Gaëlle Frenois-Veyrat

Franck Gallardo

Olivier Gorgé

Elie Marcheteau

Olivier Ferraris

Artem Baidaliuk

Anne-Laure Favier

Cécile Enfroy

Xavier Holy

Jérémy Lourenco

Rhéa Khoury

Flora Nolent

Douglas W Grosenbach

Dennis Hruby

Audrey Ferrier

Frédéric Iseni

Etienne Simon-Loriere

Jean-Nicolas Tournier

Tecovirimat is highly efficient on the Monkeypox virus lineage responsible for the international 2022 outbreak

The ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. Genomic analysis revealed a divergent phylogenetic lineage within clade 3, and atypical clinical presentations have been noted. We report the sequencing and isolation of the virus from the first clinical case diagnosed in France in May 2022. We tested the in vitro effect of tecovirimat (ST-246), a FDA approved drug, against this novel strain, showing efficacy at the nanomolar range. In comparison, cidofovir showed activity at micromolar concentrations. These results and the safety profile of tecovirimat strongly support its use in clinical care of severe forms for the 2022 MPXV outbreak.

Main text

Monkeypox virus (MPXV) is a zoonotic virus belonging to the Orthopoxvirus genus, which also includes vaccinia virus and variola virus [START_REF] Mccollum | Human monkeypox[END_REF] . Since May 2022, MPXV is causing the largest human outbreak ever recorded outside of Africa 2 . Recent studies report atypical demographics and clinical findings in cases of MPXV, mainly but not exclusively found in men who have sex with men [START_REF] Antinori | Epidemiological, clinical and virological characteristics of four cases of monkeypox support transmission through sexual contact, Italy, May 2022[END_REF][START_REF] Basgoz | Case 24-2022: A 31-Year-Old Man with Perianal and Penile Ulcers, Rectal Pain, and Rash[END_REF][START_REF] Girometti | Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis[END_REF] . The first suspected case in France was a male patient consulting at an HIV and sexual health center on May 19 th , 2022 for vesiculopustular lesions on the face and the genital organs, with no reported travel history. At the clinical examination, the patient presented a lesion on the lip, the nipple and two lesions on the genitalia. The MPXV infection at all three sites was confirmed by qPCR assays at the National Reference Center for orthopoxviruses. The PCRs, adapted from previous studies, consisted in a first screening for the genus orthopoxvirus [START_REF] Scaramozzino | Real-time PCR to identify variola virus or other human pathogenic orthopox viruses[END_REF] , followed by a second, specific, qPCR for MPXV diagnosis [START_REF] Li | Real-time PCR assays for the specific detection of monkeypox virus West African and Congo Basin strain DNA[END_REF] . The viral strain MPXV/France/IRBA2211/2022 was isolated on Vero cells (see methods) and is available upon request, as it may be useful to evaluate diagnostic tools, antivirals or vaccines. Transmission electron microscopy was performed on infected Vero cells. The resulting image (Figure 1A) showed classical pox-like intracellular virions of approximately 250 nm × 125 nm in size with an hourglass-shaped core. The genome from both the primary samples and the isolate were identical, and clustered within the newly proposed B.1 lineage within clade 3 [START_REF] Happi | Urgent need for a non-discriminatory and non-stigmatizing nomenclature for monkeypox virus[END_REF] (formerly designated as the "West African" clade 9 ) (Figure 1B).

MPXV infection leads to a wide spectrum of clinical presentation and disease severity, including pauci-or asymptomatic infection as reported within the 2022 outbreak [START_REF] Baetselier | Asymptomatic monkeypox virus infections among male sexual health clinic attendees in Belgium[END_REF] . The majority of the clinical characteristics of human MPXV infection mirror those of smallpox, although with a milder mortality rate varying from 10 % for clade 1 (former Congo Basin clade), to 3.6 % for clades 2 and 3. Human MPXV infection often begins with a combination of non-specific symptoms such as fever, chills, asthenia, lymph node swelling, back pain, and muscle aches. This prodromal phase is followed by the classical rash phase evolving swiftly in papules turning into vesicles and pustules, evolving into scabs. The number of skin lesions may range from a few to thousands. The current outbreak of MPXV infection is characterized by several atypical features such as shorter incubation phase [START_REF] Miura | Estimated incubation period for monkeypox cases confirmed in the Netherlands, May 2022[END_REF] , and milder clinical presentation often associated with localized rash and lesions in genital and perianal sites, sometimes highly painful [START_REF] Antinori | Epidemiological, clinical and virological characteristics of four cases of monkeypox support transmission through sexual contact, Italy, May 2022[END_REF][START_REF] Basgoz | Case 24-2022: A 31-Year-Old Man with Perianal and Penile Ulcers, Rectal Pain, and Rash[END_REF][START_REF] Girometti | Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis[END_REF] . Importantly, severe disease can occur in immunocompromised patients, pregnant women, and children.

No specific treatment is currently approved for MPXV infection. However, several molecules developed to treat smallpox (Tecovirimat (ST-246); Cidofovir; Brincidofovir) have shown broad spectrum activity both in vitro and in animal models against multiple orthopoxviruses including MPXV, variola virus and rabbitpox [START_REF] Huggins | Nonhuman primates are protected from smallpox virus or monkeypox virus challenges by the antiviral drug ST-246[END_REF][START_REF] Jordan | ST-246 antiviral efficacy in a nonhuman primate monkeypox model: determination of the minimal effective dose and human dose justification[END_REF][START_REF] Grosenbach | Oral Tecovirimat for the Treatment of Smallpox[END_REF] . While brincidofovir treatment of 3 MPXV infected patients between 2018 and 2021 was rapidly stopped due to elevated liver enzymes 15 , no safety signals were identified in reports of compassionate use of tecovirimat, making it a potential resource to help patients in the current outbreak. Tecovirimat has been authorized in Europe by the European medicine agency under 'exceptional circumstances', although its efficacy has not been shown on the current circulating strain 16 . Tecovirimat has been shown to target vaccinia virus (VACV) F13L gene product VP37 protein, required for extracellular virus particle formation. The protein is highly conserved within the orthopoxvirus genus. Interestingly, all 2022 MPXV genomes carry the E353K substitution in the VP37 protein, which was absent from the most recent common ancestor within clade 3 (Figure 1B), but noted in a single 2018 outbreak genome (MT903341).

To assess the activity of Tecovirimat, we performed doses response studies on Vero cells (see methods). Tecovirimat completely abolished MPXV production above 100 nM, with an IC 50 of 12.7 nM. For comparison, we used a VACV ANCHOR TM -GFP infection model, where virus infection and propagation can be visualized in living cells, revealing a comparable IC 50 (6 to 8.6 nM) (Figure S1). Cidofovir IC 50 on MPXV lineage B.1 was 30 μM (Fig. 2), 3,000 less potent than tecovirimat in vitro.

These results support the use of tecovirimat in the clinical response to the 2022 MPXV outbreak, in particular for immunosuppressed patients. Of note, tecovirimat is not recommended for pregnant women due the absence of safety data.

Considering that resistance mutations to tecovirimat under artificial culture pressure have been described for various orthopoxviruses [START_REF] Duraffour | Specific targeting of the F13L protein by ST-246 affects orthopoxvirus production differently[END_REF] (Figure S2), attention to adherence to treatment will be needed, especially in the context of milder clinical forms, and it will be important to monitor of the evolution of the virus during its outbreak circulation.

Methods

Ethics

This work has received patient consent through the national reference center for orthopoxviruses (CNR-LE orthopoxvirus).

All work with infectious virus was performed in BSL-3 containment laboratories.

Virus detection

Test and control samples were extracted using the QIAamp DNA Mini kit (Qiagen) with small modifications. Briefly, pre-extraction inactivation was performed in BSL3 by adding 200 μL of sample to a tube containing 200 μL of Qiagen Buffer AL and 20 μL of proteinase K. The tubes were incubated at 70°C for 10 min to inactivate the virus prior to extraction.

The pan-Orthopoxvirus and pan-MPXV PCR assay have been previously described [START_REF] Scaramozzino | Real-time PCR to identify variola virus or other human pathogenic orthopox viruses[END_REF][START_REF] Li | Real-time PCR assays for the specific detection of monkeypox virus West African and Congo Basin strain DNA[END_REF] . Each reaction consisted of 5 μl of extracted DNA and 15 μL of iTaq™ Universal Probes Supermix (BioRad), containing 0.4 mM of each primer, 0.25mM of probe in the pan-Orthopoxvirus PCR, and 0.2mM of probe in the pan-MPXV PCR. All assays were performed on a CFX96 thermocycler (BioRad). Data and results were analyzed and reported using Bio-Rad CFX Maestro.

