Eric Aristidi

Yan Fantéï-Caujolle

Aziz Ziad

Julien Chabé

Christophe Giordano

Catherine Renaud

Alohotsy Rafalimanana

Turbulence monitoring at Calern observatory with the Generalised Differential Image Motion Monitor

The Generalised Differential Image Motion Monitor (GDIMM) was proposed a few years ago as a new generation instrument for turbulence monitoring. It measures integrated parameters of the optical turbulence, i.e the seeing, isoplanatic angle, scintillation index, coherence time and wavefront coherence outer scale. GDIMM is based on a fully automatic small telescope (28cm diameter), equipped with a 3-holes mask at its entrance pupil. The instrument is installed at the Calern observatory (France) and performs continuous night-time monitoring of turbulence parameters. In this communication we present long-term and seasonnal statistics obtained at Calern, and combine GDIMM data to provide quantities such as the equivalent turbulence altitude and the effective wind speed.

INTRODUCTION

The Generalized Differential Image Monitor (GDIMM) is an instrument designed to monitor integrated parameters of the atmospheric turbulence above astronomical observatories. It provides the seeing 0 , the isoplanatic angle θ 0 , the scintillation index s 0 , the coherence time τ 0 and the spatial coherence outer scale L 0 . The 3 parameters 0 , θ 0 and τ 0 are of fundamental importance for adative optics (AO) correction. The scintillation has a strong impact on photometric signals from astronomical sources as well as on optical telecommunications with satellites. The outer scale L 0 has a significant effect for large diameter telescopes (8m and above) and impacts low Zernike mode such as tip-tilt [1]. The GDIMM is at the moment the only monitor to provide simultaneously all these parameters. GDIMM was proposed in 2014 [START_REF] Aristidi | SPIE Conf. Series[END_REF] to replace the old-generation turbulence monitor GSM [START_REF] Ziad | [END_REF]. It is a compact instrument very similar to a DIMM [4], with 3 sub-apertures of different diameters. GDIMM observes bright single stars up to magnitude V ∼ 2, at zenith distances up to 30 • . After a period of developpement and tests in 2013-2015, the GDIMM is operational since the end of 2015, as a part of the Calern atmospheric Turbulence Station (Côte d'Azur Observatory -Calern site, France, UAI code: 010, Latitude=43 • 45 13 N, Longitude=06 • 55 22 E). GDIMM provides continuous monitoring of 5 turbulence parameters ( 0 , s 0 , θ 0 , τ 0 and L 0 ) above the Calern Observatory. Data are displayed in real time through a website (cats.oca.eu), as a service available to all observers at Calern. The other objective is that Calern becomes an operational on-sky test platform for the validation of new concepts and components in order to overcome current limitations of high angular resolution existing systems. Several activities regarding adaptive optics are operated at the MéO [START_REF] Samain | 16th International Workshop on Laser Ranging[END_REF] and C2PU [START_REF] Bendjoya | [END_REF] telescopes and they benefit of the data given by the CATS station. The present communication is an update of previous papers [START_REF] Aristidi | SPIE Conf. Series[END_REF][START_REF] Aristidi | SPIE Conference Series[END_REF][START_REF] Aristidi | [END_REF]. We describe last improvements and the present status of the instrument in Sect. 2. Long-term statistics (5 years) of turbulence above the Plateau de Calern are presented in Sect. 3.

OBSERVATIONS AND DATA PROCESSING

GDIMM is based on a small commercial telescope (diameter 28cm) equipped with a 3 apertures pupil mask. 2 subpupils have a diameter of 6cm and are equipped with glass prisms oriented to give opposite tilts to the incident light. The 3rd sub-aperture is circular, its diameter is 10cm and it has a central obstruction of 4cm: this particular geometry is required to estimate the isoplanatic angle from the scintillation index [9]. At the focus of the telescope images are recorded by a fast camera allowing a framerate of 100 frames per second. Turbulence parameters are estimated on data cubes containing 2048 images. The first half of these cubes are taken with an exposure time of 5ms, the second half with 10ms, to allow compensation of the bias due to the exposure time. A set of parameter is calculated every 2mn and sent to a database accessible worldwide via a web interface (cats.oca.eu). More details are given in previous papers [START_REF] Aristidi | [END_REF].

The dataset analyzed here covers the period March 2015 to September 2020. The number of data points collected each month of the period is displayed in Fig. 1 (left). As the robotization of the instrument progressed during the years 2015-2016, the number of data increased. At the beginning of 2019, for a few months, we reduced the delay between successive acquisitions from 2 mn to 1mn, this resulted in a larger number of data (up to ∼ 10 4 in Februrary 2019). Fig. 1 (right) shows the total number of measurements per month. Two periods in the year present a smaller number of data: April-May and November. They correspond to technical failures or adverse weather (in particular the spring 2018 was very bad and rainy, and the gap in April 2020 was due to the covid-19 lockdown).

STATISTICS AT THE CALERN OBSERVATORY

We collected about 148 000 turbulence parameter sets during the 5 year period. The number for the outer scale L 0 is lower (54 000): this parameter is sensitive to telescope vibrations and a reliable value is not always available [START_REF] Aristidi | [END_REF].

Statistics are presented in Table 1 for the 5 turbulence parameters ( 0 , s 0 , θ 0 τ 0 , L 0 ). Note that the scintillation index s 0 is measured through a 10cm diameter sub-pupil: this causes a low-pass spatial filtering and values are lower than the actual scintillation defined for a zero-diameter pupil [10].

We also provide values for the equivalent turbulence altitude h and the effective wind speed v (weighted average of the wind speed over the whole atmosphere). A definition of these quantities can be found in papers by Roddier [10,11], and we estimated them by the following equations:

v = 0.31 r 0 τ 0 (1)
and h = 0.31 Histograms are displayed in Fig. 2 and show a classical log-normal shape for all parameters. We did not display the scintillation histogram since is is directly deduced from θ 0 by an exact analytic relation. A comparison with other astronomical sites in the world (examples for Paranal, La Silla and Mauna Kea are given in Table 1) show that the Calern plateau is an average site. Fig. 3 displays the monthly evolution of parameters. The seeing is slightly lower in summer, we measured a median value of 1.06 in July and August (the median winter seeing during the period November-March is 1.34 ). As a consequence, the median coherence time is higher in summer (2.24ms in July-August, 1.78ms in November-March). Also, Fig. 4 shows that, in Summer, there is a dependence of 0 and τ 0 with time. The median seeing decreases below 0.8 at the end of the night (while the coherence time increases). Nothing similar was observed during the winter. The isoplanatic angle and the outer scale didn't show any noticeable time dependence, both in summer and winter. The outer scale L 0 has values similar to other sites such as Mauna Kea or La Silla. Sequences of several hours of good seeing were sometimes observed, which is a good point for this site (and already known by "old" observers on interferometers during the 80's and 90's). An exemple is shown on Fig. 5. It is a time series recorded on Jan. 1st, 2020, showing a seeing below 1 during 12 hours, the median seeing for that night was 0.69 . Fig. 6 displays seasonal seeing histograms, calculated for the summer (July and August) and the winter (November-March). They appear to be well modelled by a sum of two log-normal functions (they appear as dashed curves on the plots, their sum is the solid line). This is an evidence of the existence of two regimes: a "good seeing" distribution φ 1 with a median value 1 and a "medium seeing" distribution φ 2 with a median value 2 . In summer, we have 1 = 0.68 (the good seeing distribution contains 20% of the data) and 2 = 1.04 (80% of the data). In winter we have 1 = 0.76 (21% of the data) and 2 = 1.25 (79% of the data). The time series displayed in Fig. 5 corresponds to a realisation of the good seeing distribution, during 12 hours. Winter Summer

r 0 θ 0 (2)
Figure 7: Temporal stability of parameters, given by the continuous time a parameter is better than a given value ("better" means lower for the seeing, and higher for the coherence time and the isoplanatic angle). Curves are plotted for the summer (July-August) and winter (November to Mars) datasets.

We define here an interval of stability as a continuous period of time t s in which a parameter is better than a given threshold x 0 . The term better means lower for the seeing, as low values of the seeing correspond to high Strehl ratio. It means higher for the coherence time and isoplanatic angle. In this interval, we allow the parameter to be better than x 0 during a few minutes (we took 4 mn, i.e. two sampling intervals of parameter time series). For a given value of x 0 , we calculate the distribution of t s on the whole dataset. Its median value gives the characteristic time of stability. This approach was the one used for the site characterization of Dome C by means of DIMMs [START_REF] Aristidi | [END_REF]15] and Single Star Scidar [16].

We performed this analysis for the 3 parameters 0 , τ 0 and θ 0 , for the summer and the winter periods. We could not obtain results for the outer scale, since it is not always measurable because of telescope vibrations (data sequences show large gaps that hamper the calculation of t s ). Results are displayed in Fig 7 . For the seeing, the characteristic time increases with the seeing value and saturates. It is of the order of 20mn for seeing values around 1 , and is longer during the summer. For τ 0 and θ 0 we observe that t s decrease with the threshold x 0 , down to a value of ∼10mn. Here again, summer conditions appear to be slightly more stable. Note that the curves are likely to be biased by interruptions of the observations (change of target star, clouds, daynight cycle). But the mean value of uninterrupted sequences duration is ∼ 150mn, much larger than the characteristic stability times.

CONCLUSION

We have presented statistics of optical turbulence above the plateau de Calern, measured for five years with the GDIMM monitor. GDIMM is a part of the CATS station which aims at monitoring atmospheric turbulence parameters and vertical profiles on the site of Calern. The station is fully automatic, using informations from a meteo station and an All-Sky camera to replace human interventions.

Seeing and isoplanatic measurements are given by differential motions and scintillation, according to well known techniques. The coherence time is derived from AA structure functions. The method is simple and has proven to give satisfactory results [START_REF] Ziad | Temporal characterization of atmospheric turbulence with the Generalized Seeing Monitor instrument[END_REF]. It may be used as well with a classical DIMM providing that the acquisition camera is fast enough (typically 100 frames/sec) to properly sample the AA correlation times. The outer scale is derived from ratios of absolute to relative AA motions [START_REF] Aristidi | [END_REF]. This parameter is the most sensitive to telescope vibrations, and requires a good stability of the telescope mount and pillar. Simultaneous observations of GDIMM and another instrument, the Profiler of Moon Limb, which estimates the vertical profile of turbulence, gave concordant results [18,19]. A portable version of the GDIMM has been developped in parallel to the Calern one, to perform turbulence measurements at any site on the world. Discussions with the ESO (European Southern Observatory) are currently in progress to make observations at Paranal and Armazones.

Figure 2 :

 2 Figure 2: Histograms of the seeing, isoplanatic angle, coherence time and outer scale at Calern, calculated at the wavelength λ = 0.5µm for the period June 2015-September 2020.

Figure 3 :

 3 Figure3: Monthly median values of the four parameters ( 0 , θ 0 , τ 0, L 0 ), calculated at the wavelength λ = 0.5µm for the period June 2015-September 2020. On each graph, the red curve is the median value, green curves are the first and third quartiles.

