Keywords: Embryon, placenta artificiel, utérus, bioingénierie Embryo, artificial placenta, uterus, bioengineering

L'utérus est l'organe femelle spécialisé permettant qu'une grossesse aboutisse à une naissance. Afin de traiter ou de contourner les infertilités d'origine utérine, diverses stratégies thérapeutiques sont aujourd'hui appliquées. Cette revue présente et discute les avancées récentes réalisées dans les domaines du développement péri-implantatoire de l'embryon in vitro, des dispositifs biotechnologiques mimant la fonction placentaire et de médecine regénérative de l'utérus. A ce jour, aucune des approches disponibles ne permet de s'affranchir de l'utérus pour assurer le développement de l'embryon de l'implantation jusqu'à terme, hors de l'organisme maternel.

The uterus is the specialised female organ that enables a pregnancy to result in a birth. In order to treat or circumvent uterine infertility, various therapeutic strategies are currently used. This review presents and discusses recent advances in the fields of in vitro development of peri-implantation embryo, biotechnological devices that mimic placental function and regenerative medicine applied to the uterus. To date, none of the available approaches allows the uterus to be bypassed in order to ensure the development of the embryo from implantation to term, outside the maternal body.

INTRODUCTION

Dans nos sociétés industrialisées, la prise en charge des pathologies liées à l'infertilité représente un enjeu sociétal et de santé publique majeur [START_REF] Hamamah | Ministère des Solidarités et de la Santé. Rapport sur les causes d'infertilité -Vers une stratégie nationale de lutte contre l'infertilité[END_REF]. En l'espace de quelques décennies, les traitements de l'infertilité humaine ont bénéficié des apports de l'insémination artificielle, de la congélation des gamètes et de l'embryon, de la fécondation in vitro (FIV) associée au transfert d'embryons, ainsi que du développement d'approches expérimentales telles que la transplantation utérine [START_REF] Niederberger | Forty years of IVF[END_REF][START_REF] Ayoubi | Transplantation uterine[END_REF]. Par le recours aux cohortes de patients, aux modèles impliquant les animaux et les approches in vitro, la recherche vise à améliorer de façon continue l'assistance médicale à la procréation pour (i) la prise en charge de nouvelles situations d'infertilité, (ii) accroitre le taux de réussite et diminuer les effets potentiellement préjudiciables à long terme sur la descendance associés à l'utilisation des biotechnologies de l'embryon [START_REF] Duranthon | Long term effects of ART: What do animals tell us?[END_REF], et développer de nouvelles approches thérapeutiques ou chirurgicales pour des patientes infertiles afin de diminuer la mortalité et morbidité de la descendance.

Au-delà de la phase pré-implantatoire, le déroulement et le succès de la grossesse requiert l'utérus, organe maternel indispensable et irremplaçable pour assurer le développement post-implantatoire de l'embryon puis de l'unité foeto-placentaire. Pour que ces étapes mènent à la naissance de nouveau-nés vivants et en bonne santé, il est essentiel que cet utérus soit fonctionnel, réceptif et synchronisé avec le stade de développement de l'embryon [START_REF] Sehring | Human implantation: The complex interplay between endometrial receptivity, inflammation, and the microbiome[END_REF]. Les approches liées au développement préimplantatoire ex vivo de l'embryon atteignent un niveau de maitrise déjà élevé chez les mammifères, avec un développement ex vivo pouvant atteindre 14 jours chez plusieurs espèces, humain compris. Il n'existe à ce jour aucune solution biotechnologique permettant de pallier une absence d'utérus ou une déficience ne pouvant être prise en charge par des approches cliniques et chirurgicales. Toutefois, des données récentes mettent en évidence de réelles avancées en terme de durée de développement in vitro de l'embryon, de développement ex vivo du foetus et de bio-ingénierie de l'utérus, qui font l'objet de cette revue.

A. Développement de l'embryon : le plafond de verre des 14 jours Pendant la période peri-implantatoire, l'embryon se transforme radicalement pour s'implanter dans l'utérus et se préparer à la gastrulation (Figure 1). La séquence d'événements n'est connue que grâce à des planches histologiques réalisées au siècle dernier. La ligne primitive, qui se forme au jour 14 (J14) chez l'Homme, marque le début de la gastrulation, avec l'apparition des trois lignages primordiaux, et les précurseurs des cellules germinales. Afin d'explorer plus avant cette période péri-implantatoire si critique, diverses conditions de culture ont été essayées ex vivo dans le modèle murin, permettant de reproduire avec une relative efficacité (25 à 30%), soit la période depuis le blastocyste jusqu'à la formation de l'épiblaste avec un début de polarisation antéro-postérieure (stade « oeuf cylindre ») [START_REF] Bedzhov | Self-Organizing Properties of Mouse Pluripotent Cells Initiate Morphogenesis upon Implantation[END_REF]; soit la période depuis la gastrulation jusqu'à l'organogenèse. L'étude moléculaire de ces embryons cultivés six jours et de leurs homologues développés in vivo montre une grande similitude, ce qui valide ces conditions ex vivo [START_REF] Aguilera-Castrejon | Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis[END_REF]. En fin de culture, l'embryon meurt avec des symptômes proches de l'hydrops fetalis, par insuffisance de nutriments et d'oxygène, indiquant la nécessité d'une circulation foeto-placentaire. Chez l'homme, en utilisant le même protocole, il est également possible de maintenir des blastocystes pendant une semaine ex vivo, soit de J6 à J12, avec une efficacité d'environ 15%, et un développement retardé [START_REF] Deglincerti | Self-organization of the in vitro attached human embryo[END_REF][START_REF] Shahbazi | Self-organization of the human embryo in the absence of maternal tissues[END_REF]. La plupart, si ce n'est tous les pays qui autorisent la recherche sur l'embryon humain, ont adopté la règle des 14 jours, comme limite maximale de la durée de culture. Chez le macaque, la succession temporelle des étapes depuis l'implantation jusqu'à la mise en place de la gastrulation semblent proches de celle dans l'embryon humain. Chez cette espèce, la culture a pu être poursuivie pendant 20 jours, ce qui a permis d'atteindre le stade du début de la gastrulation, avec l'apparition de cellules qui ressemblent à des précurseurs des cellules germinales [START_REF] Niu | Dissecting primate early post-implantation development using long-term in vitro embryo culture[END_REF].

Dans ces différents protocoles, l'embryon est cultivé sur support simple sur lequel il demeure attaché. Les contraintes liées à ce type de développement artificiel contribuent au retard de développement observé. Chez la souris [START_REF] Ichikawa | An ex vivo system to study cellular dynamics underlying mouse peri-implantation development[END_REF] et l'homme [START_REF] Xiang | A developmental landscape of 3D-cultured human pre-gastrulation embryos[END_REF]. Deux études récentes montrent une cinétique de développement plus proche de la normale et une meilleure efficacité lorsque les embryons sont cultivés en matrice 3D, donc sans contact avec le support. Dans ces conditions, les embryons humains se sont développés jusqu'à J14. Ce type de matrices permet de maintenir la forme de l'embryon mais ne permet pas de mimer le processus d'implantation. Chez la souris, des embryons ont été inclus dans un hydrogel plus complexe et relié à des canaux colonisés par des cellules endothéliales [START_REF] Govindasamy | 3D biomimetic platform reveals the first interactions of the embryo and the maternal blood vessels[END_REF]. Cette approche a permis de modéliser le processus de l'implantation, comprenant l'invasion des cellules du trophectoderme et leurs interactions avec les capillaires maternels.