Virus isolation, titration and production

The swabs used for sample collection were discharged in universal transport media. After homogenization, the samples were diluted in Dulbecco's Modified Eagle Medium (DMEM) containing 0.4 % fetal bovine serum (FBS). To inhibit bacterial and fungal contamination antibiotics and antifungal were added (Gentamycin: 2,5µg/ml, Mycostatin: 10 U/ml, Penicillin: 100 U/ml, Streptomycin: 100 µg/ml). Following clarification at 700 g for 10 min, we inoculated 50 μL of the sample onto monolayers of Vero (African green monkey kidney, ATCC CCL-81) cells in 96 well plates for both titration and isolation (eight replicates / dilution). The plates were incubated at 37°C under 5 % CO 2 and observed daily for potential cytopathic effect. The viral titer was calculated according to the Reed and Muench method and expressed in terms of TCID 50 /mL [START_REF] Reed | A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT ENDPOINTS[END_REF] . Supernatants from wells presenting cytopathic effect were harvested and inoculated on T25 flasks. At day 3, upon observation of 80 % cytopathic effect, the flasks were frozen/thawed 3 times and the production was clarified at 1,200 g for 10 min (passage 2). Passage 2 stock was tittered by plaque forming assay in 24-well plates and sequenced. The titer was 4.1x10 [START_REF] Scaramozzino | Real-time PCR to identify variola virus or other human pathogenic orthopox viruses[END_REF]

PFU/mL

Transmission electron microscopy Two days after infection, cells were fixed with 2.5 % (vol/vol) glutaraldehyde in sodium cacodylate buffer (0.1 M; pH 7.4; 10 mM CaCl2, 10 mM MgCl2, and 2% glucose) for 4 days at 4°C. After washing samples with a mixture of saccharose (0.2 M) and sodium cacodylate (0.1 M), cells were postfixed them with 1% (vol/vol) osmium tetraoxide in cacodylate buffer for 1 h at room temperature. Samples were stained with 2% (vol/vol) uranyl acetate for 1 h at 4°C followed by gradual dehydration with increasing ethanol concentrations. Samples were embedded in Epon LX112 resin (Ladd Research Industries) in embedding capsules and polymerized for 24 h at 60°C. Embedded samples were cut in ultrathin 80-nm sections with an UC6 ultramicrotome (Leica), placed them onto 300-mesh copper grids, stained sections with 2 % uranyl acetate and lead citrate, and examined them under a Philips CM10 TEM microscope (operating at 100 kV) and equipped with a Denka LaB6 cathode and a CCD Erlanghsenn 1000 Gatan camera. No filtering procedures were applied to the images.

Sequencing

Viral DNA was extracted from the clinical isolate or cell supernatant using the Macherey Nagel pathogen kit according to the manufacturer's instructions after DNase treatment.

Libraries were prepared in parallel for Oxford Nanopore Technologies (ONT) and Illumina.

For ONT, we used the ligation sequencing kit (SQK-LSK109) after whole genome amplification (Cytiva kit, FisherScientific), following manufacturer's instructions.

Data were filtered with kraken/bracken (v2.1.2/v2.6.2) to identify reads matching the chordopoxvirinae family. We mapped reads to Monkeypox virus strain Israel_2018 (MN648051.1) with minimap2 v2.24. From this reads mapping, a consensus sequence was extracted using nanopolish (v 0.13.2) and bcftools (v1.14). We obtained an average coverage depth of 620X (53,632 mapped reads out of 130,176).

In parallel, libraries were prepared for Illumina sequencing using the NEBNext UltraII DNA kit (New England Biolabs), after shearing with an M220 Covaris device (Covaris) following the manufacturer's recommendations. Non-amplified ("Native") as well as amplified extracts were processed. After size selection with AMPure beads (Beckman), sequencing was performed on a NextSeq 550 instrument (Illumina) using a HT 2x150 bp cartridge.

We mapped the reads with bwa mem (v0.7.17-r1188) and obtained two datasets with a marked difference between native and amplified samples. We obtained 46.2 % of mapped reads for MPXV/France/IRBA2211/2022 after amplification, and only 9.5 % for the native extract. We attributed the difference to the additional DNase treatment performed for amplified samples. There was no nucleotide difference among the two sequences, indicating that amplification did not alter original sequences.

We then aggregated the sequencing data from the two platforms by using the Nanopore consensus obtained from minimap2 as reference for mapping the Illumina reads. We filtered the sam file to remove unmapped reads and used Geneious R11 (Biomatters) to extract a consensus sequence (ON755039).

Phylogenetic analysis

All available MPXV sequences were retrieved from GenBank on July 3 rd , 2022. This dataset was subset to keep published and discussed sequences [START_REF] Isidro | Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus[END_REF] belonging to the newly proposed clade 3. We used Nextalign as implemented in the MPXV Nextstrain 20 build to align sequences, also adopting their masking strategy (https://github.com/nextstrain/monkeypox). The alignment was visually inspected for accuracy. A maximum likelihood phylogeny was inferred with IQ-TREE v.2.0.6 21 with 1,000 (ultrafast) bootstrap [START_REF] Hoang | UFBoot2: Improving the Ultrafast Bootstrap Approximation[END_REF] replicates for branch support estimates. The tree was rooted between MPXV strain Nigeria-SE-1971 (KJ642617) and sequences of subclade A in accordance with the full comprehensive MPXV phylogenetic tree.

F13L homolog alignment F13L homologs sequences were extracted from the available full genomes orthopoxviruses tested for susceptibility to tecovirimat: VACV (AY243312.1), VARV (DQ441447.1), CPXV (AF482758.2), CMLV (AY009089.1), MPXV (HM172544.1), ECTV (AF012825.2) [START_REF] Yang | An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus Challenge[END_REF] , as well as RPXV (AY484669.1) [START_REF] Nalca | Evaluation of orally delivered ST-246 as postexposure prophylactic and antiviral therapeutic in an aerosolized rabbitpox rabbit model[END_REF] . Amino acid sequences were aligned with MAFFT v7.450 [START_REF] Katoh | MAFFT multiple sequence alignment software version 7: improvements in performance and usability[END_REF] .

Annotations for mutations associated with resistance to tecovirimat [START_REF] Duraffour | ST-246 is a key antiviral to inhibit the viral F13L phospholipase, one of the essential proteins for orthopoxvirus wrapping[END_REF] were added to the alignment plot in Geneious Prime (Biomatters).

Antiviral assays

For MPXV infections, Vero cells were seeded in six-well plates (1.5 10 Data acquisition by high content microscopy was performed on a Thermo CellInsight CX7 HCS microscope using a compartmental analysis algorithm. Results were extracted, normalized over the vehicle-treated condition, and expressed as the average of three independent wells +/-SD. CC50 were calculated using GraphPad Prism v9.

Data availability

All data supporting the findings of this study are available the manuscript. The MPXV genomic data analysed here are available on GenBank (https://www.ncbi.nlm.nih.gov/genbank/, ON755039).

Figure 1 .

 1 Figure 1. A. Transmission electron microscope view of MPXV virions (MPXV/France/IRBA2211/2022) within cells captured at 48h post infection, at higher (left)

Figure 2 :

 2 Figure 2: ST-246 and Cidofovir inhibits plaque formation of the MPXV MPXV/France/IRBA2211/2022 isolate. A) Vero cells are infected with MPXV/France/IRBA2211/2022 and treated with indicated concentrations of ST-246 (A) or Cidofovir (B) for 72h. Lysis plaque inhibition is expressed in % normalized over CTL conditions. IC 50 and R 2 are indicated.

Figure S2 :

 S2 Figure S2: VP37 (F13L homologs) amino acid alignment to MPVX clade 3 multiple

Figure S3 :

 S3 Figure S3: Cytopathic effect on Vero cell line of MPXV/France/IRBA2211/2022 strain (optical

Acknowledgments

We would like to thank all the healthcare workers, public health employees, and scientists involved in the MPX outbreak response. We would like to acknowledge the technical skills of Cédric Castellarin for preparing the samples of transmission electron microscopy. We acknowledge the authors, originating and submitting laboratories of the orthopoxviruses sequences deposited on GenBank. This work used the computational and storage services provided by the IT department at Institut Pasteur, Paris.

Funding E.S.-L. acknowledges funding from the INCEPTION programme (Investissements d'Avenir grant ANR-16-CONV-0005), from the PICREID program and from the Labex IBEID (ANR-10-LABX-62-IBEID). O.F., A.F.-R. and J.-N.T. acknowledge the support from Santé Publique France for the CNR-LE orthopoxvirus. F.I. acknowledges funding from the Direction Générale de l'Armement (DGA) (Biomedef PDH-2-NRBC-4-B-4111). F.G acknowledges funding from the Agence Innovation Défense (AID) (RAPID DENALPOVIR 192906106) Competing interests F.G. and E.M. are employed by NeoVirTech SAS. F.G. is shareholder of NeoVirTech SAS. Tecovirimat is manufactured by SIGA Technologies. D.E.H. and D.W.G. are employees of SIGA technologies and hold shares of SIGA stock.

Supplementary


domain: shs info

text:
Antonietta Sanna
email: antonietta.sanna@unipi.it

Rachele Cinerari
email: rachele.cinerari@phd.unipi.it

Federico Boschetti
email: federico.boschetti@ilc.cnr.it

Ouafae Nahli
email: ouafae.nahli@ilc.cnr.it

Paul Valéry

Léon-Paul Fargue

Pirandello, Ungaretti, Saint- T S Eliot

John Perse

Hofmannsthal Rilke

Digitizing and Encoding a Multilingual Literary Review: Commerce Numérique

Keywords: Commerce Numérique Review Commerce, OCR, TEI encoding, literary review, digital resources

I. INTRODUCTION

This article describes stages of our work to create a digital version of the Commerce Journal. Section 1 allows to place Commerce review in the European cultural context at the beginning of the 20th century. Section 2 provides a descriptive study of Commerce regarding the quantity and content of articles. Sections 3 and 4 describes the stages of digitization and TEI coding of Commerce review texts. Finally, a conclusion closes the article and describes the results that will be available to the scholarly community.

II. Commerce AND THE CULTURAL CONTEXT OF EUROPE

ON THE EARLY 20TH CENTURY Commerce was a very important literary review founded in Paris after the First World War by Princess Marguerite Caetani, Prince Roffredo Caetani's wife . There were two great additions from the Parisian literary scene from 1914. The first was Adrienne Monnier with her bookshop named "La Maison des Amis des Livres". In 1917 Monnier began to hold readings by authors of contemporary French literature. In the same year, Sylvia Beach, a young American women who studied modern French literature, created a bookshop specializing in English and American books. She opened the legendary "Shakespeare and Company". Many French authors such as André Gide, Paul Valéry, Valéry Larbaud, Jules Romain, met in that modern Salon littéraire American and English writers such as Ernest Hemingway, F. Scott Fitzgerald, Ezra Pound, James Joyce.

