DOI: 10.1093/nar/gkaa122

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @bdscstockkeepers

SciCrunch record: RRID:SCR_006457

What is this?

DOI: 10.1158/1078-0432.CCR-24-4141

Resource: WinNonlin (RRID:SCR_024504)

Curator: @scibot

SciCrunch record: RRID:SCR_024504

What is this?

Este punto me resulta muy interesante porque personalmente creo que varias de las herramientas tecnológicas que conozco no están pensadas con base en las necesidades, prácticas y el contexto, o se observan con consideran solo con fines lucrativos pero no con la intención de facilitar el cuidado de las memorias personales y el conocimiento comunitario.

Esta característica también me resulta fundamental al momento de pensar la accesibilidad porque aborda el problema de la compatibilidad entre plataformas y la comunicación que puede haber entre ellas. Esto es importante porque muchas veces el conocimiento puede quedar sujeto a un formato o a un espacio en específico, restringiendo su uso y socialización en otros espacios.

Es pregunta inicial respecto a la nueva sintaxis de Cardumen me parece muy valiosa ya que apunta a la accesibilidad, unos de los aspectos centrales de la clase. Qué tan accesible es un proyecto que desarrollamos también se manifiesta en el lenguaje, así que buscar la manera de hacer más explícito lo que se quiere comunicar, sin reducirlo necesariamente a algo simple, apunta a ese camino.

Comprendo que Cardumen es nuevo y se esta desarrollando, aunque menciona que es mas fácil de usar que el tiddlywiki, pienso que las microwikis tienen un transfondo de lenguaje de programación, de manual de uso, entonces cardumen piensa en lo mas adaptable y esta bien, pero el hecho de hablar en común sobre lenguajes de programación, de sistemas, de tecnología etc, se generan estos lenguajes diferentes a Java que es muy chévere, también genera estos retos en la enseñanza y acompañamiento adecuado para que tenga el alcance que se desea.

El tema de los lenguajes en si es tenso, aprenderlo genera retos como las nuevas formas de escribir, la familiarización con los símbolos y la gramática, bien sea para interpretar de forma correcta o traducir adecuadamente, y estos elementos se encuentran en este proceso, creo que es poco a poco para que el proceso de guardar, organizar y mejorar evolucionando a formas mas claras y fáciles sea realmente efectivo, toma tiempo, porque el proceso de aprender lo técnico, los temas de programación funcionales todo esto presentando ejemplos claros incluyendo esos elementos de comunidades y juegos.

Encuentro interesante como en base a una herramienta se puede generar otra de forma mejorada y que en el transfondo siempre sea solucionar y hacer mas fácil y flexible las necesidades y las formas de uso de los usuarios, ya que estos elementos están implícitos en el acceso de la información.

se ve que Cardumem no nace solo por curiosidad técnica, sino que responde a necesidades reales de las comunidades. Me parece super valioso que lo relacionen con la memoria comunitaria y la revitalización de lenguas, esto hace que el programa también pueda tener un impacto social y humano.

Lo que entiendo es que quieren un lenguaje más fácil y práctico por que así más personas pueden usarlo sin enredarse. Si la forma de escribir la información es clara, también lo será la forma de organizar nuestras ideas. y eso me parece muy interesante.

Me llama la atención como se presenta a Cardumem, es como una especie de continuación de Tiddly Wiki, pero con un enfoque más amplio. Me parece interesante que lo llamen “álgebra de hipertexto”, porque no se trata solo de unir información como en cualquier wiki. Da la sensación de que no es solo un programa, sino también una manera de reflexionar sobre cómo organizamos el conocimiento. Esto nos invita a meditar que no es únicamente una herramienta técnica, sino un espacio para experimentar con nuevas formas de aprender y compartir.

Encuentro muy interesante el tomar a TiddlyWiki como una inspiración por su facilidad de uso y alta customización y transformarla a partir de las necesidades de una comunidad, siempre es bueno tomar una formula que ya funciona y potenciarla, por lo que aprecio que le den crédito a esta plataforma. Ahora bien, se destaca la necesidad de portabilidad entre plataformas como uno de los motivos para crear Cardumem, lo que me parece más que justificado cuando se menciona que la comunidad objetivo trabaja para proteger la memoria y el conocimiento comunitario. Sin opciones para la portabilidad es difícil construir conocimiento colectivo que permita la trazabilidad hacia el contenido original y su creador, por lo que hacer una wiki que, por medio de Lua/YueScript logre solventar este problema, me parece una excelente iniciativa.

Una persona con años y experiencia en puestos de responsabilidad, quizá crea que no necesita consejos de nadie, y se vuelva insensato porque se siente confiado y seguro, pero aprenderá rápido el poder la fama, sin humildad ni sabiduría, es efímera, y en éste caso hasta un joven, que quizás estuvo preso por éste, puede llegar a ocupar su lugar.

He is in Canada because he is motivated to learn english.

L’action de Trump est pourtant clairement orientée vers le contraire du chaos guerrier y compris en Ukraine.

Sa lutte contre le nihilisme woke est en cours et couvre toute l’étendue du désastre mis en place, depuis les transgenres dans l’armée jusqu’à l’immigration illégale massive, en passant par la grande corruption vaccinale.

La grande thèse de Todd est la quasi-annexion d’Israël, ce qui suppose que l’attaque du Hezbollah, de l’Iran, du Qatar furent faites avec son accord préalable, tout comme l’acharnement à Gaza. Cela semble hautement invraisemblable et les choses sont bien plus compliquées que cela, comme on dit.

Et puis, les humiliations et attaques caractérisées de Trump contre les européens ne sont-elles pas plutôt de raisonnables rétorsions contre la folie Européenne, et aussi des vengeances justifiées contre les dirigeants européens tous ligués contre son élection ?

Author response:

The following is the authors’ response to the original reviews

Reviewer #1 (Public review):

Shigella flexneri is a bacterial pathogen that is an important globally significant cause of diarrhea. Shigella pathogenesis remains poorly understood. In their manuscript, Saavedra-Sanchez et al report their discovery that a secreted E3 ligase effector of Shigella, called IpaH1.4, mediates the degradation of a host E3 ligase called RNF213. RNF213 was previously described to mediate ubiquitylation of intracellular bacteria, an initial step in their targeting of xenophagosomes. Thus, Shigella IpaH1.4 appears to be an important factor in permitting evasion of RNF213-mediated host defense.

Strengths:

The work is focused, convincing, well-performed, and important. The manuscript is well-written.

We would like to thank the reviewer for their time evaluating our manuscript and the positive assessment of the novelty and importance of our study. We provide a comprehensive response to each of the reviewer’s specific recommendations below and highlight any changes made to the manuscript in response to those recommendations.

Reviewer #1 (Recommendations for the authors):

(1) In the abstract (and similarly on p.10), the authors claim to have shown "IpaH1.4 protein as a direct inhibitor of mammalian RNF213". However, they do not show the interaction is direct. This, in my opinion, would require demonstrating an interaction between purified recombinant proteins. I presume that the authors are relying on their UBAIT data to support the direct interaction, but this is a fairly artificial scenario that might be prone to indirect substrates. I would therefore prefer that the 'direct' statement be modified (or better supported with additional data). Similarly, on p.7, the section heading states "S. flexneri virulence factors IpaH1.4 and IpaH2.5 are sufficient to induce RNF213 degradation". The corresponding experiment is to show sufficiency in a 293T cell, but this leaves open the participation of additional 293T-expressed factors. So I would remove "are sufficient to", or alternatively add "...in 293T cells".

We agree with the reviewer and made the recommended changes to the text in the abstract, in the results section on page 7, and in the Discussion on page 11. During the revision of our manuscript two additional studies were published that provide convincing biochemical evidence for the direct interaction between IpaH1.4 and RNF213 (PMID: 40205224; PMID: 40164614). These studies address the reviewer’s concern extensively and are now briefly discussed and cited in our revised MS.

(2) In the abstract the authors state "Linear (M1-) and lysine-linked ubiquitin is conjugated to bacteria by RNF213 independent of the linear ubiquitin chain assembly complex (LUBAC)." However, it is not shown that RNF213 is able to directly perform M1-ubiquitylation. It is shown that RNF213 is required for M1-linked ubiquitylation in IpaH1.4 or MxiE mutants, this is different than showing conjugation is done by RNF213 itself. This should be reworded.

We agree and edited the text accordingly

(3) Introduction: one of the main points of the paper is that RNF213 conjugates linear ubiquitin to the surface of bacteria in a manner independent of the previously characterized linear ubiquitin conjugation (LUBAC) complex. This is indeed an interesting result, but the introduction does not put this discovery in much context. I would suggest adding some discussion of what was known, if anything, about the type of Ub chain formed by RNF213, and specifically whether linear Ub had previously been observed or not.

We now provide context in the Introduction on page 3 and briefly discuss previous work that had implicated LUBAC in the ubiquitylation of cytosolic bacteria. We emphasize that LUBAC specifically generates linear (M1-linked) ubiquitin chains, while the types of ubiquitin linkages deposited on bacteria through RNF213-dependent pathways had remained unidentified.

(4) Figure 3C: is the difference in 7KR-Ub between WT and HOIP KO cells significant? If so, the authors may wish to acknowledge the possibility that HOIP partially contributes to M1-Ub of MxiE mutant Shigella

The frequencies at which bacteria are decorated with 7KR-Ub is not statistically different between WT and HOIP KO cells. We have included this information in the panel description of Figure 3.

(5) On page 11, the authors state that "...we observed that LUBAC is dispensable for M1-linked ubiquitylation of cytosolic S. flexneri ∆ipaH1.4. We found that lysine-less internally tagged ubiquitin or an M1-specific antibody bound to S. flexneri ∆ipaH1.4 in cells lacking LUBAC (HOIL-1KO or HOIPKO) but failed to bind bacteria in RNF213-deficient cells". In fact, what is shown is that M1-ubiquitylation in ∆ipaH1.4 infection is RNF213-dependent (5E), but the work with lysine mutants, HOIP or HOIL-1 KOs are all with ∆mxiE, not ∆ipaH1.4 (3B) in this version of the manuscript. Ideally, the data with ∆ipaH1.4 could be added, but alternatively, the conclusion could be re-worded.

We now include the data demonstrating that staining of ∆ipaH1.4 with an M1-specific antibody is unchanged from WT cells in HOIL-1 KO and HOIP KO cells. These data are shown in supplementary data (Fig. S3E) and referred to on page 9 of the revised manuscript.

(6) The UBAIT experiment should be explained in a bit more detail in the text. The approach is not necessarily familiar to all readers, and the rationale for using Salmonella-infected ceca/colons is not well explained (and seems odd). Some appropriate caution about interpreting these data might also be welcome. Did HOIP or HOIL show up in the UBAIT? This perhaps also deserves some discussion.

