Flora Gouzerh

Guila Ganem

Anaïs Pichevin

Laurent Dormont

Frédéric Thomas

Ability of animals to detect cancer odors

Keywords: Cancer odor, olfactory sensor, odor discrimination, volatile organic compounds, behavioral response

Introduction

Cancer is the second leading cause of death in the world, with an estimated 9.9 million deaths in 2020 [START_REF] Sung | GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[END_REF]. For most cancers, it is widely acknowledged that the early determination of a malignant tumor is crucial for increasing the chance of survival. Indeed, most cancer deaths are linked to a delay in the diagnosis, attributable to the fact that early stage cancers are rarely associated with clear symptoms. Early diagnosis usually increases the effectiveness of therapies by treating the tumor at a stage at which it has not yet caused significant tissue damage or transferred metastases to other organs [START_REF] Athey | Early diagnosis of lung cancer: Evaluation of a community-based social marketing intervention[END_REF]. Thus, any tool allowing early tumor detection would be particularly valuable in the fight against cancer.

For the last 20 years, a new approach for early cancer detection has been explored that is based on the hypothesis that the presence of a tumor could-for various reasons, e.g., the altered metabolism of cancer cells-result in the production of specific volatile substances (volatile organic compounds [VOCs]) that are detectable by chemical analysis techniques [START_REF] Gouzerh | Odors and cancer: Current status and future directions[END_REF]. In fact, many diseases can be detected because of the modifications they induce in body odors [4][START_REF] Sethi | Clinical application of volatile organic compound analysis for detecting infectious diseases[END_REF][START_REF]B hb Th f h m : w f volatile organic compounds as diagnostic biomarkers[END_REF][START_REF] Pereira | Breath analysis as a potential and non-invasive frontier in disease diagnosis: An overview[END_REF]. Among these diseases are infectious ones such as malaria [START_REF] Lacroix | Malaria infection increases attractiveness of humans to mosquitoes[END_REF] and tuberculosis [START_REF] Syhre | The scent of Mycobacterium tuberculosis[END_REF], and chronic diseases such as mucoviscidose [START_REF] Barker | Volatile organic compounds in the exhaled breath of young patients with cystic fibrosis[END_REF], asthma [START_REF] Ibrahim | Non-invasive phenotyping using exhaled volatile organic compounds in asthma[END_REF], and diabetes [START_REF] Phillips | Increased breath biomarkers of oxidative stress in diabetes mellitus[END_REF]. Cancer is no exception: several studies have shown that it was possible to detect differences in VOCs emission between healthy people and cancer patients, especially for lung, breast, and prostate cancers [START_REF] Gouzerh | Odors and cancer: Current status and future directions[END_REF].

For many animal species, olfaction plays an essential role in both intra-and interspecific interactions [START_REF] Blaustein | Sexual Selection and Mammalian Olfaction[END_REF][START_REF] Symonds | The evolution of pheromone diversity[END_REF][START_REF] Caro | Pheromones in birds: Myth or reality?[END_REF][START_REF] Woodley | Pheromonal communication in amphibians[END_REF]. For example, scent is involved in the identification of conspecifics, sex, social rank, or reproductive status [START_REF] Desjardins | Social rank in house mice: Differentiation revealed by ultraviolet visualization of urinary marking patterns[END_REF][START_REF] Restrepo | Odortypes and MHC peptides: complementary chemosignals of MHC haplotype?[END_REF]. There is also some evidence that olfactory capacities are used to recognize congeners who are sick following infections by pathogens [START_REF] Kennedy | Behavioral Ecology and Sociobiology Parasite load predicts mate choice in guppies[END_REF][START_REF] Clayton | The influence of parasites on host sexual selection[END_REF][START_REF] Kavaliers | Odours of parasitized males induce aversive responses in female mice[END_REF][START_REF] Scott | Female mice mate preferentially with non-parasitized males[END_REF][START_REF] B. O H . B -Tellez | Enhanced sandfly attraction to Leishmania-infected hosts[END_REF][START_REF] Poirotte | Mandrills use olfaction to socially avoid parasitized conspecifics[END_REF].

Because of their olfactory acuity, animals have been used by humans for various tasks, from hunting to scent detection. The first use of animals for their sense of smell involved dogs in a military context to detect objects such as explosives, mines, and dead bodies during the Second World War [START_REF] Rebmann | Cadaver Dog Handbook: Forensic Training and Tactics for the Recovery of Human Remains[END_REF]. Later, in the 1980s, rodents were used for the same reason. Because of their small size, mice could more easily enter small areas without triggering the explosives [START_REF] Marshall | Odor detection thresholds in the rat for the vapors of three related perfluorocarbons and ethylene glycol dinitrate[END_REF][START_REF] Poling | Using trained pouched rats to detect land mines: another victory for operant conditioning[END_REF]. The dog's sense of smell is regularly used by police to detect explosives [START_REF] Furton | The scientific foundation and efficacy of the use of canines as chemical detectors for explosives[END_REF][START_REF] Gazit | Explosives detection by sniffer dogs following strenuous physical activity[END_REF] and drugs [START_REF] Fattah | Influence of gender, neuter status, and training method on police dog narcotics olfaction performance, behavior and welfare[END_REF], and to search for cadavers [START_REF] Rebmann | Cadaver Dog Handbook: Forensic Training and Tactics for the Recovery of Human Remains[END_REF] as well as at the border for biosecurity [START_REF] Browne | The use of scent-detection dogs[END_REF]. For human diseases, it has been established that dogs,

h mm f b h h m b
odor [START_REF] Strong | Should people with epilepsy have untrained dogs as pets?[END_REF][START_REF] Francis | The ability of narcotic detection canines to detect illegal synthetic cathinones (bath salts)[END_REF]. More recently, dogs have been used to detect COVID-19 [START_REF] Jendrny | Scent dog identification of samples from COVID-19 patients -A pilot study[END_REF][START_REF] Grandjean | Diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction[END_REF]. In addition to dogs, other animal species have been found that can detect body odors, notably rodents [START_REF] Edwards | Giant African pouched rats (Cricetomys gambianus) that work on tilled soil accurately detect land mines[END_REF], bees [START_REF] Bromenshenk | Can Honey Bees Assist in Area Reduction and Landmine Detection?[END_REF], or drosophila [START_REF] Marshall | Detection of Volatile Indicators of Illicit Substances by the Olfactory Receptors of Drosophila melanogaster[END_REF]. Other insects such as wasps have also been trained to detect substances such as cocaine [START_REF] Olson | Use of a Parasitic Wasp as a Biosensor[END_REF].

Recent advances in cancer research have shown that the ability of dogs to detect tumorassociated odors could offer a relevant tool for cancer detection [START_REF] Brooks | Canine Olfaction and Electronic Nose Detection of Volatile Organic Compounds in the Detection of Cancer: A Review[END_REF][41][42]. The aim of this paper is to review current knowledge concerning the use of various animals to detect cancerous processes in humans. We examined 49 publications reporting results on this topic published between 1989-the year when the first publication in this field was reported-and 2022. We listed the species capable of detecting cancers and analyzed the different methods to test scent discrimination by detailing the advantages and inconveniences of each species. Finally, we explored the potential interest of each animal group for early detection of cancer in humans.

Material and methods

Our exhaustive review was conducted by searching for published articles on PubMed (https://pubmed. Despite knowledge of the olfactory abilities of animals and their use in different fields, it was not investigated in cancer research until reports of anecdotes from the late 1980s about particular dog behaviors toward owners harboring tumors began to surface. The first study on the subject is a case report in 1989 [START_REF] Williams | Sniffer dogs in the melanoma clinic?[END_REF]. This note refers to a 44-year-old woman who presented lesions, which were subsequently diagnosed as malignant melanoma. This patient sought medical care because her two dogs, a Border collie and a Doberman, had detected a lesion by sniffing it. Following this initial observation, no study was launched on the subject. It was not until a second case report in 2001 [START_REF] Church | Another sniffer dog for the clinic?[END_REF],

Results

History of the use of animals in cancer detection

which described the same scenario, that research was undertaken on the subject. In this second observation of spontaneous identification of cancer by a dog, the owner of a male Labrador retriever was diagnosed with melanoma following his dog's incessant reaction to the lesion (licking and sniffing). Following this second case report, animal studies were undertaken. In parallel, in the 2000s, research showed that it was possible to detect differences in odor profiles between healthy and cancerous individuals [START_REF] Gouzerh | Odors and cancer: Current status and future directions[END_REF].

Since these first case reports, 46 studies have been conducted between 2004 and the present on the ability of animals to detect cancer (Fig. 1; Table S1 andS2). Most of these publications [START_REF] Browne | The use of scent-detection dogs[END_REF] concerned dogs, following the above described case studies. Because dogs are already common subjects of research based on sense of smell, many training protocols were available. Other animal species began to be studied from 2010 onwards, although much less frequently compared to studies with dogs (Fig. 1 & 2).