Figure 4 :

 4 Figure 4: Hourly variations of the seeing 0 and coherence time τ 0 during the summer (July-August). Symbols (triangle/circle) are the median values. Error rectangles lower and upper edges are the 1st and 3rd quartiles. The data set represents a total of 27300 measurements for 5 summers (2015 to 2019).

Figure 5 :

 5 Figure 5: Exceptional conditions observed on Jan. 1st, 2020. Left: seeing time series (the median value for this night was 0.70 ), right: coherence time (median value 4.3ms).

Figure 6 :

 6 Figure 6: Left: seeing histogram for the summer (July-August). Right: seeing histogram for the winter (Nov-March). Superimposed curves φ 1 and φ 2 are a least-square fit by a sum of two log-normal distributions (individual log-normal curves are dashed lines).

Table 1 :

 1

	1

Statistics of turbulence parameters measured at Calern (at the wavelength λ = 0.5µm) during the period March 2015-Sept 2020. Paranal, La Silla and Mauna Kea values are from the GSM database.

Acknowledgments

This CATS project has been done under thefinancial support of CNES, Observatoire de la Côte d'Azur, Labex First TF, AS-GRAM, Federation Doeblin, Université de Nice-Sophia Antipolis and Reǵion Provence Alpes Côte d'Azur. We would like thanks all the technical and administrative staff of the Observatoire de la Côte d'Azur and our colleagues from the Astrogéo team from GéoAzur laboratory for their help and support all along the project namely Pierre

Temporal stability of parameters

The stability of turbulence parameters is an important concern. Temporal fluctuations were studied by different authors [12,[START_REF] Ziad | SPIE Conference Series[END_REF]. The characteristic time of stability is generally of a few minutes for temperate sites (e.g. Mauna Kea and La Silla).


Wenyu Huang
email: huangwenyu@gxu.edu.cn

Angelica Bianco

Marcello Brigante
email: marcello.brigante@uca.fr

Gilles Mailhot

UVA-UVB activation of hydrogen peroxide and persulfate for Advanced Oxidation Processes: Efficiency, mechanism and effect of various water constituents

Keywords: AOPs, pollutant degradation, chloride ions effect, hydroxyl and sulfate radical, Bisphenol A

UVA-UVB activation of hydrogen peroxide and persulfate for advanced oxidation processes: Efficiency, mechanism and effect of various water constituents

Introduction

Treatment efficiency of recalcitrant organic pollutants in aqueous effluents using oxidant species precursors such as hydrogen peroxide (H 2 O 2 ) and persulfate (S 2 O 8 2-) has been investigated under UVC radiation [START_REF] He | Degradation mechanism of cyanobacterial toxin cylindrospermopsin by hydroxyl radicals in homogeneous UV/H 2 O 2 process[END_REF][2][START_REF] Xie | Removal of 2-MIB and geosmin using UV/persulfate: Contributions of hydroxyl and sulfate radicals[END_REF][4][START_REF] Yoon | Oxidation of bisphenol A by UV/S 2 O 8 2-: Comparison with UV/H 2 O 2[END_REF]. UVC lamps are mercury made, fragile and they require considerable more energy than UVA, UVB lamps [START_REF] Beck | Evaluating UV-C LED disinfection performance and investigating potential dual-wavelength synergy[END_REF] which can also be substituted by LED to reduce the operating cost. UVC-LED efficiency is less than 3 % making their utilization not suitable for long time wastewater treatments. For these reasons, application of UVA and UVB radiation to improve water 3 depollution processes can offer many advantages. Following this idea, iron-complexes are recently used to initiate or improve pollutant removal using H 2 O 2 and S 2 O 8 2 activation in the presence of solar spectrum UV radiation (UVA and UVB) [START_REF] Wu | Sulfate radical photogeneration using Fe-EDDS: Influence of critical parameters and naturally occurring scavengers[END_REF][START_REF] Souza | Intensification of a solar photo-Fenton reaction at near neutral pH with ferrioxalate complexes: A case study on diclofenac removal from aqueous solutions[END_REF][START_REF] Zhao | Simultaneous removal of bisphenol A and phosphate in zero-valent iron activated persulfate oxidation process[END_REF][START_REF] Zhu | Efficient transformation of DDTs with Persulfate Activation by Zero-valent Iron Nanoparticles: A Mechanistic Study[END_REF][START_REF] Xia | Natural magnetic pyrrhotite as a high-Efficient persulfate activator for micropollutants degradation: Radicals identification and toxicity evaluation[END_REF]. In this photo-activated processes, generated hydroxyl and sulfate radicals ((HO • and SO 4

•-) can react with a wide range of organic pollutants due to their high redox potential. And the redox potentials vs NHE and in standard conditions of HO • and SO 4

•-is 2.7V and 2.6V respectively [START_REF] Polczynski | Stabilization and strong oxidizing properties of Ag(ii) in a fluorine-free solvent[END_REF]. ) have a series of advantages, and attract many researches [START_REF] Wang | Activation of persulfate (PS) and peroxymonosulfate (PMS) and application for the degradation of emerging contaminants[END_REF]. However, the presence of organic and inorganic species (such as carbonate and chloride ions) in natural and wastewater may strongly influence the efficiency of oxidation treatment [START_REF] Bennedsen | Influence of chloride and carbonates on the reactivity of activated persulfate[END_REF][START_REF] Liu | Significant role of UV and carbonate radical on the degradation of oxytetracycline in UV-AOPs: Kinetics and mechanism[END_REF]. For this reason, several investigations providing a better understanding of natural occurring ions effect on the oxidative process are reported [START_REF] Yang | Comparison of halide impacts on the efficiency of contaminant degradation by sulfate and hydroxyl radical-based advanced oxidation processes (AOPs)[END_REF][17][START_REF] Liang | Influences of carbonate and chloride ions on persulfate oxidation of trichloroethylene at 20 °C[END_REF]. Generally, chloride ions (Cl -) can significantly inhibit efficiency of UVC based activation of H 2 O 2 and S 2 O 8 2-due to their radical scavenging effect [START_REF] Mopper | Hydroxyl radical photoproduction in the sea and its potential impact on marine processes[END_REF][START_REF] Huie | Temperature dependence of the rate constants for reactions of the sulfate radical, SO4-, with anions[END_REF]. However, in the presence of chloride ions, generated reactive species such as chlorine radical (Cl • ) and dichlorine radical anion (Cl 2 •-) could also react with organic pollutants being more selective [START_REF] Yang | Comparison of halide impacts on the efficiency of contaminant degradation by sulfate and hydroxyl radical-based advanced oxidation processes (AOPs)[END_REF]. On the other hand, it was suggested that the chain reaction triggered by Cl -and SO 4

•-can result in the production of HO • [START_REF] Huie | Electron transfer reaction rates and equilibria of the carbonate and sulfate radical anions[END_REF][START_REF] Kiwi | Mechanism and kinetics of the OH-radical intervention during Fenton oxidation in the presence of a significant amount of radical scavenger (Cl-)[END_REF] and conflicting results are reported in different studies on this topic. For example, different researchers [17,[START_REF] Kiwi | Mechanism and kinetics of the OH-radical intervention during Fenton oxidation in the presence of a significant amount of radical scavenger (Cl-)[END_REF][START_REF] Moraes | Treatment of saline wastewater contaminated with hydrocarbons by the photo-Fenton process[END_REF] reported that the presence of Cl -would inhibit the oxidation of organics, while in other investigations, a negligible effect of chloride ions on the 4 UVC-H 2 O 2 treatment performances was observed [START_REF] Yang | Effect of matrix components on UV/H 2 O 2 and UV/S 2 O 8 2advanced oxidation processes for trace organic degradation in reverse osmosis brines from municipal wastewater reuse facilities[END_REF]. Moreover, using SO 4

•-based oxidation, pollutant's degradation mechanism was found to be modified due to the presence of chloride ions [START_REF] Fang | Sulfate radical-based degradation of polychlorinated biphenyls: Effects of chloride ion and reaction kinetics[END_REF][START_REF] Anipsitakis | Cobalt-mediated activation of peroxymonosulfate and sulfate radical attack on phenolic compounds. Implications of chloride ions[END_REF].

Inorganic carbon (HCO 3 -/CO 3 2-, pKa =10.33) is also an important water constituent that considerably influence the oxidation process. In fact, reactivity of HCO 3 -/CO 3 2-with HO • or SO 4

•generates carbonate radical anion (CO 3 •-) [START_REF] Huang | Steady-state concentrations of carbonate radicals in field waters[END_REF][START_REF] Zhang | Degradation of pharmaceuticals and metabolite in synthetic human urine by UV, UV/H 2 O 2 , and UV/PDS[END_REF] which is generally less reactive toward organic molecules (the second order rate constant with organic compounds in the range ~ 10 5 -10 9 M -1 s -1 ) than HO • or SO 4 •-. However, CO 3

•-can efficiently react with electron-rich atoms, such as N and S-containing compounds, phenols and inorganic compounds [START_REF] Liu | Significant role of UV and carbonate radical on the degradation of oxytetracycline in UV-AOPs: Kinetics and mechanism[END_REF][START_REF] Wu | Phototransformation of selected organophosphorus pesticides: roles of hydroxyl and carbonate radicals[END_REF].

Besides, even if the effect of single water constituent could mutually offset or superimpose, the contribution on the oxidation process of different water matrix as a whole was also investigated in several previous researches [START_REF] Keen | Degradation of antibiotic activity during UV/H 2 O 2 advanced oxidation and photolysis in wastewater effluent[END_REF][START_REF] Lee | Organic contaminant abatement in reclaimed water by UV/H 2 O 2 and a combined process consisting of O 3 /H 2 O 2 followed by UV/H 2 O 2 : Prediction of abatement efficiency, energy consumption, and byproduct formation[END_REF][START_REF] Rosario-Ortiz | Evaluation of UV/H 2 O 2 treatment for the oxidation of pharmaceuticals in wastewater[END_REF][START_REF] Yu | On-line sensor monitoring for chemical contaminant attenuation during UV/H 2 O 2 advanced oxidation process[END_REF][START_REF] Zhang | UV/H 2 O 2 and UV/PDS treatment of trimethoprim and sulfamethoxazole in synthetic human urine: Transformation products and toxicity[END_REF].

Irradiation experiments and analysis

Irradiations are performed in a cylindrical Pyrex reactor (500 mL) placed in a rectangular box, equipped, on the top, with four fluorescence lamps whose emitting wavelength is larger than 275 nm (UVA/B radiation). The polychromatic emission spectrum of the irradiation system reaching the solution is recorded using an optical fiber with a charge coupled device (CCD) spectrophotometer 6 (Ocean Optics USD 2000 + UV-vis) which is calibrated using a DH-2000-CAL Deuterium

Tungsten Halogen reference lamp. The total irradiance between 275 and 400 nm reaching the solution is then estimated to be 976 µW cm -2 . In Figure SM1 The flow rate is 0.25 mL min -1 and the mobile phase is a mixture of water and methanol (40/60, v/v).