As expected, HOIP (listed under its official gene name Rnf31 in the table of Fig.S2B) was identified as a candidate IpaH1.4 interaction partner as the third most abundant hit from the UBAIT screen. Remarkably, Rnf213 was the hit with the highest abundance in the IpaH1.4 UBAIT screen. To address the reviewer’s comments, we now explain the UBAIT approach in more detail and provide the rational for using intestinal protein lysates from Salmonella infected mice. The text on page 8 reads as follows: “To investigate potential physical interactions between IpaH1.4 and IpaH2.5, we reanalyzed a previously generated dataset that employed a method known as ubiquitin-activated interaction traps (UBAITs) (32). As shown in Fig. S2A, the human ubiquitin gene was fused to the 3′ end of IpaH2.5, producing a C-terminal IpaH2.5-ubiquitin fusion protein. When incubated with ATP, ubiquitin-activating enzyme E1, and ubiquitin-conjugating enzyme E2, the IpaH2.5-ubiquitin "bait" protein is capable of binding to and ubiquitylating target substrates. This ubiquitylation creates an iso-peptide bond between the IpaH2.5 bait and its substrate, thereby enabling purification via a Strep affinity tag incorporated into the fusion construct (32). IpaH2.5-ubiquitin bait and IpaH3-ubiquitin control proteins were incubated with lysates from murine intestinal tissue. To detect interaction partners in a physiologically relevant setting, we used intestinal lysates derived from mice infected with Salmonella, which in contrast to Shigella causes pronounced inflammation in WT mice and therefore better simulates human Shigellosis in an animal model. Using UBAIT we identified HOIP (Rnf31) as a likely IpaH2.5 binding partner (Fig. S2B), thus confirming previous observations (28) and validating the effectiveness our approach. Strikingly, we identified mouse Rnf213 as the most abundant interaction partner of the IpaH2.5-ubiquitin bait protein (Fig. S2B). Collectively, our data and concurrent reports showing direct interactions between IpaH1.4 and human RNF213 (36, 37) indicate that the virulence factors IpaH1.4 and IpaH2.5 directly bind and degrade mouse as well as human RNF213.”

(7) It would be helpful if the authors discussed their results in the context of the prior work showing IpaH1.4/2.5 mediate the degradation of HOIP. Do the authors see HOIP degradation? If indeed HOIP and RNF213 are both degraded by IpaH1.4 and IpaH2.5, are there conserved domains between RNF213 and HOIP being targeted? Or is only one the direct target? A HOIP-RNF213 interaction has previously been shown (https://doi.org/10.1038/s41467-024-47289-2). Since they interact, is it possible one is degraded indirectly? To help clarify this, a simple experiment would be to test if RNF213 degraded in HOIP KO cells (or vice-versa)?

We appreciate the reviewer’s suggestions. We conducted the proposed experiments and found that WT S. flexneri infections result in RNF213 degradation in both WT and HOIP KO cells. Similarly, we found that HOIP degradation was independent of RNF213. We have included these data in Figs. 5A and S3B of our revised submission. A study published during revisions of our paper demonstrates that the LRR of IpaH1.4 binds to the RING domains of both RNF213 and LUBAC (PMID: 40205224). We refer to this work in our revised manuscript.

Reviewer #2 (Public review):

Summary:

The authors find that the bacterial pathogen Shigella flexneri uses the T3SS effector IpaH1.4 to induce degradation of the IFNg-induced protein RNF213. They show that in the absence of IpaH1.4, cytosolic Shigella is bound by RNF213. Furthermore, RNF213 conjugates linear and lysine-linked ubiquitin to Shigella independently of LUBAC. Intriguingly, they find that Shigella lacking ipaH1.4 or mxiE, which regulates the expression of some T3SS effectors, are not killed even when ubiquitylated by RNF213 and that these mutants are still able to replicate within the cytosol, suggesting that Shigella encodes additional effectors to escape from host defenses mediated by RNF213-driven ubiquitylation.

Strengths:

The authors take a variety of approaches, including host and bacterial genetics, gain-of-function and loss-of-function assays, cell biology, and biochemistry. Overall, the experiments are elegantly designed, rigorous, and convincing.

Weaknesses:

The authors find that ipaH1.4 mutant S. flexneri no longer degrades RNF213 and recruits RNF213 to the bacterial surface. The authors should perform genetic complementation of this mutant with WT ipaH1.4 and the catalytically inactive ipaH1.4 to confirm that ipaH1.4 catalytic activity is indeed responsible for the observed phenotype.

We would like to thank the reviewer for their time evaluating our manuscript and the positive assessment of our work, especially its scientific rigor. We conducted the experiment suggested by the reviewer and included the new data in the revised manuscript. As expected, complementation of the ∆ipaH1.4 with WT IpaH1.4 but not with the catalytically dead C338S mutant restored the ability of Shigella to efficiently escape from recognition by RNF213 (Figs. 5C-D).

Reviewer #2 (Recommendations for the authors):

The authors should perform genetic complementation of the ipaH1.4 mutant with WT ipaH1.4 and the catalytically inactive ipaH1.4 to confirm that ipaH1.4 catalytic activity is indeed responsible for the observed phenotype.

We performed the suggested experiment and show in Figs. 5C-D that complementation of the ∆ipaH1.4 mutant with WT IpaH1.4 but not with the catalytically dead C338S mutant restored the ability of Shigella to efficiently escape from recognition by RNF213. These data demonstrate that the catalytic activity of IpaH1.4 is required for evasion of RNF213 binding to the bacteria.

Reviewer #3 (Public review):

Summary:

In this study, the authors set out to investigate whether and how Shigella avoids cell-autonomous immunity initiated through M1-linked ubiquitin and the immune sensor and E3 ligase RNF213. The key findings are that the Shigella flexneri T3SS effector, IpaH1.4 induces degradation of RNF213. Without IpaH1.4, the bacteria are marked with RNF213 and ubiquitin following stimulation with IFNg. Interestingly, this is not sufficient to initiate the destruction of the bacteria, leading the authors to conclude that Shigella deploys additional virulence factors to avoid this host immune response. The second key finding of this paper is the suggestion that M1 chains decorate the mxiE/ipaH Shigella mutant independent of LUBAC, which is, by and large, considered the only enzyme capable of generating M1-linked ubiquitin chains.

Strengths:

The data is for the most part well controlled and clearly presented with appropriate methodology. The authors convincingly demonstrate that IpaH1.4 is the effector responsible for the degradation of RNF213 via the proteasome, although the site of modification is not identified.

Weaknesses:

(1)The work builds on prior work from the same laboratory that suggests that M1 ubiquitin chains can be formed independently of LUBAC (in the prior publication this related to Chlamydia inclusions). In this study, two pieces of evidence support this statement -fluorescence microscopy-based images and accompanying quantification in Hoip and Hoil knockout cells for association of M1-ub, using an antibody, to Shigella mutants and the use of an internally tagged Ub-K7R mutant, which is unable to be incorporated into ubiquitin chains via its lysine residues. Given that clones of the M1-specific antibody are not always specific for M1 chains, and because it remains formally possible that the Int-K7R Ub can be added to the end of the chain as a chain terminator or as mono-ub, the authors should strengthen these findings relating to the claim that another E3 ligase can generate M1 chains de novo.

(2) The main weakness relating to the infection work is that no bacterial protein loading control is assayed in the western blots of infected cells, leaving the reader unable to determine if changes in RNF213 protein levels are the result of the absent bacterial protein (e.g. IpaH1.4) or altered infection levels.

(3)The importance of IFNgamma priming for RNF213 association to the mxiE or ipaH1.4 strain could have been investigated further as it is unclear if RNF213 coating is enhanced due to increased protein expression of RNF213 or another factor. This is of interest as IFNgamma priming does not seem to be needed for RNF213 to detect and coat cytosolic Salmonella.<br /> Overall, the findings are important for the host-pathogen field, cell-autonomous/innate immune signaling fields, and microbial pathogenesis fields. If further evidence for LUBAC independent M1 ubiquitylation is achieved this would represent a significant finding.

We would like to thank the reviewer for their time evaluating our manuscript and the positive assessment of our work and its significance. We provide a comprehensive response to the main three critiques listed under ‘weaknesses’ and also have responded to each of the reviewer’s specific recommendations below. We highlight any changes made to the manuscript in response to those recommendations.

(1) As the reviewer correctly pointed out, 7KR ubiquitin cannot only be used for linear ubiquitylation but can also function as a donor ubiquitin and can be attached as mono-ubiquitin to a substrate or to an existing ubiquitin chain as a chain terminator. To distinguish between 7KR INT-Ub signals originating from linear versus mono-ubiquitylation, we followed the reviewer’s advice and generated a N-terminally tagged 7KR INT-Ub variant. The N-terminal tag prevents linear ubiquitylation but still allows 7KR INT-Ub to be attached as a mono-ubiquitin. We found that the addition of this N-terminal tag significantly reduced but not completely abolished the number of Δ_mxiE_ bacteria decorated with 7KR INT-Ub. These data are shown in a new Fig. S1 and indicate that 7KR lacking the N-terminal tag is attached to bacteria both in the form of linear (M1-linked) ubiquitin and as donor ubiquitin, possibly as a chain terminator. While we cannot rule out that the anti-M1 antibodies used here cross-react with other ubiquitin linkages, we reason that the 7KR data strongly argues that linear ubiquitin is part of the ubiquitin coat encasing IpaH1.4-deficient cytosolic Shigella. Collectively, our data show that both linear and lysine-linked (especially K27 and K63) ubiquitin chains are part of the RNF213-dependent ubiquitin coat on the surface of IpaH1.4 mutants. And furthermore, our data strongly indicate that this ubiquitylation of IpaH1.4 mutants is independent of LUBAC.

(2) We used GFP-expressing strains of S. flexneri for our infection studies and were therefore able to use GFP expression as a loading control. We have incorporated these data into our revised figures. These new data (Figs. 4A, 5A, and S3B) show that bacterial infection levels were comparable between WT and mutant infections and that therefore the degradation of RNF213 (or HOIP – see new data in Fig. S3B) is not due to differences in infection efficiency.

(3) We agree with the reviewer that the mechanism by which RNF213 binds to bacteria is an important unanswered question. Similarly, whether other ISGs have auxiliary functions in this process or whether binding efficiencies vary between different bacterial species are important questions in the field. However, these questions go far beyond the scope of this study and were therefore not addressed in our revisions.

Reviewer #3 (Recommendations for the authors):

(1) An N-terminally tagged K7R-ub should be used as a control to test whether the signal found around the mutant shigella is being added via the N terminal Met into chains. As it is known that certain batches of the M1-specific antibodies are in fact not specific and able to detect other chain types, the authors should test the specificity of the antibody used in this study (eg against different di-Ub linkage types) and include this data in the manuscript.