Among the other species studied are mouse and rat. These species are widely used in medical research, including oncology [START_REF] Meuwissen | Mouse models for human lung cancer[END_REF][START_REF] Carver | Mouse Modeling in Oncologic Preclinical and Translational Research[END_REF]. Using genetically modified murine models, it is possible to induce cancers that are very similar to those occurring in humans (e.g., [START_REF] Li | Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy[END_REF][START_REF] Jiao | Recent advances targeting CCR5 for cancer and its role in immuno-oncology[END_REF] and then explore how tumorigenesis induces modifications in the mouse odor bouquet [START_REF] Matsumura | Urinary volatile compounds as biomarkers for lung cancer: A proof of principle study using odor signatures in mouse models of lung cancer[END_REF][START_REF] Hanai | Analysis of volatile organic compounds released from human lung cancer cells and from the urine of tumor-bearing mice[END_REF]. It is also known that olfaction is one of the most used senses in rodents [START_REF] Malnic | Combinatorial Receptor Codes for Odors[END_REF][START_REF] Johnston | Chemical Communication in Rodents: from Pheromones to Individual Recognition[END_REF][START_REF] Sakano | Neural Map Formation in the Mouse Olfactory System[END_REF]. However, only four publications involved mice between 2010 and 2022 [START_REF] Matsumura | Urinary volatile compounds as biomarkers for lung cancer: A proof of principle study using odor signatures in mouse models of lung cancer[END_REF][START_REF] Sato | Sniffer mice m f w h b : A f-of-principle study for non-invasive diagnosis of cancer-induced odours[END_REF][START_REF] K K Ń K -K K . W Z Z Ł . Z B J. H K. B Ł W K | z ę ł O f : h B h b f Applications[END_REF][START_REF] Gouzerh | Odours of cancerous mouse congeners: detection and attractiveness[END_REF] and only one involved rats [START_REF] Oh | Olfactory Detection of Toluene by Detection Rats for Potential Screening of Lung Cancer[END_REF].

More recently-in 2014-invertebrates began to be used in this research field [START_REF] Strauch | More than apples and oranges -w h f f[END_REF]. The emergence of these new study models is certainly linked to the constraint of experimentation on vertebrate animals, when researchers were encouraged to reduce the use of vertebrates and replace them by other models whenever possible. Olfaction in insects is highly developed and is among the most sensitive of the animal kingdom [START_REF] Gadenne | Plasticity in Insect Olfaction: To Smell or Not to Smell?[END_REF]. [START_REF] Strauch | More than apples and oranges -w h f f[END_REF]; there was another in 2015 on bees (Apis melifera) [START_REF] Schallschmidt | In vitro cultured lung cancer cells are not suitable for animal-based breath biomarker detection[END_REF], and one in 2022 on ants (Formica fusca) [START_REF] Piqueret | Ants detect cancer cells through volatile organic compounds[END_REF].

In 2015, a team in Japan began studying the ability of the nematode Caenorhabditis elegans to detect cancer [START_REF] Hirotsu | A highly accurate inclusive cancer screening test using Caenorhabditis elegans scent detection[END_REF][START_REF] Kusumoto | Behavioural Response Alteration in Caenorhabditis elegans to Urine After Surgical Removal of Cancer: Nematode-NOSE (N-NOSE) for Postoperative Evaluation[END_REF][START_REF] Ueda | Application of C. elegans cancer screening test for the detection of pancreatic tumor in genetically engineered mice[END_REF][START_REF] Kusumoto | Efficiency of Gastrointestinal Cancer Detection by Nematode-NOSE (N-NOSE)[END_REF][START_REF] Asai | Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer[END_REF][START_REF] Inaba | Accuracy evaluation of the C. elegans cancer test (N-NOSE) using a new combined method[END_REF][START_REF] Kobayashi | Caenorhabditis elegans as a Diagnostic Aid for Pancreatic Cancer[END_REF]. This organism, a study model in sensory neurobiology, offers many advantages as a model system, one of which is its small and transparent body, which allows the imaging of neuronal activity in real time [START_REF] Rengarajan | Olfactory circuits and behaviors of nematodes[END_REF]. The Japanese team produced seven publications supporting the hypothesis that nematodes can detect and distinguish odors emitted by scent sources from cancerous and healthy humans.

Figure 2 illustrates the percentage of publications made on each animal species. Many different breeds of dogs were used. Certain breeds were selected that excel in olfaction-based tasks.

For instance, dogs such as Labrador retrievers, German shepherds, and Belgian shepherds are often used in scenting tasks in the military field because of their drive and high trainability [START_REF] Polgár | A Test of Canine Olfactory Capacity: Comparing Various Dog Breeds and Wolves in a Natural Detection Task[END_REF]. However, at least 28 other dog breeds of various sizes have been tested for their ability to detect cancer-related odors. More than half of the publications used medium-sized dogs (30-60 cm); 14 different breeds of these sized were tested, especially Labrador retrievers. three size categories: small, medium, large. Some dogs were crosses between two known breeds, so we were unable to identify the size category to which they belonged and they were therefore classified in the size category "NA."

Diversity of cancers

The sense of smell of these different species was used to discriminate different cancers from non-cancer samples. A total of 12 types of cancer were studied, with 10 different odor sources (Fig. 3). Lung cancer was the focus of most studies, with 14 publications, followed by breast cancer ( [START_REF] Matsumura | Urinary volatile compounds as biomarkers for lung cancer: A proof of principle study using odor signatures in mouse models of lung cancer[END_REF][START_REF] Gouzerh | Odours of cancerous mouse congeners: detection and attractiveness[END_REF], one on melanoma [START_REF] Kokocinska-K K J. Ń K . H Z K . B Z Ń K | J z k m b discriminate urine odor of conspecifics with melanoma before clinical symptoms appear?[END_REF], and one on bladder cancer [START_REF] Sato | Sniffer mice m f w h b : A f-of-principle study for non-invasive diagnosis of cancer-induced odours[END_REF]. Only one publication on lung cancer involved rats [START_REF] Oh | Olfactory Detection of Toluene by Detection Rats for Potential Screening of Lung Cancer[END_REF].

Animals are presented with different sources of stimuli to see if they can discriminate the odors of cancerous individuals. The most commonly used source is urine. Dogs were tested with odors derived from human urine (11 publications) while mice were tested with both human (1 publication) and mouse urine (two publications) and nematodes (one publication with mouse urine and six with human urine). The second most used source is exhaled air from humans, with nine publications involving dogs and one involving rats. Breath sample collection is not invasive to humans-the person only needs to blow into a machine, similar to a stress test by a pulmonologist. Both urine and exhaled breath are simple ways to quickly obtain odor samples. There are other noninvasive methods, such as stool samples or soiled mouse bedding, in which odors emitted by mouse urine, feces, and glands can be found. Sweat is another noninvasive source that has been studied (eg. ). These odour sources are not yet widely used, with only two publications using stool samples and one using soiled bedding.

These could be further developed, particularly in the context of colorectal and digestive cancers.

Surprisingly, the most common odor sources-urine and air-are not the ones that have been tested on most organisms: Cell cultures are often used as odor sources. The three publications involving bees, ants, or drosophila all used odor stimuli from cell cultures. This stimulus was also tested in three publications with dogs and one with nematodes. The other samples presented to the animals were more invasive and requires either blood sampling or biopsies for tissue or skin samples.

Dogs were tested with a wide spectrum of samples, with eight different stimuli used. Nematodes were also tested for different cancers and different stimuli, although most studies were made using human urine [START_REF] Hirotsu | A highly accurate inclusive cancer screening test using Caenorhabditis elegans scent detection[END_REF][START_REF] Kusumoto | Behavioural Response Alteration in Caenorhabditis elegans to Urine After Surgical Removal of Cancer: Nematode-NOSE (N-NOSE) for Postoperative Evaluation[END_REF][START_REF] Kusumoto | Efficiency of Gastrointestinal Cancer Detection by Nematode-NOSE (N-NOSE)[END_REF][START_REF] Asai | Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer[END_REF][START_REF] Inaba | Accuracy evaluation of the C. elegans cancer test (N-NOSE) using a new combined method[END_REF][START_REF] Kobayashi | Caenorhabditis elegans as a Diagnostic Aid for Pancreatic Cancer[END_REF].

Experimental setup

Animals tested for cancer odor discrimination have different olfactory abilities and behavioral responses, which necessitates adapting the experimental set-up to the chosen animal model. Some methods are exclusive to one organism while others have been be generalized and used on several organisms by adapting the method to the study model. Three main techniques were identified: tests involving conditioning training, behavioral tests carried out without conditioning, and electrophysiology tests (Table 1 and Experimental setup). These tests showed similar overall capacities of the animals, although the tests using bees were inconclusive. All publications on dogs on average display good sensitivity, i.e., 71%±24, as well as a good specificity, i.e., 85%±18. Some studies obtained scores higher than 90% or even 100% success. For example, using blood serum, beagles had a sensitivity of 96.7% and a specificity of 97.5% [START_REF] Junqueira | Accuracy of canine scent detection of non-small cell lung cancer in blood serum[END_REF]. Other studies obtained much less conclusive results, with success rates below 50% [START_REF] Willis | Olfactory detection of human bladder cancer by dogs: Proof of principle study[END_REF][START_REF] Gordon | The use of canines in the detection of human cancers[END_REF][START_REF] Elliker | Key considerations for the experimental training and evaluation of cancer odour detection dogs: Lessons learnt from a double-blind, controlled trial of prostate cancer detection[END_REF]. Sensitivity and specificity vary among studies, and we noted that they vary depending on the cancers tested and the stimuli presented (Fig. 4). Sensitivity varies more than specificity, which means that dogs are more likely to make false positives -indicating that a sick person is healthy -than false negatives, which can have detrimental consequences for patients in the absence of other diagnostic methods. Detection of urine showed the lowest sensitivity among the stimuli, yet it is the most common stimulus tested on the dogs. Regarding the types of cancers tested, prostate and bladder cancers had average sensitivities close to 50%, making them the least well detected cancers by dogs. However, this poor detection level may be because only urine samples were used and that dogs are less sensitive to cancer related molecules present in the urine.

Of the other animals tested by conditioning, mice showed success rates ranging between 80 and 100% (ref). In another study, mice could distinguish cancerous conspecifics based on their urine.

