Tom Boissavy

Dante Rotili

Thomas Mouveaux

El Emmanuel Roger

Moukthar Aliouat

Christine Pierrot

Sergio Valente

Antonello Mai

Mathieu Gissot
email: mathieu.gissot@pasteur-lille.fr

El Moukhtar Aliouat

Hydroxamate-based compounds are potent inhibitors of Toxoplasma gondii HDAC biological activity

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

Introduction

Apicomplexa is a phylum of unicellular protozoan parasites that are obligate intracellular and highly transmissible. Among them are several human pathogen species, including Plasmodium spp., Toxoplasma gondii and Cryptosporidium spp. Although toxoplasmosis generally remains symptomless in healthy individuals, it can lead to serious infections in the central nervous system among those with defective immune systems. Additionally, it may result in birth defects or even death in the offspring of newly infected mothers. The prevalence of T. gondii infection worldwide is significant, with estimates indicating that it affects between 30% and 70% of the human population, varying depending on geographical regions (1).

T. gondii has a complex life cycle and infection by oocysts or bradyzoites leads to the development of rapidly growing tachyzoites responsible for the clinical manifestations in humans (2). The acute phase of the disease is caused by tachyzoite proliferation, and the latent bradyzoites can persist in the host for prolonged periods, leading to the possibility of reactivation and causing encephalitis, especially in immunocompromised patients [START_REF] Munoz | Immunology of Toxoplasma gondii[END_REF]. The current treatment for toxoplasmosis involves pyrimethamine and sulfadiazine, which target the tachyzoite, but have adverse effects that limit their use. Undesirable side effects are frequently observed with this treatment regimen, with over 30% of patients experiencing adverse events leading to discontinuation of the treatment. Among these, bone marrow suppression is recognized as one of the most severe complications [START_REF] Ben-Harari | Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review[END_REF]. Clindamycin, while being an alternative medication, carries comparable risks of side effects and is less effective in preventing relapse [START_REF] Katlama | Pyrimethamineclindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS[END_REF]. Additionally, there are presently no treatments available that specifically target the bradyzoite, which is the dormant form of the parasite found in intermediate hosts, including humans.

To address the need for a better treatment, compounds targeting epigenetic mechanisms have been tested against T. gondii (6). Enzymes mediating epigenetic modifications of histones have been shown to be promising therapeutic targets [START_REF] Alday | Drugs in development for toxoplasmosis: advances, challenges, and current status[END_REF]. Indeed, the control of gene expression is essential to the survival of parasites and more acutely during growth phases [START_REF] Gissot | New eukaryotic systematics: a phylogenetic perspective of developmental gene expression in the Apicomplexa[END_REF][START_REF] Gissot | How epigenomics contributes to the understanding of gene regulation in Toxoplasma gondii[END_REF]. Histone acetylation has been extensively investigated as a targeted epigenetic mechanism for identifying compounds that inhibit T. gondii [START_REF] Vanagas | Toxoplasma histone acetylation remodelers as novel drug targets[END_REF] and other parasites [START_REF] Fioravanti | Targeting histone acetylation/deacetylation in parasites: an update (2017-2020)[END_REF]. Enzymes involved in the regulation of histone acetylation have been identified as promising therapeutic targets since several modulators of these enzymes were shown to bear an activity against T. gondii [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF][START_REF] Araujo-Silva | HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics[END_REF][START_REF] Jeffers | Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii[END_REF][START_REF] Hailu | Lysine Deacetylase Inhibitors in Parasites: Past, Present, and Future Perspectives[END_REF]. In particular, several inhibitors of histone deacetylases (HDAC) have been shown to suppress the tachyzoite growth in vitro [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF][START_REF] Araujo-Silva | HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics[END_REF][START_REF] Zhang | In vitro and in vivo anti-Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis[END_REF][START_REF] Loeuillet | Synthesis of aminophenylhydroxamate and aminobenzylhydroxamate derivatives and in vitro screening for antiparasitic and histone deacetylase inhibitory activity[END_REF][START_REF] Jublot | A Histone Deacetylase (HDAC) Inhibitor with Pleiotropic In Vitro Anti-Toxoplasma and Anti-Plasmodium Activities Controls Acute and Chronic Toxoplasma Infection in Mice[END_REF][START_REF] Bougdour | Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites[END_REF] indicating that these enzymes are key for the survival of this fast-growing form of the parasite.

Moreover, an hydroxamate-based HDAC inhibitor (HDACi) belonging to the uracil-based hydroxyamide (UBHA) class [START_REF] Mai | Exploring the connection unit in the HDAC inhibitor pharmacophore model: novel uracilbased hydroxamates[END_REF], MC1742, was also active in vivo to prevent the consequences of the acute disease in a mouse model of toxoplasmosis [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF] and is active against other apicomplexan parasites as Plasmodium falciparum, the causative agent of malaria [START_REF] Bouchut | Identification of novel quinazoline derivatives as potent antiplasmodial agents[END_REF]. MC1742 treatment of T. gondii tachyzoites resulted in elevated levels of parasite histone acetylation, significantly influencing gene expression [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF]. These findings strongly indicate that histone deacetylation plays a vital role in sustaining the specific gene expression program during the tachyzoite phase [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF].

In this manuscript, we aimed at discovering new compounds that would show an anti-T. gondii activity both in vitro and in vivo. We investigated the anti-T. gondii activity of hydroxamate-based compounds that were designed to target the HDAC activity. We tested more than 50 compounds and demonstrated that more than 30 compounds showed potent activity against the tachyzoite form of this parasite in vitro. Two compounds presented a concentration of drug required for 50% inhibition (IC50) lower than that of other hydroxamate-based HDACi, including MC1742. Treatment with these two inhibitors strongly increased the level of parasite histone acetylation indicating that they were bona fide HDACi of the parasite. They were also shown to limit the consequences of acute toxoplasmosis in a mouse model of the disease indicating that hydroxamate HDACi are interesting candidates to further expand the therapeutic arsenal against T. gondii.

Material and methods

Parasite strains and culture

Toxoplasma gondii tachyzoites of the type I (RH and RH-LUC GFP [START_REF] Saeij | Bioluminescence imaging of Toxoplasma gondii infection in living mice reveals dramatic differences between strains[END_REF]) and type II (76K and PTG-LUC-GFP ( 21)) strains were propagated in vitro in human foreskin fibroblasts (HFF) using Dulbeccos's modified Eagles medium supplemented with 10% fetal calf serum (FCS), 2mM glutamine, and 1% penicillin-streptomycin (complete media). Tachyzoites were grown in ventilated tissue culture flasks at 37°C and 5% CO2. The luciferase gene is expressed under the control of the tubulin promoter and is therefore expressed in both tachyzoites and bradyzoites [START_REF] Saeij | Bioluminescence imaging of Toxoplasma gondii infection in living mice reveals dramatic differences between strains[END_REF].

Compounds.

The structures, source, references and molecular weight for all HDAC inhibitors used in the study are listed in the Supplementary Tables S1-S4. All compounds were originally dissolved in 100% dimethyl sulfoxide (DMSO) to a 20 mM stock solution. For in vitro experiments, the stock solutions were diluted in complete media to the required concentrations. For in vivo experiments, the stock solutions were diluted in PBS before injection. Solutions at the final concentration were prepared just before use.

Pyrimethamine was resuspended in DMSO to a 7 mg/mL concentration.

Immunofluorescence analysis (IFAs)

HFF cells were infected with T. gondii tachyzoites of the RH strain for 24 hours in presence of the compound or solvent and then fixed using 4% (paraformaldehyde) (PFA) for 30 minutes. The coverslips were incubated with primary antibodies (Table S5) and then secondary antibodies coupled to Alexa Fluor-488 or Alexa-Fluor-594. Confocal imaging was performed with a ZEISS LSM880 Confocal Microscope. All images were processed using Carl Zeiss ZEN software. Manual counting of the number of parasites per vacuole was carried out on at least 100 vacuoles for each biological replicate (n=3).

In vitro anti-T. gondii activity IC50 measurement of each compound was carried out using a luminometric assay using strains expressing luciferase (RH-LUC GFP or the PTG-LUC GFP) as previously described [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF]. Briefly, 10 compound concentrations were tested in triplicate from 2 μM to 1 nM, since we aimed at identifying compounds that showed a better IC50 than Pyrimethamine (660 nM as shown before ( 6)). Readings were performed after 24 or 40 hours for the type I or II strain, respectively. The parasite proliferation was measured by detecting the emission of light on a SPARK plate reader (TECAN). Graphpad Prism was used to plot a regression curve and calculate the IC50 for each compound.

Measurements of cytotoxic activity

HepG2 (liver hepatocellular carcinoma cells) and HFF (Human Foreskin Fibroblast) cells were used in this assay. Alamar Blue® assay is an oxidation-reduction indicator that reflects the compounds cytotoxicity. Cells were seeded in 96 wells plates and incubated with various concentrations (from 100 nM to 100 µM) of compounds in triplicates for 72h in 200 µL total volume. Then, 20µL of Alamar Blue TM HS cell viability reagent (Invitrogen) was added to the wells. After 24h of incubation, the samples' absorbance was measured using the SPARK plate reader (TECAN) at 570 nm and 600 nm. Wells without cells and with or without Alamar Blue TM HS reagent were used to account for background. Cells incubated with various concentrations of solvent (DMSO; 0,8 % to 0,006 % (vol/vol).) were used as controls. Different concentrations (400 µM to 3,125 µM) of chloroquine, that has an known IC50 on HFF cells [START_REF] Bouchut | Identification of novel quinazoline derivatives as potent antiplasmodial agents[END_REF], were used as an internal control. The measurements were analyzed as a dose-response curve to determine the IC50. Each experiment was performed in triplicate. The IC50 were calculated using the online calculator available at https://www.aatbio.com/tools/ic50-calculator.