We agree with the reviewer in principle. The anti-linear ubiquitin (anti-M1) monoclonal antibody, clone 1E3, prominently used in this study was tested by the manufacturer (Sigma) by Western blotting analysis and according to the manufacturer “this antibody detected ubiquitin in linear Ub, but not Ub K11, Ub K48, Ub K63.” However, this analysis did not include all possible Ub linkage types and thus the reviewer is correct that the anti-M1 antibody could theoretically also detect some other linkage types. To address this concern, we added new data during revisions demonstrating that 7KR INT-Ub targeting to S. flexneri is largely dependent on the N-terminus (M1) of ubiquitin. Our combined observations therefore overwhelmingly support the conclusion that linear (M1-linked) as well as K-linked ubiquitin is being attached to the surface of IpH1.4 S. flexneri bacteria in an RNF213-dependent and LUBAC-independent manner.

(2) The M1 signal detected on bacteria with the antibody is still present in either Hoip or Hoil KO’s but due to the potential non-specificity of the antibody, the authors should test whether K7R ub is detected on bacteria in the Hoil ko (in addition to Hoip KO). This would strengthen the authors’ data on LUBAC-independent M1 and is important because Hoil can catalyse non-canonical ubiquitylation.

The specific linear ubiquitin-ligating activity of LUBAC is enacted by HOIP. We show that linear ubiquitylation of susceptible S. flexneri mutants as assessed by anti-M1 ubiquitin staining or 7KR INT-Ub recruitment occurs in HOIPKO cells at WT levels (Figs. 3B, 3C, S3E [new data]). In our view , these data unequivocally show that the observed linear ubiquitylation of cytosolic S. flexneri ipaH1.4 and mxiE mutants is independent of LUBAC.

(3) For Figure 4A, do mxiE bacteria show similar invasion - authors should include a bacterial protein control to show levels of bacteria in WT and mxiE infected conditions. A similar control should be included in Figure 5A.

We used GFP-expressing strains of S. flexneri for our infection studies and were therefore able to use GFP expression as a loading control. We have incorporated these data into our revised figures. These new data (Figs. 4A, 5A, and S3B) show that bacterial infection levels were comparable between WT and mutant infections and that therefore the degradation of RNF213 (or HOIP – see new data in Fig. S3B) is not due to differences in infection efficiency.

(4) Can the authors speculate why IFNg priming is needed for the coating of Shigella mxiE mutant but not in the case of Salmonella or Burkholderia? Is this just amounts of RNF213 or something else?

In our studies we did not directly compare ubiquitylation rates of cytosolic Shigella, Burkholderia, and Salmonella bacteria with each other under the same experimental conditions. However, such a direct comparison is needed to determine whether IFNgamma priming is required for RNF213-dependent bacterial ubiquitylation of some but not other pathogens. Two papers published during the revisions of our manuscript (PMID: 40164614, PMID: 40205224) reports robust RNF213 targeting to IpaH1.4 Shigella mutants in unprimed cells HeLa cells (whereas we used A549 and HT29 cells). Therefore, differences in reagents, cell lines, and/or other experimental conditions may determine whether IFNgamma priming is necessary to observe substantial RNF213 translocation to cytosolic bacteria.

(5) Typos - there are several, but this is hard to annotate with line numbers so the authors should proofread again carefully.

We proofread the manuscript and corrected the small number of typos we identified

Oui tout à fait

Depuis quelques mois il y a une possibilité de connecter le LLM Claude à QGIS (je n'ai pas la méthode précise, mais trouvable sur Youtube et vue sur LinkedIn). Est-ce qu'il n'y a pas moyen de tester grâce à l'IA un réalignement des systèmes de coordonnées ? Au-delà, une intervention à DistamLab par un usager de l'IA dans les SIG pourrait être intéressante.

Dans une perspective de gestion raisonnée (qui tient compte des enjeux écologiques), la réflexion peut porter sur la sélection des rasters à mettre en ligne. Existe-t-il des formats autres que le TIFF qui soit aussi performant et moins volumineux ?

Reviewer #1 (Public review):

Li et al. investigate Ca2+ signaling in T. gondii and argue that Ca2+ tunnels through the ER to other organelles to fuel multiple aspects of T. gondii biology. They focus in particular on TgSERCA as the presumed primary mechanism for ER Ca2+ filling. Although, when TgSERCA was knocked out there was still a Ca2+ release in response to TG present. Overall the data supports a model where the Ca2+ filling state of the ER modulates Ca2+ dynamics in other organelles.

Comments on revisions:

I thank the authors for their careful revisions and response to my comments, which have been addressed.

Regarding the most critical point of the paper that is Ca2+ transfer from the ER to other organelles, the authors in their rebuttal and in the revised manuscript argue that ER Ca2+ is critical to redistribute and replenish Ca2+ in other organelles in the cell. I agree this conclusion and think it is best stated in the authors' response to point #7: "We propose that this leaked calcium is subsequently taken up by other intracellular compartments. This effect is observed immediately upon TG addition. However, pre-incubation with TG or knockdown of SERCA reduces calcium storage in the ER, thereby diminishing the transfer of calcium to other stores."

In their rebuttal the authors particularly highlight experiments in Figures 1H-K, 4G-H, and 5H-K in support of this conclusion. The data in Fig 1H-K show that with TG there is increased Ca2+ release from acidic stores. In all cases TG results in a rise in cytoplasmic Ca2+ that could load the acidic stores. So under those conditions the increased acidic organelle Ca2+ is likely due to a preceding high cytosolic Ca2+ transient due to TG. The experiments in 4G-H and 5H-K are more convincing and supportive of an important role of ER Ca2+ to maintain Ca2+ levels in other organelles. Overall, and to avoid a detailed, lengthy discussion of every point, the data support a model where in the absence of SERCA activity ER Ca2+ is reduced as well as Ca2+ in other organelles. I think it would be helpful to present and discuss this finding throughout the manuscript as under physiological conditions ER Ca2+ is regularly mobilized for signaling and homeostasis and this maintains Ca2+ levels in other organelles. This is supported by the new experiment in Supp Fig. 2A.

Author response:

Reviewer #1 (Public review):

In this important study, the authors develop a suite of machine vision tools to identify and align fluorescent neuronal recording images in space and time according to neuron identity and position. The authors provide compelling evidence for the speed and utility of these tools. While such tools have been developed in the past (including by the authors), the key advancement here is the speed and broad utility of these new tools. While prior approaches based on steepest descent worked, they required hundreds of hours of computational time, while the new approaches outlined here are >600-fold faster. The machine vision tools here should be immediately useful to readers specifically interested in whole-brain C. elegans data, but also for more general readers who may be interested in using BrainAlignNet for tracking fluorescent neuronal recordings from other systems.

I really enjoyed reading this paper. The authors had several ground truth examples to quantify the accuracy of their algorithms and identified several small caveats users should consider when using these tools. These tools were primarily developed for C. elegans, an animal with stereotyped development, but whose neurons can be variably located due to internal motion of the body. The authors provide several examples of how BrainAlignNet reliably tracked these neurons over space and time. Neuron identity is also important to track, and the authors showed how AutoCellLoader can reliably identify neurons based on their fluorescence in the NeuroPAL background. A challenge with NeuroPAL though, is the high expression of several fluorophores, which compromises behavioral fidelity. The authors provide some possible avenues where this problem can be addressed by expressing fewer fluorophores. While using all four channels provided the best performance, only using the tagRFP and CyOFP channels was sufficient for performance that was close to full performance using all 4 NeuroPAL channels. This result indicates that the development of future lines with less fluorophore expression could be sufficient for reliable neuronal identification, which would decrease the genetic load on the animal, but also open other fluorescent channels that could be used for tracking other fluorescent tools/markers. Even though these tools were developed for C. elegans specifically, they showed BrainAlignNet can be applied to other organisms as well (in their case, the cnidarian C. hemisphaerica), which broadens the utility of their tools.

Strengths:

(1) The authors have a wealth of ground-truth training data to compare their algorithms against, and provide a variety of metrics to assess how well their new tools perform against hand annotation and/or prior algorithms.

(2) For BrainAlignNet, the authors show how this tool can be applied to other organisms besides C. elegans.

(3) The tools are publicly available on GitHub, which includes useful README files and installation guidance.

We thank the reviewer for noting these strengths of our study.

Weaknesses:

(1) Most of the utility of these algorithms is for C. elegans specifically. Testing their algorithms (specifically BrainAlignNet) on more challenging problems, such as whole-brain zebrafish, would have been interesting. This is a very, very minor weakness, though.

We appreciate the reviewer’s point that expanding to additional animal models would be valuable. In the study, we have so far tested our approaches on C. elegans and Jellyfish. Given that this is considered a ‘very, very minor weakness’ and that it does not directly affect the results or analyses in the paper, we think this might be better to address in future work.

(2) The tools are benchmarked against their own prior pipeline, but not against other algorithms written for the same purpose.

We agree that it would be valuable to benchmark other labs’ software pipelines on our datasets. We note that most papers in this area, which describe those pipelines, provide the same performance metrics that we do (accuracy of neuron identification, tracking accuracy, etc), so a crude, first-order comparison can be obtained by comparing the numbers in the papers. But, we agree that a rigorous head-to-head comparison would require applying these different pipelines to a common dataset. We considered performing these analyses, but we were concerned that using other labs’ software ‘off the shelf’ on our data might not represent those pipelines in their best light when compared to our pipeline that was developed with our data in mind. Data from different microscopy platforms can be surprisingly different and we wouldn’t want to perform an analysis that had this bias. Therefore, we feel that this comparison would be best pursued by all of these labs collaboratively (so that they can each provide input on how to run their software optimally). Indeed, this is an important area for future study. In this spirit, we have been sharing our eat-4::GFP datasets (that permit quantification of tracking accuracy) with other labs looking for additional ways to benchmark their tracking software.

We also note that there are not really any pipelines to directly compare against CellDiscoveryNet, as we are not aware of any other fully unsupervised approach for neuron identification in C. elegans.

(3) Considerable pre-processing was done before implementation. Expanding upon this would improve accessibility of these tools to a wider audience.

Indeed, some pre-processing was performed on images before registration and neuron identification -- understanding these nuances can be important. The pre-processing steps are described in the Results section and detailed in the Methods. They are also all available in our open-source software. For BrainAlignNet, the key steps were: (1) selecting image registration problems, (2) cropping, and (3) Euler alignment. Steps (1) and (3) were critically important and are extensively discussed in the Results and Discussion sections of our study (lines 142-144, 218-234, 318-323, 704-712). Step (2) is standard in image processing. For AutoCellLabeler and CellDiscoveryNet, the pre-processing was primarily to align the 4 NeuroPAL color channels to each other (i.e. make sure the blue/red/orange/etc channels for an animal are perfectly aligned). This is also just a standard image processing step to ensure channel alignment. Thus, the more “custom” pre-processing steps were extensively discussed in the study and the more “common” steps are still described in the Methods. The implementation of all steps is available in our open-source software.