Ces différentes études ex vivo permettent d'analyser de façon fine, au niveau cellulaire comme moléculaire, les étapes du développement au-delà du stade blastocyste. Des analyses de transcriptome sur cellules uniques, générées à partir d'embryons cultivés ex vivo, ont montré l'apparition progressive des différents lignages [START_REF] Xiang | A developmental landscape of 3D-cultured human pre-gastrulation embryos[END_REF][START_REF] Molè | A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre[END_REF] qui ne peuvent être directement comparés aux stades équivalents d'embryons développés in vivo, ces stades n'étant connus chez l'homme qu'au travers de planches histologiques. Observer le processus de gastrulation in vitro, valider l'efficacité de la culture, et au niveau moléculaire, permettrait ainsi la comparaison avec les analyses de transcriptome récemment obtenues à partir d'un embryon humain au stade J19/20 , consécutivement à un avortement [START_REF] Tyser | Single-cell transcriptomic characterization of a gastrulating human embryo[END_REF]. Cela nécessiterait de remettre en question la règle des 14 jours. Quoi qu'il en soit, des comparaisons vitro/vivo sont d'ores et déjà possibles pour les modèles de primates non humains ainsi que la souris et seront informatives, comme le sont les comparaisons interespèces, qui renseignent sur le degré de conservation évolutive des phénomènes observés.

Enfin il n'est pas possible de ne pas évoquer les modèles émergents d'embryogenèse dite synthétique, qui reposent sur la capacité intrinsèque à s'auto-organiser des cellules embryonnaires. Des cellules souches pluripotentes humaines, cultivées dans des conditions qui révèlent un potentiel étendu de différentiation, s'organisent en cyste qui, soumis à des signaux différentiels, peut ensuite former un épiblaste et un amnios.

Les possibilités sans limites qu'offrent ces modèles cellulaires ouvrent la voie aux tests de milieux séquentiels, matrices complexes, systèmes de microfluidiques, qui pourront ensuite bénéficier aux cultures d'embryons ex vivo.

Bioingénierie de l'utérus : les prémices d'un utérus artificiel

Le rôle de l'utérus est central pour le succès de la grossesse. Lorsque cet organe est absent ou que des déficiences fonctionnelles ne peuvent être restaurées par des approches thérapeutiques, la transplantation utérine représente l'unique option actuelle pour traiter ce type d'infertilité. Les travaux pionniers du groupe de Pr Brännström [START_REF] Brännström | Livebirth after uterus transplantation[END_REF] ont ouvert la voie au développement de cette chirurgie, complexe et expérimentale, qui a récemment abouti à l'hôpital Foch à la naissance du premier enfant issu d'une transplantation utérine en France [START_REF] Ayoubi | Transplantation uterine[END_REF].

En l'absence d'utérus artificiel et pour contourner des difficultés liées à la transplantation utérine (nécessité d'un donneur et de traitements immunosuppresseurs), les approches d'ingénierie tissulaire se sont développées avec l'objectif de remplacer une partie d'un utérus dysfonctionnel pour le rendre compatible avec la grossesse [START_REF] Yoshimasa | Bioengineering of the Uterus[END_REF]. En s'appuyant sur des modèles rongeurs, diverses approches ont été publiées, qui font ou non appel à des matrices de biomatériaux souvent recolonisées par des cellules [START_REF] Matoba | Current status of uterine regenerative medicine for absolute uterine factor infertility[END_REF]. Le recours aux biomatériaux vise à générer des structures tri-dimensionnelles dépourvus d'immunogénicité, non toxiques, biocompatibles, biodégradables et dotées de propriétés biomécaniques pertinentes. On distingue les matrices synthétiques (polymères, céramiques, métalliques ou graphène) de celles constituées de composants naturels présents dans les matrices extra-cellulaires (ex : collagène, gélatine acide hyaluronique) ou générées par la déplétion des cellules de l'organe tout en conservant les structures de la matrice extracellulaire. Dans les deux derniers cas, les points de vigilance portent respectivement sur des risques d'infection (collagène) ou de réponse immunitaire de la femelle receveuse.

Au-delà des espèces modèles, plusieurs groupes ont travaillé sur des modèles animaux de taille plus importante, afin de tester divers protocoles de chirurgie reconstructrice sur des lésions de grande taille. Chez la brebis, modèle préclinique dont la taille est proche de celle de l'utérus humain, ont été testés plusieurs protocoles de décellularisation de l'utérus. Le groupe de M. Brannström est parvenu à générer des matrices décellularisées, potentiellement utilisables dans des protocoles de bioingénierie tissulaire appliqués à l'utérus.

La question de la recellularisation reste toutefois entière et nécessite de nouvelles investigations [START_REF] Tiemann | Towards uterus tissue engineering: a comparative study of sheep uterus decellularisation[END_REF]. Chez le lapin, une matrice artificielle recolonisée avec des cellules utérines primaires autologues a été insérée dans une corne utérine excisée sur plus de trois-quarts de sa circonférence. L'utérus ainsi reconstruit a conduit à la différenciation de toute ses composantes (endomètre et myomètre), similaire au tissu natif. Ce néo-utérus fonctionnel a permis la naissance de lapereaux bien formés, après fécondation naturelle [START_REF] Magalhaes | A tissue-engineered uterus supports live births in rabbits[END_REF]. Dans tous les cas de médecine régénérative appliquée à l'utérus, il parait indispensable de procéder à l'évaluation fonctionnelle de l'organe par la gestation.

Du développement foetal ex vivo au placenta artificiel

Le développement des embryons post-implantatoires en dehors de l'organisme maternel représente un sérieux défi. Chez les rongeurs, les premières tentatives datent des années 1930, avec des embryons en gastrulation cultivés dans des milieux liquides similaires au plasma, en conditions statiques, sous agitation ou en recirculation. Les différents procédés, associés à des temps de survie courts (24 à 48 heures), conduisent à des développements anormaux de ces embryons en gastrulation. En 2021, l'équipe de Hanna [START_REF] Aguilera-Castrejon | Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis[END_REF] a publié un protocole permettant de cultiver ex vivo des embryons murins prélevés à J7,5 de développement (stade prégastrulation) jusqu'à 11,5 j de développement, un stade qui correspond à la mi-gestation chez la souris. Chez l'homme, dans certaines situations initialement physiologiques, la grossesse ne peut pas se poursuivre jusqu'au terme attendu, que les causes soient d'origine placentaire, maternelle et/ou foetale. Ceci a pour conséquence une naissance prématurée qui peut avoir un impact négatif sur le développement ultérieur de l'enfant, d'autant plus important que l'accouchement a lieu précocement [START_REF] Ancel | Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study[END_REF]. Aujourd'hui, si l'optimisation des techniques de réanimation néonatale a permis d'améliorer de façon importante le pronostic pour ces enfants, le devenir des enfants nés avant 28 semaines d'aménorrhée (6 mois de grossesse) reste grevé de complications sévères, en raison d'atteintes cérébrales, pulmonaires et digestives [START_REF] Pierrat | Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study[END_REF].