After 1918 peace brought the revival of cultural life and Paris became a home for many artists. The Nouvelle Revue Franc ¸aise (NRF), founded by André Gide, Jean Schlumberger, Gaston Gallimard became a model of modern literary review, publishing the most important texts of European Modernism.

Marguerite Caetani regularly read the NRF that she considered indisputably France's leading intellectual review. She had met Paul Valéry before 1914, but she probably met Adrienne Monnier, Léon-Paul Fargue, and Valéry Larbaud at the events organized in the Shakespeare and Company bookshop.

At one of the many Sunday gatherings at Roffredo and Marguerite Caetani's home in Versailles, the idea of founding a review only dedicated to poetry, prose and drama, took shape. According to Marguerite it happened in the following way:

One day, Valéry said out of the blue: "Why don't continue our conversations, our dialogues, in published form? As a title I suggest 'Commerce', exchange of ideas. Everyone present was delighted by the idea. The directors (Larbaud, Valéry, Fargue) were appointed straightaway. Adrienne Monnier and I were put in charge of getting it going and we began at once. What the result was, remains for you to judge. I was helped immensely by Paulhan who allowed me to search among the manuscripts that he received for the NRF as well as by Alexis Léger who chose the poems that we published [START_REF] Dennett | An American Princess. The remarkable life if Marguerite Chapin Caetani[END_REF]. This is the origin of a brilliant chapter of a literary adventure in which Marguerite Caetani assumed the leading role between 1924 and 1932 to promote the translation like new European language. The traduction d'auteur (Author's translation) was a new form of creation destined to improve exchange between different cultures.

Marguerite Caetani could also count on the collaboration of some writers and intellectuals from other European nations: T. S. Eliot, Giuseppe Ungaretti, Rainer Maria Rilke, Hugo von Hofmannstahl, Rudolf Kassner, D. S. Mirskij [START_REF] Levie | La rivista Commerce e il ruolo di Marguerite Caetani nella letteratura europea, 1924-1932[END_REF] [START_REF] Levie | La rivista Commerce e Marguerite Caetani[END_REF]. The review included literary works -excerpts from novels, short stories, poems, drama -not only from France but also from ten different countries.

III. Commerce CORPUS: QUALITY AND QUANTITY

The most important and peculiar characteristic of Commerce was the multicultural and international vocation, and the publication of foreign literary works translated into French. Poems were translated by poets, prose texts by novelists. Some authors also self-translated some of their works in French, for example Hugo von Hofmannstahl and Giuseppe Ungaretti [START_REF] Conti | Ungaretti, mediatore culturale di Commerce[END_REF]. This characteristic made Commerce a fundamental review and gives the opportunity to nowadays researchers to better understand the European literary field of the early 20th Century, where Paris was a fundamental city, crossed by cultures and artists from all over the world.

About 240 texts were published on Commerce, most of them previously unpublished. We can count about 140 French texts, most of which written by Paul Valéry, Leon-Paul Fargue and Valéry Larbaud, but also from many other important French writers as for example Antonin Artaud, André Breton and Henri Michaux.

Thanks to the cooperation of advisors from Germany, the magazine hosted almost 20 German works including some by Franz Kafka, Friedrich Hölderlin and Friedrich Nietzsche. More than 20 texts by English authors were published on the review, including some fragments from Ulysses from James Joyce and one text from To the Lighthouse by Virginia Woolf, that were first published in the magazine. The review also hosted works by Italian authors -including Giacomo Leopardi and Giuseppe Ungaretti -and some literary works from China, Spain, Belgium, Denmark, Greece and Russia including authors like Søren Kierkegaard, Cheng Tcheng, Boris Pasternak, Jose Ortega y Gasset.

Commerce published a combination of contemporary and ancient texts, many of these were published on the review for the first time and some authors debuting at the time would soon become some of the most important authors of the 20th Century [START_REF] Levie | La rivista Commerce e il ruolo di Marguerite Caetani nella letteratura europea, 1924-1932[END_REF].

IV. CORPUS DIGITIZATION: IMAGE PRE-PROCESSING, OCR AND MANUAL CORRECTION

The corpus consists of 29 volumes and a short index of the first 16 volumes, for a total amount of more than 6,000 pages and about 2,000,000 tokens.

All the volumes provided by the library of the University of Pisa and Camillo Caetani Foundation have been scanned at the CNR-ILC. Page images have been pre-processed in order to optimize the character recognition by the usual page image operations, such as splitting, deskewing, dewarping, despeckling, binarization, performed through scanTailor 1 .

The Optical Character Recognition (OCR) has been executed through Tesseract 2 in multi-language modality (mainly French, English, Italian, German, and Spanish).

Proof reading has been performed by using the CoPhiProof-Reader, a web application for collaborative OCR correction created at the CNR-ILC, as shown in Figure 1.

The CoPhiProofReader is inspired to the WikiSource 3 correction tools, in order to take trace of multiple proof-reading and supervision phases.

V. TEI-XML ENCODING A. Encoding criteria

We chose the TEI encoding because it is a de facto standard for the community of Digital Humanists and it is extremely flexible and inclusive of most text genres. It provides elements, attributes and other mechanisms for coding prose, poetry, theater, dictionaries, linguistic corpora and other literary and academic texts. Furthermore, the TEI offers a framework where it is possible to design specific customisations while remaining compliant with the guidelines. As results, encoded texts are interoperable and can be reused, managed and archived in the future [START_REF] Dalmau | Challenges of serials text encoding in the spirit of scholarly communication[END_REF], [START_REF] Holmes | Encoding models for scholarly literature[END_REF], [START_REF] Unsworth | Computational Work with Very Large Text Collections: Interoperability, Sustainability, and the TEI[END_REF].

Commerce is historically a print-based journal and, like most print journals, it uses a traditional hierarchical structure in issues, volumes and articles.

Considering the limited budget of the first phase of the project and the large amount of contents to encode, we decided to focus our attention on the minimalist structural and formatting elements of each volume. Indeed, the main goal of the first phase is the compliance of the digital edition to the typographical aspects of the original printed edition.

Great care has been taken to render the spatial distribution of the text on the page through encoding. It is not only a typographical choice related to the mise en page (layout) of the magazine, but mainly a fundamental feature for poetic, dramatic and literary texts in general. The formal and typographical aspect is important, mainly considering that many of the texts date back to the so-called modernist period; a perioddated approximately between 1918 and 1940 -rich in formal, linguistic and stylistic experimentation, during which a dense network of exchanges, influences and contacts was formed. Literary magazines played a key role in this process [START_REF] Sanna | Tra modernismo ed europeismo: La Nouvelle Revue Franc ¸aise e Commerce[END_REF].

Each volume is preceded by a front matter and followed by a back matter, and is divided in articles, which are subdivided in sections and paragraphs for prose or strophes and verses for poetry. Articles are gathered inside the <group> element, which is provided to simplify the encoding of collections, anthologies, and cyclic works. In addition, the <group> element reflects the potentially complex internal structure of the journal.

Font styles (e.g. italics) are encoded but their semantics will be specified in a second stage of the work, in order to distinguish foreign words, quotations, key-words, etc.

The bibliographical references of Commerce have been recorded on Zotero 4 , in order to make them available in different standard formats, such as BibTeX.

B. Parallel texts

Special attention has been devoted to encode poems in parallel with their translation. Figure 2 illustrates a snippet of the poem "TRAIN-STOP : NIGHT" in Volume 5, page 128 which is translated in French at page 129. In the first phase of encoding, the poem in the original language is divided in strophes (lg: line groups) identified through the attribute @xml:id which provides a unique identifier for the element bearing it. The attribute @xml:id permits to link the original poem with the corresponding translation, strophe by strophe.

The identifier number is composed by the volume number, page and a progressive number. For example above, the verse 8 From the deep and the verse 9 Dark a voice calls like a voice in sleep belong to the fifth group of the poem in Volume 5, page 128, and recognized thanks to the identifier @xml:id="lg5_128_5".

As we have already mentioned, texts and poems are in different languages. For this reason, it is important to indicate it through the attribute @xml:lang. In the example mentioned before, the original language of poem is tagged by xml:lang="eng": <lg xml:id="lg5_128_5" xml:lang="eng"> <space dim="horizontal" unit="character" quantity="15"/><l rend="hi" n="8">From the deep ¶</l> <l rend="hi" n="9">Dark a voice calls like a voice in sleep ¶</l></lg> Figure 3 shows the French translation of the poem "TRAIN-STOP : NIGHT" in Volume 5, in page 129. It is interesting to note that, in some cases, the French counterpart is split into 4 https://zotero.org two segments and the second segment is dislocated to the top row or the bottom row. For example, the verse Noire une voix clame comme une voix entendue par un dormeur is divided in two segments: Noire ... par and un dormeur. The second segment is presented on the printed edition on the same line of the previous verse, but separated by a bracket, which suggests the correct textual order. In order to preserve both the logical order of the segments and the original rendering of the printed edition, segments have been disposed in the same order they have on the printed edition but with an ordinal indication n between the segments.

Below, an example shows how the segments are represented in order to preserve both the textual and spatial order, which is compliant to the printed page. The line <l n="9"> is composed with two segments <seg n="1">Noire ... par</seg and <seg n="2">un dormeur</seg> and we note that the second precede the first segment and it is located on the same line of the line <l n="8">.

The line <l n="8"> and the segment <seg n="2"> of the line <l n="9"> are separated by a horizontal space estimated equal to 8 characters. <lg corresp="#lg5_128_5" xml:lang="fra"> <space dim="horizontal" unit="character" quantity="19"/><l n="8">De la profondeur</l><space dim="horizontal" unit="character" quantity="8"/><l n="9"><seg n="2">[un dormeur ¶</seg> <seg n="1">Noire une voix clame comme une voix entendue par</seg></l></lg> In addition, each French line group (lg) has been linked to the original group through the attribute corresp. For example, the verses De la profondeur and Noire clame comme une voix entendue par un dormeur form the group which correspond to the English group identified by the attribute xml:id="lg5_128_5". So, it has the attribute corresp="#lg5_128_5"

VI. CURRENT RESULTS

All 29 volumes and the index of the review have been scanned, acquired by OCR and manually corrected by students with the supervision of ILC researchers. All bibliographical metadata have been entered on the Zotero platform, in order to be exported in standard formats (e.g. in BibTeX) in the next phases of the project.

