind shielding. Based on existing knowledge of Mars, it is reasonable to infer a moment magnitude detection threshold of M w 3 at 40 epicentral distance and a potential to detect several tens of quakes and about five impacts per year. In this paper, we first describe the science goals of the experiment and the rationale used to define its requirements. We then provide a detailed description of the hardware, from the sensors to the deployment system and associated performance, including transfer functions of the seismic sensors and temperature sensors. We conclude by describing the experiment ground segment, including data processing services, outreach and education networks and provide a description of the format to be used for future data distribution.

Recent reports have challenged the notion that retroviruses and retroviral vectors integrate randomly into the host genome. These reports pointed to a strong bias toward integration in and near gene coding regions and, for gammaretroviral vectors, around transcription start sites. Here, we report the results obtained from a large-scale mapping of 572 retroviral integration sites (RISs) isolated from cells of 9 patients with X-linked SCID (SCID-X1) treated with a retrovirus-based gene therapy protocol. Our data showed that two-thirds of insertions occurred in or very near to genes, of which more than half were highly expressed in CD34(+) progenitor cells. Strikingly, one-fourth of all integrations were clustered as common integration sites (CISs). The highly significant incidence of CISs in circulating T cells and the nature of their locations indicate that insertion in many gene loci has an influence on cell engraftment, survival, and proliferation. Beyond the observed cases of insertional mutagenesis in 3 patients, these data help to elucidate the relationship between vector insertion and long-term in vivo selection of transduced cells in human patients with SCID-X1.

In vitro air–liquid interface (ALI) cell culture models can potentially be used to assess inhalation toxicology endpoints and are usually considered, in terms of relevancy, between classic (i.e., submerged) in vitro models and animal-based models. In some situations that need to be clearly defined, ALI methods may represent a complement or an alternative option to in vivo experimentations or classic in vitro methods. However, it is clear that many different approaches exist and that only very limited validation studies have been carried out to date. This means comparison of data from different methods is difficult and available methods are currently not suitable for use in regulatory assessments. This is despite inhalation toxicology being a priority area for many governmental organizations. In this setting, a 1-day workshop on ALI in vitro models for respiratory toxicology research was organized in Paris in March 2016 to assess the situation and to discuss what might be possible in terms of validation studies. The workshop was attended by major parties in Europe and brought together more than 60 representatives from various academic, commercial, and regulatory organizations. Following plenary, oral, and poster presentations, an expert panel was convened to lead a discussion on possible approaches to validation studies for ALI inhalation models. A series of recommendations were made and the outcomes of the workshop are reported.

We use 6 yrs of accurate hyperfine frequency comparison data of the dual rubidium and caesium cold atom fountain FO2 at LNE-SYRTE to search for a massive scalar dark matter candidate. Such a scalar field can induce harmonic variations of the fine structure constant, of the mass of fermions, and of the quantum chromodynamic mass scale, which will directly impact the rubidium/caesium hyperfine transition frequency ratio. We find no signal consistent with a scalar dark matter candidate but provide improved constraints on the coupling of the putative scalar field to standard matter. Our limits are complementary to previous results that were only sensitive to the fine structure constant and improve them by more than an order of magnitude when only a coupling to electromagnetism is assumed.

International audience

The occurrence of mutations in the genes coding for gyrase (gyrA and gyrB) and topoisomerase IV (parE and parC) of Salmonella typhimurium experimental mutants selected in vitro and in vivo and of 138 nalidixic acid-resistant Salmonella field isolates was investigated. The sequencing of the quinolone resistance-determining region of these genes in highly fluoroquinolone-resistant mutants (MICs of 4 to 16 microg/ml) revealed the presence of gyrA mutations at codons corresponding to Gly-81 or Ser-83, some of which were associated with a mutation at Asp-87. No mutations were found in the gyrB, parC, and parE genes. An assay combining allele-specific PCR and restriction fragment length polymorphism was developed to rapidly screen mutations at codons 81, 83, and 87 of gyrA. The MICs of ciprofloxacin for the field isolates reached only 2 microg/ml, versus 16 microg/ml for some in vitro-selected mutants. The field isolates, like the mutants selected in vivo, had only a single gyrA mutation at codon 83 or 87. Single gyrA mutations were also found in highly resistant in vitro-selected mutants (MIC of ciprofloxacin, 8 microg/ml), which indicates that mechanisms other than the unique modification of the intracellular targets could participate in fluoroquinolone resistance in Salmonella spp. A comparison of experimental mutants selected in vitro, field strains, and mutants selected in vivo suggests that highly fluoroquinolone-resistant strains are counterselected in field conditions in the absence of selective pressure.

