Coralie Biache
email: coralie.biache@yahoo.fr

Olivier Kouadio

Khalil Hanna

Catherine Lorgeoux

Pierre Faure

Role of goethite during air-oxidation of PAH-contaminated soils

Keywords: contaminated soil, polycyclic aromatic compound (PAC), oxygenated-PAC, goethite, oxidation

come

Introduction

Iron oxides are the most abundant metallic oxides in soils [START_REF] Schwertmann | Iron Oxides[END_REF], they are present in most soils and encompass oxides, oxyhydroxides and hydrated oxides. Feminerals are known to play an active part in the organic contamination fate as they represent strong sorption surfaces for pollutants and they catalyze many important redox transformations [START_REF] Borch | Biogeochemical redox processes and their impact on contaminant dynamics[END_REF]. During the past decades their ability to participate in such redox reactions was involved in remediation strategies for organic contamination. For instance Fe-minerals are associated with H2O2 to produce hydroxyl radicals that can degrade organic compounds in Fenton-like reactions. Soil iron minerals i.e. magnetite, hematite, goethite, and ferrihydrite, are all able to catalyze H2O2 [START_REF] Yap | Fenton based remediation of polycyclic aromatic hydrocarbons-contaminated soils[END_REF].

Fenton-like reaction has been investigated for the remediation of water and soil contaminated with halogenated solvent, pesticides and petroleum hydrocarbons [START_REF] Watts | Mineralization of sorbed and NAPL-phase hexadecane by catalyzed hydrogen peroxide[END_REF][START_REF] Usman | Treatment of hydrocarbon contamination under flow through conditions by using magnetite catalyzed chemical oxidation[END_REF]. Fenton-like reaction shows also a great potential for polycyclic aromatic hydrocarbon (PAH, compounds constituted of two, or more, fused benzene rings) degradation in contaminated soils [START_REF] Nam | Enhanced degradation of polycyclic aromatic hydrocarbons by biodegradation combined with a modified Fenton reaction[END_REF][START_REF] Usman | Remediation of PAH-contaminated soils by magnetite catalyzed Fenton-like oxidation[END_REF]. The catalytic role of iron oxides for Fenton-like reaction is extensively studied for chemical remediation purpose. However such treatments are not automatically applied to contaminated soils and little is known about the involvement of iron oxide in processes occurring during natural attenuation of contaminated soils, especially abiotic oxidation. Some authors studied iron oxide-mediated oxidative transformations of organic compounds [START_REF] Zhang | Adsorption and oxidation of fluoroquinolone antibacterial agents and structurally related amines with goethite[END_REF][START_REF] Lin | Goethite-mediated transformation of bisphenol A[END_REF] but the experiments were designed with solids suspended in aqueous solution which is not representative of real soil conditions. [START_REF] Wang | Photodegradation of polycyclic aromatic hydrocarbon pyrene by iron oxide in solid phase[END_REF] studied pyrene degradation on iron oxide under UV radiation and evidenced photocatalytic effect of several iron oxide. In real soils UV light affects only the surface layers since its intensity decays rapidly in the solid phase. Abiotic oxidation still occurs in deeper layer but so far this process was scarcely investigated, probably due to the difficulty to study this process independently to others. This difficulty can be bypassed using experimental simulation. Indeed low-temperature oxidations (60-130 °C) are proven to successfully mimic long-term abiotic oxidation of fossil organic matter (OM) [START_REF] Faure | Behavior of organic matter from Callovian shales during low-temperature air oxidation[END_REF][START_REF] Elie | Natural and laboratory oxidation of low-organic-carbon-content sediments: comparison of chemical changes in hydrocarbons[END_REF][START_REF] Blanchart | In situ and laboratory investigation of the alteration of Boom Clay (Oligocene) at the air-geological barrier interface within the Mol underground facility (Belgium): Consequences on kerogen and bitumen compositions[END_REF]. Such experiments were extensively used in the 1980s to study coal weathering and its impact on coal heating properties [START_REF] Gethner | Kinetic study of the oxidation of Illinois No. 6 coal at low temperatures: Evidence for simultaneous reactions[END_REF][START_REF] Calemma | FT-i.r. study of coal oxidation at low temperature[END_REF][START_REF] Jakab | Effects of low temperature air oxidation (weathering) reactions on the pyrolysis mass spectra of US coals[END_REF]. More recently, lowtemperature oxidations of PAH-contaminated matrices showed that minerals (e.g. clay minerals and calcite) play an important role on the contamination fate [START_REF] Ghislain | Low-temperature, mineral-catalyzed air oxidation: a possible new pathway for PAH stabilization in sediments and soils[END_REF][START_REF] Biache | Low temperature oxidation of a coking plant soil organic matter and its major constituents: An experimental approach to simulate a long term evolution[END_REF][START_REF] Biache | Impact of clay mineral on air oxidation of PAH-contaminated soils[END_REF]. Indeed, oxidation causes a production of oxygenatedpolycyclic aromatic compounds (O-PACs: PAH with oxygenated moieties e.g. alcohol, ketone, aldehyde groups) and formation of an insoluble carbonaceous residue, supposedly through oxidative polymerization, leading to the contamination stabilization. PAHcontaminated soils often contain high proportion of iron oxide and other metal oxides [START_REF] Biache | Impact of clay mineral on air oxidation of PAH-contaminated soils[END_REF], however their influence on PAC oxidation has never been investigated in such context.

Therefore, this study reported a first investigation on the role of iron oxide (goethite) on PAC fate (including PAHs and O-PACs) during abiotic air-oxidation of contaminated soils.

Its aim was to determine which mechanisms were involved during this major process involved in natural attenuation. Goethite (α-FeOOH) was selected because it is one of the most thermodynamically stable and the most abundant iron (oxy)(hydr)oxide in natural environments [START_REF] Schwertmann | Goethite[END_REF].

Two sets of experiments were performed. The first one was conducted on extractable organic matter (EOM) previously isolated from PAC-contaminated soils. Afterwards, EOM was mixed with goethite or silica sand; the latter was used as inert support since its reactivity towards organic compounds is limited [START_REF] Ghislain | Low-temperature, mineral-catalyzed air oxidation: a possible new pathway for PAH stabilization in sediments and soils[END_REF]). The second experiment was performed directly on soils, raw or supplemented with goethite. These two sets allowed investigating two levels of increasing complexity by studying the influence of an iron oxide on the soil EOM, which could give more precise information on the involved mechanisms, and on the whole soil including indigenous minerals, which is more complex but also more realistic. Oxidations were performed at 60 and 100 °C, the latter allowing more advanced oxidation and the first one representing an intermediate between 100 °C and field temperatures.

Materials and Methods

Samples

Soils were sampled at two former coking plant sites (Homécourt and Neuves-Maisons, France), then freeze-dried, sieved (2 mm) and crushed (500 µm). EOM was recovered by extracting parts of the soils in Soxhlet apparatus (CHCl3, 24 h), it contains PACs and other organics of various size, from macromolecules (asphaltenes) to mono-aromatic units. Neuves-Maisons and Homécourt EOMs were concentrated at 1.4 and 2.4 mg/mL, respectively. Soils were also used directly or mixed with goethite.

Minerals

The silica sand was Fontainebleau sand (180-500 µm, Carlo Erba) used as a non-reactive reference in the EOM experiment.

Goethite (α-FeOOH) was synthesized according to [START_REF] Schwertmann | Goethite[END_REF].

Briefly, sample was prepared by air-oxidation of a hydrolyzed FeSO4 solution according to [START_REF] Prélot | Morphology and surface heterogeneities in synthetic goethites[END_REF] (cf. supporting information).

Minerals were washed with dichloromethane prior experiments to prevent organic contamination.

Oxidation experiment

EOMs and soils were mixed with minerals according to the following proportions: silica sand (2 g) and goethite (0.5 g) mixed with Homécourt (47.1 mg) and Neuves-Maisons (48.7 mg) EOMs, Homécourt (2.5 g) and Neuves-Maisons (5 g) soils taken alone or mixed with goethite (0.5 g) (Table S1). Soils and minerals were placed in 100 mL glass bottles equipped with open caps and PTFE/silicone septa. EOM aliquots were added to the minerals to reach the mineral/EOM proportions specified in Table S1. Bottles were left open in a ventilated hood until complete evaporation of the solvent.

Two sample sets were prepared and placed in ovens at 60 and 100 °C. CO2 released in the bottles was measured weekly by an infrared absorbance measurement (λ = 2325.6 cm -1 ) with an infrared Binos analyzer. The measured CO2 was normalized to the initial sample total organic carbon (TOC) content. After each measurement bottles were opened to renew the atmosphere and the septa were replaced. After 160 days, samples were removed from the ovens and, after CO2 measurements, were stored at -18 °C prior analyses.

Extraction

Samples were transferred to 250 mL boiling flasks and chloroform (100 mL) was added to each flask. The mixtures were heated at 60 °C and stirred for 45 min before being filtered on GF/F Whatman glass-fiber filters. The filtrates were concentrated under a gentle nitrogen flow and volumes were adjusted to 20 mL. For each sample, an EOM fraction (3 mL) was transferred to a pre-weighed bottle and the EOM content was determined after solvent evaporation.