At this stage of the work the first 5 volumes have been encoded according to the TEI guidelines, mainly focusing on multilingualism, parallel texts, poetry, spatial distribution of text. In the next future, we plan to finish encoding the remaining volumes. Then, the digital editions produced must be subjected to a final check to identify any inconsistencies and marking errors. Whereupon, we proceed with the generation of e-books in .epub and .mobi format in order to make them readable and navigable on a variety of devices.

We also intend, focusing in particular on multilingualism and translation practices, to study the journal in the cultural context of the time, tracing the different contacts made possible thanks to the journal, as well as the evolution of the texts that appeared for the first time on Commerce and then spread on a global scale.

VII. CONCLUSION

The international and transcultural vocation of the review has made it and still makes it fundamental and necessary for the work of many scholars. Commerce is one of the journals that -together with others both from France and other countries -has allowed writers, poets, playwrights and intellectuals to publish their works for a wide audience, often for the first time, and to read texts originally written in other languages.

Commerce has a fundamental importance to reconstruct the cultural landscape of the early 20th century made up of exchanges, contaminations, contacts, circulation of texts, translations and self-translations. The encoding of Commerce allows to protect an important literary document and at the same time to make it available for a worldwide audience through fully searchable digital editions.

Next steps are in the direction of the semantic web: one of the main objectives is to make the entire journal navigable both through thematic keywords and semantic relations.

----

  Fig. 1. CoPhi ProofReader

Fig. 2 .

 2 Fig. 2. English Poem

Fig. 3 .

 3 Fig. 3. Parallel French Poem


Denis Morin

Hélène Morin -Hamon

Casting

CASTING A BRONZE SWORD

A Bronze Age sword, the sword of Obernai (France), dated to the Late Bronze Age (1300-800 BC) was entirely reconstituted from an experimental metallurgical operation: the first time for an object of this size. Casting which lasted less than one hour allowed us to demonstrate the use and the relevance of the large-sized sandstone bivalve moulds for such a manufacturing, as well as the use of rudimentary bellows.

[ Experimental Archaeology... Between know-how and gestures ] [ Conclusion ]

The manufacturing of the Obernai sword allows us to approach the whole conceptal process in an objective way and to demonstrate the exceptional know-how of these first European metallurgists.

To develop weapons, tools or elements of bronze jewellery, by trying to reproduce techniques and actions of craftsmen of the Second Millennium, constitutes a particularly innovative field of research. Experiment allows the researcher to move beyond speculation and emphasize the importance of action, knowledge and know-how which represent a real anthropological dimension which is too often neglected in the analysis of the artefact. Obviously, ancient populations of the Aegean mastered the metal; remains are there to provide evidence; it is a question of showing that they made objects while conjugating a whole series of complex parameters within the constraints of material and fire, a number of traditional skills and the existence of cognitive schemas.

The swords appear in the Middle Bronze Age and multiply during the Late Bronze Age with several typological variants. The bare bronze blade found in 1969 in Obernai (Bas-Rhin) and which was used as the model for this experiment, is connected with the Krautergersheim type.

Pelike (jar) V e BC red-figure Museum: Warsaw.

Hoplite with his sword in the sheath

[First Metal]

It is probably from the VII th Millennium BC that the copper metal industry appears, in a vast geographical area which extends from Anatolia to Iran, a region which is particularly rich in metalliferous deposits. At first, copper discovered in the native state was worked under cold conditions by hammering then warmed, to make it mouldable. These techniques, very rudimentary, allow the manufacture of small objects: awls, needles, pearls, hooks... Later on, from the V th Millennium, the copper industry developed in the Near East. Metallurgists, thanks to the know-how of the potters, who had mastered perfectly the ceramic firing process, succeeded in reaching temperatures up to 1000°C, necessary to obtain copper. The fusion of this metal in crucibles made with terra-cotta allows it to be poured into stone moulds of the shape of the different artefacts to be realized.

This experiment is part of a project dedicated to the origin of mining technologies and the processing of mineral resources in Europe.

SPHS Regional

  Conference on 2nd-3rd July 2015 Swansea University TODL Technologies of Daily Life in Ancient Greece Auteurs: Denis Morin et Hélène Morin-Hamon DR Denis MORIN Archaeologist HISCANT Laboratory -denis.morin@univ-lorraine.fr Archéologie des mines et des techniques


Perla Doubinsky

Nicolas Audebert

Michel Crucianu

Hervé Le Borgne

WASSERSTEIN LOSS FOR SEMANTIC EDITING IN THE LATENT SPACE OF GANS

Keywords: GAN, Wasserstein distance, image edition

The latent space of GANs contains rich semantics reflecting the training data. Different methods propose to learn edits in latent space corresponding to semantic attributes, thus allowing to modify generated images. Most supervised methods rely on the guidance of classifiers to produce such edits. However, classifiers can lead to out-of-distribution regions and be fooled by adversarial samples. We propose an alternative formulation based on the Wasserstein loss that avoids such problems, while maintaining performance on-par with classifier-based approaches. We demonstrate the effectiveness of our method on two datasets (digits and faces) using StyleGAN2.

INTRODUCTION

GANs are known to encode the semantics of the training data in their latent space [START_REF] Shen | InterFaceGAN: Interpreting the disentangled face representation learned by GANs[END_REF][START_REF] Härkönen | GANSpace: Discovering interpretable GAN controls[END_REF][START_REF] Shen | Closed-form factorization of latent semantics in GANs[END_REF]. Moving the latent codes in certain directions results in changing specific semantic attributes in the generated images [START_REF] Shen | InterFaceGAN: Interpreting the disentangled face representation learned by GANs[END_REF]. This ability makes GANs great tools to perform image editing, especially as it can be applied to real images through inversion methods [START_REF] Richardson | Encoding in style: a StyleGAN encoder for image-toimage translation[END_REF].

The challenge is to identify the manipulations in the latent space that have the desired effect on one attribute without affecting others. To obtain such disentangled manipulations, existing supervised methods leverage the semantic knowledge learned by pretrained attribute classifiers operating either in the image domain (image classifiers) or directly in the latent domain (latent classifiers). The key idea is that manipulated latent codes (or the images they produce) shift the predictions to match the desired outcome [START_REF] Hou | Guidedstyle: Attribute knowledge guided style manipulation for semantic face editing[END_REF][START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF]. However, classifiers can easily be fooled [START_REF] Nguyen | Deep neural networks are easily fooled: High confidence predictions for unrecognizable images[END_REF], e.g. they can classify with high confidence out-of-distribution samples. As illustrated in Fig. 2a, the latent classifier of [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] steers latent codes outside the distribution resulting in edited images that are unrealistic. To address this issue, the authors employ an ad hoc L2-regularization to minimize the norm of the latent editing. While this fixes outof-distribution edits, Fig. 2b shows that on MultiMNIST [START_REF] Sun | Multi-digit MNIST for few-shot learning[END_REF] this regularization produces adversarial samples [START_REF] Szegedy | Intriguing properties of neural networks[END_REF] instead, i.e. the edited latent codes are correctly classified but the corresponding images remain unchanged. This is not surprising as changing the predicted class while minimizing the L2-norm of the edit precisely mimics the search for adversarial examples. For each semantic attribute (e.g. "Glasses") we learn a mapping H k that moves the distribution of latent codes lacking the attribute to the distribution of codes having that attribute. We enforce that each latent code is moved near a point that shares similar semantics, thus only changing that attribute. For identity preservation, the resulting distribution does not entirely match the target distribution.

To overcome these issues, we introduce a new formulation for learning semantic editing in the latent space, leading to a core solution that does not rely on classifiers.

From a global perspective, latent editing can be viewed as an optimal transport problem [START_REF] Villani | Optimal Transport: Old and New[END_REF]. Given a distribution of latent codes sharing some semantics, we propose to transport it onto the distribution of latent codes that share the same semantics except for the attribute to be edited. Since the resulting images should not exhibit any other changes than the desired one, the initial points should be transported "close" to points sharing their semantics; that is, the transport should be optimal w.r.t. a cost representing the perceptual similarity. To achieve this, we learn transformations in latent space using the guidance of the Wasserstein loss with an Euclidean cost, which can be combined with a Wasserstein loss with a cost computed in the attribute space to enforce disentanglement.

We apply our method in the latent space of StyleGAN2 to modify the number of digits and edit facial attributes. We compare quantitatively and qualitatively to the method of Yao et al. (LT) [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] that relies exclusively on a latent classifier. Without additional regularization, our method leads to realistic edited images and achieves on-par disentanglement and identity preservation than a classifier-based method.