Reviewer #2 (Public review):

Summary:

The paper introduced the pipeline to analyze brain imaging of freely moving animals: registering deforming tissues and maintaining consistent cell identities over time. The pipeline consists of three neural networks that are built upon existing models: BrainAlignNet for non-rigid registration, AutoCellLabeler for supervised annotation of over 100 neuronal types, and CellDiscoveryNet for unsupervised discovery of cell identities. The ambition of the work is to enable high-throughput and largely automated pipelines for neuron tracking and labeling in deforming nervous systems.

Strengths:

(1) The paper tackles a timely and difficult problem, offering an end-to-end system rather than isolated modules.

(2) The authors report high performance within their dataset, including single-pixel registration accuracy, nearly complete neuron linking over time, and annotation accuracy that exceeds individual human labelers.

(3) Demonstrations across two organisms suggest the methods could be transferable, and the integration of supervised and unsupervised modules is of practical utility.

We thank the reviewer for noting these strengths of our study.

Weaknesses:

(1) Lack of solid evaluation. Despite strong results on their own data, the work is not benchmarked against existing methods on community datasets, making it hard to evaluate relative performance or generality.

We agree that it would be valuable to benchmark many labs’ software pipelines on some common datasets, ideally from several different research labs. We note that most papers in this area, which describe the other pipelines that have been developed, provide the same performance metrics that we do (accuracy of neuron identification, tracking accuracy, etc), so a crude, first-order comparison can be obtained by comparing the numbers in the papers. But, we agree that a rigorous head-to-head comparison would require applying these different pipelines to a common dataset. We considered performing these analyses, but we were concerned that using other labs’ software ‘off the shelf’ and comparing the results to our pipeline (where we have extensive expertise) might bias the performance metrics in favor of our software. Therefore, we feel that this comparison would be best pursued by all of these labs collaboratively (so that they can each provide input on how to run their software optimally). Indeed, this is an important area for future study. In this spirit, we have been sharing our eat-4::GFP datasets (that permit quantification of tracking accuracy) with other labs looking for additional ways to benchmark their tracking software.

We also note that there are not really any pipelines to directly compare against CellDiscoveryNet, as we are not aware of any other fully unsupervised approach for neuron identification in C. elegans.

(2) Lack of novelty. All three models do not incorporate state-of-the-art advances from the respective fields. BrainAlignNet does not learn from the latest optical flow literature, relying instead on relatively conventional architectures. AutoCellLabeler does not utilize the advanced medNeXt3D architectures for supervised semantic segmentation. CellDiscoveryNet is presented as unsupervised discovery but relies on standard clustering approaches, with limited evaluation on only a small test set.

We appreciate that the machine learning field moves fast. Our goal was not to invent entirely novel machine learning tools, but rather to apply and optimize tools for a set of challenging, unsolved biological problems. We began with the somewhat simpler architectures described in our study and were largely satisfied with their performance. It is conceivable that newer approaches would perhaps lead to even greater accuracy, flexibility, and/or speed. But, oftentimes, simple or classical solutions can adequately resolve specific challenges in biological image processing.

Regarding CellDiscoveryNet, our claim of unsupervised training is precise: CellDiscoveryNet is trained end-to-end only on raw images, with no human annotations, pseudo-labels, external classifiers, or metadata used for training, model selection, or early stopping. The loss is defined entirely from the input data (no label signal). By standard usage in machine learning, this constitutes unsupervised (often termed “self-supervised”) representation learning. Downstream clustering is likewise unsupervised, consuming only image pairs registered by CellDiscoveryNet and neuron segmentations produced by our previously-trained SegmentationNet (which provides no label information).

(3) Lack of robustness. BrainAlignNet requires dataset-specific training and pre-alignment strategies, limiting its plug-and-play use. AutoCellLabeler depends heavily on raw intensity patterns of neurons, making it brittle to pose changes. By contrast, current state-of-the-art methods incorporate spatial deformation atlases or relative spatial relationships, which provide robustness across poses and imaging conditions. More broadly, the ANTSUN 2.0 system depends on numerous manually tuned weights and thresholds, which reduces reproducibility and generalizability beyond curated conditions.

Regarding BrainAlignNet: we agree that we trained on each species’ own data (worm, jellyfish) and we would suggest other labs working on new organisms to do the same based on our current state of knowledge. It would be fantastic if there was an alignment approach that generalized to all possible cases of non-rigid-registration in all animals – an important area for future study. We also agree that pre-alignment was critical in worms and jellyfish, which we discuss extensively in our study (lines 142-144, 318-321, 704-712).

Regarding AutoCellLabeler: the animals were not recorded in any standardized pose and were not aligned to each other beforehand – they were basically in a haphazard mix of poses and we used image augmentation to allow the network to generalize to other poses, as described in our study. It is still possible that AutoCellLabeler is somehow brittle to pose changes (e.g. perhaps extremely curved worms) – while we did not detect this in our analyses, we did not systematically evaluate performance across all possible poses. However, we do note that this network was able to label images taken from freely-moving worms, which by definition exhibit many poses (Figure 5D, lines 500-525); aggregating the network’s performance across freely-moving data points allowed it to nearly match its performance on high-SNR immobilized data. This suggests a degree of robustness of the AutoCellLabeler network to pose changes.

Regarding ANTSUN 2.0: we agree that there are some hyperparameters (described in our study) that affect ANTSUN performance. We agree that it would be worthwhile to fully automate setting these in future iterations of the software.

Evaluation:

To make the evaluation more solid, it would be great for the authors to (1) apply the new method on existing datasets and (2) apply baseline methods on their own datasets. Otherwise, without comparison, it is unclear if the proposed method is better or not. The following papers have public challenging tracking data: https://elifesciences.org/articles/66410, https://elifesciences.org/articles/59187, https://www.nature.com/articles/s41592-023-02096-3.

Please see our response to your point (1) under Weaknesses above.

Methodology:

(1) The model innovations appear incrementally novel relative to existing work. The authors should articulate what is fundamentally different (architectural choices, training objectives, inductive biases) and why those differences matter empirically. Ablations isolating each design choice would help.

There are other efforts in the literature to solve the neuron tracking and neuron identification problems in C. elegans (please see paragraphs 4 and 5 of our Introduction, which are devoted to describing these). However, they are quite different in the approaches that they use, compared to our study. For example, for neuron tracking they use t->t+1 methods, or model neurons as point clouds, etc (a variety of approaches have been tried). For neuron identification, they work on extracted features from images, or use statistical approaches rather than deep neural networks, etc (a variety of approaches have been tried). Our assessment is that each of these diverse approaches has strengths and drawbacks; we agree that a meta-analysis of the design choices used across studies could be valuable.

We also note that there are not really any pipelines to directly compare against CellDiscoveryNet, as we are not aware of any other fully unsupervised approach for neuron identification in C. elegans.

(2) The pipeline currently depends on numerous manually set hyperparameters and dataset-specific preprocessing. Please provide principled guidelines (e.g., ranges, default settings, heuristics) and a robustness analysis (sweeps, sensitivity curves) to show how performance varies with these choices across datasets; wherever possible, learn weights from data or replace fixed thresholds with data-driven criteria.

We agree that there are some ANTSUN 2.0 hyperparameters (described in our Methods section) that could affect the quality of neuron tracking. It would be worthwhile to fully automate setting these in future iterations of the software, ensuring that the hyperparameter settings are robust to variation in data/experiments.

Appraisal:

The authors partially achieve their aims. Within the scope of their dataset, the pipeline demonstrates impressive performance and clear practical value. However, the absence of comparisons with state-of-the-art algorithms such as ZephIR, fDNC, or WormID, combined with small-scale evaluation (e.g., ten test volumes), makes the strength of evidence incomplete. The results support the conclusion that the approach is useful for their lab's workflow, but they do not establish broader robustness or superiority over existing methods.

We wish to remind the reviewer that we developed BrainAlignNet for use in worms and jellyfish. These two animals have different distributions of neurons and radically different anatomy and movement patterns. Data from the two organisms was collected in different labs (Flavell lab, Weissbourd lab) on different types of microscopes (spinning disk, epifluorescence). We believe that this is a good initial demonstration that the approach has robustness across different settings.

Regarding comparisons to other labs’ C. elegans data processing pipelines, we agree that it will be extremely valuable to compare performance on common datasets, ideally collected in multiple different research labs. But we believe this should be performed collaboratively so that all software can be utilized in their best light with input from each lab, as described above. We agree that such a comparison would be very valuable.

Impact:

Even though the authors have released code, the pipeline requires heavy pre- and post-processing with numerous manually tuned hyperparameters, which limits its practical applicability to new datasets. Indeed, even within the paper, BrainAlignNet had to be adapted with additional preprocessing to handle the jellyfish data. The broader impact of the work will depend on systematic benchmarking against community datasets and comparison with established methods. As such, readers should view the results as a promising proof of concept rather than a definitive standard for imaging in deformable nervous systems.

Regarding worms vs jellyfish pre-processing: we actually had the exact opposite reaction to that of the reviewer. We were surprised at how similar the pre-processing was for these two very different organisms. In both cases, it was essential to (1) select appropriate registration problems to be solved; and (2) perform initialization with Euler alignment. Provided that these two challenges were solved, BrainAlignNet mostly took care of the rest. This suggests a clear path for researchers who wish to use this approach in another animal. Nevertheless, we also agree with the reviewer’s caution that a totally different use case could require some re-thinking or re-strategizing. For example, the strategy of how to select good registration problems could depend on the form of the animal’s movement.

Reviewer #3 (Public review):

Context:

Tracking cell trajectories in deformable organs, such as the head neurons of freely moving C. elegans, is a challenging task due to rapid, non-rigid cellular motion. Similarly, identifying neuron types in the worm brain is difficult because of high inter-individual variability in cell positions.

Summary:

In this study, the authors developed a deep learning-based approach for cell tracking and identification in deformable neuronal images. Several different CNN models were trained to: (1) register image pairs without severe deformation, and then track cells across continuous image sequences using multiple registration results combined with clustering strategies; (2) predict neuron IDs from multicolor-labeled images; and (3) perform clustering across multiple multicolor images to automatically generate neuron IDs.

Strengths:

Directly using raw images for registration and identification simplifies the analysis pipeline, but it is also a challenging task since CNN architectures often struggle to capture spatial relationships between distant cells. Surprisingly, the authors report very high accuracy across all tasks. For example, the tracking of head neurons in freely moving worms reportedly reached 99.6% accuracy, neuron identification achieved 98%, and automatic classification achieved 93% compared to human annotations.

We thank the reviewer for noting these strengths of our study.

Weaknesses:

(1) The deep networks proposed in this study for registration and neuron identification require dataset-specific training, due to variations in imaging conditions across different laboratories. This, in turn, demands a large amount of manually or semi-manually annotated training data, including cell centroid correspondences and cell identity labels, which reduces the overall practicality and scalability of the method.