We investigate the magneto-transport properties of epitaxial graphene single-layer on 4H-SiC(0001), grown by atmospheric pressure graphitization in Ar, followed by H2 intercalation. We directly demonstrate the importance of saturating the Si dangling bonds at the graphene/SiC(0001) interface to achieve high carrier mobility. Upon successful Si dangling bonds elimination, carrier mobility increases from 3 000 cm(2)V(-1)s(-1) to >11 000 cm(2)V(-1)s(-1) at 0.3 K. Additionally, graphene electron concentration tends to decrease from a few 10(12) cm(-2) to less than 10(12) cm(-2). For a typical large (30 × 280 μm(2)) Hall bar, we report the observation of the integer quantum Hall states at 0.3 K with well developed transversal resistance plateaus at Landau level filling factors of ν = 2, 6, 10, 14... 42 and Shubnikov de Haas oscillation of the longitudinal resistivity observed from about 1 T. In such a device, the Hall state quantization at ν = 2, at 19 T and 0.3 K, can be very robust: the dissipation in electronic transport can stay very low, with the longitudinal resistivity lower than 5 mΩ, for measurement currents as high as 250 μA. This is very promising in the view of an application in metrology.

We describe an experimental method to probe the adsorption of water at the surface of isolated, substrate-free TiO2 nanoparticles (NPs) based on soft X-ray spectroscopy in the gas phase using synchrotron radiation. To understand the interfacial properties between water and TiO2 surface, a water shell was adsorbed at the surface of TiO2 NPs. We used two different ways to control the hydration level of the NPs: in the first scheme, initially solvated NPs were dried and in the second one, dry NPs generated thanks to a commercial aerosol generator were exposed to water vapor. XPS was used to identify the signature of the water layer shell on the surface of the free TiO2 NPs and made it possible to follow the evolution of their hydration state. The results obtained allow the establishment of a qualitative determination of isolated NPs' surface states, as well as to unravel water adsorption mechanisms. This method appears to be a unique approach to investigate the interface between an isolated nano-object and a solvent over-layer, paving the way towards new investigation methods in heterogeneous catalysis on nanomaterials.

We show that the language of atom interferometry provides a unified picture for microwave and optical atomic clocks as well as for gravito-inertial sensors. The sensitivity and accuracy of these devices is now such that a new theoretical framework common to all these interferometers is required that includes: (a) a fully quantum mechanical treatment of the atomic motion in free space and in the presence of a gravitational field (most cold-atom interferometric devices use atoms in ``free fall'' in a fountain geometry); (b) an account of simultaneous actions of gravitational and electromagnetic fields in the interaction zones; (c) a second quantization of the matter fields to take into account their fermionic or bosonic character in order to discuss the role of coherent sources and their noise properties; (d) a covariant treatment including spin to evaluate general relativistic effects. A theoretical description of atomic clocks revisited along these lines is presented, using both an exact propagator of atom waves in gravito-inertial fields and a covariant Dirac equation in the presence of weak gravitational fields. Using this framework, recoil effects, spin-related effects, beam curvature effects, the sensitivity to gravito-inertial fields and the influence of the coherence of the atom source are discussed in the context of present and future atomic clocks and gravito-inertial sensors.

We used a quasi-spherical cavity as an acoustic and microwave resonator to measure the thermodynamic temperatures, T, of the triple points of equilibrium hydrogen, neon, argon and mercury and to measure the difference T − T90, in the range 7 K to 273 K. (T90 is the temperature on the International Temperature Scale of 1990 (ITS-90).) In the range 7 K to 24.5 K, our preliminary values of T − T90 agree with recent results from dielectric-constant gas thermometry and achieve uncertainties that are comparable to or smaller than those achievable using the interpolating constant volume gas thermometer as currently defined on the ITS-90. In the range 90 K to 273 K, the present results for T − T90 obtained using a helium-filled, copper-walled, quasi-spherical cavity agree with earlier results obtained using argon-filled, steel-walled or aluminium-walled, spherical cavities. The agreement confirms our understanding of both acoustic and microwave cavity resonators and demonstrates that resonators function as primary thermometers spanning wide temperature ranges. The mutually consistent acoustic thermometry data from several laboratories imply that the values of (T − T90)/T90 are 5 times larger than the uncertainty of T/T90 near 150 K and near 400 K. They also imply that the derivative dT/dT90 is too large by approximately 10−4 near 273.16 K and that dT/dT90 has a discontinuity of 4 × 10−5 at 273.16 K.