PAC quantification

An internal PAH standard mix of [ 2 H8]naphthalene, [ 2 H10]acenaphthene, [ 2 H10]phenanthrene, [ 2 H12]chrysene, [ 2 H12]perylene (25 µL at 16 µg/mL, Cluzeau) was added to the EOM (75 µL) before being injected in a gas chromatograph coupled with a mass spectrometer (GC-MS). The GC-MS was previously internally calibrated with the internal standards listed above for 16 PAHs plus 4 O-PACs (Table 1) at 6 concentrations (0.5, 1, 2, 4, 6 and 8 µg/mL). The GC was a Shimadzu GC-2010 Plus, equipped with a silica-glass capillary column DB-5MS (60 m × 0.25 mm i.d. × 0.1 µm film thickness) coupled with a QP2010-Ultra (Shimadzu) MS in fullscan mode with a transfer line heated at 300 °C. The oven temperature program was as follow: 70 °C for 2 min, from 70 to 130 °C at 15 °C/min, then from 130 to 315 °C at 3 °C/min and then a 15-min hold at 315 °C. Helium was used as carrier gas in constant flow mode (1.4 mL/min).

TOC content

TOC contents were determined in soils and EOM/mineral mixtures with a total carbon analyser TOC-V CSH (Shimadzu) associated with a solid sample module SSM-5000A (Shimadzu).

Results

EOM/minerals mixture

CO2 production

For both samples, CO2 production of the EOM/mineral mixture followed the same trend (Figure 1a,b). The maximum production was observed for the EOM/goethite mixtures oxidized at 100 °C and reached about 6 and 5‰ of TOC for Homécourt and Neuves-Maisons, respectively. It was followed by the CO2 produced by the EOM/goethite mixture during the 60 °C oxidation. Smaller amount of CO2 were observed for the EOM/sand mixture oxidations.

EOM contents

Overall, oxidations induced a decrease in the EOM content of the EOM/mineral mixtures (Figure 2a). It was limited for the EOM/sand mixtures oxidized at 60 °C and was more important for the same mixture oxidized at 100 °C but clearly lower than the EOM/goethite mixtures. The decrease was similar for both Homécourt and Neuves-Maisons samples at 100 °C and went from 47.1 to 24.5 mg and from 48.7 to 26.6 mg, respectively.

PAH contents

Overall, EOM/mineral mixture oxidations induced a decrease in PAH concentrations. For Homécourt EOM/sand mixture it was limited to 5% after the 60 °C experiment (Table 1). It

was more important at 100 °C (49%), mostly because of the loss of low molecular weight (LMW) compounds compared to high molecular weight (HMW), as shown by the LMW/HMW ratio which went from 3.1 to 1 (Table 1). The 60 and 100 °C experiments induced a decrease in PAH content of 27% and 59% for Homécourt EOM/goethite mixture, respectively. It affected again mainly LMW PAHs, especially the 2-and 3-ring PAHs (Table 1, Figure S3).

Contrary to the Homécourt EOM/sand mixture, PAHs decreased notably (40%; Table 1) after the 60 °C oxidation of the Neuves-Maisons EOM/sand mixture. This decrease affected both LMW and HMW compounds (Table 1, Figure S4). It was confirmed by the LMW/HMW ratio which was barely modified (Table 1). At 100 °C, the PAH decrease was more important and reached 61%. The LMW PAH, especially the 2-and 3-ring compounds were more affected (Table 1, Figure S4). Neuves-Maisons EOM/goethite mixture oxidations induced also a decrease in the PAH contents. It was relatively close whatever the temperature (63% at 60 °C and 66% at 100 °C; Table 1)

O-PAC contents

Overall, oxidations induced an increase in the O-PAC contents (Table 1). For Homécourt EOM, it was more important at 60 °C than at 100 °C. It was also higher when the EOM was mixed with goethite than when mixed with sand (Table 1). The O-PAC production concerned mostly 9-fluorenone and anthracene-9,10-dione (Table 1, Figure S5). The increase in O-PAC concentrations in Neuves-Maisons EOM/mineral mixtures was higher at 100 °C than at 60 °C (Table 1). The maximum O-PAC production reached 203% when Neuves-Maisons EOM was mixed with goethite and oxidized at 100 °C (Table 1). This increase affected mostly benzo[de]anthracene-7-one and benz[a]anthracene-7,12-dione (Table 1, Figure S6).

Soils and soil/goethite mixtures

CO2 production

For Homécourt soil, the CO2 production was higher when the raw soil was oxidized at 100 °C and reached 7‰ of the TOC at the end of the experiment (Figure 1c). The CO2 production was much lower at 60 °C and reached less than 2‰ of the TOC. It was followed by the Homécourt soil/goethite mixture oxidized at 100 °C whereas the same mixture produced nearly no CO2 at 60 °C (Figure 1c). Similar pattern was observed for the Neuves-Maisons soil with a maximum CO2 production for the raw soil oxidized at 100 °C which reached about 4‰ of the TOC. However the differences between the modalities were less pronounced and the minimum CO2 production observed for the Neuves-Maisons/goethite mixture oxidized at 60 °C reached 1.3‰ of the TOC (Figure 1d).

It should be noted that a part of the generated gas could result from CO2 desorption from soil solid surfaces (e.g. minerals, OM) over the soil thermal treatments, but this process may be insignificant under our experimental conditions (Sumner, 2000).

EOM contents

Soil oxidations led to a decrease in the EOM contents (Figure 2b). For both soils and soil/goethite mixtures, it was more important at 100 °C than at 60 °C. This decrease was enhanced by the presence of goethite in the case of Homécourt samples for which the EOM went from 26.4 to 19.0 and to 13.5 mg/g of soil after the 60 and the 100°C experiments, respectively. Surprisingly, no difference was observed with goethite addition to the Neuves-Maisons soil (Figure 2b).

PAH contents

Oxidations induced a strong decrease in the PAH concentrations for both soils. It was more important at 100 than at 60 °C and was maximum when goethite was added to the soil (92% of decrease for both samples; Table 2). For both samples, the 60 °C experiments affected slightly more HMW than LMW compounds, as shown by the increasing LMW/HMW ratios (Table 2). On the contrary, the 100 °C experiment induced a decrease in this ratio, indicating a preferential loss of the LMW PAHs (Table 2, Figures S7 andS8).

O-PAC contents

Overall, the soil and soil/goethite mixture oxidations induced a decrease in the O-PAC contents. For the raw Homécourt soils, it was limited to 3% after the 100 °C experiment and reached 12% after the 60 °C oxidation. This decrease was higher when Homécourt soil was mixed with goethite and attained 18% and 41% after the 60 and the 100 °C experiments, respectively (Table 2, Figure S9). The abatement rates were higher for the Neuves-Maisons soil with 54% and 60% after the 60 and the 100 °C experiment on the raw soil, respectively. Goethite supplementation also enhanced this decrease but the proportion of O-PAC abatement was similar for both temperatures (71%; Table 2, Figure S10).

Discussion

Mechanisms of goethite-activated EOM oxidation

Overall, goethite showed a high reactivity during the EOM oxidation as CO2 production and the PAH degradation rate were enhanced by its presence. However, it should be noted that the mineralization was of less importance because the amount of produced CO2 during the experiment remained very low (< 7‰ of TOC).

To give a better insight into the main process involved in the reduction of the PAH and EOM contents, a carbon mass balance was performed (Figure 3). It showed that most of the carbon from the initial EOM was transferred to the insoluble compartment. Such observations were made in previous studies [START_REF] Ghislain | Low-temperature, mineral-catalyzed air oxidation: a possible new pathway for PAH stabilization in sediments and soils[END_REF][START_REF] Biache | Low temperature oxidation of a coking plant soil organic matter and its major constituents: An experimental approach to simulate a long term evolution[END_REF][START_REF] Biache | Impact of clay mineral on air oxidation of PAH-contaminated soils[END_REF] where air-oxidation of PAH associated with active minerals led to the decrease in EOM content and to the formation of an insoluble carbonaceous residue resulting from oxidation-induced polymerization. EOM oxidations also induced an O-PAC production (ketones). Such compounds are known to be produced during PAH oxidation in various contexts i.e. chemical oxidation [START_REF] Lundstedt | Transformation of PAHs during ethanol-Fenton treatment of an aged gasworks' soil[END_REF], photo-degradation [START_REF] Barbas | Photochemical oxidation of phenanthrene sorbed on silica gel[END_REF] and biodegradation [START_REF] Kazunga | Products from the incomplete metabolism of pyrene by polycyclic aromatic hydrocarbon-degrading bacteria[END_REF]. As the O-PAC production was much more important in the EOM/goethite mixture than in the EOM/sand mixture, goethite seems to play an active part in the oxidation process. The oxidation of organic compounds on goethite is known to be initiated by the sorption and then formation of inner-sphere surface complexes with Fe III surface sites [START_REF] Pizzigallo | Oxidation of chloroanilines at metal oxide surfaces[END_REF].

This chemical coordination at the goethite surface is a prerequisite for the electron transfer process [START_REF] Stone | Reductive dissolution of metal oxides[END_REF]. Indeed, the sorbed molecule transfers an electron to Fe III site at goethite surfaces, leading to the formation of a very reactive cation radical that in turn interacts with oxygen to produce oxygenated species [START_REF] Mcbride | Adsorption and oxidation of phenolic compounds by iron and manganese oxides[END_REF]. Finally, dissociation of surface complexes and release of oxygenated species may occur, while the newly generated Fe II may be rapidly oxidized by O2. Such mechanism was suggested for room temperature oxidation of organic compounds by Mn VI -Mn III -oxides and Fe III -oxides (McBride, 1987; Stone and Morgan, 1987).

Our observations, i.e. important decrease in PAH contents and important production of O-PACs, were consistent with the previously mentioned mechanism. This oxidation mechanism must be favored by the increasing temperature, since more decay in EOM and PAH contents and more O-PAC production were noted at 100 than at 60°C. Generally, the electron transfer process induced by chemical complexation is considered as endothermic and therefore improved by increasing temperature [START_REF] Chidsey | Free energy and temperature dependence of electron transfer at the metal-electrolyte Interface[END_REF].