Measurement of in vivo observable adverse effect level of the compounds

To evaluate if the compound would have deleterious visible effects on mice health and behavior, we treated 5 six-weeks old Balb/c mice intraperitoneally with either DMSO (a 7% solution in PBS) or the compounds (MC2590, MC2059 or MC2125) at different doses (10, 30 or 60 mg/kg), daily, for 5 days.

As a measure of their global health status, we measured their weight and followed signs of modification of their grooming and exploration behavior following the scoring table as described in Table S6. A global score was recorded for each mouse daily for 15 days.

In vivo anti T. gondii activity in a mouse model

The Institut Pasteur de Lille's ethical committee approved the animal housing and experimentation conditions in accordance with the French Council in Animal Care guidelines for the care and use of animals (protocol #11082-2017072816548341 v2). Six to eight weeks old Balb/c mice were injected intraperitoneally with a 10 5 parasites dose (in 200 µL) of the 76K strain. The next day, the mice were injected intraperitoneally with different quantity of compounds (200 µL in a 7% DMSO solution), daily, for 5 days. Pyrimethamine was administered in tap water using a 100 times dilution of the stock solution (7mg/mL) diluted in tap water. Differences in survival curves were assessed by a Log-rank (Mantel-Cox) test with a minimal number of 15 mice per group.

Primary neurons infections and bradyzoite in vitro targeting assay

Neo-natal rat brain cells were collected from hippocampus and seeded as described in [START_REF] Mouveaux | Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and its impact on neuron biology[END_REF]. After 14 days of maturation, the primary brain cells were infected using 5000 parasites, of the PTG-LUC-GFP strain, per well of a 24 well plate at a MOI of 0.1. Fourteen days later, the infected primary cell culture was incubated with a compound ((MC2590, MC2059 or MC2125) concentration of to 3 times the IC50 (as determined above against the tachyzoite stage) or an equivalent volume of DMSO. The culture was left for 7 more days and was then collected and lysed in 100 µL of lysis buffer and processed as described before for luciferase detection.

Western-Blot

Intracellular RH strain parasites were grown for 24 hours and then treated over-night (15 hours) with 0.5 µM of MC2590, MC2125, MC2059 or DMSO. Parasites were then purified by sequential syringe passage with 17-gauge and 26-gauge needles and filtration through a 3-µm polycarbonate membrane filter. This allowed the collection of parasites free from the host-cell material. To prepare the total protein extracts, parasites were resuspended in 1X Laemmli buffer. These samples were then fractionated on a 15% SDS-polyacrylamide electrophoresis gel. The antibodies are listed in Table S5.

Chemiluminescent detection of bands was carried out using Super Signal West Femto Maximum Sensitivity Substrate.

Statistics and Reproducibility

All data were analyzed with GraphPad Prism software version 8. Differences in the means were assessed by Student's t-test. Differences in survival curves were assessed by a Log-rank (Mantel-Cox) test. In all cases, p-values are two-sided and P < 0.05 was considered as significant. All experiments were repeated at least three times using biologically independent replicates.

Results

Compounds potentially active against HDAC inhibit tachyzoite growth.

HDACi have been shown to have a potent activity against T. gondii. In particular, hydroxamate-based HDACi were shown to have an activity in vitro and in vivo against the tachyzoite stage of this parasite [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF]. Therefore, we tested internal library of more than 50 hydroxamate-based compounds that potentially targeted HDACs for their anti-T. gondii activity (Figure 1A). These compounds have different structures but all have a backbone bearing an hydroxamic acid (Supplementary Table 1,2, 3 and 4). To do this, we first investigated their ability to inhibit the parasite proliferation in its tachyzoite form in vitro. We used a luciferase expressing type II parasite strain to take advantage of the large linear range of detection of luminescence. We compared the compounds calculated IC50s to the clinically relevant pyrimethamine, another hydroxamate based HDACi (suberoylanilide hydroxamic acid; SAHA) and the previously identified HDACi MC1742 [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF]. Among these compounds, 14 had an IC50 higher than 1500 nM and therefore could not be exactly measured using the dilution range used in this assay (Figure 1A). Three other compounds showed an IC50 higher than pyrimethamine (660 nM). We found 35 potential HDACi exhibiting a lower IC50 in vitro than pyrimethamine indicating the strong inhibitory potential of HDACi against the tachyzoite stage of T. gondii (Figure 1A and Supplementary Table 1).

Three compounds (MC2125, MC2590 and MC2059) with a potential anti-HDAC activity were shown to have similar or lower IC50 than MC1742 and lower IC50 than SAHA, an hydroxamate-based HDACi that have been shown to inhibit parasite growth (Table 1). MC2125 is structurally similar of MC1742, but present a 6-time lower IC50. MC2590 is an hydroxamate-based compound that has been shown to potentially target human HDAC1-3, -6, -8, and -10 (class I/IIb-selective inhibitor) with IC50s of 15-156 nM [START_REF] Bello | Novel pyridine-containing histone deacetylase inhibitors strongly arrest proliferation, induce apoptosis and modulate miRNAs in cancer cells[END_REF]. MC2590 also inhibits human HDAC isoforms HDAC4, HDAC5, HDAC7, HDAC9, HDAC11 with IC50s of 1350-3890 nM [START_REF] Bello | Novel pyridine-containing histone deacetylase inhibitors strongly arrest proliferation, induce apoptosis and modulate miRNAs in cancer cells[END_REF]. MC2059 is also an hydroxamate-based compound and has been shown to have an HDACi activity in vitro [START_REF] Bello | Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni[END_REF].

We confirmed the compounds anti-tachyzoite activity in vitro using IFA (Figure 1B). The mean parasite number per vacuole was assessed in presence of the compounds. When treated by solvent control (DMSO), the parasites grew to a mean of 14 parasites per vacuole. The MC2125, MC2590 and MC2059 treatment resulted in a strong decrease of the number of parasites per vacuole confirming that the compound can reach the parasite (and pass through the parasite vacuole) (Figure 1B). We also found that the parasites showed different phenotypes depending on which compound was used (Figure S1), but growth arrest due to defects in the cell cycle were apparent in all cases.

We measured the IC50 of these compounds on type I or type II parasites and found similar results for both types, indicating the activity of the compounds was almost identical on different strains (Table 2).

Selected compounds present a good selectivity index.

To ensure that the selected compounds did not show cytotoxicity at the tested concentration, we measured the IC50 of these compounds against two cell types using the Alamar blue assay. The cytotoxicity of the compounds was measured on human foreskin fibroblasts (HFF) and on HepG2 cells, a hepatocellular carcinoma cell line. We were therefore able to calculate the selectivity index (SI) of these compounds and compare it to that of MC1742 (Table 2). Overall, MC2125, MC2590 and MC2059 showed better SI than MC1742 with SI values above 200. However, HepG2 cells were more sensitive to these compounds and the calculated SI values were dropped to 40, 111 and 240 for MC2125, MC2059 and MC2590, respectively. Although MC2125 was the most efficient compound on tachyzoite growth, it was also more cytotoxic than the other two compounds (Table 2).

MC2125 and MC2590 are a potent inhibitors of the parasite HDACs.

MC1742 is an inhibitor of human class I/IIb HDACs (25) and T. gondii HDACs (6). To indirectly evaluate the HDACi activity of MC2125, MC2059, MC2590, and as a negative control, DMSO, we examined the comparative acetylation levels of various parasite histones following treatment. For that, we checked the relative acetylation level of Histone H4 (acH4 and H4K8ac) and Histone H3 (H3K9ac and H3K18ac).

The level of methylation of Histone H3 at the lysine 4 position (H3K4me3) was also measured by Western-blot. MC2125 and MC2590 treatment induced a significant increase of acetylation of both histone H3 and H4, while the level of H3K4me3 was unchanged (Figure 2). In contrast, MC2059 had no effect on the acetylation levels and therefore may not target the parasites HDACs (Figure 2 andS2).

We also verified the level of acetylation of tubulin at the lysine 40 position by Western-blot and showed that the compound did not significantly influence the acetylation of this non-histone parasite protein.

MC2590 is effective at preventing acute disease

In order to assess the maximum dose that we could inject to mice without visual deleterious effects on mice behavior and health, we injected different concentration of compounds to mice and followed their body weight and behavior during 15 days (Figure S3). This experiment showed that injecting 60 mg/kg of MC2059, 30mg/kg of MC2590 or 10mg/kg of MC2125 had no observable effect on mice weight (Figure S3A) and behavior (Figure S3B). However, increasing the concentration of MC2125 to 30mg/kg was deleterious to mice (Figure S3).

To assess the ability of MC2125, MC2059 and MC2590 to prevent the outcome of the acute disease in a mouse model, we infected Balb/c mice with a lethal dose (10 5 parasites) of T. gondii type II strain.

We then recorded the survival of mice for 15 days (Figure 3A). In the control group (n=15), the survival rate was 0 %. Mice treated with MC2059 at either 30 mg/kg or 60 mg/kg did not survive the acute infection. In contrast, the mice treated with MC2125 did show a slight improvement in their ability to limit the consequences of the acute infection with 20 % of the mice surviving in the 10 mg/kg group (15 mice). Finally, MC2590 (30mg/kg) was the most efficient compound and increased the survival to 60% of the mice (n=15) indicating that MC2590 was efficient at preventing the outcome of the acute disease in this mouse model (Figure 3A). However, none of these compounds was as efficient as pyrimethamine.

The tested compounds fail to reduce cyst burden in vitro.

To test the effect of these molecules on the established chronic form of the parasite, we took advantage of the recently established primary brain cell model, that mimics in vitro the production of mature bradyzoite cysts, the latent form of the parasite [START_REF] Mouveaux | Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and its impact on neuron biology[END_REF]. This new in vitro model is an efficient alternative to the usage of mice to assess the compound ability to target established cysts. As observed previously for MC1742 (6), the HDACi tested here were not effective at eliminating the established cysts. Indeed, treatment with these compounds only marginally impacted the presence of bradyzoite cysts in the culture when compared to the DMSO treated culture and as measure by luminescence (Figure 3B).