Compared with dogs, either mice are more sensitive to informative molecules present in the urine and/or it might be easier to distinguish diseased conspecifics than non-conspecifics. The rat study used exhaled breath samples to detect lung cancer, resulting in a sensitivity of 82% and a specificity of 81%. The two studies conducted on insects using conditioning tests gave mixed results. Bees did not seem to be capable of discrimination between healthy and cancerous cell cultures with proboscis extension response (PER) tests [START_REF] Schallschmidt | In vitro cultured lung cancer cells are not suitable for animal-based breath biomarker detection[END_REF]. The failure of tests involving bees may be explained by the fact that cell cultures do not produce compounds to which the bees are sensitive. While, test based on bees olfaction were successful in other contexts, such as landmine detection [START_REF] Bromenshenk | Can Honey Bees Assist in Area Reduction and Landmine Detection?[END_REF] or in an ecological context with the use of bees to detect the presence of larvae of the Mediterranean fruit fly [START_REF] Chamberlain | Use of honey bees (Apis mellifera L.) to detect the presence of Mediterranean fruit fly (Ceratitis capitata Wiedemann) larvae in Valencia oranges[END_REF]. The study using ants [START_REF] Piqueret | Ants detect cancer cells through volatile organic compounds[END_REF] showed that when ants were conditioned with sugar water to the odor (healthy cell cultures or cancerous cell cultures), they spent much more time near the conditioned smell than the new smell. These results show that ants are able to distinguish between healthy and cancerous cells and even between two different cancerous cells. Conditioning has advantages and disadvantages, depending on the animal tested. In the context f cancer detection, for all species tested other than bees, this method resulted in sensitivity and specificity above 80%.

Conditioning tests require a learning period that can be variable in length. This training time can be a disadvantage with dogs. Dogs start training in average at 10±4.8 months, with training durations varying greatly among studies (average 41±34 weeks). Some dogs were trained for only 3-4 weeks prior to testing [START_REF] Junqueira | Accuracy of canine scent detection of non-small cell lung cancer in blood serum[END_REF][START_REF] Mcculloch | Diagnostic Accuracy of Canine Scent Detection in Early-and Late-Stage Lung and Breast Cancers[END_REF] and others were trained for seven to 24 months [START_REF] Sonoda | Colorectal cancer screening with odour material by canine scent detection[END_REF][START_REF] Horvath | Cancer odor in the blood of ovarian cancer : f b m 3 6 m h afterward[END_REF][START_REF] Mazzola | Two-step investigation of lung cancer detection by sniffer dogs[END_REF]. This makes the dog the organism that takes the longest to provide conclusive results. For all other species tested, the learning time was much shorter, from a few minutes to a few days. However, once a dog is trained, its training can last for its lifetime and thus the same individual can be used for a large number of tests, unlike, for example, insects or nematodes, which usually cannot be used more than once, due to their short lifespan. The possibility of using trained dogs throughout their lives makes them an attractive study model. Alternatively, studies involving animals that cannot be used repeatedly require a sufficient number of individuals to be statistically reliable. For example, habituation-discrimination tests typically involve between 10 and 20 mice/rats and 30 or so ants for a given experiment in contrast to dog conditioning studies, where only one to 10 dogs were involved. This results in a large number of organisms to be tested; in the case of rodents, this involves ethical constraints, while experimentation on invertebrates have fewer restrictions.

These advantages and disadvantages including the number of individuals required and the ethical issues are common to all three testing methods-the other two being behavioral tests without prior learning and electrophysiology tests. Behavioral tests were carried out on mice and nematodes.

Two types of tests were performed on mice. The first was a habituation/generalization test [START_REF] Gouzerh | Odours of cancerous mouse congeners: detection and attractiveness[END_REF], where the mouse was habituated for 14 minutes to a scent stimulus (cancerous or healthy) and then presented with two new stimuli. The mouse will typically spend more time smelling the stimulus with which it is less familiar. In this way, it can be determined whether mice can differentiate between the smells of cancerous and healthy stimuli. This study showed that mice were able to discriminate between cancerous conspecifics but-as with ants-this depended on the stimulus to which they had been habituated. Mice were able to differentiate a cancerous stimulus from a non-cancerous one if they were habituated to a non-cancerous stimulus, even at an early stage of cancer development. But when a mouse was habituated to a cancerous stimulus, mice showed difficulty discriminating among two different cancerous stimuli. This may be due to possible higher heterogeneity in odors emitted by two cancerous stimuli [START_REF] Marjanovic | Cell Plasticity and Heterogeneity in Cancer[END_REF].

The second behavioral test consists of a preference test where two different odors are placed either in a Y-maze for mice or in two Petri dishes for nematodes. Despite their ability to detect the odors, wild-derived mice did not show a preference for healthy or cancerous samples [START_REF] Gouzerh | Odours of cancerous mouse congeners: detection and attractiveness[END_REF]. This was not the case for nematodes, which were attracted to the odors emitted by stimuli of cancerous patients, regardless of the cancer type or stage [START_REF] Hirotsu | A highly accurate inclusive cancer screening test using Caenorhabditis elegans scent detection[END_REF][START_REF] Asai | Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer[END_REF][START_REF] Inaba | Accuracy evaluation of the C. elegans cancer test (N-NOSE) using a new combined method[END_REF].

Behavioral tests involving mice or nematodes have good sensitivity and specificity scores. This type of test allows a reduction in testing time by eliminating the need to learn by positive or negative reinforcement. Nevertheless, as mentioned above, the number of individuals required is much larger compared to conditioning with dogs. This disadvantage is not an issue for nematodes since there are no ethical requirements for experimentation, which allows an unlimited number of individuals that could be tested.

The last technique involves electrophysiology. As of now, it has only been tested on

Drosophila melanogaster, with calcium imaging [START_REF] Strauch | More than apples and oranges -w h f f[END_REF]. For this method, the response of drosophila to olfactory stimuli presented to h f w x m at the brain level using calcium imaging . Even if this study did not specifically identify candidate VOCs, it showed that drosophila has a network of natural chemosensors that seem to respond to odors of medical interest (i.e. [START_REF] Strauch | More than apples and oranges -w h f f[END_REF].

Medical perspectives

Cancer detection by animals-from dogs or mice to insects and nematodes-seems to be a promising avenue. Indeed, they seem to be able to detect cancer even with only slight variations in body VOCs. Twelve different cancers have been studied using animals as cancer detectors. Human cancers (18 in total) have already been studied by chemical analysis of their VOCs to identify molecular differences between cancerous and healthy patients (see the review [START_REF] Gouzerh | Odors and cancer: Current status and future directions[END_REF]). However, this review has shown that there was no universal compound associated with cancer odours. It is interesting to note that the cancers most studied by chemical analysis of human VOCs-apart from lung cancer-are different to those that have been investigated by animal detection, e.g., cervical cancer [START_REF] Guerrero-Flores | A non-invasive tool for detecting cervical cancer odor by trained scent dogs[END_REF].

To make the best use of animals in the field of disease detection and especially for cancer, it is essential to choose an experimental set-up that is easily duplicated and can be extended to a large number of cancers. Based on several studies, it appears that animals can detect cancer at very early stages of precancerous lesions [START_REF] Gouzerh | Odours of cancerous mouse congeners: detection and attractiveness[END_REF][START_REF] Hirotsu | A highly accurate inclusive cancer screening test using Caenorhabditis elegans scent detection[END_REF][START_REF] Horvath | Cancer odor in the blood of ovarian cancer : f b m 3 6 m h afterward[END_REF]. This could be useful for initial diagnoses or for cases of relapse, which are sometimes difficult to detect. Early detection is critical to more effectively treat patients. In addition, cancer detection methods must be accurate, fast, simple, and affordable. In this respect, animals that are well trained, or for which a reliable protocol can be established, can help detect early stages of cancer using primary and noninvasive screening. While the different animals that could be used all have advantages and disadvantages, all offer a non-invasive rapid diagnostic tool for human cancers.

The use of animals could be ethically problematic, especially the use of dogs and mice, so in this context it may seem preferable to use organisms such as insects or nematodes rather than mammalian detectors like dogs for instance. Another alternative is chemical analysis. Techniques such as GC-MS (gas chromatographymass spectrometry), LC-MS (liquid chromatography coupled with mass spectrometry), and PTRMS (proton transfer reaction mass spectrometry) show promise in the identification of VOCs that can help identify cancerous individuals. Although chemical analysis may b h m " " . Further, these analyses are time-consuming and tedious because cancer impact on VOCs does not always involve the same compounds, thus many samples and analyses would be necessary to identify potential cancer biomarkers. Indeed, several candidate VOC molecules have already been identified [START_REF] Gouzerh | Odors and cancer: Current status and future directions[END_REF], but there is no consensus on one or more potential biomarkers, although some compounds such as hexanal, acetone, ethanol, or nonanal have been pointed out in several publications [START_REF] Gouzerh | Odors and cancer: Current status and future directions[END_REF]. In the absence of general diagnostic markers, the use of animals to detect early stages of cancer development might be more effective.

Discussion

The use of animals in the fight against cancer, although effective, is still in its infancy. Indeed, the potential of animals to detect cancer at an early stage has only been explored in the last 20 years.

The use of several animals seem promising, with success rates above 80% for most. All species tested have advantages and disadvantages, although from an ethical point of view the development of experiments using invertebrates such as nematodes, ants, or drosophila should be given special attention. Moreover, this ability to detect cancer-with or without learning-opens the door to new questions about how and why animals are able to discriminate these odors.