Moreover, several studies dealing with the Fe III -or Mn III/IV -induced oxidation of aromatic compounds have pointed out same polymerization/condensation process as observed in this study [START_REF] Li | Role of soil manganese in the oxidation of aromatic amines[END_REF][START_REF] Arroyo | Oxidation of 1-naphthol coupled to reduction of structural Fe 3+ in smectite[END_REF][START_REF] Russo | Bioavailability of phenanthrene in the presence of birnessite-mediated catechol polymers[END_REF].

4.2. Impact of goethite addition on the soil contamination.

When comparing the PAH decrease rates of both experiments (EOMs and soils), whole soils seemed to be more reactive. Goethite addition had a different impact on the whole soil vs the isolated EOM. While more decay in PAH concentration was observed in the presence of goethite, less CO2 was produced and O-PAC concentrations decreased. The EOM content did not change significantly compared to the soil without goethite. The first explanation for these differences is the presence in the soils of other -mineral and organic-reactive surfaces.

Previous studies dealing with biotic and abiotic oxidation of PAH contaminated matrices have already pointed out a high reactivity of complex soil systems [START_REF] Biache | Low temperature oxidation of a coking plant soil organic matter and its major constituents: An experimental approach to simulate a long term evolution[END_REF][START_REF] Biache | Biodegradation of the organic matter in a coking plant soil and its main constituents[END_REF][START_REF] Biache | Impact of clay mineral on air oxidation of PAH-contaminated soils[END_REF] which has been attributed to the presence of reactive phases such as clay minerals, metal oxides and organic macromolecules. Both soils contain such reactive minerals [START_REF] Biache | Impact of clay mineral on air oxidation of PAH-contaminated soils[END_REF], which may explain why the decrease in PAH and EOM contents were already high in the soil without goethite addition. Similar mechanisms of PAH oxidation could be involved here as in the EOM experiment but other by-products may be formed. The decrease in O-PAC contents may be explained by a strong sorption/sequestration in the soil and/or incorporation in the macromolecular network via polymerization. The high decay of EOM in the whole soil compared to the EOM/mineral mixture tends to support this hypothesis.

The goethite major impact was to reduce the CO2 production in the whole soil experiment even if the CO2 amount remained very low in all investigated experiments (less than 7‰ and 4‰ of the Homécourt and Neuves-Maisons soils, respectively). This slight discrepancy "soil vs soil/goethite" might be due to CO2 adsorption on goethite surfaces, but this process cannot be quantitatively evaluated in soil complex systems [START_REF] Russell | Adsorption of carbon dioxide on goethite (α-FeOOH) surfaces, and its implications for anion adsorption[END_REF] S3) and Neuves-Maisons being dominated by 4and 5-ring PAHs (Table 1, Figure S4). It is worthwhile noting that PAHs are known to be precursors of O-PAC formation. For instance 9-fluorenone is known to be one of the oxidation product of fluorene [START_REF] Lee | Prediction of Fenton oxidation positions in polycyclic aromatic hydrocarbons by Frontier electron density[END_REF] which occurs in high concentration in Homécourt sample and, similarly, benz[a]anthracene-7,12-dione can be generated during benz[a]anthracene oxidation [START_REF] Lee | Prediction of Fenton oxidation positions in polycyclic aromatic hydrocarbons by Frontier electron density[END_REF] which is one of the major PAHs of Neuves-Maisons sample.

Difference of the initial sample composition also seems to influence the sample response to oxidation. For both EOM/mineral and soil oxidations, the decrease in EOM contents was more important for Neuves-Maisons samples than for Homécourt (Figure 2). As discussed, this decrease was a transfer of the organic carbon from the EOM to the insoluble fraction which was more important for Neuves-Maisons than for Homécourt (Figure 3). The latter observation can be due to the fact that Neuves-Maisons sample presented higher proportion of HMW compounds than Homécourt and HMW compounds are more inclined to be stabilized (condensed) in the non-extractable fraction [START_REF] Northcott | Partitioning, extractability, and formation of nonextractable PAH residues in soil. 1. Compound Differences in Aging and Sequestration[END_REF].

Summary and conclusion

In all experiments, oxidation led to (i) a decrease in PAH concentrations, (ii) a low production of CO2 and (iii) a decrease in EOM content due to a condensation/polymerization phenomenon evidenced by a carbon mass balance. Oxidation of the EOM/minerals also led to a production of O-PACs, the initial PAH soil composition governing the type of generated compounds. The oxidation effects were more pronounced for EOM/goethite mixture than for EOM/silica sand mixture. These observations are consistent with the famous goethite-induced transformation mechanism of organic compounds. After PAC sorption on goethite surfaces, electron transfer process occurs leading to the formation of reactive cation radical that in turn interacts with oxygen or oxygen-species yielding oxidized products.

As in EOM experiments, goethite addition to the whole soils affected OM oxidation, but in a lesser extent. This limited effect was likely due to the presence of a significant amount of reactive phases naturally occurring in the soils. The soil initial composition also impacted its evolution during oxidation; higher abundance of HMW compounds favoring the formation of an insoluble residue and therefore EOM stabilization.

These conclusions showed that goethite may play a part in natural attenuation of PAH contaminated soils as it contributes to contamination stabilization during low-temperature airoxidation. This work provides first results of the mechanisms involved and also underlined the potential of indigenous reactive minerals to stabilize organic contamination. Therefore their impact on the fate and transformation of PAHs in soils under different conditions (humidity, temperature, oxygen concentrations) more representative of the field should be investigated , and the long-term behavior of the refractory compounds generated during oxidation (e.g. insoluble carbonaceous residues) should be explored.

Figure 1 :

 1 Figure 1: CO2 production during the 60 and 100 °C oxidation experiments of the extractable organic matter (EOM) from (a.) Homécourt and (b.) Neuves-Maisons samples, mixed with silica sand and goethite, and (c.) Homécourt and (d.) Neuves-Maisons soils and soils mixed with goethite.

Figure 2 :

 2 Figure 2: Extractable organic matter (EOM) contents after the 60 and the 100 °C oxidation experiment of (a.) Homécourt and Neuves-Maisons EOM/mineral mixtures, and (b.) Homécourt and Neuves-Maisons soil and soil/goethite mixtures.

Figure 3 :

 3 Figure 3: Carbon mass balance of the initial and oxidized samples of extractable organic matters (EOMs) mixed with mineral phases (OC: organic carbon).

  HMW = ratio of sum of naphthalene to pyrene relative to sum of benzo[a]anthracene to benzo[ghi]perylene 212

				Homécourt					Neuves-Maisons
	µg/g	Initial EOM/sand	EOM/sand	EOM/goet.	EOM/goet.	Initial EOM/sand	EOM/sand	EOM/goet.	EOM/goet.
			60°C	100°C	60°C	100°C		60°C	100°C C	60°C	100°C
	Naphthalene	17	2.0	n.d.	n.d.	n.d.	240	7.6	n.d.	n.d.	n.d.
	Acenaphthylene	290	250	160	160	93	170		26	49	24
	Acenaphthene	600	410	n.d.	61	n.d.	150		n.d.	n.d.	n.d.
	Fluorene	410	260	20	39	22	120		2.5	7.0	1.3
	Phenanthrene	750	760	150	720	320	390		21.1	130	34
	Anthracene	220	260	120	150	67	170		37	39	31
	Fluoranthene	400	550	300	560	260	550		220	320	220
	Pyrene	290	320	240	310	200	450		180	200	150
	Benz[a]anthracene	190	150	140	140	46	480		220	160	160
	Chrysene	150	180	190	180	170	500		310	240	310
	Benzo[b]fluoranthene	210	180	260	170	190	650		350	300	340
	Benzo[k]fluoranthene	61	57	71	54	56	320		200	140	170
	Benz[a]pyrene	140	130	39	94	4.9	500		110	150	0.6
	Indeno[cd]pyrene	110	85	100	83	74	490		260	190	230
	Dibenz[a,h]anthracene	34	63	69	68	44	170		110	58	92
	Benzo[ghi]perylene	84	120	140	110	89	370		200	160	190
	Sum of PAHs	3956	3777	1999	2899	1636	5720		2247	2143	1953
	PAH decrease (%)		5	49	27	59			61	63	66
	LMW/HMW a	3.1	2.9	1.0	2.2	1.4	0.6	0.7	0.3	0.5	0.3
	9-Fluorenone	530	780	680	1500	1200	160		48	180	130
	Anthracene-9,10-dione	140	240	190	420	450	110		47	120	97
	Benzo[de]anthracene-	5.7	78	n.d.	82	n.d.	130		530	240	550
	7-one
	Benz[a]anthracene-	n.d.	n.d.	120	71	n.d.	64		430	150	630
	7,12-dione
	Sum of O-PACs	676	1098	990	2073	1650	464		1055	690	1407
	O-PAC production (%)		62	46	207	144			127	52	203
	%O-PAC (/total PAC)	15	23	33	42	50	8		32	24	42
	a LMW/
	.