We performed dataset-specific training for image registration and neuron identification, and we would encourage new users to do the same based on our current state of knowledge. This highlights how standardization of whole-brain imaging data across labs is an important issue for our field to address and that, without it, variations in imaging conditions could impact software utility. We refer the reviewer to an excellent study by Sprague et al. (2025) on this topic, which is cited in our study.

However, at the same time, we wish to note that it was actually reasonably straightforward to take the BrainAlignNet approach that we initially developed in C. elegans and apply it to jellyfish. Some of the key lessons that we learned in C. elegans generalized: in both cases, it was critical to select the right registration problems to solve and to preprocess with Euler registration for good initialization. Provided that those problems were solved, BrainAlignNet could be applied to obtain high-quality registration and trace extraction. Thus, our study provides clear suggestions on how to use these tools across multiple contexts.

(2) The cell tracking accuracy was not rigorously validated, but rather estimated using a biased and coarse approach. Specifically, the accuracy was assessed based on the stability of GFP signals in the eat-4-labeled channel. A tracking error was assumed to occur when the GFP signal switched between eat-4-negative and eat-4-positive at a given time point. However, this estimation is imprecise and only captures a small subset of all potential errors. Although the authors introduced a correction factor to approximate the true error rate, the validity of this correction relies on the assumption that eat-4 neurons are uniformly distributed across the brain - a condition that is unlikely to hold.

We respectfully disagree with this critique. We considered the alternative suggested by the reviewer (in their private comments to the authors) of comparing against a manually annotated dataset. But this annotation would require manually linking ~150 neurons across ~1600 timepoints, which would require humans to manually link neurons across timepoints >200,000 times for a single dataset. These datasets consist of densely packed neurons rapidly deforming over time in all 3 dimensions. Moreover, a single error in linking would propagate across timepoints, so the error tolerance of such annotation would be extremely low. Any such manually labeled dataset would be fraught with errors and should not be trusted. Instead, our approach relies on a simple, accurate assumption: GFP expression in a neuron should be roughly constant over a 16min recording (after bleach correction) and the levels will be different in different neurons when it is sparsely expressed. Because all image alignment is done in the red channel, the pipeline never “peeks” at the GFP until it is finished with neuron alignment and tracking. The eat-4 promoter was chosen for GFP expression because (a) the nuclei labeled by it are scattered across the neuropil in a roughly salt-and-pepper fashion – a mixture of eat-4-positive and eat-4-negative neurons are found throughout the head; and (b) it is in roughly 40% of the neurons, giving very good overall coverage. Our view is that this approach of labeling subsets of neurons with GFP should become the standard in the field for assessing tracking accuracy – it has a simple, accurate premise; is not susceptible to human labeling error; is straightforward to implement; and, since it does not require manual labeling, is easy to scale to multiple datasets. We do note that it could be further strengthened by using multiple strains each with different ‘salt-and-pepper’ GFP expression patterns.

(3) Figure S1F demonstrates that the registration network, BrainAlignNet, alone is insufficient to accurately align arbitrary pairs of C. elegans head images. The high tracking accuracy reported is largely due to the use of a carefully designed registration sequence, matching only images with similar postures, and an effective clustering algorithm. Although the authors address this point in the Discussion section, the abstract may give the misleading impression that the network itself is solely responsible for the observed accuracy.

Our tracking accuracy requires (a) a careful selection of registration problems, (b) highly accurate registration of the selected registration problems, and (c) effective clustering. We extensively discussed the importance of the choosing of the registration problems in the Results section (lines 218-234 and 318-321), Discussion section (lines 704-708), and Methods section (955-970 and 1246-1250) of our paper. We also discussed the clustering aspect in the Results section (lines 247-259), Discussion section (lines 708-712), and Methods section (lines 1162-1206). In addition, our abstract states that the BrainAlignNet needs to be “incorporated into an image analysis pipeline,” to inform readers that other aspects of image analysis need to occur (beyond BrainAlignNet) to perform tracking.

(4) The reported accuracy for neuron identification and automatic classification may be misleading, as it was assessed only on a subset of neurons labeled as "high-confidence" by human annotators. Although the authors did not disclose the exact proportion, various descriptions (such as Figure 4f) imply that this subset comprises approximately 60% of all neurons. While excluding uncertain labels is justifiable, the authors highlight the high accuracy achieved on this subset without clearly clarifying that the reported performance pertains only to neurons that are relatively easy to identify. Furthermore, they do not report what fraction of the total neuron population can be accurately identified using their methods-an omission of critical importance for prospective users.

The reviewer raises two points here: (1) whether AutoCellLabeler accuracy is impacted by ease of human labeling; and (2) what fraction of total neurons are identified. We address them one at a time.

Regarding (1), we believe that the reviewer overlooked an important analysis in our study. Indeed, to assess its performance, one can only compare AutoCellLabeler’s output against accurate human labels – there is simply no way around it. However, we noted that AutoCellLabeler was identifying some neurons with high confidence even when humans had low confidence or had not even tried to label the neurons (Fig. 4F). To test whether these were in fact accurate labels, we asked additional human labelers to spend extra time trying to label a random subset of these neurons (they were of course blinded to the AutoCellLabeler label). We then assessed the accuracy of AutoCellLabeler against these new human labels and found that they were highly accurate (Fig. 4H). This suggests that AutoCellLabeler has strong performance even when some human labelers find it challenging to label a neuron. However, we agree that we have not yet been able to quantify AutoCellLabeler performance on the small set of neuron classes that humans are unable to identify across datasets.

Regarding (2), we agree that knowing how many neurons are labeled by AutoCellLabeler is critical. For example, labeling only 3 neurons per animal with 100% accuracy isn’t very helpful. We wish to emphasize that we did not omit this information: we reported the number of neurons labeled for every network that we characterized in the study, alongside the accuracy of those labels (please see Figures 4I, 5A, and 6G; Figure 4I also shows the number of human labels per dataset, which the reviewer requested). We also showed curves depicting the tradeoff between accuracy and number of neurons labeled, which fully captures how we balanced accuracy and number of neurons labeled (Figures 5D and S4A). It sounds like the reviewer also wanted to know the total number of recorded neurons. The typical number of recorded neurons per dataset can also be found in the paper in Fig. 2E.

The same as my previous comment. During lecture you highlighted that in the table below the formula should be divided by 144 so we get our ba or Basal area in square feet.

*

lol

key element

le citazioni nelle note vanno fra virgolette basse o alte?

fu vista da Pirro

sostituire con "la divinità"

"in cui ci sembra possibile affermare si ricompongano figure selezionate da un modello compositivo di Raffaello"

forse sposterei il riferimento dopo la data, e prima della virgola appena successiva

Tema 142/TST: - A multa prevista no art. 477, § 8º, da CLT incide sobre todas as parcelas de natureza salarial, não se limitando ao salário-base.

• Informativo 1180
• ADI 4065 / DF
• Órgão julgador: Tribunal Pleno
• Relator(a): Min. NUNES MARQUES
• Julgamento: 30/05/2025 (Virtual)
• Ramo do Direito: Tributário, Financeiro
• Matéria: Benefícios Fiscais; Incentivos Fiscais; Renúncia de Receitas; Contribuições Previdenciárias / Repartição de Competências; Direito Tributário e Financeiro; Princípios Fundamentais; Tributação e Orçamento

Concessão de vantagens fiscais no último ano da legislatura no âmbito distrital

Resumo - É inconstitucional — por invadir a competência legislativa da União para dispor sobre normas gerais e por violar a separação dos Poderes e a autonomia do DF — dispositivo da Lei Orgânica do Distrito Federal (LODF) que proíbe a concessão, no último ano de cada legislatura, de isenções, anistias, remissões, benefícios e incentivos fiscais, envolvendo matéria tributária e previdenciária.

• No âmbito constitucional, destacam-se as seguintes diretrizes para a renúncia de receitas: (i) exigência de lei complementar nacional para regular as limitações constitucionais ao poder de tributar (CF/1988, art. 146, III) e para dispor sobre finanças públicas (CF/1988, art. 163, I); e (ii) competência legislativa concorrente sobre direito tributário e financeiro (CF/1988, art. 24, I), cabendo ao ente nacional a edição de normas gerais e aos demais a competência suplementar (CF/1988, art. 24, §§ 1º e 2º). Na espécie, a norma distrital tratou sobre as normas gerais validamente editadas pela União mesmo sem existir qualquer hipótese autorizativa do exercício da competência legislativa plena ou suplementar.

• Ainda que a pretexto de concretizar o princípio da moralidade ou de preservar a regularidade das eleições, a imposição de restrições à legítima competência tributária, em extrapolação aos parâmetros constitucionais, configura medida desarrazoada, pois situações concretas de desvirtuamento podem e devem ser corrigidas casuisticamente.

• No tocante às questões previdenciárias, também se observa violação à independência do governador. Os entes subnacionais podem dispor apenas sobre o sistema de previdência de seus servidores e a iniciativa de lei é reservada ao chefe do Poder Executivo (CF/1988, art. 61, § 1º, II, a e c).

• Ademais, a inconstitucionalidade persiste na redação posterior do dispositivo em análise, pois a mudança no texto visou apenas permitir, no último exercício da legislatura, a concessão de benefícios fiscais relativos ao ICMS quando deliberados de determinada forma.

• Com base nesses e em outros entendimentos, o Plenário, por unanimidade, conheceu parcialmente da ação e, nessa extensão, a julgou procedente para declarar a inconstitucionalidade do inciso II do art. 131 da LODF/1993, tanto em sua redação original quanto na redação que foi conferida pela Emenda à Lei Orgânica nº 38/2002 (1).

(1) LODF/1993: “Art. 131. As isenções, anistias, remissões, benefícios e incentivos fiscais que envolvam matéria tributária e previdenciária, inclusive as que sejam objeto de convênios celebrados entre o Distrito Federal e a União, Estados e Municípios, observarão o seguinte: (...) II - não serão concedidos no último exercício de cada legislatura, salvo no caso de calamidade pública, nos termos da lei; II – não serão concedidos no último exercício de cada legislatura, salvo os benefícios fiscais relativos ao imposto sobre operações relativas à circulação de mercadorias e sobre prestações de serviços de transporte interestadual e intermunicipal e de comunicação, deliberados na forma do inciso VII do § 5º do art. 135, e no caso de calamidade pública, nos termos da lei. (Inciso alterado(a) pelo(a) EMENDA À LEI ORGÂNICA nº 38, de 2002)”

Legislação: CF/1988: art. 24, I; art. 24, § 1º e § 2º; art. 61, § 1º, II, a e c; art. 146, III; e art. 163, I. LODF/1993: art. 131, II. Emenda à Lei Orgânica nº 38/2002.

Il est demandé de "réduire la fenêtre" mais personnellement, je n'ai pas compris. Du coup, j'ai coupé la balise img avec la propriété display et l'ai collée en dehors du "@media" et ça a fonctionné.