Many species have evolved highly developed olfactory systems, allowing them to find their prey or food, avoid predators and toxic resources, or to socially interact [START_REF] Blaustein | Sexual Selection and Mammalian Olfaction[END_REF][START_REF] Ache | Olfaction: Diverse Species, Conserved Principles[END_REF]. The need to know one's environment has led animals to develop a highly efficient olfactory system that-with or without training-allows them to identify cancerous individuals. We know about the impact of infectious parasites on the social relationships of several animal species ( [START_REF] Clayton | The influence of parasites on host sexual selection[END_REF][START_REF] Scott | Female mice mate preferentially with non-parasitized males[END_REF][START_REF] Poirotte | Mandrills use olfaction to socially avoid parasitized conspecifics[END_REF]), but we know little about cancer. No studies to our knowledge have looked at the ability of conspecifics in the wild to avoid cancerous individuals. Documentation of cancer in natural populations is limited because most wild animals live and die anonymously. The exact prevalence of cancer in a population requires detailed knowledge of the organism under study (e.g., demography, distribution, migration) as well as extensive monitoring and sampling. However, the relative paucity of cancer research in natural environments does not signify that it is not important in determining the survival of an organism and in shaping ecological dynamics. Indeed, we know that many species-from hydra to humans-can develop cancer [START_REF] Albuquerque | From humans to hydra: patterns of cancer across the tree of life[END_REF]. Although there is little information on the prevalence of cancer in nature, some studies have been able to show that cancer can be a significant cause of death in nature [START_REF] Ratcliffe | Incidence and Nature of Tumors in Captive Wild Mammals and Birds[END_REF][START_REF] Andervont | Occurrence of Tumors In Wild House Mice 1[END_REF][START_REF] Mcaloose | Wildlife cancer: a conservation perspective[END_REF][START_REF] Madsen | Cancer Prevalence and Etiology in Wild and Captive Animals[END_REF],

although population monitoring to investigate the prevalence of cancer is very difficult to set up in the wild. Only Tasmanian devils and beluga have thus far been extensively studied for cancer [START_REF] Martineau | Cancer in wildlife, a case study: beluga from the St. Lawrence estuary, Québec, Canada[END_REF][START_REF] Mccallum | Distribution and impacts of Tasmanian devil facial tumor disease[END_REF].

Concerning the impact of cancer on wild animals, i.e., whether their olfactory capacity allows them to identify a cancerous congener, no study to our knowledge has asked this question. The only study carried out on the impact of cancer on intra-or interspecies relationships was done on tumoral hydras and showed that tumorous polyps were more predated by fish [START_REF] Boutry | Tumors (re)shape biotic interactions within ecosystems: Experimental evidence from the freshwater cnidarian Hydra[END_REF]. Is this only due to their larger size, or do they emit different odors that allow fish to differentiate them? For other predators such as the wolf, the dog's ancestor, do they use their sense of smell to detect sick individuals, and can they distinguish cancerous individuals? Are cancerous individuals, which may carry more pathogens following cancer-induced immune suppression [START_REF] Dujon | On the need for integrating cancer into the One Health perspective[END_REF], excluded from the group or less frequently chosen as sexual partners (e.g., [START_REF] Vittecoq | Animal behaviour and cancer[END_REF])? These questions are even more relevant for species harboring transmissible tumors, such as Tasmanian devils [START_REF] Mcaloose | Wildlife cancer: a conservation perspective[END_REF]. In this species, the extent to which individuals may avoid each other to prevent contamination is poorly understood. There are many questions about how cancer is perceived in nature by animals and especially how animals perceive cancerous animals using their sense of smell. For species with post-reproductive cancer, selection should not play a role on social interactions since the cancer will not affect the fitness of breeders. However, oncogenic processes may appear at a younger age in some species, or in the case of transmissible cancers, it is possible that selection plays a role in the olfactory capacities of animals to enable them to avoid conspecifics in poor conditions ( [START_REF] Vittecoq | Cancer: A missing link in ecosystem functioning?[END_REF][START_REF] Thomas | Cancer Is Not (Only) a Senescence Problem[END_REF]).

Oncogenic agents such as UV radiation, oncogenic contaminants, and hormones released into waterways are increasingly present in the environment due to human encroachment and habitat degradation. Because many of these carcinogens are new, exposed organisms may not have developed effective defense mechanisms and may not have the capacity to avoid them, which might make wildlife particularly vulnerable to carcinogenesis [START_REF] Fernandez | Selection for a dominant oncogene and large male size as a risk factor for melanoma in the Xiphophorus animal model[END_REF][START_REF] Giraudeau | Human activities might influence oncogenic processes in wild animal populations[END_REF][START_REF] Sepp | Urban environment and cancer in wildlife: available evidence and future research avenues[END_REF]. Exploring the extent to which chemical ecology will be central in these novel ecological contexts will be fascinating and will require the integration of concepts and techniques from different disciplines in addition to chemical ecology (e.g., behavioral ecology, physiology, molecular biology, oncology).

Concluding remarks

Animals can use their sense of smell to detect objects, drugs, people, or even diseases such as cancer. This ability is shared by many animals that use olfaction as a means of communication in the wild. Their sense of smell allows them to obtain information about the individuals around them, including their age, sex, and health status. Using their ability to identify individuals with parasitic, chronic, or genetic diseases such as cancer is a promising avenue for the early detection of many diseases.

Different experimental techniques could be used with different animals. This review covered olfactory studies that used dogs as well as other species and highlighted the advantages and disadvantages of each species. Analyzing the neural electrophysiological responses (e.g., electroantenography) of species capable of detecting cancer and thus identifying the compounds that are different between cancer patients and healthy ones would be invaluable. However, this involves a vast number of individuals who are destined to be euthanized. In this respect, insects or other invertebrates may be an interesting avenue of research: they have highly developed olfactory capacities and their use in experimentation is not at this time subjected to any ethical constraints.

Finally, the ability of animals to detect cancer raises many interesting ecological and evolutionary questions.

I)

Conditioning training Two types of conditioning training can be used in animals: classical conditioning and operant conditioning [START_REF] Oh | Applications of animal biosensors: A review[END_REF].

 Classical conditioning

Classical conditioning, which is based on the Pavlov reflex, implies that certain stimuli automatically provoke certain responses [START_REF] Rescorla | Behavioral studies of Pavlovian conditioning[END_REF]. The first step in classical conditioning is to associate a neutral stimulus that initially has no effect on the animal-for example, the smell of a cancerous individual-with an unconditioned stimulus, such as sugar, which provokes an unconditioned response. As the neutral stimulus is closely followed by an unconditioned stimulus that naturally triggers an unconditioned response, the neutral stimulus is associated with an unconditioned stimulus, so that the association between the two becomes stronger and the unconditioned response develops.

Based on Pavlov's principle, procedures have been adapted to insects that are more commonly called differential conditioning of the proboscis extension response (PER) [START_REF] Bitterman | Classical conditioning of proboscis extension in honeybees (Apis mellifera)[END_REF][START_REF] Matsumoto | Revisiting olfactory classical conditioning of the proboscis extension response in honey bees: A step toward standardized procedures[END_REF].

 Operant conditioning

The other type of learning is operant conditioning, which refers to the fact that a behavior can be controlled by its consequence (reward, called reinforcement, or punishment). The animal's behavioral response to a stimulus will be followed by a reinforcement, i.e., the response has a favorable result such as food [START_REF] Schapiro | Positive Reinforcement Training As a Technique to Alter Nonhuman Primate Behavior: Quantitative Assessments of Effectiveness[END_REF]. In the case of negative reinforcement, the animal will be subjected to an aversive stimulus such as an electric shock, or bitter or unpleasant food [START_REF] Iwata | Negative reinforcement in applied behavior analysis: an emerging technology[END_REF]. This learning technique is used to train dogs and rats, and for some studies on mice. With conditioning, two parameters are calculated to evaluate detection capacity-sensitivity and specificity.

II) Behavioral tests

 Habituation/ generalization tests

The concept of these tests is to habituate an individual to an odor for a given period of time and then present him two new odors; it is assumed that the odor to which the organism will go more is the one that is more different [START_REF] Todrank | Odor-genes covariance and genetic relatedness assessments: rethinking odor-b[END_REF].

 Preference tests / choice tests

The choice tests take place in a Y-shaped enclosure or another container such as a Petri dish for small organisms. These containers allow the individual to move towards one of the two stimuli presented, which are placed at each end of the olfactometer branch or on opposite sides of the Petri dish. The time spent in each position indicates the preferred stimulus.

III) Electrophysiology test

The last type of test used to determine whether animals can detect cancer consists of analyzing the f m . h m b k before antennae are removed from the animal to perform the experiments.

 Electroantennography (EAG)

Electroantennographie (EAG) is a bioassay widely used in experimental entomology for the f m . Th h f z wh h olfactory receptor detects. A neurological response recorded from the antenna indicates whether the compound is detected by the organism. For this purpose, the antenna of an insect is connected to two electrodes. The antennae are exposed to an odor (a single compound or mixture of volatile components) and the electric response of the antenna is recorded by the electrodes via an amplifier [START_REF] Schneider | Electrophysiological investigation on the antennal receptors of the silk moth during chemical and mechanical stimulation[END_REF][START_REF] Weissbecker | IDENTIFICATION OF VOLATILE POTATO SESQUITERPENOIDS AND THEIR OLFACTORY DETECTION BY THE TWO-SPOTTED STINKBUG Perillus bioculatus[END_REF]. This technique has never been used to determine whether an insect is able to detect the smell of a cancerous individual.

 Calcium imaging

This technique allows an even finer level of detection compared to EAG. It consists in visualizing the activated areas of the olfactory lobes of an insect during olfactory perception [START_REF] Grienberger | Imaging Calcium in Neurons[END_REF].