  HMW = ratio of sum of naphthalene to pyrene relative to sum of benzo[a]anthracene to benzo[ghi]perylene 253

				Homécourt					Neuves-Maisons
	µg/g	Initial	Soil	Soil	Soil/goet.	Soil/goet.	Initial	Soil	Soil	Soil/goet.	Soil/goet.
			60°C	100°C	60°C	100°C		60°C	100°C C	60°C	100°C
	Naphthalene	9.4	4.5	0.3	3.6	n.d.	74	26	3.6	12	n.d.
	Acenaphthylene	160	65	48	57	40	52	15	4.0	13	4.0
	Acenaphthene	340	18	n.d.	13	n.d.	46	2.0	n.d.	1.6	n.d.
	Fluorene	230	26	13	22	9.1	36	2.4	0.3	1.9	0.2
	Phenanthrene	420	240	140	200	14	120	47	19	28	6.3
	Anthracene	130	47	24	40	21	52	18	3.3	10	2.9
	Fluoranthene	220	120	68	120	15	170	94	33	73	17
	Pyrene	160	73	26	61	n.d.	140	68	11	44	n.d.
	Benz[a]anthracene	110	32	15	20	3.6	150	55	10	22	1.7
	Chrysene	81	34	25	31	6	150	57	33	45	15
	Benzo[b]fluoranthene	120	37	39	38	23	200	81	53	75	42
	Benzo[k]fluoranthene	34	13	9.5	12	5.3	97	27	15	25	9.0
	Benz[a]pyrene	77	22	6.4	18	5.0	150	31	2.3	15	0.9
	Indeno[cd]pyrene	61	14	17	14	14	150	39	23	33	20
	Dibenz[a,h]anthracene	19	4.5	4.9	4.2	3.0	52	10	7.6	n.d.	5.3
	Benzo[ghi]perylene	47	12	13	12	11	120	32	17	28	15
	Sum of PAHs	2218	762	449	666	170	1759	604	235	427	139
	PAH decrease (%)		66	80	70	92		66	87	76	92
	LMW/HMW a	3.1	3.5	2.4	3.5	1.4	0.6	0.8	0.5	0.8	0.3
	9-Fluorenone	300	270	280	250	170	48	34	22	18	14
	Anthracene-9,10-dione	72	50	60	45	40	33	17	11	11	7.9
	Benzo[de]anthracene-
	7-one	3.2	5.0	n.d.	5.0	n.d.	39	6.5	4.2	4.9	n.d.
	Benz[a]anthracene-
	7,12-dione	n.d.	5.5	22	5.9	11	20	6.3	19	5.8	18
	Sum of O-PACs	375	331	362	306	221	140	64	56	40	40
	O-PAC decrease (%)		12	3	18	41		54	60	71	71
	%O-PAC (/total PAC)	14	30	45	31	57	7	10	19	9	22
	a LMW/

Acknowledgements

We thank the GISFI (French Scientific Interest Group -Industrial Wasteland (http://www.gisfi.prd.fr). We thank Pr. Christian Ruby from the LCPME laboratory (Nancy) for supplying us with the goethite.


J Féger
email: j.feger@orange.fr

E C Hirsch

Innovative therapeutics for neuropsychiatric disorders: the case of neurodegenerative diseases

Keywords: drug discovery, neuropsychiatric disorders, animal models, clinical research, précompétitive collaboration, medication development, research management

Cette revue a été écrite

Résumé

La littérature médico-scientifique récente a souligné l'absence de médicaments innovants pour les pathologies neurodégénératives comme la maladie de Parkinson ou d'Alzheimer. Or la forte prévalence de ces pathologies, revers de l'allongement de l'espérance de vie, entraîne un coût économique et social considérable. Malgré cela, les grandes firmes pharmaceutiques réduisent leurs activités de recherche en neuropharmacologie. Pourquoi la progression indiscutable des connaissances en neurosciences et sur la physiopathologie de ces maladies ne s'est pas traduite en innovations ?

Cette revue propose quelques explications sur l'origine possible de cette impasse et expose quelques solutions envisageables pour accélérer l'identification de médicaments innovants.

-Poursuivre l'effort des recherches fondamentales et cliniques mais avec une approche translationelle et réellement collaborative.

-Améliorer considérablement les études précliniques en construisant de meilleurs modèles animaux de ces pathologies, en introduisant l'emploi de nouveaux marqueurs et méthodologies donnant l'assurance que la molécule testée atteint bien sa cible et avec efficacité.

-Instaurer une nouvelle organisation de recherche renforçant les interactions entre recherche préclinique et clinique avec une ouverture transdisciplinaire, la mise en place de structures de recherche précompétitives dépassant le niveau national et associant équipes de recherche académiques à celles des start-up et des laboratoires pharmaceutiques.

-Renforcer l'ouverture de relations avec les autorités réglementaires dès le stade préclinique et surtout au moment du passage vers des études cliniques.

-Reconnaitre la place des associations de patients dans cette nouvelle organisation.

Ces nouvelles dispositions devraient assurer la découverte de médicaments efficaces pour lutter contre ces pathologies.

Mots clés: maladies neuropsychiatriques, développement préclinique et clinique, modèles animaux, collaboration précompétitive, organisation de recherche pharmaceutique .

A few years ago, in January 2008, a special session was held at the French Academy of Pharmacy to review perspectives on Alzheimer disease. A lecture was given by Frédéric Checler and Luc Buée [START_REF] Chécler | Fundamental data on the pathologies amyloid and Tau in Alzheimer's disease: which therapeutic perspectives?[END_REF] concerning new therapeutic avenues at the late preclinical stage and during clinical development of the disease. They emphasized strategies such as the inhibition of α-secretase or β-secretase in order to reduce the production of βamyloid. These targets, as well as the reduction of Tau protein, were also highlighted in a set of reports [START_REF] Hodges | Alzheimer's centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects[END_REF][START_REF] Masters | Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway[END_REF][START_REF] Klafki | Therapeutic approaches to Alzheimer's disease[END_REF] that had been published two years before in a commemorative tribute to the first anatomopathological report on this disease by Alois Alzheimer. Unfortunately, none of these drugs successfully completed phase III clinical studies [START_REF] Doody | Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease[END_REF][START_REF] Salloway | Phase 3 trials of bapineuzumab for mild-to-moderate Alzheimer's disease[END_REF]. This was not the first failure in a long list of drugs developed to slow down the course of the disease.

However, these failures must be seen in light of the fact that "studies of solanezumab for Alzheimer's disease have shown that there is a 36% rate of false diagnosis of Alzheimer's disease in clinical trials that were made in expert centers but based only on clinical criteria" [START_REF] Holmes | transforming the diagnosis of Alzheimer's disease The[END_REF] .

A quite similar situation arose in the case of another major neurodegenerative pathology, namely Parkinson disease. For this disease, a symptomatic strategy consists in correcting the behavioral disturbances caused by the degeneration of nigral dopaminergic neurons ending in the associative and motor striatal territories. This was first achieved using DOPAtherapy, which remains the gold standard treatment, and is only mildly challenged by the use of dopaminergic agonists. Indeed, dyskinesia, one of the main undesirable adverse effects of DOPA therapy, is only moderately reduced by using dopaminergic agonists. Moreover, some behavioral effects, such as excessive gambling [START_REF] Molina | Pathologic gambling in Parkinson's disease: A behavioral manifestation of pharmacologic treatment?[END_REF], are also observed with the use of dopaminergic agonists. Another strategy, the use of neuroprotective agents in Parkinson's disease, also remains unsuccessful.

The development of new pharmacological treatments remains a major difficulty, whatever the brain pathology, acute or chronic. A recent report [START_REF] Schwab | Plug the real brain drain[END_REF] for brain injuries such as stroke states that "In the past 10-15 years, dozens of clinical trials for stroke neuroprotection -involving thousands of patients -have failed". A similar issue has arisen in the case of translational studies in neuropsychiatric pathologies. For example, a large, comparative, multicenter clinical study, including 1432 patients treated either by perphenazine, olanzapine, quetiapine, risperidone, or ziprasidone, led to the conclusion that medication with perphenazine, a first generation antipsychotic, or olanzapine, a second generation medication or "atypical" antipsychotic, did not bring significant improvement, whereas the patients treated with the other drugs discontinued their treatment, a consequence of an insufficient efficacy/tolerance ratio [START_REF] Liebermann | Effectiveness of antipsychotic drugs in patients with chronic schizophrenia[END_REF]. As reviewed by Alison Abbott [START_REF] Abbott | The drug deadlock[END_REF], such results provoked shock wave when the codes used to mask the name of the drugs were broken: "that was frustrating and humbling for the research community".

In view of these failures, one might have expected pharmaceutical companies to start expanding their preclinical neuroscience research facilities. Yet, as emphasized in the literature [START_REF] Schwab | Plug the real brain drain[END_REF][START_REF] Abbott | The drug deadlock[END_REF][START_REF] Insel | Drug research: A plan for mental illness[END_REF], virtually all the major companies have recently withdrawn from neurosciences, a choice explained by the pressure to rein in costs coupled with the lack of any return on investment in these fields. However, the incidence of neurodegenerative pathologies is rising, largely related to the increasingly longer life expectancy.

Consequently, the economic cost is increasingly heavy, with "a greater socio-economic burden than cancer, cardio-vascular diseases and diabetes combined" ([9, see 13-15 for more detailed reports]. Moreover, as a rough estimate, the majority of patients suffering from these diseases are in developed countries, offering a creditworthiness contrasting with the situation for some tropical diseases such as malaria. On the other hand, it is commonly assumed, in the case of blockbuster drugs, that prolonged treatment in large populations of patients offers the prospect not only of large profits, but also of an increased risk of adverse events, leading to judicial inquiries. In line with this, pharmaceutical companies are aware that drugs targeting the main neuropsychiatric disorders are exposed to scientific, clinical and commercial risk. They are now turning to orphan diseases such as amyotrophic lateral sclerosis instead of Alzheimer or Parkinson disease [START_REF] Johnson | Commercial viability of CNS drugs: Balancing the risk/reward profile[END_REF].