RELATED WORK

Early works on GANs have demonstrated that their latent space contains rich semantics that can be leveraged to control some properties of the generated data. Simply translating a latent code in a given direction can lead to the variation of a semantic attribute in the corresponding generated image [START_REF] Shen | InterFaceGAN: Interpreting the disentangled face representation learned by GANs[END_REF][START_REF] Härkönen | GANSpace: Discovering interpretable GAN controls[END_REF][START_REF] Shen | Closed-form factorization of latent semantics in GANs[END_REF][START_REF] Spingarn | GAN "steerability" without optimization[END_REF]. Latent semantic directions can be extracted from the latent space without supervision by performing PCA [START_REF] Härkönen | GANSpace: Discovering interpretable GAN controls[END_REF] or by singular value decomposition on the weights of the pretrained GAN [START_REF] Shen | Closed-form factorization of latent semantics in GANs[END_REF][START_REF] Spingarn | GAN "steerability" without optimization[END_REF]. Supervised methods often employ classifiers to extract the directions. InterfaceGAN [START_REF] Shen | InterFaceGAN: Interpreting the disentangled face representation learned by GANs[END_REF] introduces a framework to edit binary facial attributes. An SVM is trained in latent space to infer the hyperplane that best separates the positive vs. negative latent codes w.r.t. a semantic attribute. The vector orthogonal to the hyperplane then constitutes the editing direction. Later works aim at learning a direction specific to each latent code by passing the input code through an MLP or an affine layer that is trained with the guidance of a classifier. GuidedStyle [START_REF] Hou | Guidedstyle: Attribute knowledge guided style manipulation for semantic face editing[END_REF] uses an attribute image classifier that classifies the images corresponding to the edited latent codes. The editing is correct if the classifier's predictions correspond to the desired change. Yao et al. [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] employ a similar objective but use a classifier trained directly in latent space. However, classifiers are unreliable [START_REF] Szegedy | Intriguing properties of neural networks[END_REF][START_REF] Nguyen | Deep neural networks are easily fooled: High confidence predictions for unrecognizable images[END_REF], potentially leading to images or latent codes that minimize the objective but do not correspond to the desired editing. Different from previous works, our core method does not rely on classifiers. Instead, we solve the problem using the optimal transport framework. To the best of our knowledge, this is the first work applying optimal transport for latent space editing.

WASSERSTEIN LOSS FOR GAN EDITING

Let G be a pretrained generator and Z its latent space such that I = G(z) where z ∈ Z is a latent code and I the corresponding generated image. Suppose we have a collection of latent codes

{z (i) } N i=1
, where each code is associated with a set of binary semantic attributes A = {a 1 , a 2 , .., a K } ∈ {0, 1}. For a given attribute a k , we aim to learn an affine transform H k in Z,

z k = z k + α • H k (z), α ∈ R (1)
such that only the attribute intensity a k differs in the resulting image I = G(z ), where α controls the strength of the change. Let µ k s be the distribution of latent codes z k that are negative with respect to the binary attribute a k and µ k t the distribution of latent codes zk positive w.r.t. the attribute a k . To increase the intensity of the attribute a k in the generated images, H k should transport the distribution of edited latent codes z k denoted by µ k s close to the distribution µ k t . However, the information encoding other attributes or properties should remain unchanged. The theory of optimal transport [START_REF] Villani | Optimal Transport: Old and New[END_REF] introduces a framework to transport a distribution to another with a minimal cost. The Wasserstein distance between two distributions represents the minimal value of this cost. Thus, we propose to use this loss as supervision to learn H k with a cost in latent space expressing similarity in image space. We call this model Latent Wasserstein (LW).

Wasserstein Distance

Let us define two discrete distributions:

µ s = ns i=1 a i δ(x i ) and µ t = nt i=1 b i δ(y i ) (2)
where δ(, ) is the Dirac function and a i , b i the probability mass associated with each sample. The Wasserstein distance between µ s and µ t is defined as:

W (µ s , µ t ) = min i,j T i,j c i,j s.t. T 1 nt = µ s , T 1 ns = µ t (3)
T is the transport matrix. T i,j represents how much probability mass must be transported from point x i to point y i and c i,j the cost of this transport. Estimating the Wasserstein distance is challenging in practice as it requires to solve the underlying optimal transport. The Wasserstein distance is usually estimated with the Sinkhorn divergence built on entropic regularization with debiasing terms [START_REF] Feydy | Interpolating between optimal transport and MMD using sinkhorn divergences[END_REF][START_REF] Cuturi | Sinkhorn distances: Lightspeed computation of optimal transport[END_REF].

Core Method

Our main objective is to minimize the Wasserstein loss between µ k s and µ k t with a squared Euclidean cost function:

L edit = W µ k s , µ k t , x i = z (i) k and y j = z(j) k c i,j = 1 2 x i -y j 2 (4)
In Eq. ( 2), the probability mass of each sample is usually set uniformly across samples, i.e. a i = 1 ns and b i = 1 nt for all i. If there are biases in the collection of training latent codes, the representation of semantically similar samples may vary significantly between the µ k s and µ k t [START_REF] Doubinsky | Multi-attribute balanced sam-pling for disentangled GAN controls[END_REF]. In this case, we propose to weight the source samples according to the number of similar samples in the target distribution. More formally, we set a i =

1 n A t ×n A s
where n A is the number of latent codes with the attribute combination A for a set of selected attributes.

Enforced Disentanglement

To ensure that the transported latent codes share the same attributes as the initial ones, we propose to minimize the Wasserstein loss between µ k s and µ k s :

confidence "Female": 100% 100%

LT [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] Ours

Input α = 1 α = 2
L edit = W µ k s , µ k s , x i = z (i) k and y j = z (j) k c i,j = 1 2 l =k (1 -γ lk ) F l (x i ) -F l (y j ) 2 2 (5)
In contrast to the previous objective, we employ a cost computed in the attribute space. We follow the cost defined in [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF], where F l is a latent classifier trained to predict a l given a latent code z. The term γ lk represents the absolute correlation between attribute a l and a k and is used to avoid disentangling naturally correlated attributes (e.g. "Smile" and "High Cheekbones"). Although we use the cost introduced in [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF], our constraint is a more relaxed constraint since we operate on the distribution.

The final objective to minimize is then L = L edit + λL pres where λ allows to balance the two losses.

EXPERIMENTS

Implementation Details

We present two editing applications: facial attributes on FFHQ/CelebAHQ and number of digits on MultiMNIST [START_REF] Sun | Multi-digit MNIST for few-shot learning[END_REF], consisting of images with 1 to 4 MNIST digits. We apply the editing in the latent space of StyleGAN2 [START_REF] Karras | Analyzing and improving the image quality of StyleGAN[END_REF] pretrained on FFHQ resp. MultiMNIST. For the training data, we employ latent codes corresponding to real images previously projected in latent space using the pSp encoder [START_REF] Richardson | Encoding in style: a StyleGAN encoder for image-toimage translation[END_REF], that projects the images into the W+ latent space. We employ respectively the 30K labeled 1024 × 1024 CelebAHQ images [START_REF] Karras | Progressive growing of gans for improved quality, stability, and variation[END_REF] for face editing and 25K 128 × 128 MultiMNIST images. To learn a transformation, we use the implementation of the Wasserstein loss provided by the GeomLoss [START_REF] Feydy | Interpolating between optimal transport and MMD using sinkhorn divergences[END_REF] library. We set the batch size as the minimum between the number of samples in the source and target distributions, and drop the last batch if it causes a strong imbalance between both. We use Adam optimizer with a learning rate of 0.001. To avoid overfitting the target distribution, we perform early stopping on a hold-out validation set. As CelebAHQ contains various biases, we weight the samples and use the disentanglement loss. Optimal value for λ is 1 for all considered attributes except for "Glasses" (λ = 15). The cost is computed on all 40 attributes of CelebA [START_REF] Liu | Deep learning face attributes in the wild[END_REF]. Samples are weighted based on the most common attributes.

Metrics

We use three metrics [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] to evaluate the different methods. The target attribute change rate indicates the percentage of images for which the target attribute is indeed modified. The attribute preservation rate corresponds to the average number of attributes, apart from the target attribute, that are preserved. The aforementioned metrics are computed by running pretrained attribute image predictors before and after the editing (for a given α) and finding which attributes have changed. An attribute is considered present if the probability is greater than 0.5. We also compute the identity preservation rate as the average of the cosine similarities between ArcFace [START_REF] Deng | Arcface: Additive angular margin loss for deep face recognition[END_REF] features of input and edited images. All metrics are evaluated on 1, 000 images from FFHQ. The attribute and identity preservation rates are reported against the target change for 10 values of Fig. 3: Qualitative results for facial attribute editing. We report the editing results for α = ±2. We observe that our approach better preserves identity and some facial attributes (e.g. expression, absence of makeup) compared to LT.

α ∈ [1 • d, 2 • d]
for a given α is comparable between the different methods. In tables, we report the mean over all values of α.

Facial Attribute Editing

We present a quantitative and qualitative comparison with Latent Transformer (LT) [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] that relies on the guidance of a latent classifier. In addition to the classification objective, the authors introduce a disentanglement loss and an L2-regularization on the norm of the transformation. The latter is used to enforce identity preservation but is also critical to obtain latent codes corresponding to realistic images. The comparison is conducted on common attributes ("Glasses", "Gender", "Smile", "Age") and rarer attributes chosen based on their representation and the performances of the image classifiers ("Pale Skin", "Bangs", "Blond Hair", "Wavy Hair"). Quantitative results from Fig. 4 show that our results are on par with LT with occasionally slightly lower attribute preservation ("Gender") but generally higher identity preservation ("Gender", "Age", "Blond Hair"). Note that this is surprising since we do not explicitly enforce identity preservation. Qualitative results in Fig. 3 showcase some advantages of our method. Nose, lips and eyes shape are much better preserved for "Gender" and "Age". LT also produces "cartoonish" edits for these attributes while ours remains naturalistic. LT 'Gender' editing is also heavily entangled with 'Makeup' while LW adds nearly none. We provide additional qualitative results in the supplementary.

Table 1: Quantitative results for the attributes "Gender" (G), "Age" (A) and "Pale Skin" (PS). We compare the classifier loss approach (LT) with our Wasserstein loss approach (LW). Setting (*) is the "core" method, w/o any regularization. Classifier vs. Wasserstein. We evaluate the ability of both methods to achieve disentangled and identity preserving editing without any explicit constraint. We denote by LT (*) the latent transformer of Yao et al. [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] trained without the disentanglement loss nor the L2-regularization. In Table 1 (top), we compare it to our model trained without the disentanglement loss (λ = 0), denoted by LW (*) . The Wasserstein baseline outperforms the classifier baseline both regarding disentanglement and identity preservation. As shown in the qualitative results presented in Fig. 5, the latter produces highly entangled edits (e.g. with the attribute "Smile") and alters the identity. Without enforcing it explicitly, the Wasserstein approach already exhibits a good disentanglement ability and the identity is also well-preserved. These abilities can be explained as the Euclidean cost in employed in Eq. ( 4) fairly reflects the perceptual distance in image space.