Reviewer #1 (Public review):

Summary:

This very thorough anatomical study addresses the innervation of the Drosophila male reproductive tract. Two distinct glutamatergic neuron types were classified: serotonergic (SGNs) and octopaminergic (OGNs). By expansion microscopy, it was established that glutamate and serotonin /octopamine are co-released. The expression of different receptors for 5-HT and OA in muscles and epithelial cells of the innervation target organs was characterized. The pattern of neurotransmitter receptor expression in the target organs suggests that seminal fluid and sperm transport and emission are subjected to complex regulation. While silencing of abdominal SGNs leads to male infertility and prevents sperm from entering the ejaculatory duct, silencing of OGNs does not render males infertile.

Strengths:

The studied neurons were analysed with different transgenes and methods, as well as antibodies against neurotransmitter synthesis enzymes, building a consistent picture of their neurotransmitter identity. The careful anatomical description of innervation patterns together with receptor expression patterns of the target organs provides a solid basis for advancing the understanding of how seminal fluid and sperm transport and emission are subjected to complex regulation. The functional data showing that SGNs are required for male fertility and for the release of sperm from the seminal vesicle into the ejaculatory duct is convincing.

Weaknesses:

The functional analysis of the characterized neurons is not as comprehensive as the anatomical description, and phenotypic characterization was limited to simple fertility assays. It is understandable that a full functional dissection is beyond the scope of the present work. The paper contains experiments showing neuron-independent peristaltic waves in the reproductive tract muscles, which are thematically not very well integrated into the paper. Although very interesting, one wonders if these experiments would not fit better into a future work that also explores these peristaltic waves and their interrelation with neuromodulation mechanistically.

DOI: 10.1101/2025.07.22.665497

Resource: RRID:MMRRC_065285-JAX

Curator: @AleksanderDrozdz

SciCrunch record: RRID:MMRRC_065285-JAX

What is this?

DOI: 10.1038/s41467-019-13174-6

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @bdscstockkeepers

SciCrunch record: RRID:SCR_006457

What is this?

DOI: 10.1210/endocr/bqaf142

Resource: (Vector Laboratories Cat# BA-1000, RRID:AB_2313606)

Curator: @scibot

SciCrunch record: RRID:AB_2313606

What is this?

DOI: 10.1038/s41590-025-02270-z

Resource: Fred Hutchinson Cancer Center Flow Cytometry Core Facility (RRID:SCR_022613)

Curator: @scibot

SciCrunch record: RRID:SCR_022613

What is this?

DOI: 10.1016/j.isci.2025.113553

Resource: (BD Biosciences Cat# 560601, RRID:AB_1727562)

Curator: @scibot

SciCrunch record: RRID:AB_1727562

What is this?

Reviewer #2 (Public review):

Summary:<br /> This article reports a cost-effectiveness comparison of intramural and extramural that NIH funded between 2009 and 2019. Using data obtained from NIH RePORTER, they linked total project costs to publication output, using robust validated metrics including Relative Citation Ratio (RCR), Approximate Potential to Translate (APT), and clinical citations. They find that after adjusting for confounders in regression and propensity-score analyses, extramural projects were generally more cost-effective, though intramural projects were more cost effective for generating clinical citations. They also describe differences in the topics of intramural- and extramural-funded publications, with intramural projects more likely to generate papers on viral infections and immunity or cancer metastases and survival, but less likely to generate papers on pregnancy and maternal health, brain connectivity and tasks, and adolescent experiences and depression. The authors aptly describe the different natures of the intramural and extramural funding models, including that extramural researchers spend much time writing grant applications and that the work described in extramural publications often receives funding from sources other than NIH grants.

Strengths:<br /> The authors leveraged publicly available data (including RePORTER and the iCite repository) and used robust validated metrics (RCR, APT, clinical citations). They carefully considered a large number of confounders, including those related to the PI, and performed several well-described regression analyses.

Weaknesses:<br /> Figure 3A shows intramural projects producing about 2.75 papers per year in 2009, whereas extramural projects are producing just over 1 paper per year. Extramural projects appear to catch up over the next five years. While the authors attempt to explain the difference in their figure legend, another explanation is that the intramural projects started well before 2009 but, as the authors state, intramural data only became available in 2009.

As the authors note, funding information is often complex and difficult to characterize for an analysis like this. How did the authors handle: i) publications linked to multiple extramural grants; ii) publications linked to intramural and extramural grants; iii) publications linked NIH grants and non-NIH grants?<br /> I would think it necessary to somehow apportion credit, as otherwise it would appear that extramural projects are more productive than they truly are.

Also, it is not clear if the authors took account of the indirect costs paid by the NIH to universities that have received extramural grants.

Saya sangat setuju dengan pernyataan tersebut. Karena kebugaran tubuh sangat berdampak pada pola pikir seseorang. Jika tubuh kita tidak bugar, maka energi negatif lh yang akan terpancar dari diri seseorang. Misalnya jangan begadang berlebihan ya, nanti kebugaran tubuhnya terganggu.

Bukankah Juventus itu klub yang berasal dari Italia?

ya, benar sekali bahwa bugar itu bukan hanya sehat, tetapi juga harus sehat dan juga bersemangat.

I would probably want the second listing because it seems a little more spacious and it looks like it is closer to Paris.

Em relação à solidariedade, não confundir as situações: - Para fins de indisponibilidade de bens = possível a solidariedade, limitado ao valor total do dano e sem necessidade de estabelecimento de quota-parte. - Atuação conjunta de agentes = possível a solidariedade na reparação do dano, uma vez verificada unidade de vontades na consumação do dano - Atuação individualizada = vedada a solidariedade, devendo cada agente responder pelo dano causado

• Processo<br /> REsp 1.955.116-AM, Rel. Ministro Herman Benjamin, Primeira Seção, por unanimidade, julgado em 22/5/2024. (Tema 1213).

REsp 1.955.957-MG, Rel. Ministro Herman Benjamin, Primeira Seção, por unanimidade, julgado em 22/5/2024 (Tema 1213).

REsp 1.955.300-DF, Rel. Ministro Herman Benjamin, Primeira Seção, por unanimidade, julgado em 22/5/2024 (Tema 1213).

REsp 1.955.440-DF, Rel. Ministro Herman Benjamin, Primeira Seção, por unanimidade, julgado em 22/5/2024 (Tema 1213).

Ramo do Direito DIREITO ADMINISTRATIVO, DIREITO PROCESSUAL CIVIL

TemaPaz, Justiça e Instituições Eficazes <br /> Improbidade administrativa. Indisponibilidade de bens. Solidariedade entre os corréus. Art. 16, § 5º, da lei 8.429/1992 (com redação dada pelo Lei 4.230/2021). Ausência de divisão pro rata. Tema 1213.

DESTAQUE - Para fins de <u>indisponibilidade de bens</u>, há solidariedade entre os corréus da Ação de Improbidade Administrativa, de modo que a constrição deve recair sobre os bens de todos eles, sem divisão em quota-parte, limitando-se o somatório da medida ao quantum determinado pelo juiz, sendo defeso que o bloqueio corresponda ao débito total em relação a cada um.

INFORMAÇÕES DO INTEIRO TEOR - Cinge-se a controvérsia em saber se, para fins de indisponibilidade de bens (art. 16 da Lei n. 8.429/1992, na redação pela Lei n. 14.230/2021), a responsabilidade de agentes ímprobos é solidária e permite a constrição patrimonial em sua totalidade, sem necessidade de divisão pro rata, ao menos até a instrução final da Ação de Improbidade, quando ocorrerá a delimitação da quota de cada agente pelo ressarcimento.

• Sobre a matéria, as Primeira e Segunda Turmas do STJ possuem entendimento pacífico de "haver solidariedade entre os corréus da ação [de improbidade administrativa] até a instrução final do processo, sendo assim, o valor a ser indisponibilizado para assegurar o ressarcimento ao erário deve ser garantido por qualquer um deles, limitando-se a medida constritiva ao quantum determinado pelo juiz, sendo defeso que o bloqueio corresponda ao débito total em relação a cada um." (AgInt no REsp n. 1.827.103/RJ,Rel. Ministro Og Fernandes, Segunda Turma, DJe 29.5.2020.). Nesse mesmo sentido: REsp n. 1.919.700/BA, Rel. Ministra; Assusete Magalhães, Segunda Turma, DJe 16.11.2021; AgInt no REsp n. 1.899.388/MG, Rel. Ministra Regina Helena Costa, Primeira Turma, DJe 10.3.2021; AREsp n. 1.393.562/RJ, Rel. Ministro Francisco Falcão, Segunda Turma, DJe 7.10.2019; AgInt no REsp n. 1.910.713/DF, Rel. Ministro Benedito Gonçalves, Primeira Turma, DJe de 16.6.2021; AgInt no REsp n. 1.687.567/PR, Rel. Ministro Mauro Campbell Marques, Segunda Turma, DJe 2.3.2018; e REsp n. 1.610.169/BA, Rel. Ministro Herman Benjamin, Segunda Turma, DJe 12.5.2017.

• O art. 16, § 5º, da Lei n. 8.429/1992, com redação dada pela Lei n. 14.230/2021, assim dispõe ao regulamentar a matéria: "Art. 16. Na ação por improbidade administrativa poderá ser formulado, em caráter antecedente ou incidente, pedido de indisponibilidade de bens dos réus, a fim de garantir a integral recomposição do erário ou do acréscimo patrimonial resultante de enriquecimento ilícito. (...) § 5º Se houver mais de um réu na ação, a somatória dos valores declarados indisponíveis não poderá superar o montante indicado na petição inicial como dano ao erário ou como enriquecimento ilícito".

• Observa-se que a lei não prescreve que a limitação da indisponibilidade deva ocorrer de forma individual para cada réu, mas, sim, de forma coletiva, considerando o somatório dos valores. Esse ponto é fundamental para se constatar que a Lei de Improbidade Administrativa, com as alterações da Lei n. 14.320/2021, autorizou a constrição em valores desiguais entre os réus, desde que o somatório não ultrapasse o montante indicado na petição inicial como dano ao Erário ou como enriquecimento ilícito, na mesma linha do que já vinha entendendo esta Corte Superior. A propósito: "(...) III. O acórdão recorrido está em conformidade com a jurisprudência do Superior Tribunal de Justiça, que possui precedentes no sentido de que, 'havendo solidariedade entre os corréus da ação até a instrução final do processo, o valor a ser indisponibilizado para assegurar o ressarcimento ao erário deve ser garantido por qualquer um deles, limitando-se a medida constritiva ao quantum determinado pelo juiz, sendo defeso que o bloqueio corresponda ao débito total em relação a cada um' (STJ, AgInt no REsp 1.899.388/MG, Rel. Ministra REGINA HELENA COSTA, PRIMEIRA TURMA, DJe de 10/03/2021)." (REsp n. 1.919.700/BA, Rel. Ministra Assusete Magalhães, Segunda Turma, DJe de 16.11.2021).