It is most certainly frustrating to compare present times with the situation that existed in the early 1960s and the advent of psychopharmacology. At that time a new era was beginning, with the introduction in therapeutics of the first antipsychotic agent, the first anxiolytic agent, the first antidepressants, such as IMAO and tricyclic agents, and dopatherapy. Then, it was presumed that advances in genetics, physiology and neurochemistry of the brain, neuropathology and the identification of neurotransmitters and their receptors would lead to more efficient, more selective and safer drugs. But, as reported by Abbott [START_REF] Abbott | The drug deadlock[END_REF], "fifteen years ago, we were naively optimistic". Some fifty years ago, no one was in doubt that neurosciences could attain a very high level of knowledge of how the brain functions and how it is altered in the disease state. Yet, this better knowledge of cerebral development, physiology and behavior also tells us that the brain is far more complex than we realized. The same paradox holds true for our understanding of neuropsychiatric disorders.

Why is innovation so difficult in the area of neuropsychiatric disorders?

At first glance, it would seem that innovation should focus on the prevention and progression of diseases. Yet, the management of acquired symptoms also needs to be substantially improved, while avoiding adverse effects. A less ambitious goal is to treat only a part of the symptoms in order to give patients a better quality of life. For instance, it is well established that the occurrence of falls, related to gait disorders and postural instability, is frequent in the elderly population and is commonly observed in parkinsonism. This symptom is not related to the dopaminergic lesion but to the loss of cholinergic neurons within the pedunculopontine nucleus, a part of the mesencephalic locomotor region [17]. Thus, this provides a rationale for the prevention of falls.

In order to develop new therapeutic approaches for neuropsychiatric disorders, several features of the diseases should be taken into account, making innovation very complex.

-Neurodegenerative diseases often occur in the elderly population.

-Their etiology is related to a wide range of factors, including genetic, developmental and environmental factors, which vary in weight and are variable in each patient and according to his/her own history.

-Cerebral development during the prenatal period is a complex sequence of events, including neurogenesis and migration of neurons, alteration of which might influence the subsequent development of neurological disorders [START_REF] Ari | Phénotypic checkpoints regulate neuronal development[END_REF][START_REF] Marin | Interneuron dysfunction in psychiatric disorders[END_REF].

-Some neurodegenerative disorders are associated with a failure in the migration of inhibitory interneurons to the cerebral cortex [START_REF] Marin | Interneuron dysfunction in psychiatric disorders[END_REF] or to the striatum. This might be the case, for instance, in the development of Tourette syndrome [START_REF] Kalanithi | Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome[END_REF]. Such a defect of the migration of GABAergic neurons to the cerebral cortex, inducing an impaired excitatory/inhibitory balance, might be involved in various other neuropsychiatric disorders [START_REF] Marin | Interneuron dysfunction in psychiatric disorders[END_REF]. Cerebral development also involves a variation of the ionic intra/extracellular balance, which could also be altered. In line with this, it is also important to stress that changes in the ionic homeostasis of chloride occur before and after birth [START_REF] Ari | Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders[END_REF]. Interestingly, cortical or subcortical failure [START_REF] Ari | Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders[END_REF] could remain asymptomatic, or could lead to the expression of pathological symptoms with an onset delayed by several years, from birth to the end of the cerebral development during adolescence or as a consequence of environmental or psychosocial triggers. Thus, another important issue is to identify these factors with the aim of prevent the occurrence of disease in at-risk individuals. In line with this, several reports strongly suggest that the use of cannabis might trigger schizophrenia in some individuals [START_REF] Insel | Disruptive insights in psychiatry: transforming a clinical discipline[END_REF][START_REF] Wobrock | Increased cortical inhibition deficits in first-episode schizophrenia with comorbid cannabis abuse[END_REF][START_REF] Van Os | The environment and schizophrenia[END_REF].

-There is general agreement that a delay occurs between the onset of the degenerative process and the first expression of the clinical symptoms. Several hypotheses might explain this latency. First, individuals each have physical and cognitive abilities that allow them to maintain their performances close to the normal level through a sort of buffering effect. Second, many biological systems allow the deficit due to the first steps of the degenerative process to be compensated for. Interventions of dopaminergic, serotoninergic and glutamatergic mechanisms have been described in Parkinson disease, in which the symptoms appear a mean 5 to 6 years after the onset of the disease [START_REF] Bezard | Compensatory mechanisms in experimental and human parkinsonism: towards a dynamic approach[END_REF][START_REF] Mounayar | A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery[END_REF][START_REF] Boulet | Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intrastriatal microdialysis[END_REF].

-Among the neurodegenerative diseases, Huntington disease is an exemplary textbook case that illustrates the difficulties in understanding the pathological mechanisms [START_REF] Ross | Huntington disease: natural history, biomarkers and prospects for therapeutics[END_REF]. The relationship between the pathological process and a mutation in a single gene is obvious: the mutation corresponds to an expanded number of CAG repeats in the huntingtin gene, which codes for polyglutamine in the protein. Expression of the symptoms starts after a long delay depending on the number of CAG repeats. Consequently, detection of this genetic feature makes it possible to determine the mean delay to disease onset. However, in spite of these favorable characteristics, there is no treatment able to prevent or slow the expression of this disease. This example with a monogenic disease due to a single mutation, demonstrates why it is so difficult to develop an effective therapy to prevent the onset or the first stages of a degenerative process characterized by complex interactions between genetic, epigenetic and environmental factors. Indeed, several issues remain unresolved. First, how will it be possible to detect the presence of such developmental alterations, in order to identify the population at a high risk of developing such disease? Second, how can the onset of the degenerative process be detected? Before these difficulties can be resolved, a few requirements will need to be taken into account [START_REF] Corvol | Neuroprevention: a new challenge[END_REF]:

-The need for biological markers is a major priority, not only to obtain an early and accurate diagnosis but also to assess the therapeutic efficacy and side effects of neuroprotective drugs. Recent reports emphasize the progress made in the identification of biomarkers, for instance for Alzheimer disease [30 and especially 31, a detailed contribution by the International Working Group and the US National Institute on Aging-Alzheimer's Association], but the jury is still out on identification of the best biomarkers in the cerebrospinal fluid (amyloid level or, more convincingly, Tau and phosphorylated Tau levels). In addition, the analytical procedures need to be standardized and harmonized [START_REF] Duits | The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean? Alzheimers Dementia[END_REF][START_REF] Lista | Cerebrospinal fluid analysis in Alzheimer's disease: technical issues and future developments[END_REF][START_REF] Blennow | Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease[END_REF]. Importantly, such biomarkers should be first characterized in experimental models used in preclinical studies aimed at validating targets for neuroprotection. Some of these measurements are coupled with PET scan or MRI imaging, an option that is interesting for research purposes but appears to be widely debatable as a diagnostic tool, due to the high cost of these tests and the great number of patients who would need to be analyzed. Furthermore, the benefit of early diagnosis is still debatable in the absence of neuroprotective treatments.

-Another way of achieving an early diagnosis is to detect the first clinical changes that are predictors of the main symptoms. Such a concept is especially relevant for Parkinson's disease. Indeed, non-motor symptoms, such as olfactory dysfunction, dysautonomia and mood and sleep disorders, occur years before the expression of akinesia, rigidity and tremor, the triad of parkinsonian motor symptoms [START_REF] Lang | A critical appraisal of the premotor symptoms of Parkinson's disease: potential usefulness in early diagnosis and design of neuroprotective trials[END_REF][START_REF] Bonnet | Nonmotor Symptoms in Parkinson's disease in 2012: Relevant Clinical Aspects[END_REF].

-Ideally, the best animal models should allow such symptoms to develop. This is the case with primate models of Parkinson disease, in which difficulties in initiation and in choice of motor program can be detected very early in the course of the disease [START_REF] Pessiglione | Impairment of context-adapted movement selection in a primate model of presymptomatic Parkinson's disease[END_REF].

Similarly, sleep disorders develop in MPTP-intoxicated monkeys before the occurrence of any motor symptoms [START_REF] Barraud | Sleep disorders in Parkinson's disease: The contribution of the MPTP non-human primate model[END_REF][START_REF] Belaid | Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion[END_REF]. Symptom improvement remains difficult since it is now clear that the main ones, for example the motor symptoms in Parkinson disease, are accompanied by a wide range of non-motor disorders, such as depression, apathy, dysautonomia and sleep disorders, that also need to be alleviated. Many of these disorders result in major disability and affect quality of life [START_REF] Bonnet | Nonmotor Symptoms in Parkinson's disease in 2012: Relevant Clinical Aspects[END_REF]. Furthermore, some of them, such as hypomania, impulse control disorders and gambling, are even related to the dopaminergic therapy itself.

Thus, there are many difficulties that could account for the lack of effective treatments for neurological disorders. Nevertheless, there are strong ethical, social and medical arguments against pharmaceutical companies withdrawing from this field. Indeed, a clear analysis of these difficulties should lead to a search to identify new strategies and organizations willing to sustain innovative research.

What are the solutions to develop new drugs for neuropsychiatric disorders?

Several review articles, cited in the introduction, emphasize the need to develop better therapies but also contain proposals for solving this issue [9,11,12 see also [START_REF] Agid | How can drug discovery for psychiatric disorders be improved? Nature rev[END_REF][START_REF] Blackburn | Neurological drug development: a guide for a start-up biotech[END_REF][START_REF] Nutt | CNS drug development in Europe -Past progress and future challenges[END_REF].

First, all of them advocate a reinforcement of preclinical research. Second, they point to the limitations of the animal models currently used and suggest they should be improved. Third, they emphasize the need to develop new ideas and new organizations for research on drug development in a context marked by a withdrawal of many pharmaceutical firms from the field of neurosciences.