Method

Disentanglement Constraint. We study the influence of adding the disentanglement constraint from Eq. ( 5). As shown in Table 1, we improve attribute preservation. Qualitatively, the results are also improved as shown in Fig. 5. "Gender" is no longer heavily entangled with "Beard" (1st row) and the slight entanglement with "Smile" is removed. As shown in Fig. 2 (left), when the disentanglement constraint is used in the classifier-based approach, the edited images are unrealistic. The attribute and identity preservation curves show atypical behavior as image classifiers are disrupted by such images. As the decision boundaries of classifiers cover areas that are larger than the area of training samples, latent codes which are far away from the training distribution can still minimize the classification objective. The L2-regularization in [START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] enforcing that the edited latent codes remain close to the initial ones is thus necessary to circumvent this limitation. Our method does not require any regularization to produce realistic edits, since our main objective enforces closeness to the target distribution.

Editing the Number of Objects

The L2-regularization in conjunction with the classification objective is similar to the formulation employed to produce adversarial examples [START_REF] Szegedy | Intriguing properties of neural networks[END_REF]. While this rarely occurs on faces, this plagues editing performance on MultiMNIST. The quantitative results in Table 2 show that for a target change of 100% according to the latent classifier, the image classifier indicates significantly lower target changes for LT. In other words, the latent classifier predicts that the number of digits has increased while it has stayed the same in the image, undermining the goal of an editing method. In contrast, our method has a high editing effect and actually adds digits in the edited images. Qualitative results are provided in Fig. 6.

CONCLUSION

We present a new method to learn semantic editing in the latent space of GANs, that proposes to model the problem as an optimal transport problem. We look for transformations that transport a collection of latent codes to the most semantically similar points in the distribution of latent codes with the desired semantic. We use the squared Euclidean distance in

2→ 3 3→ 2
Fig. 6: Qualitative results for number of objects editing. Our method adds a digit while LT fails to add one. latent space as a cost function as it fairly reflects the perceptual distances in image space. This formulation readily produces almost totally disentangled editing whereas classifier-based methods require an explicit disentanglement constraint. To achieve even more disentangled editing, we introduce an explicit loss enforcing the transported codes to remain close to the distribution of initial codes. This loss is also formulated with optimal transport but using a semantic cost computed in attribute space. On the task of facial attribute editing on CelebA/FFHQ, our method is competitive with a state-of-theart classifier-based method without requiring an additional constraint to ensure that the obtained images are realistic. Our method also alleviates other issues from using classifiers, such as the sensitivity to adversarial examples as we illustrate on the editing of the number of digits in MultiMNIST images. Our method achieves particularly strong identity preservation performances when editing facial attributes. This is unexpected as there is no explicit constraint to do so, and the train and target distributions contain different identities. We attribute this ability to a combination of early stopping, that prevents us from overfitting our edited codes on the target distribution, and of the inductive bias of the model, which defines edits as simple affine transformations in the latent space, acting as a regularization.

While the Wasserstein loss based on the latent Euclidean distance results in state-of-the-art editing performances, it does not perfectly reflect the perceptual distance in image space. This could explain why some edits are not totally disentangled. As an extension of this work, we believe that performances could be further improved by using a cost based on the perceptual LPIPS metric [START_REF] Zhang | The unreasonable effectiveness of deep features as a perceptual metric[END_REF] or an equivalent proxy learned in the latent space to reduce computation time.

Fig. 1 :

 1 Fig.1: Method overview. For each semantic attribute (e.g. "Glasses") we learn a mapping H k that moves the distribution of latent codes lacking the attribute to the distribution of codes having that attribute. We enforce that each latent code is moved near a point that shares similar semantics, thus only changing that attribute. For identity preservation, the resulting distribution does not entirely match the target distribution.

Fig. 2 :

 2 Fig.2: Failure cases of a classifier-based method. LT[START_REF] Yao | A latent transformer for disentangled face editing in images and videos[END_REF] learns edits in latent space under the guidance of a latent classifier. (a) On FFHQ: without L2-regularization on the edited codes, the edited images are unrealistic (as shown in the qualitative result on the left) before reaching the desired editing. The classifier leads to out-of-distribution regions as it allocates high confidence to regions larger than that of the training samples[START_REF] Nguyen | Deep neural networks are easily fooled: High confidence predictions for unrecognizable images[END_REF]. The quantitative analysis on attribute and identity preservation shows highly degraded results. (b) On MultiMNIST: the edited images remain unchanged (no digit is being added) while the classifier indicates the opposite (predicts 2 digits with high confidence). The classifier leads to regions close to the decision boundaries where there are adversarial samples. The quantitative analysis shows that only 32% of images are correctly edited.

Fig. 4 :Fig. 5 :

 45 Fig.4: Quantitative results for facial attribute editing. We report the attribute preservation rate (computed on all other attributes indicated here) and the identity preservation rate for different values of α (points of the curves). The x-axis is the ratio of images (among all test images) for which the target attribute is successfully flipped.

  where d is chosen such that the target change

			Gender		Glasses		Blond Hair
			Age		Bangs		Wavy Hair
	Input	LT [6]	LW (Ours)	LT [6]	LW (Ours)	LT [6]	LW (Ours)

Table 2 :

 2 Quantitative results for the manipulations "adding one digit in an image containing n digits, for n = 1, 2, 3" in real images from MultiMNIST[START_REF] Sun | Multi-digit MNIST for few-shot learning[END_REF]. Given a target change rate of 100% according to a latent classifier, we report the actual change rate as measured by an image classifier. Higher values indicate a lower rate of adversarial samples.

	Method		Target change rate
		1→2		2→3	3→ 4
	LT	0.32		0.31	0.64
	LW (ours)	0.90		0.95	0.99
		Input	LT	LW (ours)
	1→


Dr M Mohankumar

Dr M Holler

J.-F Nierengarten
email: nierengarten@unistra.fr

Dr J.-P Sauvage
email: jpsauvage@unistra.fr

L Pph

Pph

O Pph

Keywords: Copper(I), Macrocycle, Phenanthroline, Phosphine ligands, Rotaxane

Preparation of copper(I) pseudo-rotaxanes from bis-phosphine ligands Meera Mohankumar, [a] Michel Holler, [a] Jean-François Nierengarten,* [a] and Jean-Pierre Sauvage* [b] Dedicated to Prof. François Diederich on the occasion of his 60 th birthday

Copper(I) complexes combining aromatic diimine ligands of the bipy family (bipy : 2,2'-bipyridine) and phosphines have been shown long ago to display interesting photochemical properties in relation to light-induced electron transfer. [1] The photophysical properties of these complexes have been also investigated in details. [2] More recently, McMillin and co-workers have found remarkably high emission quantum yields from the long lived metal-to-ligand charge transfer (MLCT) excited state of mixedligand Cu I complexes prepared from 1,10-phenanthroline (phen) derivatives and bis[2-(diphenylphosphino)-phenyl]ether (POP). [3] This key finding has inspired significant research activities. Numerous examples of related heteroleptic Cu I complexes have been reported in recent years [4][5] and their outstanding emission properties exploited to produce efficient light emitting devices. [5] As part of this research, we have systematically investigated the preparation of heteroleptic Cu I complexes from various 2,9disubstituted-1,10-phenanthrolines (phen) and different bisphosphine (PP) ligands. [5c,6] Whereas the heteroleptic complexes are stable in the solid state, equilibrium between the homoleptic and the heteroleptic complexes is often observed in solution. This major limitation for the preparation of [Cu(phen)(PP)] + derivatives results from the exceptionally high thermodynamic stability of the corresponding homoleptic [Cu(phen) 2 ] + complexes. [7] In order to prevent the formation of a stable homoleptic complex from the phen ligand, we have decided to incorporate the 2,9-disubstituted-1,10-phenanthroline subunit in a macrocyclic structure. [8] The preparation of the heteroleptic Cu I complexes from various PP ligands (dppe, dppp, POP and dppFc) and the macrocyclic phenanthroline derivative provided stable Cu I -complexed pseudo-rotaxanes. [START_REF]To the best of our knowledge, these compounds are the first examples of pseudo-rotaxanes including coordinating phosphorus atoms. For examples of P-containing pseudo-rotaxanes, rotaxanes and catenanes[END_REF] The comparison with the analogous Cu I complexes prepared from the acyclic model phenanthroline derivative L [10] clearly revealed a strong macrocyclic effect allowing the preparation of stable heteroleptic Cu I complexes whatever the PP ligand. Importantly, this is the case even when the formation of the corresponding acyclic derivative is not favorable.

The synthesis of the macrocyclic phenanthroline ligand m37 is depicted in Scheme 1. Building block 1 was prepared in four steps according to a reported procedure. [10] Compound 1 was treated with bis-tosylate 2 in the presence of CsF in CH 3 CN. [11] Under these conditions, cleavage of the tert-butyldimethylsilyl (TBDMS) protecting groups was achieved in situ to generate the corresponding bis-phenolate intermediate, thus avoiding the preparation of desilylated 1 [10] which is highly insoluble in common organic solvents and difficult to handle. The reaction of the bis-phenolate intermediate thus generated with bis-tosylate 2 then gave m37. This macrocycle with a ring size of 37 atoms was isolated in 18% yield and characterized by NMR spectroscopy and mass spectrometry (Figures S1-3).