Commutability is a property of a reference material (RM) that relates to the closeness of agreement between results for an RM and results for clinical samples (CSs) when measured by ≥2 measurement procedures (MPs). Commutability of RMs used in a calibration traceability scheme is an essential property for them to be fit for purpose. Similarly, commutability of trueness controls or external quality assessment samples is essential when those materials are used to assess trueness of results for CSs. This report is part 1 of a 3-part series describing how to assess commutability of RMs. Part 1 defines commutability and addresses critical components of the experimental design for commutability assessment, including selection of individual CSs, use of pooled CSs, qualification of MPs for inclusion, establishing criteria for the determination that an RM is commutable, generalization of commutability conclusions to future measurements made with the MPs included in the assessment, and information regarding commutability to be included in the certificate for an RM. Parts 2 and 3 in the series present 2 different statistical approaches to commutability assessment that use fixed criteria related to the medical decisions that will be made using the laboratory test results.

Intra‐tooth sequential analysis of enamel δ 18 O is currently used to investigate birth seasonality in past animal populations, offering new insights into seasonal availability of animal resources, herd management and seasonality of site occupation. Reference data sets are still required to address two major difficulties: (1) that inter‐individual variability in the record of the seasonal cycle is affected by tooth size; and (2) that the season of birth cannot be directly estimated from the timing of tooth growth, because of a delay in enamel mineralization. We present a data set acquired on the lower second molar of 10 modern sheep from Rousay (Orkney) born within a few weeks of each other in April/May and submitted to the same environmental conditions until death. All sheep have recorded a sinusoidal pattern of δ 18 O variation spanning approximately a year. From the difference between the expected and the measured time sequence, the delay of enamel mineralization is estimated to be 5–6 months. The data set is then described using a model mainly based on a cosine function. The period, corresponding to the length of the M2 crown formed over a year, averaged 35.8 mm. A very slight variation of tooth growth rate with time and no attenuation of the isotopic signal towards the cervical margin of the crown could be detected in this data set. The lowest δ 18 O values, corresponding to the sheep's first winter, were tracked at a distance from the enamel/root junction that varied between 23.0 and 30.3 mm (x min mean = 27.6 mm); the highest δ 18 O values, corresponding to the sheep's second summer, were between 6.3 and 11.6 mm (x max mean = 9.9 mm). Most of the variability can be attributed to tooth size. When normalized on the period, x min and x max are 0.28 ( ± 0.05) and 0.78 ( ± 0.05) on average, meaning that the Rousay sheep have recorded the minimum and maximum δ 18 O values on average at 78% and 28%, respectively, of the end of the periodic cycle recorded in the second molar.

A process is described to assess the commutability of a reference material (RM) intended for use as a calibrator, trueness control, or external quality assessment sample based on the difference in bias between an RM and clinical samples (CSs) measured using 2 different measurement procedures (MPs). This difference in bias is compared with a criterion based on a medically relevant difference between an RM and CS results to make a conclusion regarding commutability. When more than 2 MPs are included, the commutability is assessed pairwise for all combinations of 2 MPs. This approach allows the same criterion to be used for all combinations of MPs included in the assessment. The assessment is based on an error model that allows estimation of various random and systematic sources of error, including those from sample-specific effects of interfering substances. An advantage of this approach is that the difference in bias between an RM and the average bias of CSs at the concentration (i.e., amount of substance present or quantity value) of the RM is determined and its uncertainty estimated. An RM is considered fit for purpose for those MPs for which commutability is demonstrated.

Abstract. To develop an accurate measurement network of greenhouse gases, instruments in the field need to be stable and precise and thus require infrequent calibrations and a low consumption of consumables. For about 10 years, cavity ring-down spectroscopy (CRDS) analyzers have been available that meet these stringent requirements for precision and stability. Here, we present the results of tests of CRDS instruments in the laboratory (47 instruments) and in the field (15 instruments). The precision and stability of the measurements are studied. We demonstrate that, thanks to rigorous testing, newer models generally perform better than older models, especially in terms of reproducibility between instruments. In the field, we see the importance of individual diagnostics during the installation phase, and we show the value of calibration and target gases that assess the quality of the data. Finally, we formulate recommendations for use of these analyzers in the field.