• Nesse sentido, efetivado o bloqueio de bens que garantam o quantum indicado na inicial ou outro estabelecido pelo juiz, devem ser liberados os valores bloqueados que sobejarem tal quantum. A restrição legal diz respeito apenas a que o somatório não ultrapasse o montante indicado na petição inicial ou outro valor definido pelo juiz.

• Não há, portanto, no § 5º do art. 16 da Lei n. 8.429/1992 determinação para que a indisponibilidade de bens ocorra de forma equitativa entre os réus e na proporção igual (e limitada) de cada quota-parte, sendo adequado se manter, mesmo no regime da Lei n. 14.230/2021, a jurisprudência consolidada no STJ no sentido da solidariedade.

• O citado artigo, ora em discussão, cuida do provimento cautelar de indisponibilidade de bens, cujo escopo é garantir a integral recomposição do erário ou do acréscimo patrimonial resultante de enriquecimento ilícito. Tratando-se de decisão interlocutória proferida no âmbito da cognição sumária, razoável que se reconheça a possibilidade de, provisoriamente, haver responsabilização solidária, ao menos até o pronunciamento final, porque, neste estágio do processo, ainda não é possível, ordinariamente, determinar a responsabilidade de cada um dos litisconsorte pelo dano, sendo razoável que se mantenha a garantia, indiscriminadamente, sobre os bens de quaisquer dos acusados, limitado ao total reclamado.

• Dessa forma, considerando a nova redação do § 5º do art. 16 da Lei 8.429/1992, afirma-se a seguinte tese jurídica: "para fins de indisponibilidade de bens, há solidariedade entre os corréus da Ação de Improbidade Administrativa, de modo que a constrição deve recair sobre os bens de todos eles, sem divisão em quota-parte, limitando-se o somatório da medida ao quantum determinado pelo juiz, sendo defeso que o bloqueio corresponda ao débito total em relação a cada um."

List all folders/files created/modified over the last two month by the owner/curator of the Peergos Name: hyperpost

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Annotate this listing for providing publicly shared information related to non public documents/folders

add secret links with passwords and expiry dates to provide controlled access to information or anchoring threaded conversations

Yes Indywiki is the Way

the alternative that completes it to o bbecome what it always dreamed to be but failed to become

create/curate information pertaining to all development by indy.player/actor 🎭/gyuri/ within the Web Hosted directory for the Peergos account: ♖/hyperpost

search for recently annotated documents by this faceted search url by Jon Udell

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Gyuri Lajos, [01/10/2025 20:48] first create/curate and CONNECT information snippets in focal cone of attention in the context of a named page being a; then turn them into Clueons and use HyperPost to Post them on the WEB in yOur Own(ed), named, networked hyperPost Spaces, which in turn are turned into publically available web pages that yOur or any one can annotate and ...rinse and repeat

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Now ready to close the loop. and share these snippets in annotations in appropriate contexts

It applies to the war.

questa è incredibile. La differenza fra un'azione concreta e solo un'idea (o concetto) è fondamentale.

A tide that overflowed every possible bank, with a strong youth presence.

les liens ne fonctionnent pas

mentionner la commune

c'est pas un escape game, c'est des ateliers de 30 minutes sur les adaptations de la faune et de la flore à leur environnement

pas la bonne date -> 18/10

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Reply to the reviewers

1. General Statements

We thank the reviewers for providing thoughtful and constructive feedback, which will help us improve the clarity and rigor of the paper. On balance, the reviews were positive. Reviewer 1 mentioned that “This is a strong manuscript with few problems and all important findings well justified, indeed this is a nicely polished…..high-quality manuscript,” and that “this paper makes a major breakthrough, showing that cell autonomous defects in hTSCs are very likely at the heart of the pathology observed in GIN-prone murine mutants.” Reviewer 3 stated that “The study is well designed, and the manuscript is very well written. The conclusions are supported by the evidence presented.” Reviewer 2 was less enthusiastic, with main concerns being that “The paper is mostly descriptive and often quite confusing leaving one not much closer to understanding the mechanistic basis for the interesting sex-biased semi-lethal phenotype.” and felt that figure titles/section headers overstated the results, and finally recommended to improve some technical aspects and tempering conclusions. The proposed edits we think address most issues raised by the reviewers either with re-writing or adding data as described below.

In response to reviewer #1 comments:

Major comments:

• I am confused as to the basis of the sex-skewing phenomenon? Is the problem that lack of maternally loaded WT Mcm4 worsens the phenotype, or is the issue that Mcm4C3/C3 dams are less able to retain pregnancies, perhaps being a more inflammatory environment? Also, while there quite consistent evidence for reduced viability of Mcm4C3/C3McmGt/+ progeny, especially for female progeny, how confident can we be that the genotype of the dam vs. sire is important? Notably on a Ddx58 background, the progeny of the Mcm4C3/C3 sire included seven live male Mcm4C3/C3McmGt/+ but no female.

Regarding the first point (sex skewing only when female is C3/C3), we also suspected either: 1) the maternal uterine environment, or 2) reduced oocyte quality. Although not reported in this manuscript, we tested #1 by performing embryo transfer experiments. Transferring 2-cell stage embryos from sex-skewing mating to WT females did not rescue the sex-bias. We then examined oocytes from C3/C3 females. We found evidence for compromised mitochondria and transcriptome disruption. However, we are not sure why this happens (poor follicle support? Oocyte intrinsic phenomenon?). We are reserving these results and additional experiments for another paper, especially since this one mainly deals with GIN and placenta development. If the reviewers feel strongly that the embryo transfer data is crucial, we can include it.

Regarding how confident we are that the genotype of the dam vs. sire is important, this stems from our previous paper by McNairn et al 2019 (the percentage of female C3/C3 M2/+ from sex-skewing mating is 20% compared to 60% from the reciprocal mating), which was quite dramatic. Consistent with this, MCM levels were significantly reduced in the placentae only when the dam was C3/C3 and the sire C3/+ M2/+, but not in the reciprocal cross. The reviewer makes a good observation about the Ddx58 cross; we can only hypothesize that the mutation somehow sensitizes females in this scenario and will make mention of it in the revision. We also realize that we neglected to write in Methods that the Ddx58 allele was coisogenic in the C3H background.

• I'm not sure what Supplementary Figure 6 is showing (faster differentiation of C3 but less TGC?). Regardless, it's hard to draw too much conclusion from one not-very-pretty Western blot. This figure requires both additional replicates and a better explanation of how it fits with the other conclusions of the paper..

We hypothesized that the JZ defect observed in the semi-lethal genotype placentas could arise either from impaired maintenance of the progenitor pool or from reduced capacity of mutant trophoblast progenitors to differentiate into the JZ lineage. The blot in Supplementary Figure 6 was intended as a qualitative demonstration that mutant trophoblast stem cells can differentiate into JZ lineages. We recognize that the figure is not definitive and will revise the text to clarify its purpose. A replicate(s) of the Western will be performed as suggested.

• Supplementary Figure 7F-G is puzzling. Half of the mESCs have gamma-H2AX at all times, including most in S or G2 phase? In Figure S7E, do the quadrants correspond to being negative or positive for gamma-H2AX? At very least, IF images showing clear gamma-H2AX foci would be much more convincing.

The gates for γH2AX FACS analysis were established using negative controls lacking primary antibody. As reported previously, embryonic stem cells display high basal levels of γH2AX staining (Chuykin et al., Cell Cycle 2008; Turinetto et al., Stem Cells 2012; Ahuja et al., Nat Comm 2016), which likely explains the broad signal observed across cell cycle phases. Regardless, we will provide immunofluorescence staining of γH2Ax and foci count in our revision.

• The methods section is well detailed, but it would be ideal to clarify how many replicates each Western Blot or flow cytometry experiment is representative of.

Thanks for the suggestion. We will update this for Fig4 and Fig5.

Minor comments:

• Is it possible that cGAS-STING and RIG pathways act redundantly to cause inflammation and lethality, or that other innate immune components are involved? I don't expect the authors to make compound mutants to test this but at least this possibility should be discussed textually.

We appreciate the reviewer’s point, and had the same suspicion. Supporting this, we will add new RNA-seq analysis of Tmem173 KO placentas revealed elevated inflammatory gene expression compared to C3/C3 M2/+ controls, consistent with potential redundancy or feedback regulation. We will update in supplementary figures to reflect this.

In response to reviewer #2 comments:

Major comments:

A major concern throughout the paper is that conclusions are often overstating their data. The title of figure 2 is "placentae with replication stress have smaller junctional and labyrinth zones". However, there is no measure of replication stress in this figure, just a histological evaluation of the placentae from the different mutants. The title of figure 3 is "Impact of GIN on LZ is less than JZ," but there is no measure of GIN, but instead measurement of number of cells in cell cycle and some bulk RNA-seq analysis. Title of figure 4 is "TSCs with increased genomic instability exhibit abnormal phenotypes." Again there is no measure of GIN, but instead staining of derived TSCs for proliferation, cell death, and a TSC marker. Title of figure 5 is "DNA damage responses and G2/M checkpoint activation drive premature TSC differentiation." However, there does not appear to be a difference in gH2AX between the two mutant genotypes. Checkpoint proteins might be up, but need quantification and reproduction. > 4C is the only marker of differentiation. Importantly, all the analyses here are associations, not connections, so cannot use the word "drive". Similar issues can be raised with a number of the supplementary figures.

The Chaos3 (chromosome aberrations occurring spontaneously 3) model is a well-established system of intrinsic chronic replication stress and GIN. It is characterized by ~20 fold elevation of blood micronuclei (Shima et al., Nature 2007), a hallmark of GIN (Soxena et al., Mol Cell 2022); a destabilized MCM2-7 helicase prone to replication fork collapse (Bai et al., PLoS Genet 2016); and increased mitotic chromosome abnormalities and decreased dormant origins (Kawabata et al., Mol Cell 2011; Chuang et al., Nucleic Acid Res 2012) that are known to cause GIN and replication stress (Ibarra et al., PNAS 2008 ). Also, in our previous work (McNairn et al Nature 2019), we showed that placentae from C3/C3 dams exhibit significantly elevated γH2Ax as well as reduced MCM2 and MCM4 protein levels. In our current study, we also observe elevated γH2Ax in mutant TSCs (C3/C3 and C3/C3 M2/+), consistent with genomic instability. Nevertheless, we acknowledge that in TSCs, we did not formally demonstrate replications stress(RS), so where appropriate, we will advise figure titles, for example to say that “cells/placentae with a GIN or RS genotype.”

We acknowledge the reviewers concern regarding western blots. We will provide quantification and statistics in our revision.