En arguant de la possibilité de retombées thérapeutiques, des systèmes de développement foetal extra-utérin ont été publiés, en alternative à la réanimation néonatale conventionnelle pour la période 22-26 SA. Une équipe américaine [START_REF] Partridge | An extra-uterine system to physiologically support the extreme premature lamb[END_REF][START_REF] Hornick | Umbilical cannulation optimizes circuit flows in premature lambs supported by the EXTra-uterine Environment for Neonatal Development (EXTEND)[END_REF] et une équipe australo-nippone [START_REF] Usuda | Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability[END_REF] ont déjà prouvé la faisabilité d'un tel système, dans un modèle ovin alliant un placenta et une cavité amniotique artificiels avec installation du foetus dans un environnement contrôlé pendant les dernières semaines de la gestation. Ce dispositif vise à se rapprocher au plus près de la physiologie du développement intra-utérin, à l'opposé de ce que doivent supporter les extrêmes prématurés à l'heure actuelle. Les échanges gazeux sont assurés par un système d'oxygénation et décarboxylation par perfusion ombilicale, qui couvre également les apports énergétiques et nutritionnels. Le

CONCLUSION

Depuis les premières tentatives visant à expérimenter l'implantation d'un embryon en-dehors du corps humain (Buletti et al., 1988), la question de la substitution de l'utérus dans les cas d'infertilité absolue liée à cet organe a pris de l'ampleur. Au-delà de l'enjeu de produire un embryon de qualité suffisante pour être transféré et assurer la naissance d'un nouvel individu vivant, l'organogénèse en dehors de l'organisme maternel représente un défi considérable [27]. L'essor d'approches innovantes permet d'envisager le développement ex vivo d'un embryon de la conception jusqu'à un stade de développement foetal compatible avec sa survie, au travers de la mise au point et de la validation (i) de nouveaux milieux de culture permettant de répondre aux besoins de l'embryon au cours des stades du développement post-implantatoire puis du foetus au cours de l'organogénèse, (ii) de modèles in vitro de complexité croissante associant embryon (ou embryoïdes), organoïdes endométriaux composés des divers types cellulaires composant l'endomètre (dont les cellules immunitaires et vasculaires) et microfluidique sur puce afin de mimer la période péri-implantatoire chez l'humain et comprendre la succession d'événements moléculaires et cellulaires qui y est associée (iii) de dispositifs alliant des liquides physiologiques spécifiques des différents stades du développement foetal, des biomatériaux et de la mécanique des fluides capables de simuler le fonctionnement d'un placenta artificiel (iv) de biomatériaux colonisés par des cellules souches pluripotentes d'origine utérine afin de procéder à la réparation partielle d'un utérus défectueux. Au-delà de la capacité à pouvoir s'affranchir de l'utérus pour l'une ou l'autre des étapes du développement post-implantatoire, le recours à ces approches associées aux modifications de génome ciblées aura un impact biomédical important pour la mise au point de nouvelles stratégies thérapeutiques dans le cadre de la médecine personnalisée.

En permettant le développement d'un embryon à terme sans environnement maternel, l'utérus artificiel pourrait fournir une alternative à la transplantation utérine et à la gestation pour autrui. A ce stade, il est important de noter qu'une vigilance s'impose. Les travaux menés chez plusieurs espèces animales ont démontré l'origine développementale de la santé et des maladies de l'adulte, concept initialement proposé dans l'espèce humaine [START_REF] Barker | Fetal nutrition and cardiovascular disease in adult life[END_REF]. La mise en évidence des propriétés dynamiques de l'endomètre a conforté le fait que les biotechnologies de l'embryon et les modifications pré-et post-conceptionnelles de l'environnement maternel sont relayées par ce tissu et influencent, dès l'initiation de la gestation, le développement embryonnaire avec de potentielles conséquences post-natales [START_REF] Sandra | Novel aspects of function: a biological sensor of embryo quality and driver of pregnancy success[END_REF]. Ainsi, au-delà de l'objectif de faire naitre un enfant vivant, le recours à des approches impliquant biotechnologies et ingénierie pour restaurer la fonction utérine ou la remplacer sous la forme d'une grossesse extracorporelle partielle voire totale doit s'accompagner d'une évaluation approfondie et rigoureuse des conséquences de leurs applications sur le développement post-natal et la santé à long terme des nouveau-nés.

REMERCIEMENTS

Les auteurs remercient le Prof François Vialard pour sa lecture approfondie du manuscrit et ses suggestions.

  foetus est placé dans une « poche » amniotique hermétique, avec un système de circulation constante du liquide amniotique synthétique. Les constantes vitales sont monitorées en continu et la surveillance des paramètres biologiques notamment sanguins est facilitée. Ce dispositif permet ainsi pendant plusieurs semaines une maturation « suboptimale » du foetus, notamment au niveau cérébral, pulmonaire et intestinal, en minimisant l'impact des éléments environnementaux inhérents à une prise en charge classique extrautérine sur le développement post-natal immédiat. Ce dispositif pourrait aussi permettre de créer un modèle physiopathologique unique permettant d'étudier le développement foetal en fonction de l'environnement et de ses variations (métaboliques, hormonales, hémodynamiques, inflammatoires, thérapeutiques…). Il demeure nécessaire d'améliorer le de survie des foetus d'agneaux au moment de la canulation et la durée de tenue opérationnelles des abords vasculaires ombilicaux pour permettre un relais dans de bonnes conditions entre le système de développement foetal ex-vivo et la réanimation néonatale classique au-delà de 28 semaines d'aménorrhée, quand le pronostic neuro-développemental et pulmonaire devient plus favorable pour le nouveau-né.

Figure 1 .

 1 Figure 1. Principales étapes du développement post-implantatoire humain ex vivo. J : jour ; MCI= masse cellulaire interne ; TE=trophectoderme ; Epi=épiblaste ; Hypo=hypoblaste; PCG=précurseurs des cellules germinales.


Martino Trevisan

Idilio Drago

Paul Schmitt

Francesco Bronzino ⋆⋆

Measuring the Performance of iCloud Private Relay

Recent developments in Internet protocols and services aim to provide enhanced security and privacy for users' traffic. Apple's iCloud Private Relay is a premier example of this trend, introducing a wellprovisioned, multi-hop architecture to protect the privacy of users' traffic while minimizing the traditional drawbacks of additional network hops (e.g., latency). Announced in 2021, the service is currently in the beta stage, offering an easy and cheap privacy-enhancing alternative directly integrated into Apple's operating systems. This seamless integration makes a future massive adoption of the technology very likely, calling for studies on its impact on the Internet. Indeed, the iCloud Private Relay architecture inherently introduces computational and routing overheads, possibly hampering performance. In this work, we study the service from a performance perspective, across a variety of scenarios and locations. We show that iCloud Private Relay not only reduces speed test performance (up to 10x decrease) but also negatively affects page load time and download/upload throughput in different scenarios. Interestingly, we find that the overlay routing introduced by the service may increase performance in some cases. Our results call for further investigations into the effects of a large-scale deployment of similar multi-hop privacy-enhancing architectures. For increasing the impact of our work we contribute our software and measurements to the community.