Cu(CH 3 CN) 4 BF 4 (1 equiv.) and the appropriate bisphosphine ligand (1 equiv.) were successively added to a solution of m37 (1 equiv.) in CH 2 Cl 2 /CH 3 CN (Scheme 1). After 1 h, the solvents were evaporated and the 1 H NMR analysis (CD 2 Cl 2 ) of the crude products revealed the almost quantitative formation of a single product (POP and dppFc) or of a largely major compound (dppe and dppp). The four [Cu(m37) confirmed by electrospray (ES) mass spectrometry. For all the compounds, the mass spectrum displays a singly charged ion peak assigned to [Cu(m37)(PP)] + . These heteroleptic complexes are remarkably stable in CH 2 Cl 2 solutions and no detectable ligand exchange reactions could be detected. The UV/vis absorption spectra of [Cu(m37)(PP)]BF 4 recorded in CH 2 Cl 2 show the diagnostic MLCT band of [Cu(phen)(PP)]BF 4 derivatives in the 380-420 nm region. [3][4][5][6] It can be also added here that an intense yellow -orange emission is observed for pseudo-rotaxanes [Cu(m37)(POP)]BF 4 , [Cu(m37)(dppe)]BF 4 and [Cu(m37) (dppp)]BF 4 in both the solid state and in solution (Figure S12). Detailed photophysical investigations are underway and will be reported in due time. Finally, the NMR data were in full agreement with the proposed structures. As a typical example, the 1 H NMR of [Cu(m37)(dppe)]BF 4 is depicted in Figure 1. Effectively, correlation peaks are observed between the Ar-H protons of the dppe moiety and the Ph-CH 2 of the m37 ligand. The latter observations clearly reveal that the phenethyl moieties of m37 and the PPh 2 subunits of dppe are spatially close in perfect agreement with the proposed pseudo-rotaxane structure. Similar observations have been also made with the three other [Cu(m37)(PP)]BF 4 derivatives thus showing the formation of pseudo-rotaxanes in all the cases. Therefore, the Cu I -mediated threading of all the bis-phosphine ligands through the m37 macrocycle was effective.

The X-ray crystal structure analysis of [Cu(m37)(POP)]BF 4 unambiguously proved the threading of the POP moiety through the macrocyclic phenanthroline ligand (Figure 2). [12] Although the resolution of the structure is only moderate because of the disorder in the hexaethylene glycol chain subunit of the m37 ligand and the inclusion of unresolved solvent molecules (CH 2 Cl 2 ), the identity of the Cu I -complexed pseudo-rotaxane is in no doubt. The Cu I center with the POP ligand and the 2,9diphenethyl-1,10-phenanthroline subunit are well resolved. Several interesting details were revealed. The copper atom is in a distorted tetrahedral environment in which both the phenanthroline and the POP moieties are chelating ligands. It can be noted that the ether O atom of the POP subunit is at a nonbonding distance from the Cu I center (> 3.25 Å). The distorted tetrahedral coordination mainly arises from the restricted bite angle of the phenanthroline ligand N(1)-Cu-N(2) (81.9(2)°), whereas the corresponding bis-phosphine bite angle P(1)-Cu-P(2) is 117.43(6)°. Finally, the intramolecular face-to-face - interaction between one phenyl ring of the POP ligand and the phenanthroline moiety of m37 induces a significant rocking of the POP ligand (ca. 17.5°). In order to highlight the influence of the macrocyclic structure of m37 on the stability of the heteroleptic Cu I complexes, the corresponding acyclic derivatives were prepared from ligand L. A solution of the appropriate bis-phosphine ligand (1 equiv.) and Cu(CH 3 CN) 4 BF 4 (1 equiv.) in CH 2 Cl 2 /CH 3 CN was stirred for 0.5 h, then L (1 equiv.) was added. After 1 h, the solvents were evaporated. The products were analyzed as received by 1 H NMR. The relative proportion of the different possible complexes, i. are depicted in Figure 3. For both dppFc and POP, [Cu(L)(PP)]BF 4 was the major reaction product [START_REF] Cu | BF4 and[END_REF] and only traces of the homoleptic complexes were detected. In contrast, when starting from dppe and dppp, the reaction with Cu(CH 3 CN) 4 BF

COMMUNICATIONDOI: 10

 10 .1002/chem.200((will be filled in by the editorial staff))

Figure 1 .

 1 Figure 1. Aromatic region of the 1 H NMR spectrum (CD2Cl2, 300 MHz) of [Cu(m37)(dppe)]BF4.

Figure 2 .

 2 Figure 2. Top and side views of the X-ray crystal structure of [Cu(m37)(POP)]BF4 (m37: pale gray, POP: dark gray, Cu: black), the counteranion is omitted. The rocking of the POP ligand allowing the establishment of an intramolecular - interaction between a phenyl ring of the POP ligand and the phenanthroline moiety of m37 is highlighted (right).

  e. [Cu(L)(PP)]BF 4 , [Cu(L) 2 ]BF 4 and [Cu(PP) 2 ]BF 4 , was deduced from the comparison with the 1 H NMR spectrum of [Cu(L) 2 ]BF 4 recorded in the same solvent (Figures S13-14). Typical examples

  4 and L led to only small amounts of [Cu(L)(PP)]BF 4 (ca. 10-15%) and the formation of the homoleptic complexes is largely preferred. All attempts to crystallize [Cu(L)(dppe)]BF 4 or [Cu(L)(dppp)]BF 4 out of the crude reaction mixture failed. Indeed, in both cases, slow diffusion of Et 2 O into a CH 2 Cl 2 solution of the crude mixture of complexes yielded only orange-red crystals of [Cu(L) 2 ]BF 4 .

  (PP)]BF 4 pseudo-rotaxanes were then recrystallized (CH 2 Cl 2 /Et 2 O) and fully characterized(Figures S4-11). Their structure was Scheme 1. Synthesis of pseudo-rotaxanes [Cu(m37)(PP)]BF4 (PP = POP, dppFc, dppe or dppp).

[Cu(L)(dppFc)]BF 4 [Cu(dppFc) 2 ]BF 4 + [Cu(L) 2 ]BF 4

Acknowledgements

This research was supported by the University of Strasbourg, the CNRS and the EC (contract PITN-GA-2008-215399 -FINELUMEN). We further thank M. Schmitt for the NMR measurements and L. Brelot for the X-ray crystal structure resolution.

When compared to the efficient synthesis of the [Cu(m37)(PP)]BF 4 derivatives from m37 and their good stability in solution whatever the nature of the PP ligand, the results obtained with the acyclic phenanthroline ligand L are very different, in particular when using dppe or dppp as starting material. In the case of L, the outcome of the reaction with Cu(CH 3 CN) 4 BF 4 and the various PP ligands is driven by the relative thermodynamic stability [START_REF] De | For a review on metal-coordination-driven dynamic heteroleptic architectures[END_REF] of the [Cu(L)(PP)]BF 4 and [Cu(L) 2 ]BF 4 species. Given the fact that the thermodynamic stability of [Cu(L) 2 ]BF 4 must be very high, the preparation of stable heteroleptic [Cu(L)(PP)]BF 4 complexes is not possible with all the PP ligands. In the case of m37, the formation of the homoleptic bis-phenanthroline Cu I complex being prevented by the macrocylic nature of the phenanthroline ligand, the formation of heteroleptic complexes becomes thermodynamically favorable. In fact, if a certain proportion of the homoleptic complex [Cu(PP) 2 ]BF 4 was formed, the stoichiometry of the reaction would necessarily imply that an equivalent proportion of uncomplexed ring be also generated, which is highly unfavourable from a thermodynamic viewpoint. This macrocyclic effect paves the way towards the preparation of new stable heteroleptic Cu I complexes with high emission quantum yields for materials science applications. Work in this direction is currently underway in our laboratories.

Experimental Section General procedure for the preparation of pseudo-rotaxanes [Cu(m37)(PP)]BF4.

A solution of m37 (1 equiv.) and Cu(CH3CN)4BF4 (1 equiv.) in a 7:3 CH2Cl2/CH3CN mixture was stirred for 0.5 h, then the appropriate bis-phosphine ligand (1 equiv.) was added. After 1 h, the solvents were evaporated. The product was then purified as outlined in the following text.

Pseudo-rotaxane [Cu(m37)(POP)]BF4. This compound was prepared from m37 (80 mg, 0.12 mmol), Cu(CH3CN)4BF4 (38 mg, 0.12 mmol) and POP (65 mg, 0.12 mmol) in CH2Cl2/CH3CN (7:3, 10 mL). Recrystallization by slow diffusion of Et2O into a CH2Cl2 solution of the crude product gave [Cu(m37) Pseudo-rotaxane [Cu(m37)(dppFc)]BF4. This compound was prepared from m37 (52 mg, 0.08 mmol), Cu(CH3CN)4BF4 (24 mg, 0.08 mmol) and dppFc (43 mg, 0.08 mmol) in CH2Cl2/CH3CN (7:3, 10 mL). Recrystallization by slow diffusion of Et2O into a CH2Cl2 solution of the crude product gave [Cu(m37)(dppFc)]BF4 (87 mg, 81%) as dark orange crystals. 1 H NMR (CD2Cl2, 300 MHz): 8.66 (d, J = 7 Hz, 2H), 8.17 (s, 2H), 7.72 (d, J = 7 Hz, 2H), 7.35 (m, 4H), 7.14 (m, 8H), 6.98 (m, 8H), 6.69 (d, J = 7 Hz, 4H), 6.22 (d, J = 7 Hz, 4H), 4.54 (s, 4H), 4.14 (m, 4H), 4.09 (m, 4H), 3.85 (m, 4H), 3.73 (m, 16H)

Entry for the Table of Contents

Macrocyclic effect 

The macrocyclic ligand makes the difference. Heteroleptic complexes prepared from a macrocyclic 1,10phenanthroline derivative (m37) and various bis-phosphine ligands (PP) are significantly stabilized when compared to analogous systems obtained from a non-cyclic 1,10phenanthroline ligand. The resulting copper(I) complexed pseudorotaxanes are strongly luminescent.