Abstract Background Titanium dioxide (TiO 2 ) is broadly used in common consumer goods, including as a food additive (E171 in Europe) for colouring and opacifying properties. The E171 additive contains TiO 2 nanoparticles (NPs), part of them being absorbed in the intestine and accumulated in several systemic organs. Exposure to TiO 2 -NPs in rodents during pregnancy resulted in alteration of placental functions and a materno-foetal transfer of NPs, both with toxic effects on the foetus. However, no human data are available for pregnant women exposed to food-grade TiO 2 -NPs and their potential transfer to the foetus. In this study, human placentae collected at term from normal pregnancies and meconium (the first stool of newborns) from unpaired mothers/children were analysed using inductively coupled plasma mass spectrometry (ICP-MS) and scanning transmission electron microscopy (STEM) coupled to energy-dispersive X-ray (EDX) spectroscopy for their titanium (Ti) contents and for analysis of TiO 2 particle deposition, respectively. Using an ex vivo placenta perfusion model, we also assessed the transplacental passage of food-grade TiO 2 particles. Results By ICP-MS analysis, we evidenced the presence of Ti in all placentae (basal level ranging from 0.01 to 0.48 mg/kg of tissue) and in 50% of the meconium samples (0.02–1.50 mg/kg), suggesting a materno-foetal passage of Ti. STEM-EDX observation of the placental tissues confirmed the presence of TiO 2 -NPs in addition to iron (Fe), tin (Sn), aluminium (Al) and silicon (Si) as mixed or isolated particle deposits. TiO 2 particles, as well as Si, Al, Fe and zinc (Zn) particles were also recovered in the meconium. In placenta perfusion experiments, confocal imaging and SEM-EDX analysis of foetal exudate confirmed a low transfer of food-grade TiO 2 particles to the foetal side, which was barely quantifiable by ICP-MS. Diameter measurements showed that 70 to 100% of the TiO 2 particles recovered in the foetal exudate were nanosized. Conclusions Altogether, these results show a materno-foetal transfer of TiO 2 particles during pregnancy, with food-grade TiO 2 as a potential source for foetal exposure to NPs. These data emphasize the need for risk assessment of chronic exposure to TiO 2 -NPs during pregnancy.

A new Watt balance project is now in progress at the Bureau National de Metrologie (BNM), Paris, France. In this paper, the general configuration and the main parts of the experimental setup currently in development are presented. The aim is to contribute to the international effort in monitoring the kilogram toward a new definition of the mass unit with a relative accuracy of 10/sup -8/ or better.

The 8th International Comparison of Absolute Gravimeters (ICAG2009) took place at the headquarters of the International Bureau of Weights and Measures (BIPM) from September to October 2009. It was the first ICAG organized as a key comparison in the framework of the CIPM Mutual Recognition Arrangement of the International Committee for Weights and Measures (CIPM MRA) (CIPM 1999). ICAG2009 was composed of a Key Comparison (KC) as defined by the CIPM MRA, organized by the Consultative Committee for Mass and Related Quantities (CCM) and designated as CCM.G-K1. Participating gravimeters and their operators came from national metrology institutes (NMIs) or their designated institutes (DIs) as defined by the CIPM MRA. A Pilot Study (PS) was run in parallel in order to include gravimeters and their operators from other institutes which, while not signatories of the CIPM MRA, nevertheless play important roles in international gravimetry measurements. The aim of the CIPM MRA is to have international acceptance of the measurement capabilities of the participating institutes in various fields of metrology. The results of CCM.G-K1 thus constitute an accurate and consistent gravity reference traceable to the SI (International System of Units), which can be used as the global basis for geodetic, geophysical and metrological observations of gravity. The measurements performed afterwards by the KC participants can be referred to the international metrological reference, i.e. they are SI-traceable. The ICAG2009 was complemented by a number of associated measurements: the Relative Gravity Campaign (RGC2009), high-precision levelling and an accurate gravity survey in support of the BIPM watt balance project. The major measurements took place at the BIPM between July and October 2009. Altogether 24 institutes with 22 absolute gravimeters(32) and nine relative gravimeters participated in the ICAG/RGC campaign. This paper is focused on the absolute gravity campaign. We review the history of the ICAGs and present the organization, data processing and the final results of the ICAG2009. After almost thirty years of hosting eight successive ICAGs, the CIPM decided to transfer the responsibility for piloting the future ICAGs to NMIs, although maintaining a supervisory role through its Consultative Committee for Mass and Related Quantities.

Adeno-associated viral gene therapy has shown promise for the treatment of inherited and acquired retinal disorders. In most applications, regulation of expression is a critical concern for both safety and efficacy. The purpose of our study was to evaluate the ability of the tetracycline-regulatable system to establish long-term transgene regulation in the retina of nonhuman primates. Three rAAV vectors expressing the tetracycline-dependent transactivator (rtTA) under the control of either the ubiquitous CAG promoter or the specific RPE65 promoter (AAV2/5.CAG.TetOn.epo, AAV2/4.CAG.TetOn.epo, and AAV2/4.RPE65.TetOn.epo) were generated and administered subretinally to seven macaques. We demonstrated that repeated inductions of transgene expression in the nonhuman primate retina can be achieved using a Tet-inducible system via rAAV vector administration over a long period (2.5 years). Maximum erythropoietin (EPO) secretion in the anterior chamber depends upon the rAAV serotype and the nature of the promoter driving rtTA expression. We observed that the EPO isoforms produced in the retina differ from one another based on the transduced cell type of origin within the retina and also differ from both the physiological EPO isoforms and the isoforms produced by AAV-transduced skeletal muscle.