Discussion

We explored the anti-T. gondii activity of compounds targeting HDACs. T. gondii encodes 5 potential HDACs (TgHDAC1 to 5) which are expressed at the tachyzoite and bradyzoite stage [START_REF] Mouveaux | Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and its impact on neuron biology[END_REF] and at least 4 of them show negative fitness scores in CrispR/Cas9 screen targeting tachyzoites [START_REF] Sidik | A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes[END_REF], indicating their importance at these stages of the parasite life cycle. These enzymes are implicated in the process of regulating the establishment and maintenance of gene expression profiles during the life cycle of the parasite, a mechanism that is likely crucial for adaptation to changing environments [START_REF] Gissot | New eukaryotic systematics: a phylogenetic perspective of developmental gene expression in the Apicomplexa[END_REF]. The fact that these compounds might be crucial for the parasite's life cycle and the potential for repurposing them as drugs makes them appealing targets for further investigation. It has been shown that other HDACi have a potent activity against T. gondii and other apicomplexan parasites [START_REF] Bouchut | Identification of novel quinazoline derivatives as potent antiplasmodial agents[END_REF]. Here, we tested more than 50 compounds potentially targeting parasite HDACs (Supplementary Table 1). Among these, 35 compounds exhibited a lower IC50 in vitro than pyrimethamine, the clinically relevant drug to treat toxoplasmosis. All of these compounds presented an hydroxamate group (Supplementary Table 1) that is known to inhibit metalloproteases or zinc hydrolases like HDACs [START_REF] Lou | Molecular diversity of hydroxamic acids: part II. Potential therapeutic applications[END_REF]. The high potency of these hydroxamate-based compounds against T. gondii tachyzoite growth suggests that this chemical group is a strong inhibitor of these enzymes in this parasite. Interestingly, the other -hydroxamate-based HDACi vorinostat (SAHA) is already approved by the FDA for the treatment of cancers [START_REF] Marks | Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug[END_REF] and has been shown to be active against Cryptosporidium parvum (29) in vivo and T. gondii [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF][START_REF] Araujo-Silva | HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics[END_REF] in vitro, suggesting that it could be repurposed to treat parasitic diseases caused by apicomplexan parasites. Surprisingly, hydroxamate-based compounds were shown to have an IC50 in the low nanomolar range against P. falciparum, but were unable to inhibit the growth of the P. berghei in vivo [START_REF] Bouchut | Identification of novel quinazoline derivatives as potent antiplasmodial agents[END_REF]. This may be due to the poor pharmacokinetics properties of many hydroxamates [START_REF] Flipo | Hydroxamates: Relationships between Structure and Plasma Stability[END_REF]. Establishing the pharmacokinetic paramaters for these compounds could guide the design of further in vivo experiments. In contrast, MC1742 [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF] and to a lesser extent MC2590 (this study) was able to limit the consequences of acute toxoplasmosis in vivo. Further research is warranted to improve these compounds activity and bioavailability.

Although, MC2590 and MC1742 were efficient at preventing the outcome of the acute disease, neither of these potential HDACi were able to eliminate the latent form of the parasite once established as it was shown in vivo for MC1742 [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF] and in vitro for MC2590 (this study). It was speculated previously that MC1742 may have low availability and/or concentration of the molecule in the brain where bradyzoite cysts reside since this experiment was performed in vivo [START_REF] Mouveaux | A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression[END_REF]. However, using the newly in vitro model to produce bradyzoite cysts [START_REF] Mouveaux | Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and its impact on neuron biology[END_REF], we were able to show that the tested inhibitors had a poor activity against these encysted latent forms (Figure 3B). This suggests that using hydroxamatebased HDACi may not be of interest to target these forms. The bradyzoites are surrounded by a thick cyst wall that lies underneath the membrane of the parasitophorous vacuole and it is unclear how permeable this structure is. Indeed, our results suggest that hydroxamate compounds are not able to reach the bradyzoites. Alternatively, HDAC activity may not be essential at this latent stage of the life cycle. Only a handful of compounds were shown to reduce cyst burden [START_REF] Martynowicz | Efficacy of Guanabenz Combination Therapy against Chronic Toxoplasmosis across Multiple Mouse Strains[END_REF][START_REF] Doggett | Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts[END_REF]. Consequently, there is a need to develop novel in vitro systems enabling the testing compounds against bradyzoites. The exploration of organoids or in vitro cultures of primary brain or muscle cells holds the potential to unlock this new research pathway [START_REF] Mouveaux | Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and its impact on neuron biology[END_REF][START_REF] Christiansen | A Novel in vitro Model for Mature Toxoplasma gondii Bradyzoites Reveals their Metabolome and a Diminished Role of the Mitochondrial Tricarboxylic Acid Cycle[END_REF]. Surprisingly, MC2059, a compound that has been shown to target human HDACs [START_REF] Bello | Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni[END_REF] was not able to induce an hyperacetylation of T. gondii histones or tubulin (Figure 2C). This indicates that this compound may have another target in the parasite. Hydroxamate-based compounds can inhibit metalloproteases or zinc hydrolases [START_REF] Lou | Molecular diversity of hydroxamic acids: part II. Potential therapeutic applications[END_REF] and MC2059 may target these enzymatic activities.

Alternatively, MC2059 may have an indirect effect on parasite growth through the inhibition of the human host HDAC activities. This may be also the case for MC2125 and MC2590, that have been proven to target the parasite HDACs, as the parasite is treated as well as the host. In the future, it would be of interest to identify the consequences of the compound treatment on the host and measure the gene expression perturbations induced by these HDACi at low concentration where no cytotoxic effect is visible on host cells. We have found that MC2125 had a cytotoxic effect on HepG2 cells at a 100 nM concentration, indicating that low concentration of these HDACi may have a direct consequence on host cells, depending on their cellular type. Moreover, increasing the MC2125 dose to 30 mg/kg showed deleterious visible effects on mice, indicating that the dose could not be increased.

Among the compounds tested in the study, MC2590 proved to be the most potent. It displayed significant efficacy in inhibiting growth in vitro, exhibiting an IC50 lower than pyrimethamine, other hydroxamate-based HDACi, and similar to that of MC1742. It also presents an attractive selectivity index and may target parasitic HDACs. Therefore, MC2590 is another example of an hydroxamatebased HDACi with a potent activity against this parasite and also highlights the importance of these enzymatic activities for the survival of T. gondii tachyzoites in vitro. MC2590 was also effective at preventing the outcome of the acute disease, although to a lesser extent than MC1742. These HDACi are therefore promising compounds to treat acute toxoplasmosis. However, they need to be chemically improved to match the in vivo activity of pyrimethamine.

In summary, we have discovered an HDAC inhibitor that demonstrates strong anti-T. gondii activity both in vitro and in vivo, as evidenced by its efficacy in a mouse model of acute disease. MC2590 is a promising compound for future treatment of the acute phase of toxoplasmosis. The signal was normalized to the signal given by the loading control (histone H3 Cterm, modified and unmodified). A Student's t-test was performed; two-tailed p-value; ns: p>0,05; mean ± SD (n=3 independent experiments).

Figure 1 :

 1 Figure 1: Compounds potentially active against HDACs inhibit tachyzoite growth. (A) Calculated IC50 for each tested compound. Intracellular tachyzoite of the type II strain PTG-LUC GFP were treated for 40 hours at different concentrations (from 2µM to 2nM). The mean IC50 for three biological replicates is presented on the graph together with SD. Compounds were ranked based on their calculated IC50. The IC50 values for Pyrimethamine (red), MC1742 (green), MC2059 (purple), MC2590 (orange) and MC2125 (blue) are highlighted in the graph. Mean ± SD (n=3 independent experiments). (B) Effect of the compounds on RH tachyzoites on intracellular growth. Tachyzoite intracellular growth was measured after 36 hours of exposure to different compounds at 2 times the IC50 concentration. The average number of parasites per vacuole is used as a metric of parasite intracellular growth and measured by IFAs. Parasites treated with DMSO (blue bars) are used as a control. We measured the effect of MC2059 (red bars), MC2590 (green bars), MC2125 (purple bars) on intracellular growth. A Student's t-test was performed with the DMSO as control; two-tailed p-value; **: p<0,01; ***: p<0,001; mean ± SD (n=6 independent experiments).

Figure 2 :

 2 Figure 2: Acetylation levels of T. gondii histones after treatment with MC2125, MC2590 and MC2059. The purified RH parasite samples were treated either with DMSO or MC2125, MC2590 and MC2059 (0,5 µM). (A): Quantification of the signal for each indicated modified histone after treatment with DMSO (blue bars) or MC2125 (red bars). The signal was normalized to the signal given by the loading control (histone H3 Cterm, modified and unmodified). A Student's t-test was performed; two-tailed pvalue; ns: p>0,05; **: p<0,01; ***: p<0,001; mean ± SD (n=4 independent experiments). (B) Quantification of the signal for each indicated modified histone after treatment with DMSO (blue bars)

Figure 3 :

 3 Figure 3: Effect of the compounds on the outcome of the acute and latent toxoplasmosis. (A): Effect of MC2059, MC2125 and MC2590 treatment on the outcome of the acute disease. One day after peritoneal injection of tachyzoites, mice were treated with different concentration of compounds once a day for 5 days. The percentage of survival is represented for each day during 15 days. Mice treated with DMSO (same regimen, blue line) are used as a negative control. Mice treated with Pyrimethamine (black line) are used as a positive control. The percentage of surviving mice after treatment with MC2059 (30mg/kg, light green or 60mg/kg, dark green), MC2590 (30mg/kg, brown) and MC2125 (10mg/kg, red). A Log-rank (Mantel-Cox) test was performed; **: p< 0,01; ****: p< 0,0001; mean ± SD (n=15 mice per group). (B): Treatment of the bradyzoite (latent) form of the parasite with the different compounds. Latent bradyzoite cysts were obtained after 2 weeks of culture in primary brain cells and then treated with 3 times the IC50 for 7 days. The inhibition percentage was calculated when comparing the compound treated group to the control (DMSO treated cultures). Mean ± SD (n=3 independent experiments).