Meera Mohankumar

Michel Holler

Michel Schmitt

Jean-Pierre Sauvage

Jean-François Nierengarten

Dynamic topomerization of Cu(I)-complexed pseudorotaxanes

Dynamic molecular motions resulting from the folding of a flexible macrocyclic component in a Cu(I)-complexed pseudorotaxane have been evidenced by variable temperature NMR experiments. The proposed conformational changes are also supported by the X-ray crystal structures of the compounds

and computational studies.

Molecular motions and conformational changes of proteins play a major role in biological systems. Heterotopic allosterism in which the binding of a specific substrate induces conformational changes in the peptidic backbone of a protein to regulate its biological activity is a classical example. 1 The rotary mechanism evidenced for ATP synthase [START_REF] Boyer | [END_REF] and the motion of the myosin-actin complex in muscles 3 are other fascinating examples in which conformational changes generate mechanical movements. Large amplitude molecular motions are also involved in the folding of 20 biomolecules and intensive research efforts have been carried out to understand the mechanism and the dynamics of protein folding. 4 Over the two last decades, chemists have prepared a large variety of molecular and supramolecular systems capable of mimicking the molecular motions and conformational changes observed for biomolecules. [START_REF] Shinkai | [END_REF][6][7] In this particular field, threaded or interlocking molecules are particularly interesting as they offer the possibility of large-amplitude molecular motions. 7 Numerous examples of molecular shuttles in which a macrocyclic component threaded onto a molecular rod can undergo a more or less controlled translation movement have been reported. 7 Dynamic studies of catenanes in which a macrocycle can glide and spin within another one have been also described. 7 There are however only a few systems for which large amplitude folding motions are observed. 8 In this paper, we now report Cu(I)complexed pseudorotaxanes 9 prepared from a macrocyclic phenanthroline derivative and bisphosphine ligands (Fig. 1). Xray crystal structural analysis, variable temperature NMR studies and computational calculations allowed us to evidence particularly original dynamic molecular motions resulting from 40 the folding of the flexible macrocyclic component.

Macrocycle m30 was obtained in 3 steps from 2,9-dimethyl-1, 10- and electrospray mass spectrometry. Crystals suitable for X-ray crystal analysis were also obtained for both compounds. ‡ As shown in Fig. 2, the X-ray crystal structural analysis of [Cu(m30)(dppe)]BF 4 reveals a perfect threading of the dppe moiety through the macrocyclic phenanthroline ligand. The two 55 diphenylphosphino subunits are effectively located at opposite sides of the mean plane of the m30 macrocycle as suggested by the C 2v symmetry deduced from the NMR data of [Cu(m30)(dppe)]BF 4 . It is noted that due to some rotational freedom, one of the phenyl groups of the dppe ligand is 60 disordered. However, only one of the two possible orientations in the crystal lattice is shown in Figure 1 for the sake of clarity. As typically seen for [Cu(phen)(PP)] + complexes, packing induced distortions from an idealized pseudotetrahedral geometry are observed. 10,11 Close inspection of the crystal packing reveals that 65 interactions involving a phenyl unit of the dppe ligand and the phenanthroline belonging to an adjacent molecule induce a slight rocking (ca. 10°) of the dppe ligand (Fig. S1). Whereas the C 2v symmetrical pseudorotaxane structure deduced from the NMR data was confirmed by the X-ray crystal structure analysis of [Cu(m30)(dppe)]BF 4 , the structure of the Cu(I) complex prepared from POP revealed only a partial 75 threading of the PP ligand through m30 (Fig. 2). Actually, one phenyl group of the POP ligand is located within the cavity of the macrocyclic ligand, whereas all the others are located on the same side of m30. This peculiar conformation results from the between different conformers on the NMR timescale. As a result, the two P atoms appear as equivalent in the 31 P NMR spectrum recorded at room temperature. In order to confirm this hypothesis, 31 P NMR spectra were recorded at different temperatures. As shown in Fig. 3, by cooling the solution, the exchange between different conformers becomes slow on the NMR timescale, as attested by the two sets of doublets ( 2 J = 115 Hz) observed for the P atoms of the POP ligand. This is in perfect agreement with the partially threaded conformation observed in the X-ray crystal structure. From the coalescence temperature (T c = 278 K) and the separation between the two signals in the absence of exchange ( = 1017 Hz), the rate constant for the dynamic exchange (k C ) and the free enthalpy of activation (G ‡ ) were estimated to be 2350 s -1 and 12 kcal.mol -1 , respectively. [START_REF] Friebolin | Basic One-and Two-Dimensional NMR Spectroscopy[END_REF] Interestingly, a singlet is also observed at  = -20.4 ppm. The latter is attributed to a C 2v symmetrical conformer (B) in which the POP ligand is fully threaded through the macrocycle. The minor population of this particular conformer suggests that it might be destabilized by steric congestion when the large phenyloxyphenyl bridging unit of the POP ligand is located 40 within the cavity of m30. Indeed, the flexible m30 macrocycle preferentially adopts a folded conformation in order to minimize steric congestion, the partially threaded conformer is thus energetically favored and its population largely major in solution. This view was fully supported by computational studies. The molecular geometry was optimized at the PM6 semi-empirical level for both conformers A and B (Fig. 3). The calculated energy difference between these two conformers is significant (5.2 kcal.mol -1 ) and explains the preferential population of the A conformers in good agreement with the low temperature 31 P 50 NMR spectrum. The energy barrier for exchange between the A and B conformers is low thus allowing a fast dynamic exchange at room temperature. In this way, each of the four phenyl rings of the POP ligand is alternatively located inside or outside the cavity of the m30 macrocycle, the exchange taking place through the 55 less energetically favoured conformer (B). It is also worth noting that conformer A is chiral and the dynamic 65 molecular motions of the flexible chain of m30 are responsible for a dynamic racemization, i.e., a fast exchange between A and A' (Fig. 3). This was clearly evidenced from the 1 H-NMR spectra recorded over a large range of temperatures (from -80°C to 100°C, see ESI and Fig. 4). At high temperatures, two doublets 70 are seen for the phenanthroline protons H (3-8) and H(4-7). Indeed, the exchange between the different conformers is fast on the NMR timescale under these conditions and both pairs of protons [H(3)-H (8) and H(4)-H( 7)] appear equivalent in the 1 H-NMR spectrum. By cooling the solution, the NMR study revealed 75 a clear coalescence and a reversible splitting of these peaks. Indeed, the exchange of conformers becomes slow on the NMR timescale at low temperature and four sets of signals are observed for the phenanthroline protons H(3), H(4), H (7) and H( 8) at -80°C. In other words, these pairs of protons are diastereotopic structures is obtainable through local backbone folding transformations that do not disrupt the covalent bonding of the peptide backbone, [START_REF] Debe | Proc. Natl. Acad. Sci[END_REF] we propose to name these particular conformers in equilibrium topomers, i.e. conformers having different topographies. Variable temperature NMR studies were also carried out with [Cu(m30)(dppe)]BF 4 . In this case, no dynamic exchange between 15 topomers could be evidenced. Whatever the temperature, a single resonance is observed in the 31 P NMR spectrum (Fig. 3). The C 2v symmetrical topomer is this time largely preferred and the partially threaded one could not be detected. These observations are in full agreement with the X-ray crystal structure of 20 [Cu(m30)(dppe)]BF 4 . When compared to POP, the bridging unit is smaller for dppe and does not generate particular steric congestions; thus the threaded topomer is not destabilized. Actually, computational studies revealed a significant energy difference between the fully and partially threaded topomers (6.1 kcal.mol -1 , see ESI). There is a clear energy penalty for the folding of the macrocycle. Indeed, in the case of POP, the fact that topomer A is favoured shows that the steric congestion in fully threaded B must be relatively important to displace the dynamic conformational equilibrium towards the partially threaded situation. This research was supported by the University of Strasbourg, the CNRS and the EC (contract PITN-GA-2008-215399 -FINELUMEN). We further thank L. Brelot and C. Bailly for the X-ray crystal structure resolutions.

35

Notes and references

a Laboratoire de Chimie des Matériaux Moléculaires, Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux , 25 rue Becquerel, 67087 Strasbourg Cedex 2, France. E-mail: nierengarten@unistra.fr

Fig. 1 .

 1 Fig. 1. Cu(I)-complexed pseudorotaxanes prepared from m30 and PP ligands (dppe and POP).

  70

2 | 10 Fig. 2 .

 2102 Fig. 2. X-ray crystal structures of (A) [Cu(m30)(dppe)]BF 4 and (B) [Cu(m30)(POP)]BF 4 (m30: blue, dppe and POP: green, Cu: yellow, the counteranion is omitted). The 31 P NMR spectrum of [Cu(m30)(POP)]BF 4 recorded at room temperature shows a single resonance at  = -13.57 ppm and suggests that the two P atoms of the POP moiety are equivalent. The latter observation is apparently in contradiction with the solid state structure of [Cu(m30)(POP)]BF 4 for which the two P atoms are different. Indeed, the four phenyl groups of the POP ligand may exchange their position inside and outside the cavity of m30 in solution. In other words, the chain of the m30 ligand is flexible enough to allow a fast dynamic exchange 20

Fig. 3 .

 3 Fig. 3. (A) 31 P NMR spectra (CD 2 Cl 2 , 162 MHz) of [Cu(m30)(POP)]BF 4 (left) and [Cu(m30)(dppe)]BF 4 (right) recorded at different temperatures. (B) Calculated structures of 60

Fig. 4 .

 4 Fig. 4. 1 H NMR spectra (CD 2 Cl 2 , 400 MHz) of [Cu(m30)(POP)]BF 4 recorded at different temperatures.