More and more basic research but with a translational trend Research has to move from serendipity or accidental discovery to new, evidencebased models. But, as reported by Abbott [START_REF] Abbott | The drug deadlock[END_REF], "We'd been tuning the engine, when what we really needed was a new engine", introducing the idea of applying new strategies whilst withdrawing from the replication and implementation of known mechanisms [START_REF] Agid | How can drug discovery for psychiatric disorders be improved? Nature rev[END_REF].

This implies setting other targets than those previously chosen, such as moving from the too simple receptor-ligand interaction towards a more subtle action on the different allosteric sites present on receptors coupled to ion channels as well as metabotropic receptors coupled with G-protein, taking into account their various isoforms [START_REF] Nickols | Development of allosteric modulators of GPCRs for treatment of CNS disorders[END_REF]. It is well known that the nervous system uses many neuropeptides, frequently colocalized with classical neurotransmitters within the synaptic vesicles. Nevertheless, the title given by Leslie Iversen to a short survey, "Neuropeptides: promise unfulfilled?" published in 1993 [START_REF] Iversen | Neuropetides: promise unfulfilled?[END_REF], remains valid at least regarding the therapeutic applications.

These needs also increased attempts to develop translational research between basic research and the clinical field. It is really important to fill the gap between medical reality and some current biomedical research that has "few points of interaction with real medical problems" [START_REF] Horrobin | Modern biomedical research: an internally self-consistent universe with little contact with medical reality?[END_REF]. This opinion should not be misconstrued as indicating opposition to experimental studies on animals, since the author voiced a vigorous plea for physiological studies in intact normal animals in order to understand the complexity of the whole body and to acquire knowledge on functional capacities. Nutt and Attridge [START_REF] Nutt | CNS drug development in Europe -Past progress and future challenges[END_REF] wrote that there is a need to look "outside the box". As a matter of fact, this is a current issue in basic as well as applied research. Innovation arises from a cross-cultural trade-off between researchers at the most basic research level and clinicians, a difficult challenge but one that must necessarily be met. Then "molecular biology researchers have gone full circle from genotype to phenotype knock-out and knock-in animals of neurological disorders and evaluating in animal central nervous system models" [START_REF] Blackburn | Neurological drug development: a guide for a start-up biotech[END_REF]. This openminded attitude helps to track down new drugs resulting from advances in neurosciences as well as drugs otherwise used in other branches of medicine [START_REF] Nutt | CNS drug development in Europe -Past progress and future challenges[END_REF].

Such a strategy is nicely illustrated by an example arising from the psychiatric field. In autism, it was noticed that babies expressing the first signs of the disease maintained the prenatal type of chloride distribution, resulting in an intracellular excess of chloride. In the normal condition, at birth, the oxytocin surge prompts an inversion of this ratio, allowing GABA receptors linked to chloride ionic channels to play their usual inhibitory function. The administration of bumetamide, a diuretic antagonist of a chloride cotransporter, to babies with an early expression of autism restored the normal extra/intracellular ratio of chloride and alleviated the symptoms [START_REF] Lemonnier | The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects[END_REF][START_REF] Lemonnier | A randomised controlled trial of bumetanide in the treatment of autism in children[END_REF][START_REF] Tyzio | Oxytocin-mediated GABA inhibition during delivery atténuates autism pathogenesis in rodent offspring[END_REF][START_REF] Zimmerman | Could autism be treated prenatally[END_REF].

The successes of this collaborative study demonstrate how open collaboration

between basic scientists and clinicians can be fruitful, leading to innovative therapies with an old drug.

Solutions to improve animals models of neuropsychiatric disorders

Preclinical studies are a prerequisite in translational research in order to allow the most reliable testing of new drugs before their use in clinical trials. They help to avoid two major pitfalls: a lack of clinical efficacy and the occurrence of unacceptable adverse effects, including toxicological issues [for examples, see 50]. Yet, the reliability of experimental models needs to be greatly improved as "too many compounds that seem to treat a disease in animals end up having little impact in humans" [START_REF] Insel | Drug research: A plan for mental illness[END_REF]. Based on the results of animal studies, too many drugs have been introduced too quickly, a really costly and unethical mistake leading to unsuccessful clinical trials. A greater likelihood of success could be achieved with a stricter observance of the fundamental principles of preclinical studies, named the three pillars: drug exposure at the target site, target occupancy and functional modulation of the target [START_REF] Morgan | Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival[END_REF]. Nevertheless, in the case of drugs intended to act on the central nervous system, it can be difficult to identify the target (or targets), due to a limited understanding of the disease [START_REF] Pasqua | Translational pharmacology: from animal to man and back[END_REF]. In addition, there are some basic explanations for the failures that have occurred:

-The specificity of the brain, and, more specifically, the blood-brain barrier, which strongly limits the access of the drugs to the nervous system. Hence, in vitro trials cannot be reliably predictive of efficacy in the clinical setting. An additional difficulty arises as drugs cross the blood-brain barrier more easily in rodents than in primates [START_REF] Gad | Safety and regulatory requirements and challenge for CNS drug development[END_REF];

-The neurodegenerative diseases are associated with ageing, whereas the classical tests are conducted on quite young rodents;

-Pharmacological tests are performed on normal animals and do not account for possible changes in reactivity or in pharmacokinetics induced by the disease [START_REF] Markou | Removing obstacles in neuroscience drug discovery: the future path for animal models[END_REF].

-There are some interactions between hormonal impregnation and brain activities, but the animals used are almost exclusively male.

Generally speaking, it is not easy to obtain animal models of neuropsychiatric disorders and more especially of neurodegenerative diseases [START_REF] Nestler | Animals models of neuropsychiatric disorders[END_REF]. For instance, the characterization of cognitive and emotional/motivational impairments, such as those observed in many neurodegenerative diseases, is very difficult to identify and measure in rodents. However, such symptoms can more easily be modeled in non-human primates [START_REF] Pessiglione | Impairment of context-adapted movement selection in a primate model of presymptomatic Parkinson's disease[END_REF][START_REF] Féger | Modèles expérimentaux de la maladie de Parkinson[END_REF][START_REF] Pessiglione | Disruption of selforganized actions in monkey with progressive MPTP-induced parkinsonism. I. Effects of task complexity[END_REF][START_REF] Pessiglione | Disruption of self-organized actions in monkey with progressive MPTP-induced parkinsonism. II. Effects of reward preference[END_REF][START_REF] Féger | Ganglions de la base et troubles psychiatriques : une modélisation expérimentale[END_REF]. As quoted by McLeod [START_REF] Macleod | Animal models of neurological disease: are there any babies in the bathwater?[END_REF], the use of suitable animal models should be improved whereas new models have to be developed. The general criteria for validating animal models, as stated by Willner [START_REF] Willner | Validation criteria for animal models of human mental disorders : learnd helplessness a a paradigm case[END_REF], namely predictive, face and construct validity, remain valid. The limitations of animal models have been discussed within the American College of Neuropsychopharmacology. A review [START_REF] Markou | Removing obstacles in neuroscience drug discovery: the future path for animal models[END_REF] reports the main conclusions of the discussions and the proposals that were made to improve these models. Even though they were made some years ago, these conclusions and proposals remain valid today. It was recognized that "the use of whole animal models is an integral part of CNS drug discovery". The authors emphasized the need for preclinical and clinical measures to be "as closely as possible homologous" in a translational effort. This is especially relevant in Alzheimer disease models. In a recent review on this topic [START_REF] Laurijssens | Animal models of Alzheimer's disease and drug development Drug discovery today[END_REF], the authors list three categories of reasons that could account for the failure of these models in the translation of preclinical results to patients:

-The models are based on an incorrect hypothesis, and do not reflect the clinical disease in humans;

-The model investigates a relevant target, but which has a different reactivity in humans versus animals, or differences in drug pharmacokinetics impede it in reaching its target or in reaching its target at the appropriate concentration (see, for example, a comment and a report on the failure of a clinical trial of a neuroprotective drug in progressive supranuclear palsy [START_REF] Tariot | When should neuroprotective drugs move from mice to men?[END_REF][START_REF] Boxer | Davunetide in patients with progressive supranuclear palsy: a randomised, doubleblind, placebo-controlled phase 2/3 trial[END_REF]; -The clinical trial has an inappropriate design, particularly with regard to the dose or administration regimen, the duration of treatment before the endpoint evaluation and the criteria used to determine the endpoints.

One common criticism relates to the need to improve the predictive value of animal tests, for example by using similar motor and behavioral scales and similar biomarkers in both the preclinical and clinical trials [START_REF] Markou | Removing obstacles in neuroscience drug discovery: the future path for animal models[END_REF]. Moreover, such tests should enable treatment efficacy to be monitored, especially in the case of a neuroprotective drug. The use of brain imaging methods offers interesting possibilities in preclinical studies and sound comparison with clinical tests [START_REF] Nutt | CNS drug development in Europe -Past progress and future challenges[END_REF][START_REF] Matthews | Technologies: preclinical imaging for drug development[END_REF][START_REF] Hargreaves | Translational PET Imaging research[END_REF]. The following are particularly suitable in research on brain diseases:

-Magnetic resonance imaging (MRI), which could be combined with magnetic resonance spectroscopy providing information on tissue bioenergetics. Both these techniques allow longitudinal studies on the effect of a treatment. MRI devices have been designed for rodents, allowing comparison with human MRI studies.

-Positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) provide accurate data on the distribution of the labeled drug to the different cerebral structures, and provide information on occupancy of receptor sites [START_REF] Hargreaves | Translational PET Imaging research[END_REF]. Special devices are needed to perform such studies on rodents owing to the spatial resolution of around 1 to 2.5 mm, an irreducible physical parameter.

The acquisition of imaging data, especially those obtained with PET, is expensive, but provides data that are reliable enough to go on with a new molecule of interest on the basis of the accessibility and activity on the aimed target. Furthermore, the expense involved will be far less than the losses that would be incurred if a clinical trial were launched on an erroneous assumption. The situation in France is that pharmaceutical companies can have access to publicly funded research facilities and platforms dedicated to the use of imaging in animal models, mainly investigating neurodegenerative diseases.

It is reasonable to expect that the improvement of animal models, better identification of targets and use of biomarkers and new methodologies, such as imaging, will enable sound preclinical trials to be performed.

Towards a new organization of drug research

There are many reasons why pharmaceutical companies have left the field of the neurosciences [see16,42]. This withdrawal from research leaves the door open "to rethink how academia and industry can work together for the public good" [START_REF] Insel | Drug research: A plan for mental illness[END_REF]. In fact, the gap between academic researchers and pharmaceutical industries has appeared progressively over time for many reasons, including, first, the large growth of academic research institutions, and their ability to perform their research in-house. This has led to a change in their relationship with pharmaceutical companies [START_REF] Vallance | The future is much closer collaboration between the pharmaceutical industry and academic medical centers[END_REF].

Innovative research needs to build on new ways of collaboration between the different partners: academic basic scientists and clinicians involved in clinical research, start-up companies in biotechnology, frequently interfaced with academic structures, pharmaceutical industries and also patient lay organizations.

The distance between basic science and clinical research has long been a key issue in translational research for neuropsychiatric disorders. Leaders of academic research have consequently been trying to bridge the gap between basic and applied research, especially in the clinical field. Some years ago, a first step was taken with the creation of clinical units dedicated to clinical pharmacology or translational medicine, called centers of clinical investigation. These centers allow access to patients for therapeutic trials. In these centers it is possible to run "small-scale carefully monitored studies" in a "learn and confirm approach" in contrast to the larger and more expensive clinical trials [START_REF] Vallance | The future is much closer collaboration between the pharmaceutical industry and academic medical centers[END_REF]. In France, these "Centers for Clinical Investigation (CIC)" allow clinical trials to be performed using academic funding in collaboration with pharmaceutical companies. More specialized research institutes in the neurosciences are localized within university hospitals, such as the ICM (Brain and Spinal Institute) located at the Pitié-Salpêtrière Hospital in Paris, which enables preclinical, clinical and industry research to be performed in one place, and gives companies the opportunity to work in a biotech incubator located in the Institute. The general scientific and clinical goal is to bridge the gap between basic scientists and clinical researchers and to mobilize all the various partners to work on the identified scientific projects.

Another illustration of the work undertaken to improve the effectiveness of drug research in France is the creation of AVIESAN (Alliance nationale pour les Sciences de la Vie et de la Santé). This umbrella structure was founded in 2009 with the aim of developing synergies between all the research organizations involved in the fields of biology, life sciences and health [67]. The AVIESAN alliance is composed of ten thematic institutes, including one that concentrates on neurosciences, cognitive sciences, neurology and psychiatry [68]. A few years ago it was hard to imagine that researchers in these fields would agree to cooperate and work together. Now, these institutes are promoting better coordination between programs, expanding transdisciplinary and translational research with a trend towards clinical applications and making it easier to develop industrial and European partnerships.

There is another way of inducing new relationships, namely precompetitive collaboration between academic research and industry research, where "competitors share early stages of research that benefit all" [START_REF] Wagner | Open-minded to open innovation and precompetitive collaboration[END_REF]. This new concept relies on a publicprivate partnership and can be defined as "open collaborations between companies that usually are intellectual property competitors" [START_REF] Vargas | Arguments against precompetitive collaboration[END_REF]. There is evidence that fundamental biological research leads to an exponential accumulation of data whereas "the barriers to information sharing have never been lower " [START_REF] Wagner | Open-minded to open innovation and precompetitive collaboration[END_REF]. In line with this, the general purpose of precompetitive collaboration is to reach the following goals: (1) facilitate data sharing, with development of mutual standards [START_REF] Sidders | Precompetitive activity to address the biological data needs of drug discovery[END_REF]; (2) enable high throughput of new data, using new biological technologies in genomics and proteomics; (3) improve the discovery of biomarkers and models of disease by the accumulation of shared knowledge; (4) promote product development [START_REF] Altshuler | Opening up to precompetitive collaboration[END_REF][START_REF] Vassal | Recherche précompétitive, une mise en synergie des ressources publiques et privées: pour quels objectifs, comment et dans quel cadre juridique[END_REF]. It is assumed that breakthrough therapies will arise from the integration of knowledge and expertise from multiple sources [START_REF] Melese | Open innovation networks between academia and industry: an imperative for breakthrough therapies[END_REF]. A first precompetitive collaboration was reported with the announcement of collaboration between Astra Zeneca and the Naomi Berrie Diabetes Center at Columbia University Medical Center [START_REF] Hughes | Pharma pursues novel models for academic collaboration[END_REF]. As with the other major pharmaceutical groups, the first motivation was to develop institutional relationships instead of the personal relationships between academics and industrialists that often encountered in the past. In Europe, such precompetitive collaboration is being initiated with the Innovative Medicine Initiative (IMI) Joint Undertaking (IMI JU) launched in 2007, under the patronage of the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in order to boost the discovery and development of new and safer drugs. Two projects are related to neuropsychiatric diseases, grouping together a large set of multidisciplinary expertise using coherent evaluation in their approaches: (1) "Novel methods leading to new medications in depression and schizophrenia" has provided a big database for therapeutic research in psychiatry; (2) the IMI PharmaCog project [76] is devoted to Alzheimer disease with a focus on "Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in early clinical development". This program includes new approaches to evaluate treatment efficacy, with identification of markers based on imaging, cognitive, electrophysiological and biochemical approaches, usable in animals as well as in patients, and able to predict the dose range and efficacy of new molecules in order to define the priorities, as comprehensively detailed in a recently published report [START_REF] Deguil | Evaluation of symptomatic drug effects in Alzheimer's disease: strategies for prediction of efficacy in humans[END_REF].

Precompetitive collaboration also has to take into account difficulties related to cultural shortcomings in the personality of academic researchers and industrial researchers [START_REF] Melese | Open innovation networks between academia and industry: an imperative for breakthrough therapies[END_REF]. The question of intellectual property can be seen as a critical issue with divergent interests between confidentiality and fast publication [START_REF] Vallance | The future is much closer collaboration between the pharmaceutical industry and academic medical centers[END_REF][START_REF] Wagner | Open-minded to open innovation and precompetitive collaboration[END_REF][START_REF] Vargas | Arguments against precompetitive collaboration[END_REF][START_REF] Melese | Open innovation networks between academia and industry: an imperative for breakthrough therapies[END_REF]. This is reported as a limitation on precompetitive collaboration [START_REF] Vargas | Arguments against precompetitive collaboration[END_REF], but there have been some positive proposals on this subject [START_REF] Vassal | Recherche précompétitive, une mise en synergie des ressources publiques et privées: pour quels objectifs, comment et dans quel cadre juridique[END_REF]. Another issue is related to the multiple sources of financial support, often originating from both public and private sources, and the subsequent sharing of intellectual property. Yet, consortia agreements can easily resolve this issue. The management of communication and data exchange also requires constant attention due to the large number of organizations involved: for example, in PharmaCog, there are 12 academic partners, 12 large pharmaceutical groups, 5 small and mediumsized firms, and 1 patients' association (Alzheimer Europe), with, in addition, the active presence of the European Medicines Agency [START_REF] Vassal | Recherche précompétitive, une mise en synergie des ressources publiques et privées: pour quels objectifs, comment et dans quel cadre juridique[END_REF][START_REF] Deguil | Evaluation of symptomatic drug effects in Alzheimer's disease: strategies for prediction of efficacy in humans[END_REF].

Another topic of importance is the relationship between the different partners involved in drug research and the regulatory authorities, such as the EMA in Europe This unique organization can be used for anatomopathological research and to better understand the pathophysiology of neurodegenerative disorders. Some of the topics discussed in this review such as redefining the target, translational research, utility of a brain bank and use of suitable animal models, are of utmost importance for the identification of new targets for neuroprotection, especially in the field of Alzheimer disease. Until now, the "amyloid hypothesis" was seen as the main clue to explain the development of the disease. A toxic effect was attributed to the accumulation of β amyloid protein. At the same time, others have pointed to the accumulation of paired microtubule-associated protein tau, which might also be related to the neurodegenerative process. As this anatomopathological stigma was also observed in other neurodegenerative diseases, the concept of tauopathies was introduced. However, the β amyloid protein remained the target and much research, using various biological possibilities, was consequently directed at preventing the production and accumulation of this peptide in order to reduce the amyloid-related damage. Only recently, the "amyloid hypothesis" was strongly questioned in a report concluding that accumulation of β-amyloid is a consequence and not the cause of the neuronal lesion [START_REF] Drachman | The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease[END_REF]. Thus, tau protein appears as another interesting target with some interesting features: (1) the expression of IP3 kinase is increased in the brain of patients suffering from Alzheimer disease, a change correlated with hyperphosphorylation of tau protein [START_REF] Stygelbout | Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates Mouse Alzheimer pathology[END_REF]; (2) the interaction of a protein FKBP52 belonging to the immunophilin family with abnormal tau induces the formation of oligomers evolving into a fibrillar structure [START_REF] Giustiniani | Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy[END_REF]; (3) the topographical progression of lesions and of neurofibrillary deposit localized using an immunoreaction for hyperphosphorylated tau protein follows a predictable sequence, roughly from subcortical nuclei close to the brainstem towards neocortical areas [START_REF] Braak | Neuropathological stageing of Alzheimer-related changes[END_REF][START_REF] Braak | Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry[END_REF]; (4) convergent results [START_REF] Jucker | Self-propagation of pathogenic protein aggregates in neurodegenerative diseases[END_REF][START_REF] Chécler | Alzheimer's and prion diseases: PDK1 at the crossroads[END_REF], conclude in favor of a propagation, in a prion-like manner, of pathogenic tau protein in Alzheimer disease. Similar mechanisms might be involved in α-synuclein pathology in Parkinson's disease [START_REF] Recasens | Lewy body extracts from Parkinson disease brains trigger a-synuclein pathology and neurodegeneration in mice and monkeys[END_REF].