Introduction

The privacy of Internet users has become one of the most discussed issues in the field of networking. New protocols and services are being developed with strong privacy guarantees, while privacy-enhancing technologies are opening opportunities for new markets. iCloud Private Relay (PR) is a new service recently created by Apple that is integrated into the company's operating systems (i.e., MacOS, iOS, iPadOS). Initially launched in 2021, it offers users the possibility of forwarding traffic via a multi-party relay [START_REF] Schmitt | The decoupling principle: A practical privacy framework[END_REF], offering a service that in many ways resembles a VPN but differs in privacy guarantees. The architecture results in no party (neither Apple nor their infrastructure partners) holding both user identity and the contacted servers, whereas a VPN architecture simply shifts trust to the VPN which has access to both. The seamless integration of the service in the Apple OSes, its low cost ($0.99 per month for the cheapest plan) and its low entry barrier suggest that a large adoption of the service is very likely, with an anticipated major impact on Internet traffic [START_REF] Sattler | Towards a tectonic traffic shift? Investigating Apple's new relay network[END_REF] moving forward.

iCloud Private Relay works with a multi-party relay architecture: The client operating system connects to an ingress proxy (operated by Apple) using an encrypted connection over QUIC [START_REF]Apple. iCloud Private Relay Overview[END_REF]. The ingress proxy routes the client traffic to an egress proxy (currently operated by one of Akamai, Cloudfare, and Fastly) that forwards the traffic to the destination server requested by the user. With this architecture, the ingress and egress proxies can only see the client's or the server's IP address, respectively, but never both. Equally, eavesdroppers (e.g., ISPs) can observe the traffic of multiple users to/from ingress and egress proxies and thus cannot easily profile individual users' activity from the traffic [START_REF] Trevisan | Does domain name encryption increase users' privacy?[END_REF].

The possibility of a major adoption of the service in the short term raises questions about its impact on the internet. Similar privacy protection mechanisms, such as VPNs, onion routing [START_REF] Paul F Syverson | Anonymous connections and onion routing[END_REF] and Tor [START_REF] Dingledine | Tor: the second-generation onion router[END_REF] have been studied in terms of both performance and privacy [START_REF] Akshaya Mani | Understanding tor usage with privacy-preserving measurement[END_REF][START_REF] Alsabah | Performance and security improvements for tor: A survey[END_REF]. For example, the authors of [START_REF] Arp | Torben: A Practical Side-Channel Attack for Deanonymizing Tor Communication[END_REF] uncover the websites a user is visiting when connected via Tor by relying on side channels such as packet sizes and timing. Similarly, multiple authors [START_REF] Pudelko | Performance analysis of vpn gateways[END_REF][START_REF] Alsabah | Performance and security improvements for tor: A survey[END_REF] have studied the impact of privacy-enhancing technologies on Internet performance. For PR, however, we are aware of a single study focusing on the service [START_REF] Sattler | Towards a tectonic traffic shift? Investigating Apple's new relay network[END_REF], which focused on describing the system architecture and its deployment footprint, neglecting implications on performance and user-perceived quality of experience.

In this work, we focus on the impact of iCloud Private Relay on web performance. We set up active experiments using Apple devices and design multiple workloads to assess the effects of PR on different scenarios. We deploy our testbed across multiple locations and gather several metrics associated with users' Quality of Experience (QoE), such as page load time, throughput, and latency. Apple notes [START_REF]About iCloud Private Relay[END_REF] that iCloud Private Relay can negatively affect web speed tests as such tests routinely use "several simultaneous connections to deliver the highest possible result", but goes on to claim that "actual browsing experience remains fast." Therefore we design our experiments to assess these claims, including speed tests and web browsing with and without PR in place.

Our results show that iCloud Private Relay does impact performance. We confirm a significant reduction in the throughput measured with speed tests, e.g., with up to 10-fold slower download throughput when using PR. We notice a performance penalty in web browsing too, observing a 60% increase in page load time in some cases. Performance impairments also occur in cases where a single connection is used to download a large file, thus questioning the claim that several simultaneous connections are the root cause of performance penalties. Interestingly, the selection of the egress proxy operator appears to have crucial implications on performance. We also observe that client traffic over PR outperforms traffic over an unmodified connection in some cases, suggesting that the system's overlay routing can result in more optimal paths. Overall, our study is a first step towards understanding the impact of largescale, well-provisioned, privacy-enhancing services such as iCloud Private Relay on Internet performance. To increase the impact of our study and allow for reproducible comparisons, we release our measurements and source codes[1].

Background and Related Work

iCloud Private Relay Architecture

Apple launched the PR service during its Apple Worldwide Developers Conference (WWDC) in 2021 [START_REF]Apple. iCloud Private Relay Overview[END_REF]. The service employs a multi-hop proxy architecture, also known as a Multi-Party Relay (MPR) [START_REF] Schmitt | The decoupling principle: A practical privacy framework[END_REF]. The architecture provides privacy benefits by decoupling the users' network identity (i.e., the client IP address) from their Internet usage (i.e., the destination servers). This is accomplished by the client setting up two nested tunnels: the first to an ingress proxy (Proxy A in Figure 1), operated by Apple, which provides authentication and localization; the second to egress proxy (Proxy B in Figure 1) operated by one of Apple's infrastructure partners (currently including Akamai, Cloudflare, and Fastly), which in turn connects to the destination server(s) on the client's behalf. Proxy A only has visibility into the client's IP address and cannot inspect the encrypted and tunneled web traffic. Proxy B knows the servers that the clients connect to, but cannot see the client's IP address. Likewise, the destination server does not see the client IP addresses as connections are initiated by Proxy B. PR is currently limited to Apple-specific applications (i.e., Safari).

The PR architecture relies on well-known web protocols rather than custom protocols. The connection to Proxy A uses QUIC by default, with a fallback to HTTP/2 and TLS if the QUIC connection fails or is blocked. The connection to Proxy B defaults to HTTP/3 and MASQUE [START_REF] Schinazi | HTTP Datagrams and the Capsule Protocol[END_REF][START_REF] Schinazi | Proxying UDP in HTTP[END_REF], which allows building efficient QUIC connections over a QUIC proxy. If HTTP/3 is not supported, the connection to Proxy B falls back to the classical HTTP CONNECT over TLS.

The PR does not act as a classical VPN and handles the traffic coming uniquely from the Safari web browser. Only HTTP(S) browser traffic goes through the PR, while we notice that, in the case of audio/video calls, We-bRTC traffic (RTP, DTLS, and STUN/TURN protocols) is not captured by the PR. The traffic of other applications in the system uses classical routing too, including other browsers and mail clients. Interestingly, the curl command-line facility uses PR, but only for clear-text HTTP traffic. The fact that only some applications support PR is a problem, since PR may give users a false sense of privacy while routing only a share of their traffic to the PR tunnel.

Moreover, the usage of such an architecture will impact the efficacy of existing Internet services. For instance, services that rely on client IP address information for localizing content (i.e., IP geolocation) no longer have access to clients' actual IP addresses. Other services that require insight into user traffic, such as middleboxes that provide content filtering (e.g., corporate networks or parental control services) will be unable to access user content. Lastly, the additional hops introduced by the service may hamper performance, as we investigate in this paper.

Related Work

Onion routing [START_REF] Paul F Syverson | Anonymous connections and onion routing[END_REF] and Tor [START_REF] Dingledine | Tor: the second-generation onion router[END_REF] are perhaps the most similar systems compared with PR in terms of privacy goals for Internet traffic. These systems enhance users' privacy by obfuscating sender and receiver endpoints using ad-hoc "circuits" to transit user traffic. iCloud Private Relay differs in that it utilizes fewer relay hops (Tor's default is three, PR uses two), and the relays are operated on well-provisioned commercial infrastructure rather than on volunteers' systems. PR also differs from Tor in that it uses the standard HTTP and QUIC protocols rather than a custom protocol, arguably making PR more difficult to block and/or censor.