The column is a Zorbax C18 of 150×4.6 mm with particle size 5 μm. BPA disappearance is followed at 225 nm.

HPLC-MS an GC-MS conditions used for degradation identification are reported in the supplementary material section.

The pseudo-first-order decay of BPA is determined by plotting BPA disappearance vs time and using following relation:

Where = k app × [BPA] 0 . Degradation efficiency (DE) of considered system is determined using the following equation:

% 100 1 ] [ ] [ / ] [ ] [ (%) 0 0                            S R BPA BPA BPA BPA DE where R BPA BPA         0 ] [ ] [
and

s BPA BPA         0 ] [ ] [
are the value of remaining BPA in solution in absence (R) and in the presence (S) of inorganic ion determined experimentally.

Sewage Treatment Plant Water (STPW) is obtained from urban sewage treatment plant of Clermont-Ferrand, France (April 29 th , 2016) and main physico-chemical characteristics are reported in Table 1. STPW is used for photochemical experiments immediately after PTFE (0.45 µm size pore) filtration in order to avoid bacteriological and chemical modifications. All experiments are performed in triplicates in order to ensure the reliability of the results.

Laser flash photolysis

The laser flash photolysis apparatus has been previously described [START_REF] Brigante | Photochemistry of 1-Nitronaphthalene: A potential source of singlet oxygen and radical species in atmospheric waters[END_REF] and a brief description of radical species detection is given in this section. The fourth harmonic (λ exc = 266 nm) of a Nd:YAG laser is used for the excitation ( the energy of pulse is 40 mJ •-) decay is followed at 450 nm corresponding to the maximum absorption of this species [START_REF] Hayon | Electronic spectra, photochemistry, and autoxidation mechanism of the sulfite-bisulfite-pyrosulfite systems. SO 2 -, SO 3 -, SO 4 -, and SO 5 radicals[END_REF]. Dichlorine radical anion (Cl 2 •-) and carbonate radical anion (CO 3 •-) species are generated using electron transfer reaction between photogenerated sulfate radical and chloride/carbonate ions. The same approach has been previously used to generate Cl 2 •-in solution and follow the reactivity toward organic molecules [START_REF] Wu | Activation of persulfate by Fe(III) species: Implications for 4-tert-butylphenol degradation[END_REF]. Details concerning the second order rate constant determinations are reported in Figure SM2. The second order rate constant between selected radicals (SO 4 •-, Cl 2 •-and CO 3

•-) and BPA or STPW is determined from the regression lines of the logarithmic decays of radical transient (monitored at 450 nm, 340 nm and 600 nm respectively) as a function of the quencher concentration (for BPA) or normalised for the carbon concentration (for STPW). Each value is the average of 4 consecutive laser pulses and the reported error is ± 3σ, obtained from the scattering of the experimental data from the fitting line.

Kinetic modelling

A kinetic modelling approach is used to estimate the radical species formation during irradiation time in the presence of chloride ions. Table SM1 shows the chemical reactions considered for kinetic modelling (reactions are reported from M1 to M21). The pseudo-first order decay and second-order rate constants are obtained from the literature or experimentally (see results and discussion section). The numerical differential equations of the reaction rates are integrated using 9 the ode15s solver function of Matlab. The initial species concentration is implemented in the m-file as the input data. Pseudo-first order constant for the formation of hydroxyl and sulfate radicals (k 1 and k 2 ) are determined under adopted photochemical conditions (irradiance and initial precursor concentrations of 2 mM).

Results and discussion

Comparison of UVA/B activation of H 2 O 2 and S 2 O 8 2-

In Figure 1 the disappearance of 43.8 µM BPA (expressed as [BPA]/[BPA] 0 ) is followed when 2 mM of H 2 O 2 and S 2 O 8 2-are irradiated using UVA/B using phosphate buffered and unbuffered solutions at pH 8.0 (which is representative of STPW pH value). Despite no direct photolysis of BPA is observed in pure water (milli-Q), in the presence of persulfate, the degradation rate results to be faster than in the presence of hydrogen peroxide. Such degradation was not observed under dark condition (direct oxidation) indicating that hydrogen peroxide and persulfate can be photochemically activated leading to the degradation of BPA through formation of highly oxidative radical species. In UVA/B-H 2 O 2 system, the faster BPA degradation observed at pH 8.0 without buffer can be explained considering the change of pH value during irradiation. In fact, the solution pH slowly decreases up to pH 6.4 at the end of the experiment. This modification is correlated to the radical efficiency oxidation increase as reported in Figure SM3 (BPA degradation rate (R BPA )

increases from ~ 1.2 × 10 -9 M s -1 at pH 10 to ~ 5.3 × 10 -9 M s -1 at pH 4.6). In fact, it has been reported that the standard redox potential of HO • in acidic pH is about 2.4-2.7 eV which is higher 10 than that in alkaline pH (1.9-2.0 eV) [START_REF] Wardman | Reduction potentials of one-electron couples involving free radicals in aqueous solution[END_REF]. On the contrary, in the UVA/B-S 2 O 8 2-system, where sulfate radical are generated, a similar value for the BPA degradation rate is found between 4.6 and 9.0 (~ 8 × 10 -9 M s -1 ). Such effect can be explained considering that persulfate radical redox potential does not depend on the pH [START_REF] Neta | Rate constants for reactions of inorganic radicals in aqueous solution[END_REF]. Concerning the possible effect of phosphate buffer constituents, the bimolecular rate constants between photogenerated hydroxyl or sulfate radicals and

HPO 4 2-
/H 2 PO 4 -are ≤ 10 6 M -1 s -1 [START_REF] Maruthamuthu | Phosphate radicals. Spectra, acid-base equilibriums, and reactions with inorganic compounds[END_REF] so we can argue that the quenching effect of buffer could be negligible under adopted experimental conditions.

Effect of chloride ions

3.2.1 UVA/B-H 2 O 2 system
In Figure 2, the effect of chloride ions on the BPA degradation efficiency using 2 mM of H 2 O 2 is investigated at pH 4.6 and 8.0 under irradiation. At pH 8.0, slight inhibition of chloride ions (from 2 to 10 mM) is observed compared to the degradation using hydrogen peroxide alone (increasing the chloride ion concentration up to 100 mM the inhibition reaches ~15%). However, the detrimental effect of chloride ions is more marked at pH 4.6 where the BPA removal efficiency strongly decreases in the presence of 5 mM Cl -. The different BPA degradation trend at pH 8.0 and 4.6 can be justified considering that photogenerated hydroxyl radicals are in equilibrium with ClOH The effect of chloride ions on the radical species formation can be partially predicted using the chemical kinetic modelling approach that estimates a negligible effect of Clon the hydroxyl radical formation rate at pH 8.0. Despite no significant inhibition of chloride ions on the hydroxyl radical concentration (the initial concentration of HO • decreases from ~ 4.1 × 10 -13 M to ~3.9 × 10 -13 M in the presence of 5 mM of Clat pH 4.6 as reported in Fig. SM4), the amount of chlorine radical

species such as Cl • , Cl 2 •-
and ClOH •is strongly enhanced (Fig. SM5). In fact, the kinetic model predicts that Cl system is found to be strongly influenced by chloride ions (Fig. SM6). Two contrasting effects can be observed increasing the chloride ion concentration:

the first (from 0 to 2 mM of Cl -) is the drastic decrease (up to 80%) of the degradation efficiency (DE), whereas the second ([Cl -] > 2 mM) is a positive effect up to the enhancement of BPA degradation observed in the presence of 100 and 200 mM of Cl -(Fig. 3). This opposite trend (inhibition and enhancement) is investigated considering the radical species generation as a function M whene 2 mM of persulfate are irradiate using UVA/B radiation at pH 8.0 (Fig. 4). The presence of 2 mM of chloride ions is able to scavenge about 66% of sulfate radicals leading to the formation of Cl • which is a source of other radical species such as Cl 2 •-and ClOH •-through a more complex reaction system (M13 to M15). Increasing the chloride ions concentration, despite no effect observed on the hydroxyl radical steady-state concentration, sulfate radical concentration decreases of about 2 order of magnitude (from 10 -12 to 10 -14 M). This trend can be explained considering that sulfate radical are able to oxidize chloride ions into chlorine radicals (M16) that can be responsible for the BPA degradation increase observed at high chloride ions concentrations. For instance, the reactivity of Cl • with phenol has been estimated to be 2.5 × 10 10 M s -1 [START_REF] Alfassi | Reactivities of chlorine atoms and peroxyl radicals formed in the radiolysis of dichloromethane[END_REF]. BPA degradation enhancement observed when persulfate are irradiated in the presence of chloride ions can be also explained considering the formation of new reactive species (that are not considered by our kinetic model) such as hypochlorous acid/hypochlorite ions (HOCl/OCl -pka = 7.5) as suggested by Yuan and co-workers [START_REF] Yuan | Effects of chloride ion on degradation of Acid Orange 7 by sulfate radical-based advanced oxidation process: Implications for formation of chlorinated aromatic compounds[END_REF]. Chlorine active species are responsible for direct oxidation of organic molecules or represent a photochemical source of hydroxyl and chlorine radical under UV radiation [START_REF] Watts | Chlorine photolysis and subsequent OH radical production during UV treatment of chlorinated water[END_REF][START_REF] Deborde | Reactions of chlorine with inorganic and organic compounds during water treatment-Kinetics and mechanisms: A critical review[END_REF].

Effect of HCO

3 - /CO 3 2-
The effect of carbonates (HCO 3 -/CO 3 2-pka = 10.33) is investigated for UVA/B activation of H 2 O 2 and S 2 O 8 2-at pH 8.0 and pH 9.0 using buffer solutions (see Figure SM9). The presence of 5 mM of carbonates at pH 8.0 in UV-H 2 O 2 system inhibits about 50 % of the BPA degradation (the pseudo first order decay decreases from 5.3 × 10 -5 s -1 to 2.6 × 10 -5 s -1 ) while the effect on the UV-S 2 O 8

2-

system is estimate to be around 18 % (the pseudo first order decay decreases from 1.9 × 10 -4 s -1 to 1.5 × 10 -4 s -1 ).

The scavenging effect of carbonates on photo-activation of hydrogen peroxide and persulfate can be predicted considering the reactivity of hydroxyl and sulfate radicals toward ) [START_REF] Huie | Electron transfer reaction rates and equilibria of the carbonate and sulfate radical anions[END_REF][START_REF] Buxton | Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (OH/O-) in aqueous solution[END_REF] and BPA determined by laser flash photolysis experiments (see Table 2). In Figure 5 ) as a function of carbonates concentration and pH. It is interesting to observe that, while for sulfate radical the inhibition is not affected by the pH of the solution, for hydroxyl radical a negative effect is correlated to the pH increase. In fact, after pH ~8.2

14
we expect the presence of CO 3 2-species, which have higher reactivity toward hydroxyl radical (at pH 9.5 ~13 % of CO 3 2-and 87% of HCO 3 -are present in solution).