These studies on neurodegenerative disorders illustrate how translational research can influence clinical trials and identification of targets for neuroprotection. Now, a new era in drug research is beginning. First, preclinical studies need to improve in terms of the animal models used and their predictive values, with the use of markers that will be suitable in animals as well in patients. Second, a major shift in approach is now apparent with an undeniable trend towards translational research. Third, the development of new methods of coordinating research is leading to greater integration of all researchers, including both basic scientists and clinicians. All these developments are clear evidence that the distant and sometimes suspicious [START_REF] Vallance | The future is much closer collaboration between the pharmaceutical industry and academic medical centers[END_REF], relationships that used to exist between researchers, pharmaceutical companies and clinicians have largely called into question and are being replaced by a new model allowing stronger integration between all partners. All these factors give cause for optimism and bode well for the future of CNS drug discovery.

  [78],and the Food and Drug Administration (FDA) in the United States. Their guidelines and scientific advice result, at least in their initial versions, from bilateral discussions between representatives of pharmaceutical companies and public authorities. It is beyond the scope of this review to give a detailed description and to assess how regulatory authorities could boost research on innovative drugs. A discussion on some of the methodological features is more relevant. For example, a group of scientific advisors validate new endpoints to be used in clinical trial evaluation in Alzheimer disease: for example, determination and follow-up of hippocampal size through anatomical MRI, PET imaging of amyloid deposit and determination of β amyloid and tau protein in cerebrospinal fluid.Standardization of these markers will then enable their use in preclinical and clinical trials [see 78 and follow > Human regulatory > Scientific advice and protocol assistance > Qualification of novel methodologies for medicine development], Similar observations could be made regarding the multidisciplinary guidelines due to the International Conference on Harmonisation (ICH) of scientific and technical requirements for registration of pharmaceuticals for Human use [79]. ICH bring together the regulatory authorities and pharmaceutical industry in Europe, Japan and USA. Among the ICH contributions, some guidelines, like M3, are related to preclinical safety studies. Finally, these dialogues increase the intelligibility of the problem, validate the proposals of researchers for new methodologies, and allow sounder choices to be made when moving from preclinical to clinical studies. Another partner should not be neglected in the long road towards the development of innovative therapeutics, namely the patients' associations. There are numerous philanthropic foundations, such as The Michael J. Fox Foundation for Parkinson's Research [80], and patients' associations, such as Association France Parkinson and Association France Alzheimer. The latter two and other associations dedicated to brain diseases have together created an umbrella organization named "Federation pour la Recherche sur le Cerveau" [81]. Initially, their activity was directed at supporting and informing patients and their families, collecting information about undesirable side effects from a pharmacovigilance standpoint and raising public awareness of neuropsychiatric diseases. However, patients' organizations have gradually become partners in research activities: (1) funding of research projects and grants to young investigators, a system offering considerable flexibility; (2) more recently they have become active players within research organizations, such as PharmaCog, submitting patients' claims and also urging the public administration to promote research on these diseases. Moreover, their advocacy can be helpful in the process of recruiting selected cohorts of patients for clinical studies. This interface even extends to brain donation for research purposes through a special organization: Neuroceb [82], aimed at collecting brains for a brain bank and partly financed by Association France Parkinson, ARSEP and Association France Alzheimer.

Disclosure of interest : The authors declare they have no conflict of interest concerning this article.

The research leading to these results has received funding from the program "Investissements d'avenir" ANR-10-IAIHU-06.

Acknowledgments :

The authors thank the following colleagues who gave stimulating and comprehensive lectures during the meeting held on 19 march 2014 at the French Académie nationale de Pharmacie, which nicely contributed to some ideas expressed in this Review.

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Eddy currents self-tuning dynamic vibration absorber for machine tool chatter suppression

G. Aguirre 1 , M. Gorostiaga 1 , T. Porchez 2 , J.Muñoa 1 1 IK4-IDEKO, Spain 2 CEDRAT TECHNOLOGIES, France gaguirre@ideko.es

Abstract

The current trend in machine tool design aims at stiffer machines with lower influence of friction, leading to faster and more precise machines. However, this is at the expense of reducing the machine damping, which is mainly produced by friction, and thus increasing the risk of suffering from a self-excited vibration named chatter, which limits the productivity of the process [START_REF] Munoa | Effect of mode interaction on stability of milling processes[END_REF]. Dynamic vibration absorbers (DVAs) offer a relatively simple and low cost solution to reduce chatter appearance risk by adding damping to machine tools. The proper tuning of the dynamic characteristics of the damper to the machine/process dynamics is the key for productivity improvement.

A DVA which can detect its optimal tuning frequency and adapt its dynamics accordingly is proposed here. The main design and working principles of this damper, and the improvement of the machining conditions allowed by the damper will be demonstrated by real milling experiments.

Design of Dynamic Vibration Absorber

Dynamic vibration absorbers consist of a mass connected to the machine with a certain stiffness and damping, so that its resonance frequency is tuned to the frequency of the machine mode leading to chatter, by adding damping to it and allowing higher cutting depths [START_REF] Sims | Vibration absorbers for chatter suppression: A new analytical tuning methodology[END_REF]. Tunable DVAs are needed so that their dynamic characteristics can be adapted to a range of machine and process conditions.

The main challenges that need to be addressed are how to obtain the desired stiffness and damping values, and how to detect the frequency to which it needs to be tuned.

The solution proposed here allows independent stiffness and damping tuning, with online stiffness tuning capability, with a highly repetitive and linear behaviour, compared to typical solutions based on elastomers.

In-process optimal tuning frequency detection is proposed too, based on processing an accelerometer signal, thus without need of an experimental modal analysis, which requires specialized equipment and personnel, and does not consider changes during machine operation (e.g. different workpiece mass, position dependent stiffness, etc.).

Variable stiffness spring

The stiffness of the DVA proposed here can be varied thanks to a variable stiffness spring controlled by a rotary stepper motor (see Figure 4a). Within 90º rotation, the stiffness of the spring changes between two values, easily defined at design stage through a and b parameters (see Fig. 1), providing a repetitive and linear stiffness tuning.

Eddy current damping tuning

Eddy current damping is generated by the relative motion of copper plates within a magnetic field generated by magnets, and it provides a close-to-viscous damping effect. Since it generates no stiffness, and the spring presented above provides little damping to the system, the stiffness and damping of the DVA can be tuned independently, which is a great advantage over other typical solutions such as elastomers.

Figure 2: Magnet configuration and orientation, design and prototype

Self-tuning strategy

Optimal performance can be achieved if the tuning frequency can be calculated online during the machining process. A chatter detection algorithm is proposed here, which based on the information provided by an accelerometer placed on the DVA, detects whether chatter is being generated and at which frequency, and tunes the damper accordingly by commanding the stepper motor to move the rotary spring according to a calibrated angular positionresonance frequency relationship. damping, values which are in range with the optimal [START_REF] Munoa | Effect of mode interaction on stability of milling processes[END_REF]. As it can be seen on Figure 4, the moving mass is formed by the four magnet racks, with the copper plates fixed to the frame, providing thus a very compact system. An accelerometer is placed on the frame to measure machine vibration. By performing an experimental modal analysis of the machine, the stability lobes of the cutting process have been calculated, in order to show the maximum cutting depth that can be achieved without the damper. A number of machining tests show the validity of this prediction. The DVA was placed on the machine next, and it was tuned automatically during the cutting process, without using the information from the modal analysis. The process was found to be stable up to the maximum cutting depth defined by the tool (5 mm), compared to the unstable conditions with 1 mm depth without damper. A time simulation of the cutting and tuning process predicts much higher stable cutting depths, but they cannot be reached due to tool limitations. These results demonstrate the effectiveness of the self-tuning DVA principle presented here. In real applications, productivity improvement will not be so high, but it will outperform existing DVAs by providing a low cost solution that does not require a previous experimental modal analysis and that works in close-to-optimal conditions even when process dynamics change during operation.

Figure 1 :

 1 Figure 1: Rotary spring

Figure 4 :

 4 Figure 4: DVA component a) rotary spring and motor b) magnets c) assembly 4 Machining results

Figure 3 :

 3 Figure 3: Machine tool and DVA setup

Figure 5 :

 5 Figure 5: Machining test and simulation results, with and without DVAIn Figure6, the part that was used for the machining tests is shown. Clear chatter vibration marks can be seen without damper and 3mm depth, while a smooth surface is produced using the DVA with 5 mm depth, for several spindle speeds.

Figure 6 :

 6 Figure 6: Workpiece surface: a) no DVA, 3 mm depth b) with DVA, 5 mm depth 5 Conclusions

Proceedings of the 13 th euspen International Conference -Berlin -May 2013