Figure 1 :

 1 Figure 1: Compounds potentially active against HDACs inhibit tachyzoite growth. (A) Calculated IC50 for each tested compound. Intracellular tachyzoite of the type II strain PTG-LUC GFP were treated for 40 hours at different concentrations (from 2µM to 2nM). The mean IC50 for three biological replicates is presented on the graph together with SD. Compounds were ranked based on their calculated IC50. The IC50 values for Pyrimethamine (red), MC1742 (green), MC2059 (purple), MC2590 (orange) and MC2125 (blue) are highlighted in the graph. Mean ± SD (n=3 independent experiments). (B) Effect of the compounds on RH tachyzoites on intracellular growth. Tachyzoite intracellular growth was measured after 36 hours of exposure to different compounds at 2 times the IC50 concentration. The average number of parasites per vacuole is used as a metric of parasite intracellular growth and measured by IFAs. Parasites treated

Figure 2 :

 2 Figure 2: Acetylation levels of T. gondii histones after treatment with MC2125, MC2590 and MC2059. The purified RH parasite samples were treated either with DMSO or MC2125, MC2590 and MC2059 (0,5 µM). (A): Quantification of the signal for each indicated modified histone after treatment with DMSO (blue

Figure 3 :

 3 Figure 3: Effect of the compounds on the outcome of the acute and latent toxoplasmosis. (A): Effect of MC2059, MC2125 and MC2590 treatment on the outcome of the acute disease. One day after peritoneal injection of tachyzoites, mice were treated with different concentration of compounds once a day for 5 days. The percentage of survival is represented for each day during 15 days. Mice treated with DMSO (same regimen, blue line) are used as a negative control. Mice treated with Pyrimethamine (black line) are used as a positive control. The percentage of surviving mice after treatment with MC2059 (30mg/kg, light green or 60mg/kg, dark green), MC2590 (30mg/kg, brown) and MC2125 (10mg/kg, red). A Log-rank (Mantel-Cox) test was performed; **: p< 0,01; ****: p< 0,0001; mean ± SD (n=15 mice per group). (B): Treatment of the bradyzoite (latent) form of the parasite with the different compounds. Latent bradyzoite cysts were obtained after 2 weeks of culture in primary brain cells and then treated with 3 times the IC50 for 7 days. The inhibition percentage was calculated when comparing the compound treated group to the control (DMSO treated cultures). Mean ± SD (n=3 independent experiments).

Table 1 :

 1 IC50 of selected hydroxamate-based compounds and pyrimethamine.

	446

Table 2 :

 2 IC50 of the selected compounds in T.gondii Type I and Type II strains and toxicity of the selected compounds in HFF and HepG2 cells.The IC50 was determined in at least three independent experiments. Selectivity index was calculated based on the IC50 of the Type II strain. ( 1 ) MC1742 IC50 in human fibroblasts (HFF cells) was determined in[START_REF] Bouchut | Identification of novel quinazoline derivatives as potent antiplasmodial agents[END_REF]. ( 2 ) The X indicates values that were not available.

		MC1742	MC2059	MC2590	MC2125
	Type I IC50 (nM)	39 ± 7	89 ± 6	30 ± 6	10 ± 3
	Type II IC50 (nM)	30 ± 8	75 ± 9	23 ± 6	5 ± 1
	HFF IC50 (nM)	3000 (1)	15800 ± 1536	34553 ± 9386	16313 ± 2529
	HepG2 IC50 (nM)	X (2)	8364 ± 125	5531 ± 1879	198 ± 55
	Selectivity index (IC50 HHF/ IC50 Type II)	100	211	1502	3263
	Selectivity index (IC50 HepG2/ IC50 Type II)	X (2)	111	240	40

Acknowledgments

The authors wish to thank the BioImaging Center Lille for access to instruments. Bibliography 1. Montoya,J.G. and Liesenfeld,O. (2004) Toxoplasmosis. Lancet Lond. Engl., 363, 1965-1976. 2. Kim,K. and Weiss,L.M. (2004) Toxoplasma gondii: the model apicomplexan. Int J Parasitol, 34, 423-32.

Funding

This work was supported by Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), and a Region Haut de France together with iSITE grant (START-AIRR) to MG.


Helen Giunashvili

The XVII-XVIII Centuries Persian Manuscripts in Georgian Script from Georgian Archives

Résumé

Iranian-Georgian cultural-historical contacts have a centuries-old tradition.These influences significantly touched all the spheres of the Georgian cultural life -language, literature, art and science Scientific works of Georgian scientists, created in the Middle Ages, contain rich material for studying Georgian-Oriental cultural relations, revealing the role of Georgian intellectuals, translators and "(re)interpreters" in the formation of scientific thought of that period. During the XVI-XVII centuries, Georgians held important positions in the governmental and cultural spheres of Safavid Iran (1501-1736). Many distinguished Georgian intellectuals (historians, interpreters, painters, poets) significantly contributed to the development of science and art. Parsadan Gorgijanidze (1626-96) is the most eminent figure in the second half of the seventeenth century of the latter group. He served in the Safavid administration as deputy governor (nāeb-e dāruḡa) of Isfahan and royal chamberlain (išik-āqāsi ); he was also a linguist.

Gorgijanidze undertook various creative activities and most importantly, compiled a Georgian-Persian-Arabic dictionary. This first terminological dictionary was based on the XVII century Georgian, Persian and Arabic sources; Arabic and Persian correspondents of Georgian lexemes were given in Georgian transcription.

Gorgijanidze was an author with mutual Georgian and Persian cultural traditions, and undoubtedly, he had many followers who remained in Isfahan and followed in his creative footsteps.

For the relations between Iran and Georgia in the XVI-XVIII centuries there are many contemporary documents preserved at the Korneli Kekelidze Georgian National Center of Manuscripts and the National Archive of the Ministry of Justice of Georgia, such as Georgian-Persian historical documents and Persian manuscripts written in Georgian script.

One of them is of particular interest: the Persian Gospel translation, transcribed in Georgian script and kept at the Korneli Kekelidze National Centre of Manuscripts (S-16). The manuscript contains all four Gospels, but it lacks the last part of Mark's Gospel. The handwriting is in the Georgian script, Mkhedruli.

The original version of the manuscript is preserved at the Saint Petersburg Institute of Oriental Manuscripts (C-268), in the collection of the Georgian Prince Teimuraz Bagrationi * Intervenant sciencesconf.org:let2021:335830 . According to the preface of the original version, the Gospel was translated from Arabic into Persian during Nader Shah's reign (1736)(1737)(1738)(1739)(1740)(1741)(1742)(1743)(1744)(1745)(1746)(1747). The manuscript written in Isfahan was taken to Tbilisi and given its final form in Georgian.

The Georgian transcription of the Persian Gospel might have been the result of scientific activities (particularly, translations) originally established by Parsadan Gorgijanidze. The Persian Gospel manuscript in Georgian script raises a number of important issues concerning the comprehension of the Christian Holy Book by a Muslim author, textual interrelations of the Persian translation with the transcribed version, linguistic peculiarities of the text (phonetic, morphologic, syntactic), and the requirements and trends of a specific historical period, among others.

Mots-Clés: Safavid Iran and Georgia, cultural relations, Persian Manuscripts (Gospel) in Georgian script


Jessica Lombard
email: jess.lombard77@laposte.net

Джессика Ломбард

Biotechnological Agencies in our Information Society: The Emergence of Biocitizenship and Genetic Language

Keywords: Biosociality, Biocitizenship, Biocommunities, Postgenomic knowledge, Optimization of life, Ethical agencies

It is not uncommon to consider deoxyribonucleic acid, most commonly called DNA, as the expression of the genesis and mutation of living species. This molecule is composed of a double helix that carries genetic instructions for all known organisms and several viruses. However, in the Molecular Age, this metaphoric landmark is moved and stretched as we discover and study new structures that impact the genome. Important work is done nowadays in order to understand the consequences and causal relations that intertwine this language and the environment, in many fields such as genetic engineering, bioinformatics and genomic medicine. By giving new access to the architecture that constitutes living beings, technological artefacts and activities translate into a biological shift that opened our lives to new susceptibilities and risks, but also new rationalities and values revolving around DNA. All those technological discoveries inevitably led to a new framework in the Information Society; the Molecular Age. This paper focuses on the new agencies that are constituted in our Molecular Age. From the technology and researches revolving around DNA emerge specific modalities of action in our biosociality. Since genomic-related technologies and researches have constituted DNA as a meaningful structure of signs and symbols we are confronted with the traditional view according to which genomics is the new determinism of the 21st century. On the contrary, however, this paper shows the constitution of new forms of active empowerment based on DNA-related issues and researches. Thereby biological agencies and subjectivities arise from the constitution of a genetic biosociality that provides biocitizens and biocommunities with a discursive, ethical and technical self-understanding, and enables them to gather around the technological and informational meanings that this new knowledge has opened.

INTRODUCTION

By revealing to us the absolute mechanism of all action, and so freeing us from the self-imposed and trammelling burden of moral responsibility, the scientific principle of Heredity has become, as it were, the warrant for the contemplative life. It has shown us that we are never less free than when we try to act. […] It is Nemesis without her mask. It is the last of the Fates, and the most terrible. It is the only one of the Gods whose real name we know. [START_REF] Wilde | The Critic as Artist: The True Function and Value of Criticism[END_REF][START_REF] Wilde | The Critic as Artist: The True Function and Value of Criticism[END_REF] In what is currently called Genomic era or Molecular age1 , advances in molecular biology, genomics and biochemistry have been studied in conjunction with shifts in governance and agency. The theoretical base of those works is that changes in the conception of the biological body had and still have repercussions on the political way in which appears and acts the social body and the individual agent.