However, generated carbonate radicals are expected to react with BPA partially counterbalancing the sink of hydroxyl and sulfate radicals. Interestingly, degradation profiles of BPA at pH 9.0 comparted to the pH 8.0 (see Figure SM9) show a less pronounced negative effect of carbonates on the inhibition of BPA degradation. Such effect can be explained considering the reactivity between CO 3

•-and phenol/phenolate groups. Moore and co-workers reported that reactivity of CO 3

•-with phenolate is about 6 times higher than the value measured for phenol ( ) [START_REF] Moore | Reaction of the carbonate radical anion with substituted phenols[END_REF]. We can reasonably expect a similar trend for BPA where increasing formation of carbonate radical at higher pH can enhance degradation of target pollutant in water.

Transformation products identification

Different experiments are conducted using BPA concentration of 43.8 µM in the presence of i) hydrogen peroxide (2 mM), ii) hydrogen peroxide (2 mM) + chloride ions (100 mM), iii) persulfate (2 mM) and iv) persulfate (2 mM) + chloride ions (100 mM). Table SM2 summarizes the chemical structures of transformation products identified using HPLC-MS (negative mode) and GC-MS on the basis of molecular peak, fragmentation and literature data.

Interestingly, hydroxylated BPA products are mainly found by HPLC-MS indicating that first reaction step of sulfate and hydroxyl radicals is the hydrogen abstraction on the aromatic ring and consequent water addition. Sharma et al. investigated the intermediates of BPA degradation using UVC-peroxymonosulfate system and considered that hydrogen abstraction is not the only process occurring, but one of the most important initial steps of BPA degradation [START_REF] Sharma | Oxidative removal of Bisphenol A by UV-C/peroxymonosulfate (PMS): Kinetics, influence of co-existing chemicals and degradation pathway[END_REF]. The authors concluded that BPA is oxidized by SO in the presence of sulfate radical anions suggesting the formation of dimeric molecules produced via radical-radical recombination.

BPA degradation in STPW

To test the feasibility and performances of UVA/B activation of hydrogen peroxide and persulfate in simulated treatment systems, STPW are spiked with 4.3 µM and 430 nM of BPA (1 and 0.1 mg L -1 16 respectively) before irradiation in the presence of 2 mM of radical precursors. Due to the complexity of the STPW matrix, the inhibition effect of naturally constituents is investigated through several experiments. First, the degradation of BPA is carried out in STPW previously acidified using HClO 4 to pH < 3 in order to remove inorganic carbon (i.e. carbonate ions), and then basified back to pH around 8 (indicated above as STPW*). The purpose of this experiment is to discriminate the effect of organic and inorganic carbon on the degradation efficiency of considered system. These experiments show that the degradation of BPA in STPW and STPW* is almost the same; only a slight BPA inhibition (less than 5%) is observed in the presence of persulfate indicating a negligible effect of inorganic carbon (i.e. carbonates) on the degradation treatment efficiency (Fig. 6). Since the concentration of inorganic carbon is 4.16 mM in our STPW, it could be concluded that in this concentration level the degradation of organic compound is almost not affected by inorganic carbon. This trend can be also investigated considering the reactivity constant determined between hydroxyl and sulfate radicals and STPW normalizing the value to the carbon concentration (organic and inorganic). In Table 2 it is interesting to observe that reactivity constants using not modified STPW are about two times for hydroxyl radical and three times for sulfate radical lower than those determined after inorganic carbon removal (i.e. STPW*).

Considering the second order rate constant between hydroxyl radical and sulfate radical anion with STPW matrix, HCO 3 -(the main species present at pH 8.0) and BPA reported in this study (see Table 2), it is possible to investigate the formation pathways of photogenerated radicals in solution. For this purpose we considered that hydroxyl radicals (or sulfate radicals) can react with STPW constituents or BPA in solution.

In the system UVA/B-H 2 O 2 , we can argue that about 98.4 % of hydroxyl radicals react with constituents of STPW (16.6 % of which accounted for by carbonates) while 1.6 % directly with BPA (Table 3). In the system UVA/B-S 2 O 8 2-about 99.8 % of the sulfate radical reactivity is attributed to the STPW constituents, while only 0.2% is accounted by for BPA (Table 3). However, the BPA degradation results to be faster in the system UVA/B-S 2 O 8 2-(Fig. 6).

The high efficiency degradation using UVA/B-S 2 O 8 2-system could be explained considering that about 72 % of sulfate radicals react with chloride ions leading to the formation of chlorine radical which is a secondary source of hydroxyl radical and other chlorine reactive species in alkaline media. In order to assess the occurring reactive involvement using UVA/B-S 2 O 8 ) [START_REF] Buxton | Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (OH/O-) in aqueous solution[END_REF][START_REF] Clifton | Rate constants for hydrogen abstraction reactions of the sulfate radical, SO4-. lcohols[END_REF]. In the presence of 50 mM of t-But the degradation rate is inhibited of ~ 50 %, while, using 2-Pr, only 5% of BPA degradation is observed (Fig. 7). This result confirms that a significant fraction of sulfate radicals are converted into hydroxyl radical in STPW through a complex mechanism. In fact, chlorine radical can be converted into ClOH

BPA

(8.6±1.0)×10 9 M -1 s -1 (4.7±1.1)×10 9 M -1 s -1 (8.3±0.8)×10 7 M -1 s -1 (9.2±1.0)×10 7 M -1 s -1

STPW

(2.9±0.4)×10 3 L mgC -1 s -1 (1.3±0.2)×10 4 L mgC -1 s -1 STPW* (6.1±1.1)×10 3 L mgC -1 s -1 (4.1±0.3)×10 4 L mgC -1 s -1

HCO 3 -

 3

3 -

 3 the inhibition of the reactivity toward BPA due to the presence of HCO the ratio between the pseudo-first order decays of considered radicals with carbonates and BPA (

Figure 2

 2 Figure 2 Degradation profile of BPA ([BPA]/[BPA] 0 ) at pH 4.6 (full symbols) and 8.0 (empty

Figure 3

 3 Figure 3 BPA degradation efficiency (DE) using different chloride ions concentrations at pH 8.0

Figure 4 :

 4 Figure 4: Modeled radical concentration in the system UVA/B-S 2 O 8 2-(2 mM) in the presence of

Figure 5 :

 5 Figure 5: Inhibition effect of carbonates as a function of initial concentration and pH of solution

Figure 6 :

 6 Figure 6: BPA 430 nM (0.1 mg L -1 ) degradation in STPW using UVA/B-H 2 O 2 (2 mM) and

Figure 7 :

 7 Figure 7: 4.3 µM BPA degradation in STPW using S 2 O 8 2-(2 mM) under UVA/B irradiation in the

Figure 1 29 29

 129 Figure 1

Figure 2 30 30

 230 Figure 2

Figure 3 31 31 Figure 4 32 32

 331432 Figure 3

Figure 5 33 33

 533 Figure 5

Figure 6 34 34

 634 Figure 6

Figure 7

 7 Figure 7

  2

  [START_REF] Xie | Removal of 2-MIB and geosmin using UV/persulfate: Contributions of hydroxyl and sulfate radicals[END_REF]

  •- specie in the presence of chloride ions (R1 and see reaction M13 in table SM1 for reactivity constant value) leading to the formation of Cl • only in acidic media (R2).

	ClOH		+    H Cl H O 2   	(R2)
	On the other hand, at pH 8.0 only a negligible amount of hydroxyl radical are expected to be finally
	converted into Cl •	compared to pH 4.6.
	HO Cl  	-	   	ClOH		(R1)
							11

Table 1 :

 1 pH, main anions concentrations and TOC determined for STPW used in this work.

	•-(R3 and R4)

Table 2 :

 2 Second order rate constant determined for BPA and STPW before and after carbonates removal. STPW indicated Sewage Treatment Plan water without chemical modification while STPW* is STPW after removal of carbonates (see materials and methods). Second order rate constants are normalized for the number of all carbons (organic and inorganic). Errors are estimated to ± 3σ, which was obtained from the scattering of the experimental data from the fitting line

	HO k 	4 SO k 	2 Cl k 	CO 3 k 

Table 3 .

 3 Percentage of photogenerated radicals reactivity in STPW and STPW*, on hydrogenocarbonates and on BPA estimated considering the pseudo-first order decay determined as products of the second order rate constant (obtained in this work or from literature) and initial concentrations. BPA degradation in the presence of H 2 O 2 (2 mM) and S 2 O 8 2-(2 mM) in buffered and unbuffered solutions at pH 8.0 under UVA/B radiation.

				HO •		SO 4 •
	STPW			98.4 %		99.8 %
	STPW*	HCO 3	-	81.5%	16.6 %	98.9 %	~1 %
	BPA			1.6 %		0.2 %

presence of 50 mM of 2-propanol (2-Pr) and 50 mM of tert-Butanol (t-But).

Acknowledgements

This work was partially supported by Natural Science Foundation of China (No. 21367003) and Guangxi Natural Science Foundation (No. 2014GXNSFBA118217). We also gratefully acknowledge the Haina Project of Guangxi University for providing financial support for W.H. to stay at the Clermont Auvergne University in Clermont-Ferrand, France. Authors acknowledge financial support from the Region Council of Auvergne, from the "Féderation des Recherches en Environnement" through the CPER "Environment" founded by the Region Auvergne, the French government, FEDER from the European Community and PRC program CNRS/NSFC n°270437. 20


Cédric Galera
email: cedric.galera@u-bordeaux.fr

Susana Barbosa

Ophélie Collet

Olfa Khalfallah

Bruno Aouizerate

Anne-Laure Sutter-Dalley

Muriel Koehl

Lucile Capuron

Judith Van Der Waerden

Maria Melchior

Sylvana Côté

Barbara Heude

Nicolas Glaichenhaus

Laetitia Davidovic

Cédric Galéra

Cord Serum Cytokines at Birth and Children's Anxiety-Depression Trajectories From 3 to 8 Years: The EDEN Mother-Child Cohort

Keywords: Cord cytokines, birth cohort, Anxiety/depression, epidemiology, immunology, biostatistics

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

The fetal origin of neurological and mental illness has long been known through the severe impact of in utero exposure to infectious teratogenic agents on the developing fetal brain (e.g. Toxoplasma, Rubella, Cytomegalovirus, Herpes, Influenza) [START_REF] Guma | The role of maternal immune activation in altering the J o u r n a l P r e -p r o o f neurodevelopmental trajectories of offspring: A translational review of neuroimaging studies with implications for autism spectrum disorder and schizophrenia[END_REF][START_REF] Nazzari | The programming role of maternal antenatal inflammation on infants' early neurodevelopment: A review of human studies: Special Section on « Translational and Neuroscience Studies in Affective Disorders » Section Editor[END_REF]. The risk these infections carry for direct fetal cerebral damage, leading to cognitive, socio-emotional, motor and sensory deficits, makes them the cornerstone of the primary obstetric focus on infection prevention. Recently, less severe common infections and immune system dysfunctions during gestation have also been shown to have an adverse impact on fetal brain development in the long term, indirectly through immune activation and irrespective of etiology [START_REF] Al-Haddad | The fetal origins of mental illness[END_REF].