Figure 1 :

 1 Figure 1: Number of papers by year published between 1989 and 2022 that addressed the ability of animals to detect cancer odors. Studied animals were divided into dogs and other species, which included nematodes, bees, drosophila, ants, mice, and rats.

Figure 2 :

 2 Figure 2: Proportions of different animals used for odor detection. The dog breeds used (28 different breeds in referenced publications) were classified into

Figure 3 :

 3 Figure 3: Summary of cancers and odor sources used with each animal, including the number of publications identified per cancer type and source of odour.

setup) .

 . This type of test can be used with dogs, insects, and rodents. To estimate the success rate of 218 conditioning tests, we can calculate the sensitivity and specificity as follows: 219 220 Sensitivity = CP/ (CP+ MI) 221 Specificity= CN/ (CN+FA) 222 223 where CP indicates a correct positive response, when animals detected the target sample; MI indicates 224 a false negative response, when animals did not detect the target sample; CN indicates a correct negative response, when animals did not detect a control sample; and FA indicates a false positive alert, when animals detected a blank or control sample.

Figure 4 :

 4 Figure 4: Global sensitivity and specificity for all experiments with dogs as a function of cancer type and odor sample. Boxplots represent the first, median, and third quartiles on the 95% extent. The dots represent the outliers and when there was only one data point.

Table 1 :

 1 Summary of the advantages and disadvantages of techniques using each species to detect cancer associated odours. Test details are given in the supplementary material.

	Test technique	Species	Advantages	Disadvantages
	Conditioning training Dogs	 Good sensitivity and specificity	 Long training time
			 A single trained individual is useful for	required (several
			several years	months).
			 Many samples tested	 Cost (over US$50,000
			 Animal not killed	per dog)
				 Few
				individuals/replicates
				 Ethical documents are
				needed for the
				experiment
		Bees	 Good sensitivity and specificity	 No discrimination of
			 Short testing time (than 3 hours)	cancerous individuals
			 The individual can be killed or returned
			to the colony after the test (even though
			in the study mentioned bees have been
			killed)
		Ants	 Good sensitivity and specificity	 Many individuals are
			 No ethical documents needed for	necessary
			experimentation
			 Large number of individuals available
			 Short testing time (a few minutes)
			 The individual can be killed or returned
			to the colony after the test
		Rats	 Good sensitivity and specificity	 Many individuals are
			 Short training time (a few days)	necessary
			 Animals can be used several times on	 Ethical documents are
			multiple samples (even though rats in	needed for the
			the study mentioned have been	experiment
			euthanized after the experiment)
		Mice	 Good sensitivity and specificity	 Many individuals are
			 Short training time (a few days)	necessary
			 Animals can be used several times on	 Ethical documents are
			multiple samples (even though mice in	needed for the
			the study mentioned have been killed	experiment
			after the experiment)

see Experimental 217

  This capacity to detect cancer could allow a much more accurate diagnosis than current cancer screening tests, such as MRI. However, there are different experimental setups depending on which animal is used and different behavioral responses and measures, such as digging, rolling over,

sitting, rearing, and barking with dogs; physiological measurements such as electroantenography (EAG) coupled with calcium imaging with insects; and attraction or repulsion responses with mice or nematodes. Furthermore, a number of different stimuli can be presented to animals. The optimization of these stimuli for each type of cancer and for each animal must be considered. Some stimuli are currently little used even though they are potentially reliable. Other stimuli, such as urine, are often used even though they do not necessarily give the best results (e.g. in studies with dogs). Furthermore, given the detection capacity of insects, it is important to test stimuli other than cell cultures to see if this capacity could be extended to other commonly used stimuli, e.g., urine or exhaled air.

Acknowledgements

This work is supported by an ANR TRANSCAN grant (ANR-18-CE35-0009), the MAVA Foundation, and a CNRS International Associated Laboratory Grant. FG was supported by a doctoral fellowship from the University of Montpellier.

Author's Contribution

FG and AP collected the data. FG analyzed the data and wrote the paper. LD, FT, and GG supervised the project and contributed to the final manuscript.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.


J.-M Malherbe

F Sayède

Keywords: imaging spectroscopy, polarimetry, MSDP, solar physics, photosphere, chromosphere

Note concerning a high spectral resolution slicer for imaging spectro-polarimetry with the new generation Multichannel Subtractive Double Pass (MSDP) onboard the future EST telescope

-Introduction

The Multichannel Subtractive Double Pass is an imaging spectroscopy technique introduced by [START_REF] Mein | Multi-channel subtractive spectrograph and filament observations[END_REF]. It is based on a slicer which provides line profiles with N sampling points (or N channels) over a 2D field of view (FOV); for that purpose, the MSDP uses a rectangular entrance window instead of a thin slit. The technique was progressively developed and implemented on many telescopes [START_REF] Mein | Four decades of advances from MSDP to S4I and SLED imaging spectrometers[END_REF]. The first instrument with N = 7 channels was incorporated to the 14 m spectrograph of the Meudon Solar Tower. It was mainly running with the Hα line in order to study the dynamics (via the Doppler effect) of chromospheric features. It was followed by the MSDP of the Pic du Midi Turret Dome [START_REF] Mein | Multi-channel Subtractive Double Pass Spectrograph[END_REF] with N = 11 channels and a better spectral resolution. The third instrument was integrated to the 15 m spectrograph of the german Vacuum Tower Telescope (VTT) in Tenerife [START_REF] Mein | Solar 2D spectroscopy -A new MSDP instrument[END_REF]. Meanwhile, polish colleagues introduced the technique on the large Bialkow coronagraph to observe prominences [START_REF] Rompolt | The MSDP Recently Installed at the Spectrograph of the Large Coronograph[END_REF]. The next instrument was put inside the 8 m spectrograph of the THEMIS telescope [START_REF] Mein | The MSDP of THEMIS: capabilities, first results and prospects[END_REF]. For the first time, the MSDP worked there in polarimetric mode using achromatic waveplates and a calcite beam-splitter. [START_REF] Mein | Fast imaging spectroscopy with MSDP spectrometers: Vector magnetic maps with THEMIS/MSDP[END_REF] used the full Stokes capabilities of this high performance MSDP (N = 16) to investigate the vector magnetic field above an active region.

The slicers of these first generation instruments were based on multi-slits in the spectrum and prism beam-shifters. However, this technique does not allow to increase much the spectral resolution (limited to about 80 mÅ) and the number of channels. For that reason, the second generation of slicers uses now micromirrors, which allow to reach about 30 mÅ of spectral resolution and can deliver more than 50 channels. The first slicer using this technology was installed at the Meudon Solar Tower (N = 18). The Solar Emission Line Dopplerometer, in project with polish, british and slovakian colleagues for the Lomnicky coronagraph (N = 24) is dedicated to velocity measurements in the hot corona using the forbidden lines of iron (Malherbe et al, 2021) and is intended to operate in 2025. The future EST telescope could benefit of a state-of-the-art MSDP with N = 56 channels, as suggested by [START_REF] Sayède | EST Praha meeting[END_REF] and [START_REF] Malherbe | A proposal for imaging spectro-polarimetry with a new generation Multichannel Subtractive Double Pass (MSDP) onboard the EST telescope[END_REF]. Two slicers were proposed for chromospheric and photospheric lines providing spectral resolutions in the range 40-100 mÅ. The present paper discusses the opportunity of an optional slicer with a special resolution of 30 mÅ (or less) for thin photospheric lines, such as those of FeI.

-Capabilities of the optional high spectral resolution slicer

The MSDP project for the future EST is described by [START_REF] Sayède | EST Praha meeting[END_REF] and the optical capabilities are summarized by [START_REF] Malherbe | A proposal for imaging spectro-polarimetry with a new generation Multichannel Subtractive Double Pass (MSDP) onboard the EST telescope[END_REF]. It includes two 56-channel slicers inside the 8-meter spectrograph. The micro-mirrors step is Δx = 0.18 mm and 0.27 mm, corresponding to spectral resolutions (depending on the grating dispersion) in the range 40-100 mÅ, well adapted to photospheric and chromospheric lines. [START_REF] Malherbe | A proposal for imaging spectro-polarimetry with a new generation Multichannel Subtractive Double Pass (MSDP) onboard the EST telescope[END_REF]. The FOV is two times smaller in x-direction (3.1 mm instead of 6.2 mm, or 4" instead of 8") in order to observe simultaneously I+S and I-S which are cospatial. The line profile at disk centre and its first derivative are displayed. The bandpass centred on the line core is 220 mÅ.

However, for specific requirements concerning thin photospheric lines such as those of FeI, a slicer with a better spectral resolution could be proposed as an option. The step of such a slicer would be about Δx = 0.13 mm, providing spectral resolutions of 30 mÅ in the red part of the spectrum (28 mÅ for FeI 6173, Figures 1 &2), and even better in the blue part.

Figure 1 shows the wavelength transmission of the 56 channels with no polarimetry, or in the case of polarimetry using a high speed modulator providing successive measurements of I-Q, I+Q, I-U, I+U, I-V, I+V (at high cadence over a stabilized FOV by the AO system). The sampling points are given by λn(x) = λ0 + (x/d) + n (Δx/d), for 0 < x < xm (xm = 6.2 mm is the maximum FOV in x-direction, it corresponds to 8"). In this formula, n is the current channel (1 < n < N, N = 56), d is the dispersion of the spectrograph (mm/Å), Δx the slicer step (mm, the spectral resolution in Å is Δx/d). Generally, a cubic interpolation between sampling points is used for the determination of precise line shifts produced by the Doppler or Zeeman effects.