The concept of biosociality was coined upon the notion of biopower of the French philosopher Michel Foucault, by Paul Rabinow, who is well-known for introducing the work of Foucault in the USA [START_REF] Dreyfus | Michel Foucault: Beyond Structuralism and Hermeneutics[END_REF][START_REF] Rabinow | The Foucault Reader[END_REF]. Biopower is defined by Foucault as "what brought life and its mechanism into the realm of explicit calculations and made knowledge-power an agent of transformation of human life." (Foucault, 1978, p. 139) As a result, biosociality refers to the political moment and place where biology includes itself in the social field, as a source of expertise and new practices. With the increasing weight of DNA, it sheds light on the central role of biomedical knowledge in constructing genetic identities and producing (and reproducing) social relationships. Accordingly, it does not only describe our current social framework; Rabinow coined "biosociality" in order to go beyond the banalization of the word "sociobiology", conceived as a biological metaphor for modern societies. His own concept embodies a form of new social interactions that "will become instead a circulation network of identity terms and restriction loci, around which and through which a truly new type of autoproduction will emerge, which I call biosociality." (Rabinow, 2010, p. 29) Our paper acknowledges this paradigm, but focuses on highlighting how this technological agency led to a biosocial knowledge, where the political power of citizens in liberal democracies is being shaped by the rise of DNA-related researchers and practices.

It is not uncommon to consider deoxyribonucleic acid, most commonly called DNA, as the expression of the genesis and mutation of living species. This molecule is composed of a double helix that carries genetic instructions for all known organisms and several viruses. It is only logical that this expression of mutation and growth, this same coded instruction of development, was properly translated on an alphabetical Special Topic: Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 76 soctech.spbstu.ru language, based on four nitrogen-containing nucleobases (cytosine [C], guanine [G], adenine [A] and thymine [T]; plus uracil [U] for the RNA). This translation is the starting point to a linguistic metaphor that shows DNA as an alphabet that can be translated through technology.

However, in the Molecular Age, this metaphoric landmark is moved and stretched as we discover and study new structures that impact the genome. Important work is done nowadays in order to understand the consequences and causal relations that intertwine this language and the environment, in many fields such as genetic engineering, bioinformatics and genomic medicine. By giving a new access to the architecture that constitutes living beings, technological artefacts and activities translate a biological shift, opening our societies to new susceptibilities and risks, but also new rationalities and values revolving around DNA. All those technological discoveries inevitably led to a new framework in the Information Society; a (genetic) biosocial knowledge in what is called the Molecular Age.

Consequently, our paper is based on philosophy of technology and medicine, to confront traditional views according to which genomics is the new determinism of the 21 st century. On the contrary, it focuses on new structures that are constituted in our Molecular Age, when the technology and researches revolving around DNA roots the emergence of specific modalities of action in our biosociality. As genomic-related technologies and researches have constituted DNA as a very meaningful carrier of signs and symbols, we show the constitution of new forms of active empowerment based on DNA-related issues and researches. Thereby, we claim that biological agencies and subjectivities rise from the constitution of a genetic biosociality that provides biocitizens and biocommunities with a discursive and technical self-understanding, and enables them to gather around the technological and informational meanings that this new structure has opened. We show that this multiform biosociality comes with the emergence of dedicated systems where economics, ethics and politics intertwine.

To this end, we first make clearer the characteristics of the Molecular Age by explaining which political knowledge emerges from genetic advances and what genomic medicine is. In this medical framework, we detail the consequences of the inclusion of a third term between the normal and the pathological: namely susceptibility. We show how susceptibility impacts the paradigm of heredity, hence the individual's actions linked to his own lineage, by introducing the notion of "genetic risk".

As the individual is part of a political process where the knowledge of genetic defects leads to an ethical responsibility that affects the very notion of family descent and the management of risk, we demonstrate how contemporary insights into genetics foster the emergence of a new political referee; a "biocitizen", which acts as a decisionmaking agent in the technical environment that shapes him.

As a result, this biological citizenship is part of a new form of "vital politics", which re-explores Foucault's sanitary-related biopolitics in the light of genetic advances. This new paradigm sets up a web of previously unheard-of institutions and engages the biocitizen in new social and political actions. In this regard, technology is a new means to communicate around a shared language, DNA, that grounds the emergence of new soctech.spbstu.ru biocommunities and platforms and leads to unprecedented forms of active ethical rationalities.

THE BIOLOGICAL SHIFT: HOW DID TECHNOLOGY CHANGE DNA IN A MEANINGFUL STRUCTURE?

The Biovalue of our DNA

There is a whole new consumerism based on the information that can be extracted from our genetic code. We observe the emergence of new private actors that are constituted by very diverse institutions, such as biotech companies, pharmaceutical corporations, data banks, sequencing enterprises… Those new economic structures have opened circuits of capital and investments related to what is called the production of biovalue [START_REF] Waldby | The visible human project: Informatic bodies and posthuman medicine[END_REF].

But the value of health is not only a biological one, it is also an economic one: health is something affordable (or not), and health services are to be paid for even in the countries where social security is guaranteed. The direct-to-consumer (DTC) genetic testing industry is a good example of the biotechnological value that comes from those institutions. Through DTC genetic testing, "individuals are able to purchase [online] personal genome tests directly from companies supplying both sequence data and interpretation of health risks." (Kelly et al., 2018, p. 32) We can see here that the consumerism revolving around DNA information drives today's biosociality precisely because of the importance of the citizen, seen as an active subject willing to take individual decisions on his health, to gather in biocommunities and to judge his condition partly-independently from traditional health institutions.

The Molecular Body of Genomic Medicine

The industry revolving around biovalue is mostly based on the emergence of genomic medicine, for which are developed many DNA-related tasks, such as screening, analysing, stocking, developing and marketing genetic data, tests and targeted therapies. But this genomic medicine is still quite new and ongoing. Historically, it appeared after a biological shift in the understanding of the body, based on the fact that the somatic body and the genetic body are conceived on totally different scales.

20 th century medicine inherited from the 19 th century a somatic conception of the body: it was seen as a living organism that encloses interconnected organs, tissues, feedbacks, controls, and so on. Michel Foucault highlighted the fact that, in the 18 th and 19 th centuries, European authorities were preoccupied by illness as it can develop in a social body, and set up strategies to intervene upon them on local spheres, i.e. towns, health institutions or families 2 . However, the 20 th (and 21 st ) century show the construction of more complex and hybrid technologies for the management of illnesses Special Topic: Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 78 soctech.spbstu.ru and reproductive activities, where "technologies" is to be understood both as practices (or techniques, as diverse as sterilization or prenatal diagnosis), and as instruments (such as new vaccines, gene engineering tools or even institutions e.g. data banks).

This biological shift was grounded in the progress of a research field, genomics, that led to visualize life phenomena at the sub-microscopic scale. The perception of life itself became molecularized, with the idea that DNA was the language that contains our digital instructions. As such, technology began to translate this structure, and dilemmas about what we are, what we can do or hope took a "molecular form". Life was considered as a sub-cellular process, controlled by a genomewhose symbolical and concrete determinism we are only beginning to refute.

Thereby, several scientific facts need to be mentioned briefly to underline the importance of this renewal in human knowledge and genetic understanding, which constitutes genomic medicine and biomedicalization [START_REF] Clarke | Biomedicalization: Technoscientific Transformations of Health, Illness, and U.S. Biomedicine[END_REF].

The Constitution of Genomic Medicine:

As one of the main discoveries, it was understood that the genome of each individual differs, even for twins, and 90 percent of human DNA is "junk"3 which was unexpected. But one of the more recent, and still-under-study, aspects of this expertise is our growing understanding of epigenetics. Epigenetics is the science of the natural mechanisms that can modify gene expression in a reversible, transmissible and adaptive manner without changing DNA sequence. For instance, the very same turtle egg can give a male or a female depending only on the environmental temperature; in this case, sex determination depends on an epigenetic phenomenon, which will determine the use of genes coding for male or for female, without any internal modification of DNA.

As a result, the development of genomic medicine led to new questions and outcomes. The Human Genome Project (1990Project ( -2003)), an international scientific research project that intended to index the base pairs that make up human DNA, and to identify and map all of the genes of the human genome, is the framework in which genomic medicine found its impetus.

Genomic medicine stands for the reorganization of many illnesses and pathologies along a genetic axis, where DNA is seen as the new force-form of our last decades, which composes an infinite diversity in infinite combinations. "The best example of this "unlimited-finite" is DNA: an infinity of beings can and has arisen from the four bases out of which DNA is constituted4 ." [START_REF] Rabinow | Artificiality and Enlightenment: From Sociobiology to Biosociality[END_REF] 181) It has 3 main aspects: (1) Predictive medicine: it envisions a probabilistic future health history for each individual. (2) Preventive medicine: it places the defective genes in the context of their impact and learns how to circumvent them. (3) Personalized medicine: it treats each individual with their unique sets of genetic predispositions. soctech.spbstu.ru

In this area, genomics-related researches, as the source of an increase of biological knowledge, are strengthened by new tools and systems. Genome editing tools, for instance, enable us to encode, recode and decode biological materials, like translating "wet" DNA (physical samples) into "dry" DNA (information). DNA-related systems, for their part, are mainly linked to computer-engineering and bio-engineering, like AIaided medical procedures, genomic platforms, databases, bioinformatics and biobanks. Biobanks for the storage of biological samples; genomics platforms for generating genetic data from biological samples; databases for the storage of genetic data; bioinformatics platforms for the production of clinical information from genetic data (and other raw data). As a consequence, "the "transformation" of scientific research areas, such as genetics, bioinformatics and biostatistics, into clinical specialties has led to the emergence of a new vision of care." (Stoeklé et al., 2018, p. 311) Genomic medicine marks a renewal in medicine per se and reorganizes medicine along a genetic axis, by considering the body as a cluster of cells and DNA, i.e. as a molecular body.