A compelling body of animal and human research connects infectious and non-infectious inflammation processes in pregnancy (e.g.maternal history of autoimmune disorder, atopia, obesity, psychosocial stress, depression) to a range of adverse neuropsychiatric outcomes across offspring's life course [START_REF] Estes | Maternal immune activation: Implications for neuropsychiatric disorders[END_REF][START_REF] Gumusoglu | Maternal Inflammation and Neurodevelopmental Programming: A Review of Preclinical Outcomes and Implications for Translational Psychiatry[END_REF]. In humans, beyond schizophrenia and autism spectrum disorders, exposure to maternal infection in pregnancy has been linked to the excess risk of the most common psychiatric conditions, namely depression and anxiety [START_REF] Al-Haddad | Longterm Risk of Neuropsychiatric Disease After Exposure to Infection In Utero[END_REF][START_REF] Brown | Prenatal Infection and Schizophrenia: A Review of Epidemiologic and Translational Studies[END_REF][START_REF] Lee | Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders[END_REF][START_REF] Lydholm | Parental Infections Before, During, and After Pregnancy as Risk Factors for Mental Disorders in Childhood and Adolescence: A Nationwide Danish Study[END_REF]. The strongest evidence regarding the contribution of in utero immune function to later risk of anxiety/depression-like symptoms comes from preclinical research. Animal models (i.e.rodents and primates) showed that patterns of immune activation/dysfunction in pregnancy, irrespective of their timing, predict offspring behavioral and cerebral anomalies compatible with anxiety/depression [START_REF] Depino | Perinatal inflammation and adult psychopathology: From preclinical models to humans[END_REF][START_REF] Knuesel | Maternal immune activation and abnormal brain development across CNS disorders[END_REF][START_REF] Kreitz | Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring[END_REF][START_REF] Ronovsky | Animal Models of Maternal Immune Activation in Depression Research[END_REF][START_REF] Ronovsky | Maternal immune activation transgenerationally modulates maternal care and offspring depression-like J o u r n a l P r e -p r o o f behavior[END_REF]. These latter anomalies are varied, encompassing neuroinflammation with activation of microglia and astrocytes, oligodendrocyte dysfunction, neuronal loss, dysgenesis of serotonergic neurons, and dysregulation of the hypothalamic-pituitary-adrenal-axis [START_REF] Al-Haddad | The fetal origins of mental illness[END_REF][START_REF] Goeden | Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain[END_REF][START_REF] Majidi | Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety-and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice[END_REF]. Interestingly, the role of the placental-fetal immune response may be key. In normal gestation, the placental-fetal unit is physiologically under the influence of the immune system and any disruption may have pathological consequences [START_REF] Ander | Immune responses at the maternal-fetal interface[END_REF]. In addition, immune dysregulation in pregnancy modulates placental serotonin secretion, which in turn modifies serotonin concentrations in the fetal brain [START_REF] Al-Haddad | The fetal origins of mental illness[END_REF][START_REF] Estes | Maternal immune activation: Implications for neuropsychiatric disorders[END_REF][START_REF] Goeden | Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain[END_REF]. Placental-fetal blood (as assessed in the umbilical cord) hence represents a relevant biological material to investigate immune biomarkers at birth. Among these biomarkers, cytokines may be crucial because their balance regulates not only the immune system but also plays a critical role with regard to brain function, neurodevelopment, neurogenesis and neurotransmission, with cytokine receptors being expressed in microglia, astrocytes and neurons [START_REF] Morimoto | Role of the Immune System in the Development of the Central Nervous System[END_REF]. In particular, Interferon (IFN)-γ, IL-1β, IL-6, IL-8, IL-10, IL-17A, and Tumor Necrosis Factor (TNF)-α are thought to play a role in the association between immunity and mental/physical health. According to the neuroimmune network hypothesis [START_REF] Nusslock | Early-Life Adversity and Physical and Emotional Health Across the Lifespan: A Neuroimmune Network Hypothesis[END_REF], early-life J o u r n a l P r e -p r o o f adversities could be bidirectionally related to later behavior, brain structures and functions through immune dysregulation processes.

Current knowledge regarding the interaction between cytokines at birth and behavior later in life is limited. First, while there is lack of human data, extrapolations from animal models to humans regarding mental health can be speculative. Second, epidemiological data have hardly considered the relationship between perinatal immune biomarkers as assessed in the cord serum and anxiety/depression in offspring, despite its pathophysiological pertinence. Third, by focusing on individual cytokines, studies have disregarded cytokine networks, thereby overlooking potentially important information regarding their interrelationships. Fourth, no study has explored the emergence of anxiety/depression symptoms and their trajectory in childhood in relation to in utero immune function, yet emotional disturbances may begin early on, especially in the event of antenatal exposures. Overcoming these shortcomings is critical to understanding the mechanisms associating perinatal immunity and subsequent anxiety/depression in offspring.

Using longitudinal data from a birth cohort study, we aimed: (1) to describe the network of cord serum cytokines and its links with the trajectories of anxiety/depression symptoms in offspring from age 3 to 8 years; (2) to test whether cord serum cytokines are associated with subsequent trajectories of anxiety/depression symptoms in offspring.

METHODS

Study design and participants

The study sample is nested within the EDEN cohort which is a mother-child cohort study investigating pre-/postnatal determinants of child development and health [START_REF] Heude | Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development[END_REF]. Pregnant women (N=2002) were recruited before 24 weeks of amenorrhea in the maternity clinics of Nancy and Poitiers (France, 2003(France, -2005)). We then included 1907 newborns. Exclusion criteria were multiple pregnancy, pre-pregnancy diabetes, illiteracy, and planning to move outside the region within three years. At birth, cord serum samples were collected for 1427 mother-child pairs. Data collection was conducted in multiple waves (pregnancy, at the child's birth, 4/8/12/24 months, 1/2/3/5/8 years).

Participating mother-child pairs at ages 1, 2, 3, 5 and 8 years of the child were respectively 1717, 1611, 1527, 1255 and 883. Data were collected from medical records (pregnancy, birth) by trained interviewers (pregnancy, birth, 1/2/3/5/8 years) and by mothers' and fathers' self-reports (all waves). Informed written consent from the parents was obtained at enrollment. The EDEN cohort was approved by the Bicêtre Hospital ethics committee and the Commission Nationale Informatique et Libertés. The initial EDEN sample was similar to a nationally representative French sample of pregnant women, except for its higher educational attainment [START_REF] Heude | Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development[END_REF][START_REF] Blondel | Trends in perinatal health in metropolitan France between 1995 and 2003: results from the National Perinatal Surveys[END_REF]. The current study sample J o u r n a l P r e -p r o o f comprised the subset of 871 participants for whom both cord blood serum and anxiety/depression trajectories were available. This subset differed from the initial sample in comprising fewer families in which the mother had a low educational level and low income, was younger, did not live with the child's father, smoked during pregnancy, had more depressive symptoms in pregnancy, and whose child had a lower birth weight. However, the significant effect sizes were small to very small (Table S1).

Measures Outcome variable: children's anxiety/depression trajectories from 3 to 8 years

Children's symptoms of anxiety/depression were assessed through the Strengths and Difficulties Questionnaire (SDQ) completed by mothers when children were aged 3, 5 and 8 years [START_REF] Goodman | The Strengths and Difficulties Questionnaire: a research note[END_REF]. This validated tool includes an emotional symptoms subscale comprising the following five items: "often unhappy, depressed or tearful", "nervous or clingy in new situations, easily loses confidence", "many fears, easily scared", "often complains of headaches, stomach-aches or sickness", "many worries or often seems worried". All items refer to the past six months or the current school year and are scored 0 (never), 1 (sometimes true) or 2 (certainly true). At each time-point, a quantitative score (range 0-10) was obtained by summing the items. We conducted latent class mixed-effect models for nonlinear outcomes to model anxiety/depression symptoms trajectories at 3, 5 and 8 years. Changes in anxiety/depression symptoms scores were modeled using quadratic splines with five internal knots (at quantiles of time). The statistical model included an intercept that represented the anxiety/depression symptoms score at baseline, the quadratic mean trajectory for the latent process and correlated random intercept and slope to account for intra-individual variability (the random quadratic slope was removed as the model did not converge). The SDQ data were available as follows: N=797 at 3 years, N=871 at 5 years, N=869 at 8 years. We identified five groups of symptoms (Figure S1). For further analyses, symptoms of anxiety/depression were dichotomized (high symptoms vs other groups, n=135 (15.50%) and 736 (84.50%), respectively). The other groups were merged because they likely corresponded to clinically non-problematic groups. 24)), diagnosed gestational diabetes (yes/no), maternal urinary/cervical/vaginal infection during pregnancy (yes/no), and maternal diet during pregnancy: healthy pattern (i.e. high in nutrient-dense food, lowest quartile vs. others) and western pattern (i.e. high in fats and sugar, highest quartile vs. others) [START_REF] Yuan | Early factors related to carbohydrate and fat intake at 8 and 12 months: results from the EDEN mother-child cohort[END_REF]. Children's characteristics at birth included sex (male/female), birth weight (kg), gestational age (weeks of amenorrhea), delivery mode (vaginal, forceps/ventosa, C-section), and birth trimester.

Data Analyses

Network of cord serum cytokines and anxiety/depression in offspring

Skewed distributions of standardized cytokines were normalized using the nonparanormal transformation [START_REF] Zhao | The huge Package for High-dimensional Undirected Graph Estimation in R[END_REF]. Based on partial correlations, we estimated the Mixed Graphical Models (MGMs) [START_REF] Haslbeck | How well do network models predict observations? On the importance of predictability in network models[END_REF] (mgm:Estimating time-varying mixed graphical models in high-dimensional data. arXiv preprint http://arxiv.org/abs/1510.06871v2) for the cytokines and trajectories of anxiety/depression symptoms (R software package, mgm). We used LASSO regularization regression to identify the most relevant edges among the large number of pairwise associations. The penalty parameter of the LASSO was selected using the Extended Bayesian Information Criterion (EBIC) for which the tuning parameter gamma was set to 0. We then used the Fruchterman-

J o u r n a l P r e -p r o o f

Reingold algorithm to determine the layout of the graph by positioning the strongly connected nodes on the center of the network and weakly connected nodes on the periphery (R package, qgraph). This provided a node distribution layout where edges represent conditional dependences relations between nodes (controlling for the effects of all network variables). Accuracy and stability were assessed by 100 non-parametric bootstraps of the edge weights [START_REF] Efron | Bayesian inference and the parametric bootstrap[END_REF] and displaying the proportion of non-zero estimates (R package, bootnet). We used the node strength centrality index to assess the strength of internode connections.