On the contrary, Figure 2 displays the wavelength transmission of the channels with polarimetry using a dual beam polarimeter (simultaneous measurements of I-S and I+S, with S = Q, U, V sequential). In that case, the FOV is divided by 2 by a mask which allows to form I-S at left (0 < x < xm/2) and I+S at right (xm/2 < x < xm). Please notice that both regions are strictly cospatial on the Sun, but for a given abscissa in xdirection, such that 0 < x < xm/2, the line profiles of I-S and I+S use different sampling points, respectively given by λn(

x) = λ0 + (x/d) + n (Δx/d) and λn(x) = λ0 + [(x + xm/2)/d] + n (Δx/d).
For that reason, interpolations are necessary to restore the same sampling points, in order to compare I-S and I+S profiles for Dopplershift and magnetic field calculations.

-Simulation of the channels provided by the high resolution slicer in the case of full FOV sequential measurements of I+S (S = -Q, +Q, -U, +U, -V, +V) using the FeI 617spectral line

This section presents a simulation of the 56 channels of the MSDP in the case of the FeI 6173 line. It is the line used by the HMI instrument onboard the SDO satellite, and also the line used by the PHI instrument onboard the SOLAR ORBITER mission. This is a thin line (85 mÅ for the Full Width at Inflexion Points, FWIP) very sensitive to the photospheric magnetic field (equivalent Landé factor 2.5). The depth of the line lies around 63 % of the continuum in the quiet Sun. SDO produces, in this line, high cadence magnetograms of the full Sun (4000 x 4000 pixels) every minute (pixel size = 0.5") with moderate spectral resolution (6 sampling points), assuming that the line profile has a gaussian shape (which helps a lot to derive Dopplershifts and magnetic fields).

The MSDP onboard the European Solar Telescope (EST) could work using, at least, two polarimetric modes already discussed by [START_REF] Malherbe | A proposal for imaging spectro-polarimetry with a new generation Multichannel Subtractive Double Pass (MSDP) onboard the EST telescope[END_REF] and detailed by Figure 3 : -High cadence modulation (100 Hz), allowing to observe in sequence I+Q, I-Q, I+U, I-U, I+V, I-V with adaptive optics providing image stabilization ; in that case, the full FOV of the MSDP is preserved (8" in x-direction, 120" in y-direction). -Simultaneous observations of I+S and I-S (S = Q, U, V in sequence) of the half FOV (4" in xdirection, 120" in y-direction) using a mask (grid) and a birefringent beam-splitter. This method has the advantage of simultaneous polarimetric measurements, but the disadvantage of FOV reduction, so that two successive observations are required to record the full FOV.

Please notice that the full FOV at the telescope focus is a square of 32" x 30" ; for the MSDP, it is optically split in 4 parts which are rearranged to form a rectangle of 8" x 120", as shown by Figure 3 (left), before injection into the spectrograph. For simultaneous measurements of I+S and I-S signals with a calcite beam splitter, a mask is used (Figure 3, right) under the form of a grid of 8" step (method suggested by [START_REF] Semel | Un analyseur précis de polarisation optique[END_REF]. The mask covers the half FOV, so that two consecutive observations are needed to record the full FOV.

The following figures simulate the two polarimetric methods using SDO/HMI data of 15 September 2023 at 12:00 UT, such as the continuum intensity, dopplergram and Line Of Sight (LOS) magnetogram. Figures 4 & 5 show a simulation of MSDP observations with the Δx = 0.13 mm/N = 56-channel slicer, that could be got using the fast modulation method, preserving the full FOV, but with I+V and I-V not simultaneous (but very close in time). Figure 4 displays I+V (image_1), while Figure 5 shows I-V (image_2), which must be observed at high cadence (100 Hz) with adaptive optics turned on. The wavelength sampling points are those of Figure 1. The circular polarization rate V/I = (Image_1 -Image_2) / (Image_1 + Image_2) is shown by Figure 6, from which it is easy to deduce the LOS magnetic field B// using the weak field theory. An alternative method consists in measuring the wavelength shift between the I+V and the I-V line profiles, as this shift is proportional to the LOS magnetic field B//. Both I+V and I-V profiles are globally translated of the same quantity in case of Dopplershifts V// of the plasma. Figure 7 shows the simulation of MSDP line profiles, in polarimetric mode over the full FOV derived from sequential observations of I+V, I-V, that could be delivered by the 56-channel slicer with a high cadence modulator. The sampling points are those given by Figure 1 for 3 locations in the x-direction of the FOV, x = 0, x = xm/2 and x = xm (xm = 6.2 mm or 8"). The profiles of the circular polarization rate V/I are also displayed.

Figure 8 shows the simulation of line profiles derived from sequential observations of I+Q, I-Q, that could be got with the same modulator. The sampling points are also those of Figure 1 for the 3 locations in the xdirection. The profiles of the linear polarization rate Q/I are indicated. 4 -Simulation of the channels provided by the high resolution slicer in the case of half FOV simultaneous measurements of I+S and I-S (S = Q, U, V sequential) using the FeI 6173 spectral line

Figure 9 shows a simulation of MSDP observations with the 56-channel slicer, that could be obtained using simultaneous observations of I+V and I-V of the half FOV with a birefringent beam-splitter and a mask (grid).

Each channel is divided into two subchannels showing the same half FOV (4" x 120"). I+V and I-V are strictly cospatial and simultaneous, and their profiles can be reconstructed using the chart of Figure 2. In order to recover the full FOV of 8" x 120", corresponding to the square FOV of 32" x 30" split in 4 parts at the focus of the telescope, a second observation is needed and requires to move the telescope of 4" in the x-direction.

-Line shape discussion and wavelength sampling

This short section discusses the gaussian assumption that was used in the simulations. Figure 12 shows a gaussian fitting of the atlas profile at disk centre of FeI 6173 for different samplings (crosses), respectively 30, 75, 105 and 135 mÅ. We found that the gaussian fitting of this almost symmetric profile works well for sampling better than 60 mÅ, so that a high resolution slicer (0.13 mm) is not necessary in that special and restrictive case, for which the standard slicers (0.18 mm and 0.27 mm steps) are convenient. Indeed, the fitting of lines close to the gaussian shape does not require very high spectral resolution, as demonstrated by the high quality of SDO/HMI data. (30, 75, 105 and 135 mÅ), for respectively the red, blue, green and violet curves.

Figure 13, on the contrary, does not make any hypothesis on the line shape, which can be asymmetric (this would be the case in a complex atmosphere) and far from a simple mathematical curve. A cubic interpolation was just done between the sampling points (crosses). In such a case, a high resolution slicer (0.13 mm) becomes necessary. The 30 mÅ sampling of the slicer provides excellent results, but above this value, the reconstruction of the profile is more and more degraded. For that reason, a high resolution slicer is a good option for thin and disturbed photospheric lines, as many of them (such as FeI 5250, 6173, 6302, CaI 6103) are very magnetically sensitive.

-Conclusion

The error at line centre, when the line has a nearly gaussian shape (this is the case of the atlas profile of FeI 6173 in the quiet Sun), remains below 1 % up to 60 mÅ sampling. When the line profile is asymmetric or far from a mathematical curve, the cubic interpolation is required to derive LOS velocities and magnetic fields ; it provides very good results (error less than 1 %) for sampling better than 30 mÅ. The SOT spectropolarimeter onboard the HINODE satellite offered a similar resolution on FeI 6301 and 6302. Hence, a high resolution slicer for the MSDP onboard EST could be useful in order to avoid assumptions on the line shapes.

Figure 1 :

 1 Figure 1: the MSDP wavelength transmission λn(x) for the 56 channels (0.028 Å spectral resolution) for FeI 6173. The line profile at disk centre and its first derivative are displayed. For a given bandpass of 220 mÅ centred on the line core, the graph shows that the full FOV (xm = 6.2 mm = 8" in x-direction) is covered for no velocity and that 85% of the FOV is covered for velocities less than 5 km/s.

Figure 2 :

 2 Figure 2: the MSDP wavelength transmission λn(x) for the 56 channels (0.028 Å spectral resolution) for FeI 6173 and for simultaneous polarimetric measurements I+S and I-S (S = Q, U, V in sequence) with the method

Figure 3 :

 3 Figure 3: simulation of the MSDP in polarimetric mode using SDO/HMI data (continuum intensity, LOS magnetic field B// and LOS velocity field V//) of 15 September 2023, 12:00 UT. We start with a 32" x 30" FOV at the F/50 focus of the EST telescope. This FOV is transformed into a 8" x 120" FOV for the MSDP by splitting the primary image in 4 parts (A, B, C, D) which are optically re-aligned vertically before injection into the spectrograph. The fast modulation method (left) delivers sequential measures of I+S (S = -Q, +Q, -U, +U, -V, +V) over the full FOV. The beam-splitting method (right) requires grid masking, delivering the half FOV, but in that case I+S and I-S (S = Q, U, V in sequence) are simultaneous. A second observation is needed to observe the parts masked by the grid during the first observation.

Figure 4 :

 4 Figure 4: simulation using SDO data (continuum, LOS magnetic field B//, LOS velocity field V//) of the 56channel slicer (28 mÅ resolution, Δx = 0.13 mm) with FeI 6173 line (assumed gaussian), here the I+V spectra image (image_1). I+V profiles can be reconstructed using the chart of Figure 1. The FOV is 8" x 120".

Figure 5 :

 5 Figure5: simulation using SDO data (continuum, LOS magnetic field B//, LOS velocity field V//) of the 56channel slicer (28 mÅ resolution, Δx = 0.13 mm) with FeI 6173 line (assumed gaussian), here the I-V spectra image (image_2). I-V profiles can be reconstructed using the chart of Figure1. The FOV is 8" x 120", it corresponds to the telescope FOV of 32" x 30" after MSDP re-arrangement.