The Establishment of Our Genetic Susceptibility:

By considering the body on a molecular scale, genomic medicine entails a new way to relate to care that implies to treat people before the (genetic) condition even appears on a phenotypical scale, or to try to prevent this appearance5. Therefore, genomic medicine looks for the susceptibility of being affected, i.e. looks for a genetic condition that makes a person susceptible to a diseaseincluding in the case of epigenetics [START_REF] Happe | Epigenetics and the Biocitizen: Body Temporality and Political Agency in the Postgenomic Age[END_REF].

Susceptibility can be thus considered as the third element between the "normal" and the "pathological", and as the moment where predictive medicine intervenes to calculate the probability of the proto-disease's development. Although predictive medicine is nothing new in itself, the means of gathering genetic information through the study of DNA was logically unseen before the development of genomic medicine. Until its eruption into real illness, we mostly ignored symptomless proto-diseases. However, genomic medicine reverses this disregard and makes these hints of future troubles central to its diagnostic and therapeutic hopes; as such, it expands the notion of economy of hope [START_REF] Novas | The Political Economy of Hope: Patients' Organisations, Science and Biovalue[END_REF].

As a consequence, the development of genomic medicine has created a new agent, the patient of a disease which is not here and may never be. Before the pathological state and during the normal state, it permits "to define and diagnose a state of potential disease, or protodisease, and in doing so, to render the person a "pre-patient"." (Rose, 2007, p. 85) We observe here the emergence of a new form of active citizenship, concerned with his statistical health, where individuals can gather information on their Special Topic: Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 80 soctech.spbstu.ru DNA instructions to prevent the onset of a disease, and monitor the malleable risk of contracting it.

Thereby, genomic medicine does not erase the fact that we are also subjective agents. On the contrary, genomic medicine helped to deepen our biosocial vocabulary and to create technological subjectivities and agencies, by fostering the emergence of a new citizenship. This unique citizenship must not be understood as something theoretical. It is deeply endorsed by practical factors and theories of action that lead to adapted individual behaviours and unprecedented socio-political forms of commitment. Moreover, this citizenship rarely focuses only on ideas or convictions, but on a previously unheard-of range of genetic discoveries; the main one being the genetic (hence statistical) susceptibility of having a disease, leading to a new agency based on genetic risks.

THE RISE OF BIOSOCIALITY: WHAT NEW TECHNOLOGICAL AGENCIES ENTAIL BIOLOGICAL KNOWLEDGE?

The Computability of Our Genetic Risk

One of the main aspects of this new agency is that individuals are susceptible to be labelled genetically at risk for a particular condition, prior to any symptoms appearing. This sends us back to a form of determinism. Indeed, it is sometimes considered that we are facing "the whole-scale geneticization of identity with the consequent reduction of the human subject to a mere expression of their genetic complement 6 ." (Rose, 2007, p. 109) This geneticization argument is strongly rooted in the idea of determinism and fatality, since to ascribe genetic identity to individuals and groups would allegedly reify them. To suffer a genetic predisposition for a disease could be "as if the individual's nature and destiny was "marked" by this genetic flaw." (Rose, 2007, p. 197) It could be a total cut in the potentiality to act as freely as possible for an individual.

However, this paper strongly supports that the opposite argument should be examined to understand why this shift in the understanding of our biological knowledge does not only create new (bio) patients, but an entirely new biocitizenship and, consequently, new theories of action regarding the management of our life. But how could a susceptibility to a disease open some technological agencies?

Because it is a statistical risk, only a certain percentage of individuals will suffer the disease on a phenotypical scale, and the timing of onset and severity of most disorder are unpredictable. Therefore, the generation of predictions and their analysis entails a new "biological control", which strengthen the links between knowing and choosing; feasibility and responsibility to act.

This new responsibility rests mostly on the social significance of any genetic disease. Social is to be understood here as related to one's family core, mainly but not only on account of heredity. For instance, an individual genetically at risk could want to soctech.spbstu.ru avoid transmitting unsafe genes to his children. The individual who is responsible for his health sees at the same time his body through the lens of "genetic inheritance", which is to be managed wisely. New genetic responsibilities will organize the life action plans of the individual (genetically at risk or not) and of his family. It is a new description of the management of life, where the genetic coloration of life strategies creates new ethical responsibilities, expressed in an increasing obligation to act in the present in relation to the potential futures that come into view. By making pre-patients (patients that have "only" a statistical probability of being ill), genomic medicine allows subjects to anticipate, and give genetic risk a new computability, after which to act.

For this reason, genetic images and imaginations, as long with their values and fears, get entangled within the language of self-description and self-judgment that is usually called the "regime of the self". Individuals are said to increasingly recognize the "self" as the bearer of a genetic risk, around which daily routines and future plans must be organized with prudence. Active responsibility now implicates both corporeal and genetic responsibility: "one has long been responsible for the health and illness of the body, but now "somatic individuals" must also know and manage the implications of one's own genome." (Rose, 2007, p. 134) Embodiment itself becomes a place of association concurred by a common understanding of risks, rooted in a new sociopolitical age of "biological control". "This means that we can no longer assume that the biological "itself" will impose limits on human ambitions. As a result, humans must accept much greater responsibility toward the realm of the biological, which has, in a sense, become a wholly contingent condition." (Franklin, 2003, p. 100) Here, a whole new theory of actions is meet through technology, considered as the medium through which DNA instructions, risks, susceptibilities and agencies are translated. As the genetic knowledge inscribes itself into the heart of corporeal existence and reshapes self-description, it creates new ways of conceiving and acting upon bodies and, consequently, in the field of biopolitics, upon social and political bodies. Therefore, the molecularization of life and the individualization of risk have given rise to a new form of agency and sociality around their management; namely biocitizenship [START_REF] Happe | Biocitizenship: The Politics of Bodies, Governance, and Power[END_REF][START_REF] Rose | Special Topic: Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 92 soctech.spbstu[END_REF].

As such, we will show that the new possibilities that DNA-related researches have opened, for biocitizens to manage their genetic risks or to simply understand it, created a new technological agency around the optimization of life itself, based on a biological knowledge.

The Optimisation of Active Biocitizens' Lives:

The optimisation of life is not an idea born after the discovery of DNA, but we focus on how it was strengthened by the new modalities of agencies that arose in the last century, and followed both by governmental policies and individual health measures.

In 1950, Thomas Marshall theorized an historical evolution of citizenship. According to him, the civil rights of the 18th century called the emergence of a political citizenship in the 19 th century, which led to a social citizenship in the 20 th century [START_REF] Marshall | Citizenship and Social Class: And Other Essays[END_REF]. This evolution brings about the notion of "citizenship project"; the Special Topic: Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 82 soctech.spbstu.ru construction of citizenship by the authorities through the perception of some (but not all) individuals as citizens, and their specific actions upon them.

For instance; defining those who are entitled to vote, or to adopt children; imposing a national currency, or a single national language, etc. Nowadays, we fully understand that biological theories of actions are and always were deeply inscribed in a political way, as part of any (biological) citizenship projects; e.g. the ideas of race, species, blood line, DNA pool; or the policies around women, motherhood, and family; the controversies about homosexuality, adoption, and reproduction; or the sociopolitical weight of the notions of heredity, and demography. Numerous citizenship projects were framed in biological terms and this "biological citizenship" can only get strengthen by the current framework that sees the development of a new branch of knowledge revolving around the understanding of genomic instructions and causal relations. But the intensification, in the last centuries, of biological citizenship-related policies necessarily entails the rise of a new subject, the biocitizen.

If indeed there are state-supported public health measures that indicate that biocitizenship remains an issue within the (national) political rationalities, liberal democracies are nonetheless said to promote an emerging "regime of the self." In this regard, the empowerment of the citizen, independently of national citizenship projects, appears clearly of paramount importance. Biocitizenship describes a condition where "each individual is engaged as a prudent yet enterprising individual, actively shaping his or her life course through acts of choice, activities that extend to the search for health in the face of the fear of illness, and the management of the risksnow the genetic susceptibilitiesof disease 7 " (Rose, 2007, p. 154). While citizenship has long had a biological dimension, new kinds of biocitizenswith new subjectivities, new politics and new ethicsare forming around the biological understanding that genomic medicine and genetic researches provide.

Naturally, this does not concur with the decline of citizenship projects themselves, nor this signifies the complete erasure of sovereign power in favour of pervasive forms of pastoral power. The attempts to "empower" the recipients of medical care are also representative of a global shift: a biocitizenship itself is fostered by national and international policies, as exemplify the notions of "responsible consumption" [START_REF] Giesler | Creating the Responsible Consumer: Moralistic Governance Regimes and Consumer Subjectivity[END_REF] and of "active citizenship 8 ."

An active and responsible biological citizen is required to be in life-long training, to perform, to improve himself (especially through consumption), to monitor and manage his health (e.g. with the modulation of his behaviour through sport, diet, lifestyle, and drug regime). This behaviour constitutes what is sometimes called a 7 Rose specifies that "biological citizenship is a more general version of what Deborah Heath, Rayna Rapp, and Karen-Sue Taussig have termed "genetic citizenship": a way of understanding human differences, especially those related to health, in terms of genetic influences" [START_REF] Heath | Genetic Citizenship[END_REF]Rose, 2007, p. 136). We acknowledge this distinction, but we strongly believe that biocitizenship is all the more so relevant today because of the transposition of the soma into the gene. This biological shift is the starting point of a previously unheard-of range of socio-political practices and measures. The main example of a major democratic investment towards a disease which is not directly linked to DNA could be the biocitizen fight against the HIV/AIDS [START_REF] Girard | Is HIV prevention creating new biosocialities among gay men? Treatment as prevention and pre-exposure prophylaxis in Canada[END_REF]). 8 "Active citizenship" is a notion where organizations, enterprises, governments or educational institutions advocate that each and every citizen have roles and responsibilities towards its society and the environment. It is generally used to stimulate the people's involvement in their communities even when they possess little decision-making power. soctech.spbstu.ru "good" (Lee, 2020) biocitizenship. Through genetic counselling, for instance, individuals are placed under the guidance of counselling authorities and encouraged to reflect upon their inherited constitution, with the explicit aim of affecting their daily behaviour. Pat O'Malley labelled "genetic prudence" (O' Malley, 1996) this new field of practices and discourses that introduces distinctions between right (and wrong) ethical choices regarding biological susceptibility. Those socio-political processes inscribe themselves in a specific space of competition worldwide. That is the reason why it can be considered that biopolitics today is less oriented towards health and illness, procreation and capital stock, than it is towards the (bio) optimization of life itself, where politics arise strongly and governments cannot be evacuated.