Longitudinal associations between cord serum cytokines and anxiety/depression in offspring

First, covariates with missing data were imputed based on exposure (cytokines), outcome, and all other covariates to generate 40 datasets using the Fully Conditional Specification method (mice R packages). Second, a non-parametric bootstrap with replacement was conducted, involving 100 resamplings with the full sample size for each of the 40 multiple imputed datasets. Third, we used an Elastic Net regularized logistic regression model to conduct a variable selection procedure enabling the most relevant predictors for the final multivariate model to be determined. This procedure makes it possible to account for multicollinearity between variables, and deals well with low events per variable in the minority class and reduces over-fitting. In the Elastic Net procedure, we randomly partitioned the data into a training sample (75%) and a holdout sample (25%). In the training sample, we chose the optimal tuning hyperparameters (alpha and lambda) for the Elastic Net regression via 10-fold cross-validation, to maximize the Area Under the Receiving Operator Curve (Caret and Glmnet R packages) [START_REF] Pavlou | Review and evaluation of penalised regression methods for risk prediction in low-dimensional data with few events[END_REF]. The holdout sample was used to test the predictive performance of the model by estimating the AUROC. As the Elastic Net is not a deterministic method, the optimization step was repeated three times, leading to 12,000 models. To select the subset of variables associated with the outcome, we computed the Variable Inclusion Probability (VIP, i.e.percentage of runs in which the associated coefficient was different from zero) out of the 12,000 models. The VIP can be interpreted as the posterior probability of including a variable in the model. We set a stringent VIP threshold at 80% to select variables stably associated with trajectories of anxiety/depression symptoms. Fourth, we tested associations between cytokines and anxiety/depression trajectories (high trajectory vs. others) adjusting only for covariates selected by the Elastic Net (multivariable logistic analyses), therefore limiting over-adjustment. To account for multiple testing, we applied a Bonferroni correction. We tested pairwise interactions between all the variables kept in the model, notably the interactions between maternal depressive symptoms and the cytokines retained in the final model after the variable selection procedure. Finally, we conducted a sensitivity analysis to test the robustness of our findings by adjusting additionally on sex and on J o u r n a l P r e -p r o o f conditions known to involve low-grade chronic inflammation or to influence cytokine profiles (prenatal BMI, gestational diabetes, nutrition profiles, infections, alcohol/tobacco consumption, social factors, delivery mode) in order to limit the risk of residual confusion. Here again we tested pairwise interactions between all the variables kept in the model and the cytokines, looking for moderating effects of the third variables on the cytokines.

Role of the funding source

The EDEN study sponsors were not involved in the study design, data collection or data analyses.

RESULTS

Descriptives

The study sample included 871 children (462 (53%) males, 409 (47%) females). Table 1 shows sample characteristics by childhood anxiety/depression trajectory. Table 2 displays the standardized cytokine levels by childhood anxiety/depression trajectory. Figure S2 shows the correlations between all cytokine pairs.

Network of cord serum cytokines and anxiety/depression in offspring

The network of the 19 cord serum cytokines and anxiety/depression trajectories is displayed in

Longitudinal multivariate associations between cord serum cytokines and anxiety/depression in offspring

Given the large number of covariates potentially impacting cytokine levels or anxiety/depression trajectories, we first used an Elastic net penalized regression to eliminate covariates with a J o u r n a l P r e -p r o o f negligible impact on anxiety/depression predictions. The predictive performance of the model by estimating the AUROC was 0.70. Multiparity, birth trimester, maternal depressive symptoms, IL-7 and IL-10 were selected as main predictors of anxiety/depression trajectories (Table S3). Table 3 shows adjusted associations between selected cord serum cytokines and childhood anxiety/depression trajectories adjusting for the above selected variables. IL-7, second birth trimester and multiparity were negatively associated with the outcome (respectively adjusted odds ratio (aOR)=0.73, 95%CI=(0.57, 0.93); aOR=0.53, 95%CI = (0.29, 0.98), aOR=0.50, 95%CI=(0.32, 0.77)). Prenatal maternal depressive symptoms were significantly associated with childhood anxiety/depression trajectories (aOR=1.06, 95%CI = (1.03, 1.09). There was no statistically significant interaction between variables included in the model, notably the interaction terms maternal depressive symptoms * IL-7 (p=0.88) and maternal depressive symptoms * IL-10 (p=0.39), which suggests that maternal depression does not play any moderating role. The sensitivity analysis additionally adjusting for sex, prenatal BMI, gestational diabetes, nutrition profiles, infections, alcohol/tobacco consumptions, social factors, and delivery mode showed the same pattern of results (Table S4). None of the interaction terms tested in the sensitivity analysis was significant (all p non-significant), which suggests that prenatal and social variables do not play any moderating role.

DISCUSSION

Principal findings of the study

To our knowledge, this birth cohort study is the first to test whether cord serum cytokines are associated with the emergence of anxiety/depression symptoms in early childhood. We found that no birth cytokine other than IL-7 was directly related to anxiety/depression. Only higher IL-7 levels in the cord serum at birth were associated with a lower likelihood of symptoms of anxiety/depression between ages of 3 and 8 years in offspring, and vice-versa. This relationship was not confounded or moderated by a wide range of other factors (including prenatal BMI, gestational diabetes, nutrition profiles, infections, alcohol/tobacco consumption, social factors, and delivery mode), as shown by the multivariate models. The association between IL-7 and anxiety/depression was consistent while accounting for 18 other cytokines, as revealed by the network analysis.

Interestingly, IL-7 was related to four of the seven most influential cytokines in the network (i.e. CXCL10, IL-1β, IL-8, and IL-17A). Although caution is needed and no firm conclusion can be drawn from our findings, it might be that the influence of IL-7 on anxiety/depression is due to complex interactions with other cytokines of the network, since cytokines act in multiple and J o u r n a l P r e -p r o o f 10 interactive cascades. Our findings are new since a) previous knowledge regarding relations between cytokines and behavior was mostly based on studies tapping a limited range of cytokines, and b) human studies to date measured cytokines in maternal serum, which poorly reflects the placentalfetal immune compartment. Notably, IL-7 has previously been cross-sectionally associated with depression in adolescent/adult/geriatric populations, although the direction of this link remains controversial [START_REF] Becerril-Villanueva | Alterations in the Levels of Growth Factors in Adolescents with Major Depressive Disorder: A Longitudinal Study during the Treatment with Fluoxetine[END_REF][START_REF] Dahl | The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery[END_REF][START_REF] Hall | IL-7 and Depression: The importance of gender and blood fraction[END_REF][START_REF] Lehto | Serum IL-7 and G-CSF in major depressive disorder[END_REF]. Moreover, we have previously shown in the EDEN cohort that IL-7 measured in serum at age 5 was positively associated cross-sectionally with anxiety/depression symptoms at 5 years [START_REF] Barbosa | Serum cytokines associated with behavior: a cross-sectional study in 5-year-old children[END_REF]. This reverse pattern of association between IL-7 and anxiety/depression symptoms measured at different waves (i.e. birth and age 5 years) suggests the role of IL-7 in susceptibility to anxiety/depression and calls for this research path to be extended. Variations in IL-7 levels could correspond to different functional patterns of immunity depending on the timing due to the environmental milieu in the brain and/or the periphery, but also to life experience, which could shape the brain and psychosocial factors that impact development in children.

Interpretation

The finding that IL-7 was the only cytokine significantly and directly associated with children's anxiety/depression was somewhat unexpected. Particularly, the absence of a significant link between IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-17A, TNF-α and anxiety/depression was surprising, given the rich literature on their potential role in prenatal immune activation and/or in the pathophysiology of depression. It is challenging to interpret these negative findings since this study is unique in its design and methodology. Indeed, most prior research relied on animal models when exploring prenatal immune activation or considered cytokines in serum/blood samples and not in cord blood in human data, which make comparisons tricky. However, the fact that IL-7 was itself related to IL-1β, IL-8 and IL-17A in the network is noteworthy and might suggest indirect effects through complex interactions. This interpretation remains speculative and requires further research.

Considering IL-7 specifically, it is an essential cytokine for the homeostasis of the immune system, particularly for B and T cell development and maturation, such as CD4 + /CD8 + /Th17 lymphocytes [START_REF] Dahl | The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery[END_REF][START_REF] Barata | Flip the coin: IL-7 and IL-7R in health and disease[END_REF][START_REF] Park | IL7 receptor signaling in T cells: A mathematical modeling perspective[END_REF]. Importantly, the pathophysiology of depression and anxiety have been related to impaired T cell function, notably Th17 [START_REF] Beurel | Th17 cells in depression[END_REF][START_REF] Fan | Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior[END_REF][START_REF] Grosse | Deficiencies of the T and natural killer cell system in major depressive disorder: T regulatory cell defects are associated with inflammatory monocyte activation[END_REF][START_REF] Kowalczyk | An immune gate of depression -Early neuroimmune development in the formation of the underlying depressive disorder[END_REF]. Hence, reduced circulating levels of IL-7 at birth may contribute to T cell defects acquired during early immune programming at birth, thereby triggering the susceptibility towards anxiety/depression, with lasting effects beyond the perinatal window of early brain development. IL-7 and its receptors are expressed early in the developing brain [START_REF] Michaelson | Interleukin-7 is trophic for embryonic neurons and is expressed in developing brain[END_REF], suggesting that it could play a role in neural system development and function from the early stages onwards, with J o u r n a l P r e -p r o o f sustainable influences after initial programming of brain regions that govern emotional, cognitive and self-reflective functions. Indeed, the unbalanced prefrontal cortical inhibition of the limbic brain regions (amygdala, insula, hippocampus and anterior cingulate cortex) observed in patients with anxiety/depression could result from early neurodevelopmental defects [START_REF] Marwood | Meta-analyses of the neural mechanisms and predictors of response to psychotherapy in depression and anxiety[END_REF]. Several mechanisms could underlie the link between IL-7 and neurodevelopment. First, IL-7 is expressed in embryonic hippocampal progenitor cells in rodents and induces a shift of differentiation toward the glial lineage of human embryonic neural progenitors [START_REF] Michaelson | Interleukin-7 is trophic for embryonic neurons and is expressed in developing brain[END_REF][START_REF] Moors | Interleukin-7 (IL-7) and IL-7 splice variants affect differentiation of human neural progenitor cells[END_REF]. This possibly involves the significant early contribution of IL-7 to formation of the neurocircuitry possibly involved in vulnerability to anxiety/depression. Second, IL-7 likely prevents neuroinflammation in response to non-specific stimuli [START_REF] Smolders | Characteristics of differentiated CD8(+) and CD4 (+) T cells present in the human brain[END_REF]. Although speculative, increased IL-7 could confer lasting protection against neuroinflammation during neurodevelopment. Alternatively, and finally, the association we found could be non-causal and merely correlative, due to other unmeasured confounders.