Figure 6 :

 6 Figure 6: simulation using SDO data (continuum, LOS magnetic field B//, LOS velocity field V//) of the 56channel slicer (28 mÅ resolution, Δx = 0.13 mm micro-mirrors) with FeI 6173 line (assumed gaussian). Here, we display the circular polarization rate V/I = (image_1 -image_2) / (image_1 + image_2), where image_1 (I+V) and image_2 (I-V) are those of figures 4 & 5. I+V and I-V line profiles can be reconstructed using the wavelength chart of Figure 1 and have exactly the same sampling points. The weak field theory was used for the simulation.

Figure 7 :

 7 Figure 7: simulation of I+V (solid line) and I-V (dashed) line profiles of FeI 6173 (bottom), that could be delivered by the Δx = 0.13 mm / N= 56-channel slicer. The spectral resolution is 28 mÅ. Line profiles were computed for B// = 1000 G. Profiles for 3 locations in the FOV are drawn, x = 0 (left FOV, blue), x=xm/2 (centre, green) and x = xm (right, red) for xm = 8" (or 6.2 mm). Sampling points are raw data (no interpolation between them). Top: the V/I circular polarization rate (theoretical maximum 0.76 for 1000 G).

Figure 8 :

 8 Figure 8: simulation of I+Q (solid line) and I-Q (dashed) line profiles of FeI 6173 (bottom), that could be got using the Δx = 0.13 mm / N= 56-channel slicer. The spectral resolution is 28 mÅ. Line profiles were computed for BꞱ = 1000 G. Profiles for 3 locations in the FOV are drawn, x = 0 (left FOV, blue), x=xm/2 (FOV centre, green) and x = xm (right FOV, red) for xm = 8" (or 6.2 mm). Sampling points are raw data (no interpolation between them). Top: the Q/I linear polarization rate (theoretical maximum 0.48 for 1000 G).

Figure 9 :

 9 Figure9: simulation using SDO data (continuum, LOS magnetic field B//, LOS velocity field V//) of the 56channel slicer (28 mÅ resolution or 0.13 mm) with FeI 6173 line (assumed gaussian). The calcite beam splitter and the grid produce 56 x 2 = 112 cospatial subchannels. I+V and I-V are simultaneous, implying the FOV reduction by a factor 2 in the x-direction (4" x 120" instead of 8" x 120"). I+V and I-V line profiles can be reconstructed using the chart of Figure2for the two cospatial subchannels.

Figure 10

 10 Figure10shows the simulation of MSDP line profiles, in polarimetric mode over the half FOV with a birefringent beam-splitter, derived from simultaneous observations of the cospatial subchannels I+V, I-V,

Figure 10 :

 10 Figure 10: simulation of I+V (solid line) and I-V (dashed) line profiles of FeI 6173 (bottom), that could be got using the Δx = 0.13 mm / N= 56-channel slicer. Profiles for 3 locations in the FOV are drawn, x = 0 (left FOV, blue), x=xm/4 (centre, green) and x = xm/2 (right, red) for xm/2 = 4" (or 3.1 mm). Top: V/I polarization rate.

Figure 11 :

 11 Figure 11: simulation of I+Q (solid) and I-Q (dashed) line profiles of FeI 6173 (bottom), that could be got using the Δx = 0.13 mm / N= 56-channel slicer. Profiles for 3 locations in the FOV are drawn, x = 0 (left FOV, blue), x=xm/4 (centre, green) and x = xm/2 (right, red) for xm/2 = 4" (or 3.1 mm). Top: Q/I polarization rate.

Figure 12 :

 12 Figure 12: gaussian fitting of the atlas profile (black) of FeI 6173 at disk centre for various samplings (30, 75, 105 and 135 mÅ), for respectively the red, blue, green and violet curves.

Figure 13 :

 13 Figure13: cubic interpolation of the atlas profile (black) of FeI 6173 at disk centre for various samplings(30, 75, 105 and 135 mÅ), for respectively the red, blue, green and violet curves.


João Pedro Norenberg

Americo Cunha

Piotr Wolszczak

Grzegorz Litak

Piezomagnetic vibration energy harvester with an amplifier

Keywords: Nonlinear energy harvesting, Piezoelectric, Displacement amplifier, Bistable potential

We study the effect of an amplification mechanism in a nonlinear vibration energy harvesting system where a ferromagnetic beam resonator is attached to the vibration source through an additional linear spring with a damper. The beam moves in the nonlinear double-well potential caused by interaction with two magnets. The piezoelectric patches with electrodes attached to the electrical circuit support mechanical energy transduction into electrical power. The results show that the additional spring can improve energy harvesting. By changing its stiffness, we observed various solutions. At the point of the optimal stiffness of the additional spring, the power output is amplified a few times depending on the excitation amplitude.

The increasing applications of electricity with the limited conditions of renewable sources have resulted in the search for more efficient uses of available ambient kinetic energy [START_REF] Yang | High-Performance Piezoelectric Energy Harvesters and Their Applications[END_REF]. Different ways of energy transduction engage electromagnetic, piezoelectric, and magnetostrictive phenomena [START_REF] Mitcheson | Energy Harvesting From Human and Machine Motion for Wireless Electronic Devices[END_REF]. Account for the high energy density the piezoelectric transducers were adopted for kinetic energy harvesting. Initially, investigations were focused on linear systems, which had a good performance provided that they worked in the resonance conditions [START_REF] Beeby | Energy Harvesting Vibration Sources for Microsystems Applications[END_REF]. However, variability of the ambient vibration conditions, including frequency and amplitude, denies the wide applications. To overcome this deficiency, the nonlinearities were introduced to the system [START_REF] Erturk | A piezomagnetoelastic structure for broadband vibration energy harvesting[END_REF][START_REF] Daqaq | On the Role of Nonlinearities in Vibratory Energy Harvesting: A Critical Review and Discussion[END_REF] to obtain a broadband frequency effect. Among the nonlinear systems bistable [START_REF] Erturk | A piezomagnetoelastic structure for broadband vibration energy harvesting[END_REF][START_REF] Cottone | Nonlinear Energy Harvesting[END_REF][START_REF] Litak | Magnetopiezoelastic energy harvesting driven by random excitations[END_REF][START_REF] Norenberg | Global sensitivity analysis of asymmetric energy harvesters[END_REF] or multistable [START_REF] Zhou | Numerical analysis and experimental verification of broadband tristable energy harvesters[END_REF] systems attracted more interest from the researchers.

In this context, multiple degrees of freedom systems were also studied [START_REF] Erturk | Modeling of Piezoelectric Energy Harvesting from an L-shaped Beam-mass Structure with an Application to UAVs[END_REF][START_REF] Margielewicz | Energy Harvesting in a System with a Two-Stage Flexible Cantilever Beam[END_REF]. In such a situation, frequency bandwidth is broadened by the multiple resonances appearance [START_REF] Caetano | Multimodal pizza-shaped piezoelectric vibration-based energy harvesters[END_REF]. The other possible consequence can be the internal resonance and quasi-periodic solutions [START_REF] Muralidharan | Theoretical Investigations on an Internally Resonant Piezoelectric Energy Harvester in: Advances in Nonlinear Dynamics[END_REF][START_REF] Hu | Theoretical Study of a Two-Degree-of-Freedom Piezoelectric Energy Harvester under Concurrent Aeroelastic and Base Excitation[END_REF]. Based on two degrees of freedom system, the displacement amplifier to the resonator was proposed [START_REF] Liu | Design and characteristic analysis of magnetostrictive bistable vibration harvester with displacement amplification mechanism[END_REF]. This structure can help to supply a higher amplitude of excitation dealing with bistable piezoelectric systems [START_REF] Erturk | A piezomagnetoelastic structure for broadband vibration energy harvesting[END_REF] that require a large amount of input energy to overcome the potential barrier.

In the present work, we continue this direction of study, quantifying how the amplifier stiffness affects energy harvesting. We also contribute to briefly investigating the dynamic behavior of a higher amplification factor system. Our system is composed of a piezomagneto-elastic beam energy harvester with an additional spring and a damper (Fig. 1). Figure 1a shows the real system, Fig. 1b illustrates the model schematics, and Fig. 1c exhibits the double-well potential of the piezo-magneto-elastic beam. The main resonator is a ferromagnetic beam with piezoelectric patches attached to the moving frame. Two magnets destabilize the vertical position of the beam by attraction to the left and right stable equilibrium positions. Two coupled masses m 1 and m 2 (Fig. 1b) are governed by the set of two differential equations (Eq. 1). They are forced by a harmonic base excitation. Finally, the piezoelectric elements provide the electromotive force to the resistive circuit (Eq. 2). The corresponding set of the equations of motion reads:

x 1 (t) x 2 (t) Y (t) m 1 m 2 k 1 c 1 k 2 , k 2n c 2 θ R l k 2 < 0 k 2n > 0 (a) (b) (c)
m 1 ẍ1 = -c 1 ( ẋ1 -Ẏ) + c 2 ( ẋ2 -ẋ1 ) -k 1 (x 1 -Y) + k 2 (x 2 -x 1 ) + k 2n (x 2 -x 1 ) 3 + θv, (1)
m 2 ẍ2 = -c 2 ( ẋ2 -ẋ1 ) -k 2 (x 2 -x 1 ) -k 2n (x 2 -x 1 ) 3 -θv, C p v + 1 R l v + θ( ẋ2 -ẋ1 ) = 0, (2)
where the symbols (appearing in Eqs. 1-2) represent the system parameters, and they are specified in Tab. 1 together with their values (see in [START_REF] Dutoit | Experimental Verification of Models for Microfabricated Piezoelectric Vibration Energy Harvesters[END_REF][START_REF] Xia | Bistable attachments for wideband nonlinear vibration attenuation in a metamaterial beam[END_REF]) used in the following simulations, while x 1 , x 2 are the displacements of the first and the second masses and Y(t) is the kinematic base excitation.