This bio-optimization of life is not just an idea to reduce genetic susceptibility. The main form of DNA-related biocitizenship follows concrete damages that the biological body, understood as molecularized, suffered or could have suffered.

An interesting example of strong biocitizenship endorsed by a government was studied by Adriana Petryna on her work of post-Chernobyl Ukraine. The independent Ukraine based its right to govern on the explicit will of its citizens, who claimed that they were entitled to health services and social support after the nuclear explosion in the name of their damaged biological bodies. [START_REF] Petryna | Life Exposed: Biological Citizens after Chernobyl[END_REF] explains that "the very idea of citizenship is now charged with the superadded burden of survival… a large and largely impoverished segment of the population has learned to negotiate the terms of its economic and social inclusion using the very constituent matter of life" (p. 5). Biological citizenship can thus embody a demand for particular protections, and an access to special resources or to a form of social welfare based on medical, scientific, and legal criteria that both acknowledge biological injury and compensate for it. This also shows that responsible biocitizenship, or true agency in genetic decision-making, are better exercised from a place or group of cultural inclusion, where the stakes are locally understood [START_REF] Reuter | Testing Fate: Tay-Sachs Disease and The Right to Be Responsible[END_REF].

As a counterpoint, some voices are raised to promote a "bad" biocitizenship, to counter what they call a "coloniality of good biocitizenship" [START_REF] Kolopenuk | Provoking Bad Biocitizenship[END_REF]; as such, they underline how the optimization of life results both from a specific culture or government and from a group of subjects.

Furthermore, those aforementioned examples typically clarify a unique characteristic of biocitizenship: each case claims on political authorities and corporate entities are being made by those who have suffered biological damage, in terms of their "vital" rights as citizens9 . The rise of biocitizenship is enlightened by the fact that mostly prejudiced people are likely to undertake any fight against genetic conditions; even if susceptibility to genetic risk, given their number, is universal and diverse. The Biocitizenship in Our Information Society:

As a consequence, our information society is one of the spearheads of biocitizenship. It expands the place where responsible biocitizenship is a "local" issue by expanding the places where to exchange and gather. This major element echoes our current postmodern paradigm, where the "right to know" is seen as intrinsically linked to the enlightened exercise of active citizenship. Although this right is usually fostered by mass-media, biocitizenship also involves the collation of specialized scientific and medical sources; usual forms of activism such as campaigning for better treatment, or for the education of the population regarding a genetic condition.

It also shows the emergence of a "digital biocitizenship" [START_REF] Petrakaki | The Cultivation of Digital Health Citizenship[END_REF]) that uses the Internet for sharing experience and making kin. With the help of contemporary information and communications technologies, biosocial dynamics are spread through online gathering platforms or social media, helped by new digital tracking devices and apps, and analyzed through quantification and agent-based models [START_REF] Costa | Manufacturing Biocitizens: The Quantification of Bodies as a Method for Incorporating a New Biomedical Ethics[END_REF][START_REF] Dyer | Quantified Bodies. A Design Practice[END_REF][START_REF] Sharon | Self-Tracking for Health and the Quantified Self: Re-Articulating Autonomy, Solidarity, and Authenticity in an Age of Personalized Healthcare[END_REF]. Under the current circumstances of the COVID-19 pandemic, we see a demonstration of this digital biocitizenship that was promoted both by governments or citizens, for instance with the use of contact tracing apps and geolocation apps, and the creation of long covid support groups or post-covid syndrome groups [START_REF] Convertino | Editorial: COVID Ecology and Evolution: Systemic Biosocial Dynamics[END_REF][START_REF] Tadić | Modeling Latent Infection Transmissions Through Biosocial Stochastic Dynamics[END_REF].

Those forms of democratic participation incidentally blur the boundaries between public and private interests by promoting a horizontal formation and distribution of knowledge. As a consequence, biocitizens are not "alone, required to cope with their fate only with their own family, accompanied by the advice of experts, the solitary reading of informative material. […] It is not the fate of the citizen genetically at risk to be an isolated atom" (Rose, 2007, p. 144).

Nowadays, communication technologies and the aforementioned access to information make new forms of sociality possible, which led Frédéric Keck to make this interesting comparison: "No doubt the genetic maps of the individual body (linkage, physical, and sequence) […] have replaced the totemic maps of the collective territory […]. But the map is still the form of knowledge that enables us to find our bearings together in an unknown area: it provides landmarks, grips, shared markers." (Rabinow, 2010, p. 41) It is in this mention of shared markers that lies the basis of how any technological structure addresses theories of action; through the communication between agencies and the creation of new active structures. As biocitizenship is a proper modality of action, mostly restricted in size to prejudiced people and their families, there is a special need for active gathering through biocommunities. soctech.spbstu.ru

A SYSTEMIC BIOSOCIALITY: HOW DID THE EMERGENCE OF NEW ACTORS REACH OUT TO NEW ETHICAL RATIONALITIES?

The Emergence of Biocommunities as Structured, Operative and Discursive Agents

As a shared map, sociality is by definition intrinsically linked to the formation of groups or communities. As we said, Rabinow proposed the concept of "biosociality" to characterize these forms of collectivization organized around the commonality of a shared somatic or genetic status. Biosociality embodies not only a new paradigm, testifying of the implication of DNA both as a symbol and as matter in the lives of individuals. It gathers also group members united by a common (and somewhat new) "relationship" with their DNA. Where we had national "biological citizenship projects", we now see the emergence of "biological citizenship communities" (i.e. biocommunities), whose concern about biology (and mainly genetics) is more grounded in one's socio-political life. Those biosocial communities of active biocitizens have key roles in the structuration and the translation of genomic knowledge in the 21 st century.

Biocommunities are forming through physical meetings, but also on the Web. As such, information technology itself is the language that translates another entangled structure, DNA, for different agents to understand it. Generally speaking, the Internet has been a vital tool for the development of biosociality; be it for the online availability of DNA-related information and products, or for forging those translocal biocommunities gathering individuals willing to engage in the process of biomedical self-shaping. These new de-territorialized "body-geographies" challenge local cultures of health and traditional aetiologies of disease. "A key feature of the Internet is that it does not only give access to material disseminated by professionals, it also links an individual to self-narratives written by other patients or carers." (Rose, 2007, p. 142) The aims and reasons to gather in biocommunities are diverse: pre-patients who share a genetic condition or a high probability to trigger it; support groups for the families… Yet, they all function with the common feeling that an active biomedical citizenship is to be raised and voiced around "technoscientific illness identities" [START_REF] Sulik | Our Diagnoses, Our Selves': The Rise of the Technoscientific Illness Identity[END_REF][START_REF] Wehling | The "Technoscientization" of Medicine and its Limits: Technoscientific Identities, Biosocialities, and Rare Disease Patient Organizations[END_REF]. For instance, during the parent-led conferences organised in the UK between 2007 and 2010 around the 22q11 deletion syndrome10 . This can seem too precise a genetic condition to be believable, but this example shows the kind of groups that are constituted on the basis of technologies that efficiently shed light on a few numbers of genes.

At the beginning of the nineties, Rabinow noted that "there already is, for example, neurofibromatosis groups who meet to share their experiences, lobby for their disease, educate their children, redo their home environment, and so on" (Rabinow, 2005, p. 188). He also suggested, as the aforementioned example rightly confirms, that Special Topic: Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 86 soctech.spbstu.ru "it [was] not hard to imagine groups formed around the chromosome 17, locus 16,256, site 654,376 allele variant with a guanine substitution." (Rabinow, 2005, p. 188) Biocommunities gather information and expert knowledge by themselves (doing DNA sequencing, studying the reports of medical trials, sharing and voicing other citizens' experiences of the same condition, and so forth), rather than referring only to traditional medical instances, i.e. doctors, hospitals. The role of patient communities in civic societies have been well documented in raising awareness of little-known medical conditions, explaining to the public medical terms and categorizations inherent to the genetic vocabulary and knowledge; and campaigning for access to research funding and healthcare resources [START_REF] Allsop | Health consumer groups in the UK: a new social movement[END_REF][START_REF] Swan | Health 2050: The Realization of Personalized Medicine through Crowdsourcing, the Quantified Self, and the Participatory Biocitizen[END_REF]. As another example, we also see the emergence of theories of (genetic) victimization, which try to revitalize biocitizenship and empower biocommunities by studying how genetic influences might be related to the odds of being victimized [START_REF] Beaver | Biosocial Perspectives on Victimization[END_REF].

DNA is seen as a code giving very diverse instructions and advices about the structuration of one's life. As such, individuals are empowered through the formation of translocal communities, engendering a sense of kinship, where protection and support are offered, differences normalised and values reproduced.

The Ethical Rationalities of the Biological Power:

Within those new forms of genetic citizenship, individuals and groups have made their biological existence a matter of ethical concern and a basis for political action. Between all those actors, some new ethical rationalities 11 must be discussed.

Rose called the biocommunities "ethical pioneers" (Rose, 2007, p. 146), as they open a way through the still unknown land of genetic citizenship, and enters exactly in the sub-governmentality 12 that was theorized as "technologies of the self". Technologies of the self, of which the ethics of biocitizens and biocommunities pertain, refer to practices and strategies by which individuals demonstrate their own ethical selfunderstanding. And indeed, the actions of biocommunities do not aim at a general ethical moratorium but at the daily management of a condition (or a pre-condition), and at the freedom of decision-making processes. Mitchell [START_REF] Dean | Governmentality: Power and rule in modern society[END_REF], who considers that neoliberal governmentality rests upon the production of a particular kind of subject who understands himself in terms of making (wise) choices, and thus in terms of individual responsibility, noticed that we are now compelled to "make choices" about our health. As such, the categories of susceptibility, risk and genetic disease have become vehicles for the self-production and exercise of agencies endowed with the faculties of choice and will.