Several works have studied these privacy-enhancing services, investigating possible attacks against users' privacy. Different website fingerprinting techniques, for example, have been tested against the Tor network in [START_REF] Sirinam | Deep Fingerprinting: Undermining Website Fingerprinting Defenses with Deep Learning[END_REF][START_REF] Wang | Effective Attacks and Provable Defenses for Website Fingerprinting[END_REF][START_REF] Arp | Torben: A Practical Side-Channel Attack for Deanonymizing Tor Communication[END_REF]. In terms of performance, some studies [START_REF] Pudelko | Performance analysis of vpn gateways[END_REF][START_REF] Alsabah | Performance and security improvements for tor: A survey[END_REF] benchmark popular VPN services as well as Tor, finding major impairments in some scenarios. We share a similar goal with these related efforts, focusing on iCloud Private Relay.

A single work studied specifically PR [START_REF] Sattler | Towards a tectonic traffic shift? Investigating Apple's new relay network[END_REF]. The authors analyzed the network infrastructure that iCloud Private Relay has been deployed on and highlighted the geographic footprint of the service. In contrast, we study PR from the Internet performance point of view, shedding light on possible impairments users face when using the service. Indeed, our work focuses on performing an empirical evaluation of the impact on performance caused by the PR architecture, differently from [START_REF] Sattler | Towards a tectonic traffic shift? Investigating Apple's new relay network[END_REF] which focuses on the study of PR's architecture, uncovering its ingress and egress points location (geographically and network wise).

Testbed and Dataset

We design three measurement campaigns aiming at quantifying iCloud Private Relay performance from different perspectives. Our experiments have been per-formed from three locations using three identical Apple MacBook Pro laptops running macOS Monterey. We deployed the laptops at three University networks, connecting them to the Internet through Gbit/s Ethernet links. Two laptops are deployed in large European cities, Lyon in France and Trieste in Italy. The third laptop is deployed in Hawaii (USA). Note that, although our study does uncover some of the potential impacts that PR has on network performance, our locations cannot be considered representative of the entire internet. Instrumenting more locations for extending our findings, e.g., by hosting probes in distributed cloud infrastructure, is left for future work.

We fully automate the experiments through custom-made testbed scripts. Common to all measurement campaigns is a script in the AppleScript format that automates the activation and deactivation of the Private Relay functionality of the laptop. All these scripts are contributed to the community to allow others to extend and validate our findings. We set up PR with the default option that preserves user location as much as possible.

Ethical Considerations. During our measurements, we took care to avoid harming the crawled web services. Considering that the targets of our analysis were some of the most popular websites and CDNs in Western countries, our belief is not to have caused an overload on the servers or any undesirable side effects.

Throughput Measurements

Active throughput measurements are a common tool to measure the speed of the slowest segment (the bottleneck) between a test device and a server deployed in the network. Modern speed tests commonly aim to deploy their servers in a region close to end-users, under the assumption that the bottleneck will be located at the access network. While these tests are not always representative of the user's experience [START_REF] Martino Trevisan | Impact of access speed on adaptive video streaming quality: A passive perspective[END_REF], they can spot the performance impact caused by i) traversing additional middleboxes, i.e., iCloud PR's proxies, and ii) taking a different path between the user and the test infrastructure of the speed test service.

We perform active throughput measurements using Ookla's Speed Test service [START_REF] Ookla | [END_REF], one of the de facto standards for Internet speed test measurements. We instrument our machines to automatically perform speed tests by accessing Ookla's web page. Doing so requires i) accessing the web page; ii) detecting Ookla's privacy banner and accepting it (in Europe, not in the US); and iii) starting the test by clicking on the "GO" button. We automate this process using Selenium [START_REF]Selenium. Selenium automates browsers. that's it![END_REF] tools and instrumenting the Safari browser. We run 200 speed tests from each location, half with PR enabled and half without PR.

Bulk Downloads

Architecturally, PR achieves privacy by decoupling information on users and the services they access. When iCloud Private Relay is enabled, all Safari traffic goes through the system by default. This has implications not only for web browsing but also for downloads of large files -i.e., performing bulk downloads of data through HTTP. We measure PR performance on bulk downloads using the curl command-line tool. When Private Relay is enabled, curl traffic uses it, allowing us to easily test HTTP downloads in isolation. We use curl to download a 1 GB file several times. We select a 1 GB test file made available on the Hetzner CDN, a standard file used for evaluating content distribution speeds [START_REF] Hetzner | Test-files[END_REF]. From each location, we download the test file 200 times with and without Private Relay and record the download time.

Web Measurements

iCloud Private Relay is mainly designed to allow web browsing with stronger privacy guarantees. Our goal is ultimately to study to what extent Private Relay impacts the user's perceived performance and, in turn, its implications for web QoE. To this end, we instrument Safari to visit a set of web pages automatically and collect statistics regarding page loading. We target the 100 most popular websites in each country according to the public ranking provided by SimilarWeb analytics [START_REF] Similarweb | Effortlessly analyze your competitive landscape[END_REF].

We use the BrowserTime toolset to automate the visits to the websites and the collection of the statistics [23]. For each website, we run five visits with and without PR enabled. Out of each visit, we collect statistics about each HTTP transaction carried out during the page loading. Essential to our analysis, we collect the Page Load Time (also called onLoad time) that we use as a practical proxy for measuring the web performance. Page Load Time represents the time elapsed between the beginning of the visit and the instant when the last object of the web page is retrieved. The Page Load Time has previously been shown to be correlated with users' QoE [START_REF] Neves Da Hora | Narrowing the gap between qos metrics and web qoe using above-the-fold metrics[END_REF].

Finally, note that in our experimental campaign, we do not measure explicitly the end-to-end RTT. Indeed, our measurement infrastructure cannot observe the layer-4 RTT, as we rely on browser instrumentation. Measuring the RTT poses some challenges in the case of tunneled traffic (such as PR), e.g, one could instrument the SO kernel to monitor TCP statistics. This is by no means trivial, in particular considering the proprietary software offering PR. We thus focus on user-perceived quality, showing higher-level metrics such as Page Load Time or Throughput, leaving these additional aspects for future work.

Results

We now present results across the three workloads. We observe that, in general, PR negatively impacts performance, particularly for scenarios that require long-lasting network flows, i.e., bulk download and speed test measurements. Further, in these experiments, PR usage results in a higher level of variability in performance, even for stable and fast Ethernet network connections. Interestingly, these takeaways do not apply across all results: in one case, i.e., bulk download in France, we observe that PR outperforms an unmodified connection.

Throughput

We first evaluate the performance impact of PR on active throughput measurements using Ookla's infrastructure. Overall, we expect performance to be, at the very least, impacted by the overhead of the PR tunnels, as disclaimed on Apple's support website [START_REF]About iCloud Private Relay[END_REF]. Here, we look to quantify this overhead, shedding light on the incurred performance penalties. Figures 2 and3 show the Empirical Cumulative Distribution Function (ECDF) for the downstream and upstream throughput with and without PR, respectively. Overall, we observe that performance is drastically impacted across the vast majority of scenarios, both for downstream and upstream throughput. This impact is particularly significant for our France measurement location (Figures 2a and 3a), where measurements experience a median speed reduction of 87% and 63% respectively. The sole scenario that does not present an evident reduction in performance is the uplink throughput in our US measurement location, where performance is capped at around 23 Mbit/s for both experiments. This suggests that the bottleneck, in this case, is most likely to be found in the path between the client and Proxy A. In sum, PR seemingly does not impact performance when the client-side connections are the bottleneck.

Interestingly, we observe that speed tests performed when PR is enabled result in a much higher performance variability. For example, we observe that in multiple configurations, in particular for downstream experiments in France and the US (Figure 2a and 2c, respectively), experiments result in bimodal speed distributions, possibly caused by either ephemerally congested paths or congested proxies that negatively impact performance in a subset of experiments.