Strengths and weaknesses

The strengths of the present study include the novelty of the finding that lower IL-7 at birth is associated with a higher risk of anxiety/depression symptoms later. It also has methodological strengths: the measurement of cord serum cytokine biomarkers in a large population-based sample, the use of a widely validated instrument to assess anxiety/depression symptoms longitudinally, the use of state-of-the-art modeling strategies (mixed-effect modeling approach for anxiety/depression trajectories, network analysis, Elastic Net) and the robustness of the results in sensitivity analyses.

However, the findings should be considered and interpreted in light of the study's limitations. First, the selection of a more socially advantaged sample and the self-reported nature of some covariates as well as symptoms of anxiety/depression possibly introduced a selection bias and measurement errors. This may have led to conservative findings by lowering the strength of the associations between IL-7 and anxiety/depression. Second, it is important to note that the measure of anxiety and depression using the SDQ in early childhood may not be the most sensitive, although it is certainly appropriate for children over 6. This could lead to underestimating associations between risk factors and internalizing problems. Third, measurement error regarding cytokines is possible. Cord blood is susceptible to clot easily, which can interfere with downstream assay quality. In addition, cytokine levels can spike during labor/delivery, which was not adjusted for in the analyses. A potential measurement error could attenuate the associations between cytokines and anxiety/depression and thus contribute to their non-significance. Fourth, we did not explore central cytokines directly. It is hence not clear how levels of cord serum cytokines reflect the actual levels in the neonatal brain. To our knowledge, whether IL-7 crosses the blood-brain barrier remains unknown, even though J o u r n a l P r e -p r o o f peripheral immune patterns very likely influence central immune patterns [START_REF] Knuesel | Maternal immune activation and abnormal brain development across CNS disorders[END_REF]. Fifth, the period reflected by the cord serum measurement is uncertain. Assessment at birth could reflect either longor very short-term cytokine patterns. Here again this could lead to underestimated associations and limit the extrapolation of these findings in terms of a developmental window. Sixth, we lacked detailed information on other factors such as maternal medications or physiological stress at birth and could not include these variables in the models. Finally, other residual confounders (e.g. unmeasured genetic/epigenetic/environmental factors) may also hamper the study's interpretation.

Unanswered questions and future research

Importantly, practical implications of the findings lie ahead. The association between IL-7 cord serum levels and anxiety/depression symptoms in offspring appears robust. However, it cannot be used as yet for predictive purposes in clinical or public health practice. Rather, these preliminary findings pave the way for conducting further etiological studies in humans and potentially experimenting new treatments in the field of preventive psychiatry, firstly in animals. The modulation of IL-7 and its downstream IL-7R signaling pathway could represent a new therapeutic target to prevent anxiety/depression symptoms before their emergence. Both molecules targeting the IL-7/IL-7R signaling pathway and larger immuno-modulating drugs could be experimented. IL-7based molecules (e.g.recombinant Human IL-7, Cytheris cyt107) exist and have been tested in fields such as HIV+ infection and cancer. From a mechanistic perspective, it is relevant to understand whether and how the characteristics of immune dysregulation (such as timing, intensity, patterns of immune response, accumulation of inflammation challenges) relate differentially to the emergence of anxiety/depressive symptoms. It is also important to consider the notion of vulnerability to immune dysregulation. In other terms, whether certain factors (e.g.genetic/epigenetic background, microbiome and other environmental factors) confer a particular liability towards anxiety/depression as result of immune dysregulation remains to be confirmed. In addition, it would be appropriate in the future to use detailed information on physiological stress related to birth to test whether the change in the levels of IL-7 could reflect an altered response specifically related to birth stress, or a more long-lasting pattern of altered levels of IL-7. Finally, how early life and chronic stresses (e.g.low socioeconomic status, maltreatment) magnify the crosstalk between central/peripheral inflammation and the neural system deserves further research in the future [START_REF] Nusslock | Early-Life Adversity and Physical and Emotional Health Across the Lifespan: A Neuroimmune Network Hypothesis[END_REF].

Overall, we found evidence that IL-7 in the cord serum is associated with the risk of anxiety/depression symptoms in offspring at ages 3 to 8 years. Despite the modest magnitude of the association, the results point to the role of the immune system as a pathway in the fetal origins of J o u r n a l P r e -p r o o f mental disorders, at least for a subpart of the anxiety/depression spectrum. Ultimately, the quest for early primary prevention of anxiety/depression linked to immune dysregulation, although still far off in humans, is now clearly on the agenda of animal research.

  Main exposure: cord serum cytokines Cord serum concentrations of cytokines were determined for the 871 individuals of the study sample. Concentrations of Chemokine (C-C motif) ligand (CCL) 2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL26, C-X-C motif chemokine 10 (CXCL10), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interferon (IFN)-γ, Interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, J o u r n a l P r e -p r o o f IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, Tumor Necrosis Factor (TNF)α, and TNF-β were initially measured. More details are available in eSupplement 1. Covariates Parental characteristics at baseline included maternal and paternal education (less than 12 years, between 12 and 14 years, and more than 14 years), maternal age at inclusion (years), maternal prepregnancy body mass index (BMI) (low -less than 19kg/m²-, normal -between 19 and 25kg/m 2 -, and high -more than 25kg/m 2 ), parental separation during pregnancy (biological father not living with the mother and child (yes/no)), and family income at birth (mean of the eight class numbers, (1):<450€/month, (2):450-800€/month, (3):800-1500€/month, (4):1500-2300€/month, (5):2300-3000€/month, (6):3000-3800€/month, (7):3800-4500€/month, (8):>4500€/month). Pregnancy characteristics included maternal alcohol intake (>2 glasses per week/0-2 glasses per week), maternal daily smoking throughout pregnancy (mean number of cigarettes), maternal daily caffeine intake (0 / 0-100mg / 100-200mg / 200mg+), multiparity (firstborn/other), maternal depression (depressive symptoms measured with the Center for Epidemiologic Studies Depression Scale Revised, CES-D (mean score)(

Figure 1 .

 1 Figure 1. Non-parametric bootstraps on edge weight are shown in Figure S3. The node strength centrality indices for the 20 variables of the network are shown in Figure S4. Coherently, cytokines formed communities in the network structure. IL-6, TNF-α, and CXCL10 were the most central cytokines of the network. The most influential cytokines in the network were IL-6, TNF-α, CXCL10, CCL11, IL-8, IL-1β, and IL-17A. Notably, IL-7 was the only cytokine directly connected (negatively) with the anxiety/depression trajectory, with a regularized edge weight equal to -0.046. IL-7 was also negatively related to IL-1β and CXCL10 (regularized edge weights respectively equal to -0.052 and -0.035) and positively related to CCL17, IL-15, IL-17A, CCL4, and IL-8 (regularized edge weights respectively equal to 0.250, 0.146, 0.080, 0.067, and 0.044).

Figure 1 .

 1 Figure 1. Network displaying relationship between 19 standardized cord serum cytokines and anxiety/depression (A/D) symptoms trajectories measured at ages 3, 5 and 8 years, n=871Green edges indicate positive relationship and pink negative relationships. The absolute value of associated edge-parameter is proportional to the width and saturation of the edges.

  [START_REF] Barbosa | Serum cytokines associated with behavior: a cross-sectional study in 5-year-old children[END_REF] a Odds ratios and their confidence intervals (97.5% confidence from Bonferroni correction) J o u r n a l P r e -p r o o f

Table 1 . Sample sociodemographic characteristics by childhood anxiety/depression trajectory, EDEN, n=871

 1 Calculated as Cohen's d effect size or success rate difference (very small: <0.20; small: 0.20-0.50; medium: 0.50-0.80; large: 0.80-1.20; very large: 1.20-2.0; huge: > 2.0). p values are based on unpaired t test or Mann-Whitney test for continuous variables and chi2 test for categorical variables.

	Characteristics	N	Reference	High anxiety/	Effect-
			group	depression	size a
				trajectory
			n=736	n=135
	Male, No. (%)	871	397 (53.94)	65 (48.15)	-0.06
	Prenatal and biological factors
	Gestational diabetes, No. (%)	871	55 (7.47)	8 (5.93)	-0.02
	Maternal pre-pregnancy BMI	871			-0.07
	(kg.m2), No. (%)
	Low pre-pregnancy BMI		90 (12.23)	12 (8.89)
	Normal pre-pregnancy BMI		456 (61.96)	93 (68.89)
	High pre-pregnancy BMI Urinary/Cervical/Vaginal infection during pregnancy, No. (%) Multiparity, No. (%) 1st child 2nd child or more Caffeine consumption (mg/day), No. (%) 0 0 to <100 100 to <200 >=200 Alcohol consumption during pregnancy, No. (%) No or ≤ 2 glasses/week Yes (> 2 glasses/week) Smoking during pregnancy J o u r n a l P r e -p r o o f 190 (25.82) 30 (22.22) 870 246 (33.42) 45 (33.33) 871 318 (43.21) 83 (61.48) 418 (56.79) 52 (38.52) 858 65 (8.83) 12 (8.89) 354 (48.10) 64 (47.41) 208 (28.26) 44 (32.59) 97 (13.18) 14 (10.37) 871 683 (92.80) 120 (88.89) 53 (7.20) 15 (11.11) 859 0.99 (2.67) 0.96 (2.58)	-0.001 0.18 b 0.003 0.04 0.02
	(cigarette(s)/day), mean (SD)
	Maternal diet during pregnancy	871
	Lowest quartile of healthy pattern		252 (34.24)	49 (36.30)	0.02
	Highest quartile of Western pattern		151 (20.52)	27 (20.0)	-0.005
	Perinatal factors
	Birth weight (kg), mean (SD)	871	3.32 (0.48)	3.30 (0.53)	-0.04
	Gestational age (week of	871	39.29 (1.55)	39.11 (1.76)	-0.01
	amenorrhea), mean (SD)
	Delivery mode, No. (%)	870			0.001
	Vaginal		565 (76.77)	104 (77.04)
	Forceps / Ventosa		78 (10.60)	14 (10.37)
	C-section		92 (12.50)	17 (12.59)
	Birth trimester, No. (%)	871			0.01
	1st trimester		179 (24.32)	41 (30.37)
	2nd trimester		224 (30.43)	27 (20.0)
	3rd trimester		186 (25.27)	33 (24.44)
	4th trimester		147 (19.97)	34 (25.19)
	Social factors

Table 2 . Sample standardized cord serum cytokine characteristics by childhood anxiety/depression trajectories, EDEN, n=871.