Hence, the ethics of those "pioneers" forms a counterbalance to the ethics of official health-related systems, such as national bioethics committees 13 . This situation 11 By "ethical rationalities" or "ethopolitics", we do not mean to discuss the evolutionary perspective on morality, such as the development of altruism and empathy. [START_REF] Riley | Morality in a Biosocial Context[END_REF] 12 "Governmentality" is a concept invented by Foucault in his lectures at the Collège de France to describe the organized practices (mentalities, rationalities, and techniques) through which subjects are governed. 13 Bruce Braun notes that bioethics is "a professional field which always seems to arrive too late, after biomedicine, biotechnology and finance capital have ushered in the future, and thus can act only to incorporate new biotechnological realities within law" (Braun, 2007, p. 13). However, we do not disregard the importance of official soctech.spbstu.ru may be compared to the ethical management of the Internet; where isolated citizens (users, tweeters, hackers, hacktivists…), groups of citizens (Anonymous, WikiLeaks…), and multinational companies (Google, Facebook, Amazon, Apple…) indisputably replace national governmentalities.

According to Nikolas Rose, this situation implicates a shift from a biopolitics of populations to an ethopolitics characterized by the individual management of the biological self. "I have suggested that we are living in an ethopolitical age, where issues as diverse as crime control and political apathy are problematized in terms of ethics. No longer posed in the languages of justice, welfare, or equity, ethopolitics here is about the value of different forms of life, styles of life, ways of living, and how these should be judged and governed." (Rose, 2007, p. 97) As a direct consequence, the molecularized body has become the site of different political rationalities, gathered around the concept of "(bio) security".

On this question, the perspective of Bruce Braun raises interesting questions. Braun considers that the current situation overtakes the concept of ethopolitics, because the management of life is intimately related to the exercise and extension of sovereign power [START_REF] Braun | Biopolitics and the Molecularization of Life[END_REF]. We can infer from it the rise of an independent exercise of choicemaking processindependent even from ethics. Bruce Braun projects this situation on a very global scale, which includes the environment. He reminds us that Bernard Vallat, Director General of the World Organization for Animal Health (OIE), considers that we are now immersed in the "great biological cauldron" of the 21 st century, where biology is virtuality (the opposite of determinism), and where the future is less about "care of the self" than it is about imminent catastrophe to manage. This is the reason why several major ethical works turn towards the sociology of risks [START_REF] Castel | La Gestion des risques : De l'anti-psychiatrie à l'après-psychanalyse [Risk management: From anti-psychiatry to post-psychoanalysis[END_REF][START_REF] Castel | La Gestion des risques : De l'anti-psychiatrie à l'après-psychanalyse [Risk management: From anti-psychiatry to post-psychoanalysis[END_REF][START_REF] Chateauraynaud | Les sombres précurseurs. Une sociologie pragmatique de l'alerte et du risque [The dark precursors. A pragmatic sociology of alert and risk[END_REF][START_REF] Collier | Biosecurity: Towards an Anthropology of the Contemporary[END_REF][START_REF] Collier | The Vulnerability of Vital Systems: How 'Critical Infrastructure' Became a Security Problem[END_REF], 2008a), as "the apparatuses that inform on the perception of environmental threats and set off collective forms of rallying." (Rabinow, 2010, p. 44) The length of this article prevents us from making an expeditious analysis of the balance between ethopolitics and sovereigntyif we are to understand sovereignty as the full right and power of a governing body over itself. However, if we are to understand sovereignty as the exercise of power by a state (as it is the case in international law), we already explained that governmental biocitizen projects are an important part of the biopolitical management of lives. But we also demonstrated that biosecurity itself was implemented not only by official authorities but first and foremost by biocitizens and biocommunities. As such, we can conclude here on a shift on health "cultural authority" [START_REF] Epstein | From Medicine to Health: The Proliferation and Diversification of Cultural Authority[END_REF], from the social authority of physicians to the proliferation of new forms of agency, information and ethopolitics regarding health-related issues.

bioethics committees, which are becoming a necessary supplement to the imperatives of political decision making concerning the biological and social life [START_REF] Wahlberg | From Global Bioethics to Ethical Governance of Biomedical Research Collaborations[END_REF]. They intend to fill the gap between economic imperatives and ambitions, clinical demands and citizens' claims to treatment and rights to health "under conditions of moral uncertainty and lack of consensus." (Rose, 2007, p. 97) Special Topic: Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 88 soctech.spbstu.ru Therefore, we strongly believe that the balance between ethopolitics and state governmentality also depends on the position of private corporations and companies that strengthen the consumerism around this new biovalue that DNA embodies.

As the fertile ground for new ethical rationalities, DNA-related information and technologies meet theories of action and agency because genomics is a totally new field for ethical self-problematization. Genes themselves have been constituted as a language, which does not mean as an alphabet, but as an "ethical substance […] working in relation to the self (genetic identity, reproduction, health) and in relation to others (siblings, kin, marriage, children)." (Rose, 2007, p. 125) Nevertheless, not just anyone can participate in building this ethical and informational web, since the growing availability of medical information on the Internet and the activism of biocommunities does not compensate for sometimes expensive scientific testing, like diagnosis or gene sequencing.

CONCLUSION

The growing knowledge we gathered on our genome those last decades impacted us in what it means to belong to our societies and act in them. The "discovery" of our DNA and of its complexity has made us genetic individuals, pertaining to new forms of democratic agencies and ethics, and created in response the rising field of biosociality. Genomic-related technologies meet theories of action because genetics is a totally new field of communication, action, consumption and values, where DNA is a proper language. Not only an alphabetical language with four nucleobases as letters, but also the support of very meaningful signs and symbols, for societies to build biosocial knowledge and power, for agents to communicate and act on, for governments to make jurisdiction on, and for more structured communities to emerge on. Here, we see the roots of the etymological meaning of "symbol", as the Greek symbolon first designated a "sign of recognition".

Since we showed that this biological shift has socio-political consequences for the ways in which individuals are governed, and the ways in which they govern themselves, we believe that criticisms posed in terms of genetic determinism may fail to recognize a significant change that occurs in the conception of life itself. In tracing out, experimenting with, and contesting the new relations between ethics, power, and economics, "active biological citizens are redefining what it means to be human today." (Rose, 2007, p. 154) This human agency rests on the overcoming of deterministic biological structures, led by an emerging form of power that modern knowledge and researches about postgenomics entail. The active biocitizenship is not only based on the possibility to anticipate known genetic diseases and to gather in biocommunities, but on the framework of biological ownership and self-understandingeven of our genetic risks. The aforementioned changes that are now at stake in our politics are indeed reflecting ontological modifications in the understanding of mankind. Moreover, this evolution is encrusted in the development of hitherto unheard-of technoscientific tools. As an interesting starting-point for metaphysical debates, we can suggest with Nikolas

  Technology as Language -Understanding Action in a Technical Condition Спецвыпуск "Техника как язык: понимание и действие в техническом мировоззрении" 84 soctech.spbstu.ru

This Genomic era (sometimes directly called Postgenomic era) refers to the time period from after the completion of the Human Genome Project (April

2003) to the present day. Molecular Age can also be found: it includes more broadly the rise of the knowledge and practices revolving around genetics, due to the discovery of DNA, and the beginning of biomedicine and of gene editing.

Naturally, the management of social health by the government in charge goes back before the 18 th century; we can think of the political answers that were given in the Middle-Age to the plague (surveillance) and the leprosy (exclusion)[START_REF] Foucault | Folie et déraison. Histoire de la folie à l'âge classique [Madness and unreason[END_REF].

The molecular biologist Sydney Brenner insists that junk is not garbage. Garbage is worthless and thrown away, when junk is something one store for some unspecified future use. Rabinow concurs; "it seems highly unlikely that 90 percent of our DNA is evolutionarily irrelevant, but what its precise relevance could be remains unknown."(Rabinow, 2005, p. 183) Another interesting perspective on our genomic "junk" is to rethink, in this specific matter, the notion of function and utility.[START_REF] Brzovic | Postgenomics Function Monism[END_REF]

Theorized by Deleuze, "unlimited-finite" ("fini-illimité") refers to the third force-form ("formes de forces"); in which something finished gives way to a never-ending play of forces and forms.(Deleuze, 1986, p. 140)

The identification of a genetic disease may be: (1) Precise, where genetic screening is able to identify the variation of DNA on one's genotype. The precise identification of a genetic condition does not necessarily lead to the development of a disease, since several other triggering factors may not be expressed. (2) Probabilistic, depending on the identification of genetic markers associated with increased likelihood of being affected, or on the identification through family histories and heredity.

Nikolas Rose does not share this conviction, but he echoes here major technocritic views[START_REF] Kass | Life, liberty and the defense of dignity: The challenge for bioethics[END_REF][START_REF] Lippman | Prenatal Genetic Testing and Screening: Constructing Needs and Reinforcing Inequities[END_REF].

This mention does not imply that only biocitizens genetically at risk feel concerned by the genetic optimization of life itself, but underline a general trend. Neither does it try to erase important reflections on biopedagogies and rescue missions, that demonstrate that an health imperative to save "bio-others"[START_REF] Rail | Reflections on Biopedagogies and/of Public Health: On Bio-Others, Rescue Missions, and Social Justice[END_REF] can be promoted by private and public institutions and organizations in neoliberal societies.

This specific example was described, observed and reported as part of a multi-sited ethnography in the article What Binds Biosociality?, which allows it to be easily accessible[START_REF] Dimond | What Binds Biosociality? The Collective Effervescence of the Parent Conference[END_REF].

soctech.spbstu.ru Rose that, in this process, "the human becomes not less biological, but all the more biological." (Rose, 2007, p. 20)