We investigate this aspect further in Figure 4, where we dissect throughput distribution according to Proxy B selected as the egress node by PR. Sattler et. al [START_REF] Sattler | Towards a tectonic traffic shift? Investigating Apple's new relay network[END_REF] found that Proxy B selection changes multiple times in a day. For France, we observe that all speed tests achieving throughput below 200 Mbit/s are those using a Cloudflare-owned Proxy B, while the faster ones are all using Akamai's Proxy B. In the US, we observe the opposite scenario, with CloudFlare Proxy B leading to better performance compared with Akamai, even if the two distributions partially overlap. We do not report the figure for Italy as all experiments for this case resulted in an Akamai Proxy B egress, leading to the performance shown in Figure 2. We also observe that when PR is in place, the Ookla's measurement server is often further from the user than without PR for both Italy and France. With native connection, the speed test is served from a server within 120 km, while, with PR, the server is 200-300 km far away. We detail this in the Appendix. In a nutshell, the choice of egress node has paramount implications on the achieved throughput, and this choice is not under the user's control.

Overall, these results appear to confirm Apple's disclaimer that PR can negatively impact speed test performance. Apple justifies this performance loss to the normal behavior of speed test experiments. In particular, they state that "Private Relay uses a single, secure connection to maintain privacy and performance. This design may impact how throughput is reflected in network speed tests that typically open several simultaneous connections to deliver the highest possible result." To verify whether the performance loss experienced can be solely linked to the use of multiple connections, in the next section, we replicate the performance comparison in a scenario where only a single connection is used, i.e., the single file bulk download over HTTP.

Bulk Download

We now compare the performance achieved with and without PR downloading a large 1 GB file from a CDN. Figure 5 shows the obtained results for our three locations. We observe that, although to a different extent, the US and Italy locations still experience a similar negative performance impact when downloading the file via PR, even when using a single network flow.

For the US case, we see that PR reduces performance by 53% in the median case. For the Italian case, we notice that median throughput is usually similar with and without PR, except for the tail of the distributions. In particular, in this case, PR performance is very stable, never exceeding around 80 Mbit/s. In contrast, similar tests without PR can exceed 300 Mbit/s. We conjecture that, for the Italian location, the traffic traversing PR takes a path where traffic cannot exceed 80 Mbit/s. This can be due to congestion or route peering arrangements, even if we cannot precisely pinpoint the root causes for these differences.

Most interestingly, we observe that for our experiments in France, results show very similar behavior, but with inverse outcomes, i.e., PR downloads experience higher throughput while non-PR traffic is capped at around 35 Mbit/s. We investigate this behavior further using traceroute and we observe that the selected CDN node changes when connected to PR and, consequently, packets follow different routes. More precisely, we observe that, when PR is not enabled, packets traverse an operator (GEANT) that is otherwise not observed when using PR. This suggests that, when not using PR, packets encounter a bottlenecked link, which is at the root of the impaired performance. Effectively, the presence of PR-induced overlay routing overrides default routes taken by client traffic in the French location. These results call for further investigation of the routing of traffic when PR is enabled, which we leave for future work.

Web Browsing

Lastly, we study the performance impact that the use of PR has on web browsing. To this end, we measure the Page Load Time for the top-100 ranked websites in each of the three test locations. According to Apple's claim, web experience should remain "fast" even with PR active, while our results suggest that performance varies. Figure 6 shows the distribution of Page Load Time for the three locations, with and without PR active.

At a first glance, we observe that PR consistently introduces an additional delay to page loading regardless of the location. The performance impact is particularly evident in France, where the median Page Load Time increases by almost 60%. For the other locations, we observe a more moderate increase of 7% and 17% for Italy and the US, respectively. Interestingly, our measurements show that TLS handshake time increases by 9-14% when using PR, depending on the location. This increase likely impacts the page-loading process negatively, but only partially explains the performance degradation with PR.

Overall, while web performance is not as heavily impacted as throughput measurements, the claim that the architecture of PR exclusively impacts speed tests might be reductive. More detailed experiments might be required to shed light on the root causes of the additional page load times. We speculate that these results are caused by the additional overhead caused by the traversal of multiple middleboxes and the necessarily longer path packets must travel. Network latency is known to impact web QoE directly [START_REF] Cui | On the relationship between qos and qoe for web sessions[END_REF][START_REF] Maria Mandalari | Measuring roaming in europe: Infrastructure and implications on users' qoe[END_REF], and even a small deterioration in page load time has a large impact on the web ecosystem [START_REF]How one second could cost amazon $1.6 billion in sales[END_REF].

Discussion and Open Questions

We now elaborate on the limitations of our findings and possibilities for future work. In general, answering the questions listed below requires further measurements from different locations. While our measurements include several campaigns, they cannot be considered representative of the whole Internet. Indeed, we will extend our measurements in future work by deploying new probes i) in other locations -e.g., by leveraging cloud infrastructure in more countries, and ii) in heterogeneous scenarios -e.g., by deploying probes in wireless and cellular networks. Ultimately, we contribute our scripts to the community to allow others to validate and extend our results in autonomy, considering novel scenarios.

Overriding Routing

In Section 4.2, our results illustrate how the use of PR can lead to better performance compared to native connectivity in particular cases. We find that overlay routing appears to result in the avoidance of a congested network when using PR in one particular case. This result demonstrates one of the potential impacts that Multi-Party Relay architectures can have on network performance: The chosen traffic paths are dictated by the combination of the user's ISP, Apple, and Apple's infrastructure partners for Proxies B, rather than simply the user's ISP and the destination server. In effect, at the ISP, packet routing mechanisms with PR will significantly diverge from existing patterns. Where, today, ISPs observe a fan-out pattern, routing client traffic to the many destination networks on the Internet, networks with high usage of PR in the future will see a many-to-one pattern, with all client traffic routing to a single destination network (Apple or whoever is operating the ingress proxy of a multi-party relay).

Indeed, our initial experience while running measurements in mobile networks in France and Italy shows that performance metrics (with and without PR) are more susceptible to variations throughout the day. Additional factors, such as the cellular network load during the day, make the study of PR on mobile networks largely more complex. Longitudinal measurements in such environments are needed to draw robust conclusions and we will pursue that in future work.

Localization

iCloud Private Relay is designed to prevent destination servers from observing client IP addresses. Clearly, this design negatively impacts the ability of IP geolocation services to map clients to their geographical location. These services are widely used by content providers to localize users and determine access rules based on geographical constraints. The PR architecture aims to minimize this issue by roughly localizing the client using Proxy A, and carefully selecting the Proxy B egress based on the location that the client is purported to be. This would preserve, at least roughly, the geographic location of the user from the server's point of view. To support IP geolocation services in mapping the users' geographical location, Apple publishes Proxy B IP addresses along with the location of the users aggregated through them [START_REF]Apple. Prepare Your Network or Web Server for iCloud Private Relay[END_REF].

In many cases, low-fidelity location information is sufficient to provide localized content. Unfortunately, some services require very accurate location information to serve content (e.g., live streaming of sporting events), which may not be possible using services such as PR. Further study is required to study the tradeoff between privacy and usability in terms of localization. Additionally, previous work [START_REF] Sattler | Towards a tectonic traffic shift? Investigating Apple's new relay network[END_REF] has shown that the IP-to-location mappings offered by Apple's partners are not always a direct representation of the physical location of the proxy holding the given IP. This is done to overcome the lack of PR proxies in certain regions of the world. This could impact performance for users who connect to the PR infrastructure from locations that are not physically served by it. The network paths would be extended beyond their geographical location, adding latency to communications and crossing national borders.