The original system in the set of Eq. 1 is bistable, while the additional spring and damper provide a linear coupling between the system and the excitation. The results of them are presented in the next figures. The mean power output against the additional spring stiffness value is presented in Fig. 2. We computed the system responses for three different excitation amplitudes (1, 3, 10 mm) for an excitation frequency of 10 Hz. The power outputs are represented by non-monotonic curves with a maximum value of stiffness of 500N/m. Note that in the lower stiffness limit, the system is very flexible, suppressing the energy transfer, while in the higher stiffness limit, the additional spring is very rigid, leading to the original system [START_REF] Erturk | A piezomagnetoelastic structure for broadband vibration energy harvesting[END_REF]. The horizontal flat line represents this limit. The logarithmic scale is used to show the amplification more clearly. In this limit power output of the energy harvester is broadband in terms of frequency as was studied in the previous papers [START_REF] Erturk | A piezomagnetoelastic structure for broadband vibration energy harvesting[END_REF][START_REF] Litak | Magnetopiezoelastic energy harvesting driven by random excitations[END_REF][START_REF] Norenberg | Global sensitivity analysis of asymmetric energy harvesters[END_REF]. Still, the amplitude amplification mechanism does not work.

In the next three figures (Figs. 345), we study with more detail the cases marked in Fig. 2 by arrows and numbered 1-3, respectively. Figure 3 Table 1: System parameters Furthermore, the solution of the resonating beam corresponds to intra-well oscillation. The relative displacement x 2x 1 is periodic, with a leading frequency coinciding with the excitation frequency and a small superharmonic 2 component. In contrast to these results, Figs. 4 and5 show large orbit solutions with inter-well oscillations of the resonator. The highest power output is visible in case 2 for the additional spring stiffness of 500 N/m (see Fig. 2) and studied with details in Fig. 4. This is the optimum stiffness case. The thick line indicates the presence of some fluctuation in the main path on the phase portrait. This effect could appear because of the vicinity of the bifurcation point concerning the stiffness value. This solution is rich in frequencies and possibly possesses small irrational components leading to quasi-periodicity or chaotic behavior. In this case, we observe two leading peaks for the excitation and double-excitation frequencies. There are also many medium and smaller features in the frequency spectrum. At last, Fig. 5 shows the original solution of the reduced system [START_REF] Erturk | A piezomagnetoelastic structure for broadband vibration energy harvesting[END_REF]. There is also a high value of power output and a larger orbit with passing through the potential barrier. Here the leading frequency in the frequency spectrum coincides with the excitation. However, the super-harmonic 3 component is also significant. This frequency modifies the shape of the resonator phase portrait. To show the system responses in the best condi- tion, we estimate the amplification factor for the three cases of amplitude excitation in Fig. 6. The amplifier demonstrated more efficiency in low excitation amplitude conditions. This result is essential because it can improve the power recovered by the bistable oscillator in its critical situation. Finally, we want to draw attention to the advantages of the proposed system. Our results show that the power output can be amplified significantly. Furthermore, the optimum condition is robust against the excitation am- plitude variation. From the preliminary calculations, the optimum condition would be shifted accordingly by changing the excitation frequency. The bifurcations point were found and will be discussed in the next works with more detail. In the limit of high stiffness, the additional degree of freedom is unimportant, and our system reproduces the original system without the amplifier [START_REF] Erturk | A piezomagnetoelastic structure for broadband vibration energy harvesting[END_REF]. The quasi-periodic solution presented in Fig. 4 deserves more explanation. In that system, various solutions could appear. Their properties can be investigated further using nonlinear time series methods as the Lyapunov exponent [START_REF] Wolf | Determining Lyapunov exponents from a time series[END_REF] and multi-scaled entropy [START_REF] Litak | Dynamics and Entropy Analysis of a Frictionally Loaded Pendulum[END_REF]. It should also be noted that the optimal amplifier stiffness should be determined after more systematic studies with various initial conditions and excitation frequency sweeps.

Figure 1 :

 1 Figure 1: Piezo-magneto-elastic beam energy harvester with displacement amplifier mechanism: (a) real system schematic, (b) electromechanical model, and (c) general shape of double-well potential. Symbols and coordinates are defined in Eqs. 1-2 and Tab. 1.

  shows the low stiffness case. The power and voltage outputs are small. Mass of the amplifier, m 1 66 g Mass of the beam, m 2 22 g Damping coef. of the amplifier, c 1 0.1 N•s/m Damping coef. of the beam, c 1 0.125 N•s/m Stiffness of the amplifier, k 1 0.1-10 6 N/m Linear stiffness of the beam, k 2 -63.451 N/m Nonlinear stiffness of the beam, k 2n 634509 N/m 3 Effective piezoelectric coupling, θ -4.57 m•N/V Effective piezoelectric capacitance, C p 43 nF Electrical loading, R l 5 kΩ

Figure 2 :Figure 3 :

 23 Figure 2: Mean power recovered against the stiffness values of the amplifier mechanism under different excitation displacements when the excitation frequency is 10 Hz. The results are obtained for a single set of initial conditions of minimum energy. The three cases highlighted will be discussed later.

Figure 4 :Figure 5 :

 45 Figure 4: Dynamic behavior of case 2 that the stiffness is 500 N/m: (a) serial time of the amplifier displacement, beam displacement, and the recovered voltage, (b) phase portrait of the beam, and (c) Fourier transform of the voltage.

Figure 6 :

 6 Figure 6: Amplification factor against the additional stiffness values under different excitation displacement when the excitation frequency is 10 Hz.

Acknowledgement

The authors would like to thank Prof. Shengxi Zhou for usefull discussions.

Funding This research was funded by National Science Centre, Poland (Grant No. 2021/40/Q/ST8/00362), and Brazilian agencies: Coordenac ¸ão de Aperfeic ¸oamento de Pessoal de Nível Superior (CAPES), Finance Code 001, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Grant No. 305476/2022-0), and Fundac ¸ão Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (Grant Nos. 210.167/2019, 211.037/2019 201.294/2021).

Data Availability Statement

The data supporting this study's findings is openly available in STONEHENGE GitHub [START_REF] Norenberg | STONE-HENGE -Suite for Nonlinear Analysis of Energy Harvesting Systems[END_REF].

Conflict of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


domain: chim phys

text:
Emanuele Zanda
email: emanuele.zanda@ijclab.in2p3.fr

Osian Fonquernie

Veronika Zinovyeva

Sofia Gama

Stéphane Brandes

Jean-Claude Chambron

Michel Meyer

Vladimir Sladkov

Complexation of Th(IV) and U(VI) with a new tetrahydroxamic acid by affinity capillary electrophoresis

come   L'archive ouverte pluridisciplinaire

The transfer of metal cations in soils and sediments is not only controlled by geological and physico-chemical parameters (clay and organic matter contents, pH, Eh, etc.) but also by microorganisms. The latter take part in the mobilization/immobilization of trace metals [1]. Siderophores, as natural iron-specific chelators, have to be considered in this context. These low molecular weight, water-soluble compounds are excreted by bacteria and fungi to overcome the limited bioavailability of iron under aerobic conditions (ca. 10 -18 M at neutral pH) by dissolving iron oxohydroxides present in the soils. Because of their high affinity for hard Lewis acid cations, like Fe(III), hydroxamic siderophores are also able to effectively bind actinides (U, Th, Pu) [2][3][4]. The development of high affinity chelators for f-elements and the understanding of their coordination chemistry is of fundamental interest for the management and remediation of contaminated fields or the disposal of nuclear wastes [4]. This work is devoted to the complexation study of Th(IV) and U(VI) with (DFO(Me)PIPO)H4 (Figure 1), a new hydroxamic acid obtained by coupling the 6-membered 1-hydroxypiperidine-2-one moiety [5] to the bacterial siderophore desferrioxamine B [3,4]. This compound, which contains four hydroxamic acid groups, is an effective ligand of Zr 4+ [6], as well as actinides, such as Th 4+ and UO2 2+ even at pH values of about 2. Protonation constants of (DFO(Me)PIPO) 4-were obtained by potentiometry and UV absorption spectrophotometry, before unravelling the speciation of the ligand in the presence of Th 4+ and UO2 2+ by affinity capillary electrophoresis (ACE). This electromigration technique, which requires only a few μL of solutions, is based on the change in the electrophoretic mobility of the UV-detected analyte due to the interaction with the other species (metal or ligand) present in the electrolyte. These sets of runs were performed using (H,Na)ClO4 mixtures to keep both the pH and the ionic strength (I = 0.1 M) constant. The electrophoretic mobility changes with the increasing concentrations of the reagent dissolved in the background electrolyte solution were used to assess the speciation and equilibrium constants. This method is fruitful for studying metal complex formation equilibria and gives valuable information for further modelling of their behaviour under environmental conditions [7]. Formation of 1:1 metal-toligand complexes was further ascertained by high-resolution ESI-MS spectrometry and circular dichroism (CD) measurements using the optically pure ligand.

Figure 1 .

 1 Figure 1. Structure of (DFO(Me)PIPO)H4.

Acknowledgments:

The Agence Nationale de la Recherche (ANR project PLUTON, grant N° ANR-17-CE08-0053) is gratefully acknowledged for financial support.