 2 Calculated as Cohen's d effect size or success rate difference (very small: <0.20; small: 0.20-0.50; medium: 0.50-0.80; large: 0.80-1.20; very large 1.20-2.0; huge: > 2.0). p-values are based on unpaired t test or Mann-Whitney test with Bonferroni's multiple testing correction. b p < 0.01 J o u r n a l P r e -p r o o f

	Cytokines	Reference group	High anxiety/depression	Effect
	(pico/ml)	n=736 (84.50%)	trajectory n=135 (15.50%)	size a
		Mean	Standard deviation	Mean	Standard
					deviation
	CCL2	330.51	263.23	329.37	154.05	-0.01
	CCL3	36.45	173.79	22.32	13.85	-0.09
	CCL4	266.90	137.35	258.00	102.81	-0.07
	CCL11	224.93	93.75	212.73	91.96	-0.13
	CCL17	1481.86	1066.65	1435.02	1226.92	-0.04
	CCL26	13.08	15.45	13.14	20.21	0.01
	CXCL10	203.98	464.10	201.62	324.84	-0.01
	IFN-γ	2.81	3.43	2.58	2.13	-0.07
	IL-1b	1.15	5.63	0.51	0.70	-0.12
	IL-6	27.04	191.63	12.32	52.43	-0.08
	IL-7	9.45	3.95	8.26	2.92	-0.31 b
	IL-8	65.31	358.19	22.87	50.46	-0.13
	IL-10	1.05	2.78	1.87	9.57	0.18
	IL-12p40	656.94	251.26	653.82	242.71	-0.01
	IL-15	2.90	7.83	2.23	1.06	-0.10
	IL16	456.94	605.51	402.68	378.10	-0.09
	IL-17A	9.74	6.65	8.85	5.96	-0.14
	TNF-α	3.64	2.67	3.31	1.06	0.13
	TNF-β	0.81	0.57	0.70	0.40	-0.21
	a

Table 3 . Adjusted associations between childhood anxiety/depression trajectories and standardized cord serum cytokines, EDEN, n=871 OR (97.5% CI) a Prenatal and biological factors

 3

	Multiparity (2nd child or more vs. 1st child)	0.50 (0.32, 0.77)
	Birth trimester
	1st trimester	1 (REF)
	2nd trimester	0.53 (0.29, 0.98)
	3rd trimester	0.87 (0.49, 1.55)
	4th trimester	1.01 (0.56, 1.80)
	Maternal prenatal psychopathology
	Depressive symptoms	1.06 (1.03, 1.09)
	Cord serum cytokines
	IL-7	0.73 (0.57, 0.93)
	IL-10	1.13 (0.95, 1.

ACKNOWLEDGEMENTS AND DISCLOSURES

This study was supported by the Fondation de France, Fondation pour la Recherche Medicale, the French Ministry of Research Institut Federatif de Recherche and Cohort Program, the INSERM Nutrition Research Program, the French Ministry of Health Perinatal Program, the French Agency for Environment Security, the French National Institute for Population Health Surveillance, Paris-Sud University, the French National Institute for Health Education, Nestle, Mutuelle Generale de l'Education Nationale, the French-Speaking Association for the Study of Diabetes and Metabolism (Alfediam), the National Agency for Research (ANR, French National Research Agency nonthematic program), the National Institute for Research in Public Health (Institut de Recherche en Sante Publique, the Tres Grande Infrastructure de Recherche Cohorte Sante 2008 Program), and the French National Research Agency Grant No. ANR-12-DSSA-0005-01. Pr. Galera reports having received research funding from the ANR and the Fondation de France, Dr. Barbosa reports having received research funding from the Fondation de France, Dr. Sutter-Dalley reports having received research funding from the ANR, Dr. Koehl reports having received research funding from the ANR, Dr. Van der Waerden reports having received research funding from the ANR, Dr. Melchior reports having received research funding from the ANR, Pr. Côté reports having received research funding from the ANR, Dr. Heude reports having received research funding from the ANR, Dr. Glaichenhaus reports having received research funding from the Fondation de France, Dr. Davidovic reports having received research funding from the Fondation de France, and all other authors report no biomedical financial interests or potential conflicts of interest.

The authors thank the children and families whose ongoing participation made this study possible.

They also thank the participating families, the midwife research assistants for data collection, the psychologists and the data entry operators.


Brandon Foubert
email: brandon.foubert@inria.fr

Routing in Multi-Technologies Wireless Sensor Networks

Wireless Sensor Networks (WSN) are constrained by their Radio Access Technologies' (RAT) capabilities. In Multiple Technologies Network (MTN) nodes are able to use several RAT in a multi-hop scheme. The routing and RAT selection is handled by the nodes with dedicated protocols. In this article, we present our current work and future plans for a Routing Over Different Existing Network Technologies (RODENT) protocol designed for MTN. It enables dynamic (re)selection of the best route and RAT based on the data type and requirements. RODENT is based on a multi-criteria route selection via a custom lightweight TOPSIS method. We have implemented a functional prototype on Pycom FiPy devices. RODENT increases flexibility, coverage and energy savings while supporting multiple data requirements.

Introduction

Wireless Sensor Networks (WSN) enable a remote monitoring of various metrics and many more use cases [START_REF] Ye | Application of wireless sensor networks in environmental monitoring[END_REF]. Such networks usually rely on a single medium distance Radio Access Technology (RAT) (e.g., IEEE 802.15.4). Deployments are constrained by the limits of the chosen RAT, in terms of coverage and throughput. Some RAT are even so constrained that they may not be able to comply with specific data requirements such as delay-intolerant data. Additionally, outdoor nodes have to bear the weather changes (e.g., rain) which impacts the communication quality.

Many different RAT are available for WSN nowadays [START_REF] Foubert | Long-range wireless radio technologies: A survey[END_REF]. Different RAT come with different performances and capabilities. Multiple Technologies Networks (MTN) can overcome the aforementioned issues [START_REF] Foubert | Autonomous Collaborative Wireless Weather Stations: A Helping Hand for Farmers[END_REF]. With several RAT builtin, the nodes' range of deployment is extended, as nodes' can switch RAT and relay data through multi-hop. Nodes that have several data requirements (e.g., temperature and video monitoring) can use several path accordingly. Currently available routing protocols are not suited for MTN. Thus we conceived a novel Routing Over Different Existing Network Technologies protocol (RODENT) designed for MTN. Our contribution takes account of every nodes' RAT for the route selection. Nodes select the best route from the set of known routes by means of a customized Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) method [START_REF] Foubert | Sélection d'interface de communication dans les réseaux de capteurs multi-technologies[END_REF]. Criteria for the best route depend on the use case and the requirements data has to meet (e.g., data size, deadline).

RODENT is implemented and we assessed its performances through experimental evaluation on an MTN prototype composed of Pycom FiPy devices featuring multiple RAT. Results show that RODENT increase network flexibility and reliability, decrease energy consumption and enable better consideration of the data requirements while maintaining a good packet delivery ratio.

Routing overview

The distinctive feature of RODENT is to enable multi-RAT routes. Each route has different cost and performances. This Section offers an overview on RODENT's operations.

Let's consider the operations of ND and NE from Fig-

Selection method

In MTN a single node owns several RAT. This hardens the route selection as nodes must consider many routes over many RAT. In this Section, we present a sketch of the selection method used by RODENT to chose the best route.

The selection has to be based on multiple criteria e.g., the energy consumption, delay etc. of each route. Several tools are available in the literature for multi-criteria decision, such as utility and cost functions, Markov chains, fuzzy logic, game theory, data mining and Dempster-Shafer theory. We found the Multiple Attribute Decision Making (MADM) methods to be the most fitting for route selection.

MADM methods formalize the problem as a decision matrix. The matrix is composed of the candidates and the attributes considered for the ranking. Each candidate has a set of attribute's values that reflects its performance. An MADM method takes the decision matrix as input and outputs a ranking of all the candidates. Several MADM methods are available in the literature, such as Simple Additive Weighting (SAW), Weighting Product (WP), Analytical Hierarchy Process (AHP) and Gray Relational Analysis (GRA). Among those methods, we find the most interesting to be Technique for Order Preference by Similarity to Ideal Solution (TOP-SIS). TOPSIS compares each candidate based not only on its closeness to the best theoretical candidate but also on its distance from the worst theoretical candidate.

TOPSIS however suffers from rank reversal and a complex ranking computation algorithm. Several works tries to tackle the rank reversal issue, but at the expense of an increased complexity. In a previous work, we designed a lightweight TOPSIS for hardware-constrained devices which avoid rank reversal [START_REF] Foubert | Sélection d'interface de communication dans les réseaux de capteurs multi-technologies[END_REF]. We leverage this lightweight TOP-SIS method to perform the route selection in RODENT.

We refer to the route matrix of node x as RM x . For route selection, RM x is composed of all the routes available for node x. RM x 's attributes are relative to the routes e.g., the number of hops and the total energy consumption. For example, ND in Figure 1 could have a route matrix RM D such as the one in Table 2. TOPSIS takes as input a set of weights for

Conclusion

WSN deployments are constrained by the coverage and performances of the devices' RAT. The use of several RAT allows to overcome these shortcomings. In this article, we show the feasibility and utility of MTN and we overview the Routing Over Different Existing Network Technologies protocol (RODENT). It is designed for routing in MTN and enable the use of multi-technologies routes. For future works, we plan to precisely measure the energy savings and extend RODENT to support downlink communication. We plan to conceive an efficient link layer protocol for accurate link costs and performances assessment for multi-RAT.

Figure 1 .

 1 Figure 1. MTN example.

Table

  . Example link matrix LM D .

		Energy Money Bit-rate
	Sigfox BS	12	102	22
	NB-IoT BS	151	87	174
	Node E (LoRa)	37	0	72

  ure 1 as example. ND boots without any knowledge of its surroundings. ND's link layer scans the environment with every RAT and builds its link matrix LM D in Table1. Each link is associated to a neighbor and a RAT. Based on LM D the network layer starts to build the route matrix RM D . The link from ND to the base stations are registered in RM D as singlehop routes. NE meanwhile does the same, and selects its only available route toward the Sigfox base-station. NE advertises its route which is received by ND through their LoRa link. ND constructs its third route by adding the route's and LoRa link's costs. RM D is then similar to Table2. ND then selects a best route for each of its RV . The selection is made independently of the RAT and based only on the routes' costs and performances. In this case and considering Table the best route for RV monitoring is the one toward the Sigfox base station because low energy consumption is favored. The best route for RV alarm is the one toward the NB-IoT base station because high bit-rate is favored. ND then starts to advertise and use its best routes.

Table 2 .

 2 Example route matrix RM D .

		Energy Money Bit-rate Hops
	Sigfox BS	12	102	22	1
	NB-IoT BS	151	87	174	1
	Node E (LoRa)	49	102	94	2

Table 3 .

 3 Requirements vectors. The weights represent the importance of each attribute in the ranking process. We refer to a set of weights as a Requirements Vector (RV ). RV x is the requirements vector for use case x e.g., RV monitoring . For route selection RV 's values are set based on the data requirements that the node have to meet e.g., prioritize speed over energy consumption, and such that RV {e n ∈ RV | ∑

		Energy Money Bit-rate
	RV monitoring	0.6	0.3	0.1
	RV alarm	0.1	0.1	0.8
	each attribute. |RV | n=1 e n = 1}. Examples require-
	ments vectors are depicted in

Table 3 .

 3

Acknowledgments

This work was partially supported by a grant from CPER DATA, Sencrop, FEDER, I-SITE and Lirima Agrinet project. I would like to express my gratitude to my advisor Dr. Nathalie Mitton for her valuable comments and suggestions to improve this work.