Cost

While the PR design seems beneficial for privacy, the real benefits have been left unquantified and largely unexplored. Future work is necessary to understand the benefits offered by such as system. This is particularly true considering the inherent tradeoffs that Multi-Party Relay architectures have on network traffic and the capability required to process it: In PR, clients' traffic passes through multiple middleboxes in order to achieve the privacy guarantees associated with decoupling network identity from behavior. This has implications on performance, at the center of this paper, as well as on energy consumption (e.g., due to the additional servers and the multiple layers of encryption they have to handle). For example, by nesting encrypted channels as the PR architecture does, Proxy A could be wasting significant computing resources "double encrypting" traffic. To avoid this overhead, QUIC-Aware Proxying Using HTTP has been proposed, where Proxy A simply moves the traffic along the path towards Proxy B without double encryption [START_REF] Schinazi | HTTP Datagrams and the Capsule Protocol[END_REF][START_REF] Schinazi | Proxying UDP in HTTP[END_REF]. Other similar optimizations are likely to be introduced as the architecture becomes more mature and more widely adopted.

Conclusions

Apple's iCloud Private Relay is one of the recent attempts at deploying Multi-Party Relay architectures at scale. Given Apple devices' pervasiveness and the company's push towards privacy, it is possible that this architecture will be quickly adopted as the de facto standard for privacy-oriented network architectures. In this work, we present a first study of the impacts that PR architecture can have on users' performance. Through experiments across three locations in France, Italy, and the US, we find that PR not only impacts active throughput measurements but also negatively affects page load time and file download, indicating potential impacts on the users' web QoE. We show for example that PR substantially changes the paths taken by traffic (e.g., during speed tests), impacting performance. Our paper sheds light on new problems and calls for further research on how to avoid them when deploying privacy-preserving services.

This work opens up a number of potential future venues to explore Multi-Party Relay architectures such iCloud Private Relay, not solely in terms of performance, but also across multiple dimensions such as privacy-costs tradeoffs, content access, and the impact on network routing at large. To engage the community to search for the answer to these questions, we release the source code of the software used to perform the experiments presented in this paper.

Fig. 1 :

 1 Fig. 1: Overview of the iCloud Private Relay architecture. Client traffic passes through two proxies: i) Proxy A operated by Apple; and ii) Proxy B operated by one of Akamai, Cloudflare, or Fastly.

Fig. 2 :Fig. 3 :

 23 Fig. 2: Download throughput measured with speed test measurements.

Fig. 4 :

 4 Fig. 4: Download throughput with PR and different Proxy B operators.

Fig. 5 :

 5 Fig. 5: Average download speed during downloads of a large file.

Fig. 6 :

 6 Fig. 6: Page Load Time distribution.

Appendix

In this Appendix, we break down the distance between the user and Ookla's speed test measurement servers, with and without PR. In the following two tables, we show the measurement server chosen by Ookla, detailing its location and distance from the testing location. We report data for the Italian and French locations and separate the cases with and without PR. We omit the US location as, in all cases, the measurement server is located at the same location, i.e., Hawaii.

When PR is in place, it is more likely that the speed test server is far away from the client. For example, for the Italian location, without PR, speed tests are served within 120 km, while with PR, servers are at 200 km or more from the client.

Ookla obviously cannot identify the true location of the users, since its servers observe only egress IP addresses. Indeed, hiding the users' IP addresses is the ultimate goal of PR and, as such, these differences are expected. We here show that the servers selected by Ookla when PR is enabled deliver poorer throughput figures, and our conjecture is that the root causes for such performance penalties are in the path from clients to the selected servers.

The same situation may occur with other services relying on IP geolocation, such as content providers and CDNs. Our measurements, while preliminary, show that the introduction of the PR tunnels impact performance (see our discussion on future work in Section 5).


domain: sde sdv

text:
Christian Mougin

Peter G C Campbell

Michel Couderchet

Patrice Denèfle

Fabrice Martin-Laurent

Philippe Roland

Vera I Slaveykova

Tatiana Vincent

Delphine Delaunay

Fabrice Martin- Laurent

Academic expertise in assisting private companies in the fields of environment and environmental toxicology: the role of individual expertise (Editorial)

Keywords: Ecotoxicology, Toxicology, Health, Expertise, Academic research, Private companies

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

Introduction

Scientific expertise is defined as "the expression of knowledge formulated in response to a request from those who have a decision to make, knowing that this response is intended to be integrated into a decision process" (INRA 2011;[START_REF] Roqueplo | Entre savoir et décision, l'expertise scientifique[END_REF]. In this context, the scientific knowledge produced by academic research can be valued in all sectors of human activity, thanks to the numerous interfaces of academics with the different components of the society, including the private sector.

The ROVALTAIN Foundation is a nonprofit organization dedicated to scientific cooperation in the Environmental field. The main mission of the foundation is to help moving towards a pollution-free world, which it chooses to achieve by supporting research in Health and Environment with a strong orientation towards the fields of ecotoxicology and environ-mental toxicology and by ensuring the up-to-date dissemination of these research results, towards the citizens. The foundation also has the mission to favour synergies between the various actors in the health-environment field (researchers, elected representatives, companies, citizens, farmers, govern-mental and non-governmental institutions) to facilitate the dialogue and the setting up of concrete and efficient partner-ships. One main action of the foundation is to assist private companies by providing them innovative training courses and top-notch scientific partners when the companies are in need of scientific expertise.

In this paper, we report the points of discussion addressed during the course of the round-table "academic expertise in assisting private companies" which was held during the ROVALTAIN Foundation on November 15, 2019, in Alixan, France. This round-table focused on scientific expertise intended for the business world and brought together experts from both academia and industry to consider the advantages and limitations encountered in this particular type of collaborative framework.

What is the academic research/private partners interface: a relationship of trust, a common vision? Academic expertise resulting from researches funded by public funding, industry or raised funds from the public is essential for knowledge and technology transfer [START_REF] Kotiranta | Forms and varieties of research and industry collaboration across disciplines[END_REF].

Depending on the objectives involved, they take many forms [START_REF] Boardman | University researchers working with private companies[END_REF].

Institutionalized or collective, it can most often shed scientific light on a given subject based on critical analysis and the synthesis of international peer-reviewed literature. Individuals can carry out the expertise by connecting an academic scientist with a private partner to meet an identified need.

On the industrial side, the practical vision of both fundamental applied research work as well as the mastering of technical and commercial stages guarantee value creation.

During the round-table, the important place that individual expertise of researchers should take in relations between academic research and private partners in the coming years was acknowledged.

Carrying out any project between partners of different origins and skills requires overcoming their isolation in order to find collaborative solutions. The use of individual academic expertise makes it possible to bring together a field of in-depth knowledge and industrial or societal know-how. It allows a better understanding of the constraints and expectations of each of the parties. "You have to formulate the right question to find the right solution". Often, companies encapsulated in hermetic silos identify the problem correctly but struggle to ask the right questions to solve it.

Likewise, academic researchers are focused on the scientific valorization of their discoveries, but most of them have not always in mind the application potential of their work. Helping and supporting companies to formulate the right questions and develop creative answers amounts to cobuilding a common vision that is the first keystone of new partnership model between academic and private research. This co-construction is not limited to the concepts of the one who knows/the creator opposed to the learner/payer, or even to a customer/supplier relationship, but rather results from a real cooperative work that leads to a unique and original solution enriching both parties. In addition, exchanges of processes and management from industry to academics and vice versa is a real added value to publicly funded research that benefits to society.

An advance in the "path of innovation" then relies on a real interface established by shared expertise and knowledge. However, a private company, more than an academic partner, is looking for a profit in the more or less long term and may retain part of the information to avoid loss of expertise and leadership, until it is certain to receive this benefit. To resolve this problem, the signature of a non-disclosure agreement is highly recommended at the start of the appraisal, followed by a research and development contract that explicitly defines the input of each partner and the outlines of the collaboration and stipulates the distribution of intellectual property. Despite these contractual aspects, which are necessary to define the partnership relations, it is important to increase mutual trust between the two parties to develop an effective win-win strategy.

What place for academic expertise in the corporate world? Academic expertise finds its place when answering a precise, punctual question for the company, which does not necessarily have the resources to address it internally. It also makes it possible to explore more forward-looking avenues, for example, upstream of regulations, in order to anticipate changes before they become necessary. Gaps can exist between current or future regulations and knowledge, for example, on the use of chemical compounds (active substances). In that case, it is important that the company, whose know-how is at the heart of its strategy and therefore uses a strategic watch on all technological and regulatory fields, can be assisted in the implementation of regulations by providing scientific data to sup-port its reasoning. Many manufacturers are directly concerned today by the impact of their activities on the environment and on health and wish to be supported in the implementation of long-term action plans. Individual expertise can turn into longterm collaboration between manufacturers and re-searchers from different laboratories.

Academic expertise also finds its place in the corporate world by bringing in rare skills. This is often the case in the medical sector, where the need for independence reduces the choice of competent external experts. Even if one has to keep in mind the question posed by the "revolving door", excessive prudence in the exercise of the precautionary principle aimed at avoiding any potential conflict of interest can thus lead regulatory agencies to seek opinions from inexperienced and under-qualified evaluators, which leads to absurd situations, especially during the management of health crises. Here again, we must trust expert researchers in their capacity to give in-formed opinions while regulating the actions of lobbyists with more transparency.

In addition, a survey of US university scientists revealed a synergy between a wide range of academic activities and roles and interactions with the private sector [START_REF] Boardman | University researchers working with private companies[END_REF].

What are the advantages of involving academic researchers in expertise for the private sector?

The development of scientific expertise for the private sector boosts the career of .scientists by offering new opportunities and developing networks. They are required to build cutting-edge projects in response to calls open for funding. However, the value of an appraisal activity linked to the business world is perceived differently depending on the seniority (or age) of the expert, and the country. When they become experts, scientists find themselves working according to different rules and in different contexts than when they carry out their activity as academic researchers [START_REF] Maxim | Entre recherche académique et expertise Scientifique: des mondes de chercheurs[END_REF] is recognized by the evaluation board. Being part of a working group or expertise at national or international levels appears prestigious and can contribute to the promotion of the career of scientists. This recognition is much less true when we speak of academic scientific expertise towards private sector companies, which is still viewed as the dark side by a part of the scientific community. This perception shared by society is reinforced by various scandals involving scientists with questionable ethical practices. In Quebec, for example, the experience of an academic expert is considered to be a potential resource for the community, and it is thus taken into account in the professorial evaluations. This is an integral part of the academic curriculum. Unlike many European countries, North American countries have fully integrated the value and importance of the contribution of the scientific expertise of academic researchers to industrial development.

Furthermore, the benefits received are reciprocal. It should not be forgotten that this type of expertise allows the academic researchers to confront the concerns of the socio-economic world and to get in touch with other management and process strategies, by getting out of their "ivory tower". This sometimes destabilizing yet enriching experience, which also favours the dissemination of the finalized benefits of academic works, is then an asset, which can, and must, be transferred to students in training. In a second step, the relationship forged with industry personnel can be sustained over time and lead to the achievement of big scientific projects, which can be the opportunity to set up shared industry-oriented PhDs partly funded by public grants (CIFRE programme in France). These collaborations transcend the boundaries between the academic and private sectors and facilitate transitions from one sector to another for young graduates. Like private re-search, academic research is bound to innovate. Financing innovation, in particular the acquisition of new equipment, can also go through a partnership with the private sector.

Despite everything, if certain scientific tools and platforms, for example, grouped in research infrastructures (national and international, i.e.; Biochem-Env, http://www.biochemenv.fr), are by nature open to partnerships with the private sector, we must however be careful not to limit academic research to collaborative research programmes with the private sector. An equilibrium has to be found in which academic research has to remain able to work in a free, autonomous manner and have its own research avenues. This depends upon researchers but mainly on political choice to support public research to lead to improve scientific knowledge, which is the source of innovations promoting the competitiveness of our society. Research activities financed without compensation (i.e. patronage) can be foreseen when public money is lacking, but scientific partnerships or a cocreation activity must systematically be preferred, in particular to service contracts. The most reliable indicators of co-creation activity are the percent-age of co-ownership of patents or the cosignature of possible research output including scientific articles and conference presentations.

What are the limits of the academic world involvement in expertise towards the private sector?

For various reasons, the scientific culture is often being restricted to the "knowledge spheres" of the academic and private sectors. Knowledge still percolates poorly towards the different components of society (citizens, students, politicians, etc.), which can be an obstacle to the involvement of the academic sector outside its usual sphere. The mixture of the two cultures, academic and private, also finds its limits due to the suspicious positioning of society towards academic re-searchers, when they interact with a private society. This partnership often generates a perception of loss of independence or conflict of interest, which results in a loss of confidence and consideration, sometimes relayed by peers. Therefore, the excessive use of the precautionary principle can lead to a real problem of availability of competent so-called "independent" experts in the evaluation of a partnership project by the authorities. This partnership conducted on an individual basis can also generate obstacles to communication and scientific publication (confidentiality clauses, embargoes on data, which are known and mentioned in the contract signed by both parties). That fact can have negative consequences, not only on the career of scientists but also (and above all) on the careers of the involved students (doctoral and post-doctoral) who need to publish quickly to expand their CV if they decide to embark on an academic career.

What could be the role for the ROVALTAIN Foundation in building the interface between academic research and private partners?

A third-party structure such as the ROVALTAIN Foundation in ecotoxicology/toxicology can act as a catalyst to reduce invisible but existing barriers (often cultural) between the academic research/private sector in order to develop a win-win partnership for a priori and a posteriori assessment of the risks posed by different anthropogenic activities on environmental and human health. By positioning itself as a network pilot, facilitator and one-stop shop, and through its knowledge of both the academic world and the private sector, the foundation can help define business issues, facilitate communication among players and offer the most relevant help to mobilize funding and incubators that will speed up the interaction process. It can also contribute to the administrative support.

  . Today, in research institutes, carrying out expertise for regulatory bodies (government agencies, French Agency for Food, Environmental and Occupational Health & Safety (ANSES), European Food Safety Authority (EFSA)…; standardization structures, French Association for Standardization (AFNOR), International Organization for Standardization (ISO)…)

Acknowledgements

The authors thank the ROVALTAIN Foundation (Alixan, France) for organizing this round-table meeting. Biochem-Env (https://doi.org/10.15454/HA6V6Y) is a service of the investment d'Avenir infrastructure AnaEE-France, overseen by the French National Research Agency (ANR-11-INBS-0001). Delphine Delaunay, Fabrice Martin-Laurent and Christian Mougin are members of the ECOTOX network (https://www6.inrae.fr/ecotox/).

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