1) A deeper analysis of the cell lines is likely to be the most fruitful path to reveal interesting mechanisms. It is very surprising that there is no phenotype in ESCs. Authors should check for increased apoptosis. Maybe the phenotypic cells are lost. Or do ESCs use different MCMs/mechanisms of DNA replication or are they better able to handle replication stress and GIN? How many passages were the TSCs and ESCs cultured for? Does GIN (i.e. aneuploidy, CNVs) develop in TSCs and ESCs with passaging? How do the MCM mutations impact the molecular identity of the ESC and TSC cells including their heterogeneity in the population.

We assessed apoptosis using cleaved caspase 3 flow cytometry in mutant ESCs and observed no difference compared to controls (we will add this data as Supplementary Fig. 7).

We believe there are intrinsic differences in TSCs and ESCs in their ability to respond to and counteract replication stress and DNA damage. ESCs are known to license more replication origins than somatic cells at a higher rate, which protects them from short G1-induced replication stress (Ahuja et al., Nat Comm 2016; Ge et al., Stem Cell Rep 2015; Matson et al., eLife 2017). Human placental cells physiologically exhibit high levels of mutation rate and chromosomal instability in vivo (Coorens et al., Nature 2021). Supporting this, Wang, D., et al (Nat Comm 2025) reported that several cell cycle and DDR regulators are differentially expressed in human TSCs vs human pluripotent stem cells. Whether such transcriptional differences directly contribute to functional outcomes remains to be determined.

All experiments in this study were conducted using early-passage ESCs and TSCs (i.e. Finally, we showed that close to 90% mutant ESCs are KLF4+ (a naive pluripotency marker) whereas EOMES+ cells were significantly reduced in TSCs carrying the GIN genotype (Fig. 4E–F and Supplementary Fig. 7), highlighting lineage-specific differences.

Minor Comments:

1) There is a lack of quantification and repeats for all Westerns. At minimum there should be three repeats for each experiment, quantification including normalization to a reference protein, and stats confirming any proposed differences between conditions.

We will update our revision with quantification and statistics for western blots.

2) I would recommend moving the results in supp table 1 to figure 1. While negative, they are the newer results. The results shown in current figure 1 are essentially a reproduction of their previous work.

The placental observations presented in Fig.1 are new. In particular, the placental and embryonic weight measurements graphed in Fig1B and C have not been published by our group. Fig1A reproduces our previous observation on embryo viability in GIN mutants (McNairn et al., Nature 2019), while the schematic was provided for better flow and readability given the complex mating schemes. We are agnostic on the Suppl Table 1. It could be changed to a new Table 1 in the main section depending on the journal.

In response to reviewer #3 comments:

Major Comments

While the inclusion of bulk RNAseq data of whole placental tissue is appreciated, the interpretation of the results is somewhat problematic, as it is acknowledged that the cell type composition of the placentas is drastically different between groups. Making conclusions based upon GSEA analysis of two different groups with drastically different cell type composition is somewhat misleading, as based on the results, it is a direct reflection of the cell types present. It would be more helpful to perform cell type deconvolution of the RNAseq data to estimate the proportion of each cell type within the bulk samples and compare that to what is seen histologically and not dive too deeply into the pathways since the results could just be a reflection of the cell types e.g. angiogenesis pathways from more endothelial cells. Additionally, the RNAseq data can be leveraged to look at expression of inflammatory genes by sex, which may show interesting patterns based on the other results.

We agree that the representation of cell types in the placenta is problematic especially for underrepresented genes. We propose to use the BayesPrism tool (Chu et al., Nat Cancer 2022) to deconvolute bulk RNA-seq for better representation of transcriptional changes in the placenta.

Section: GIN impairs trophoblast stem cell establishment and maintenance. To support the assertion in the first paragraph, beyond measuring apoptosis, it would be helpful at this stage to look at RNA expression levels indicative of the activation of DNA damage checkpoint genes

We have performed RNA-seq on mutant ESC and TSCs and are in the process of data analysis. We will update these results in the revision.

Please include additional methodological details in the methods section on the statistical analysis done for differential expression analysis. Specifically, what type of normalization was used, if lowly expressed genes were filtered out and at what cutoff, what statistical model was used (did you include covariates?), what comparisons were made? Did you stratify by sex? What cutoff was used for statistical significance? Did you perform multiple testing correction?

We will update RNA-Seq data analysis methods in our full revision.

2. Description of the revisions that have already been incorporated in the transferred manuscript

Reviewer #1 comments:

• Supplementary Table 1. would be enhanced greatly showing comparable tables for Mcm4C3/C3 x Mcm4C3/+McmGt/+ in mice without the Tmem173 or Ddx58 mutations. It is fine to recycle data from McNairn 2019 here, as long as the source is indicated, but a comparison is needed.

Thanks for pointing this out. We have updated this suggestion in Supp table 1.

• In Figure S3E-F, is the box above each graph supposed to show the genotype of the dam?

Yes. Thanks for pointing this out. We have added a description in the figure legend to make it clear.

• "Indeed, the placenta and embryo weights of E13.5 Mcm4C3/C3 Mcm2Gt/+ Mcm3Gt/+ animals were significantly improved vs. Mcm4C3/C3 Mcm2Gt/+ animals, rendering them similar to Mcm4C3/C3 littermates (Fig. 6A-C). The JZ (but not LZ) area in Mcm4C3/C3 Mcm2Gt/+ Mcm3Gt/+ placentae also increased to the level of Mcm4C3/C3 littermates (Fig. 6D-H)." There are two problems here. First, the figure calls are wrong. Second, the description of the data is not quite right, it looks like the C3/C3 and C3/C3 M2/+ M3/+ LZs are a similar size to each and are statistically indistinguishable.

Thanks for catching this. We have updated these in the main text.

*Reviewer #2 comments: *

Minor comment

• Need to review citations to figures. For example, no citations are made to figure 4a and 4c.

Thanks for catching this. We have updated the text.

Reviewer #3 comments:

Define the first use of >4C DNA content to help readers understand this potentially unfamiliar term.

We have edited this part to indicate cells with more than 4C DNA content for better clarity.

iDEP tool - please include citation to manuscript instead of link

We have updated this citation.

Check citations. Some citations to BioRxiv that are now published e.g. 13.

We have updated this citation.

3. Description of analyses that authors prefer not to carry out

Reviewer 2

2) Along similar lines, most of the in vivo phenotypic analyses are performed at E13.5, long after defects are likely beginning to express themselves especially given that they see phenotypes in the TSCs, which represent the polar TE of a E4.5. To understand the primary defects of the in vivo phenotype, they should be looking much earlier. Supplemental figure 5 is a start but represents a rather superficial analysis.

The peri-implantation period, namely E4.5, represents a “black box” of embryonic development given that this is a critical stage for implantation. Aside from being an extremely difficult stage to analyze technically, we don’t think it is essential to the conclusions (or doable in a timely manner), especially given the use of TSCs. If we complete EdU studies on E6.5 embryos, we will include them.

3) Fig. 6 would benefit from evidence that MCM3 mutant is rescuing MCM4 levels in the chromatin fraction of cells and the DNA damage phenotype.

The genetic evidence presented is strong, and although we didn’t do the suggested experiment, we feel that our previous studies (McNairn et al., Nature 2019 and Chuang et al., PLoS Genet 2010) on the effects of MCM3 as a nuclear export factor (as it is in yeast (Liku et al., Mol Biol Cell 2005)) are a reasonable basis for not repeating such experiments. Furthermore, we are no longer maintaining the Mcm3 line and it would take over a year to reconstitute and rebreed triple mutants.

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Referee #2

Evidence, reproducibility and clarity

The manuscript, "Chronic replication stress-mediated genomic instability disrupts placenta development in mice" by Munisha et al follows up a 2019 paper in Nature by the same group where they show that mutations to the MCM genes lead to a sex-skewed semi-lethal phenotype starting after embryonic day 9.5 and extending to birth. In the paper, they hypothesized that the semi-lethality is secondary to genomic instability (GIN) driven inflammation due to activation of the innate immune pathways sensing cytoplasmic DNA. In this paper, they start by disproving that hypothesis and then go on to present data arguing lethality is due to a placental development defect rather than inflammation. The paper is mostly descriptive and often quite confusing leaving one not much closer to understanding the mechanistic basis for the interesting sex-biased semi-lethal phenotype that was described in their original paper. The most interesting aspect of the paper is the derivation of TSC and ESCs and initial analysis suggesting that the TSCs are more sensitive to the MCM mutations, but the analysis is rather shallow. Importantly it is unclear how the phenotype explains the sex-skewing of the phenotype. Are the TSC phenotypes sex-skewed and if so why? Also, why is the JZ and especially GlyTCs most effected?

A major concern throughout the paper is that conclusions are often overstating their data. The title of figure 2 is "placentae with replication stress have smaller junctional and labyrinth zones". However, there is no measure of replication stress in this figure, just a histological evaluation of the placentae from the different mutants. The title of figure 3 is "Impact of GIN on LZ is less than JZ," but there is no measure of GIN, but instead measurement of number of cells in cell cycle and some bulk RNA-seq analysis. Title of figure 4 is "TSCs with increased genomic instability exhibit abnormal phenotypes." Again there is no measure of GIN, but instead staining of derived TSCs for proliferation, cell death, and a TSC marker. Title of figure 5 is "DNA damage responses and G2/M checkpoint activation drive premature TSC differentiation." However, there does not appear to be a difference in gH2AX between the two mutant genotypes. Checkpoint proteins might be up, but need quantification and reproduction. > 4C is the only marker of differentiation. Importantly, all the analyses here are associations, not connections, so cannot use the word "drive". Similar issues can be raised with a number of the supplementary figures.

Major Comments:

1) A deeper analysis of the cell lines is likely to be the most fruitful path to reveal interesting mechanisms. It is very surprising that there is no phenotype in ESCs. Authors should check for increased apoptosis. Maybe the phenotypic cells are lost. Or do ESCs use different MCMs/mechanisms of DNA replication or are they better able to handle replication stress and GIN? How many passages were the TSCs and ESCs cultured for? Does GIN (i.e. aneuploidy, CNVs) develop in TSCs and ESCs with passaging? How do the MCM mutations impact the molecular identity of the ESC and TSC cells including their heterogeneity in the population.

2) Along similar lines, most of the in vivo phenotypic analyses are performed at E13.5, long after defects are likely beginning to express themselves especially given that they see phenotypes in the TSCs, which represent the polar TE of a E4.5. To understand the primary defects of the in vivo phenotype, they should be looking much earlier. Supplemental figure 5 is a start but represents a rather superficial analysis.

3) Fig. 6 would benefit from evidence that MCM3 mutant is rescuing MCM4 levels in the chromatin fraction of cells and the DNA damage phenotype.

Minor Comments:

1) There is a lack of quantification and repeats for all Westerns. At minimum there should be three repeats for each experiment, quantification including normalization to a reference protein, and stats confirming any proposed differences between conditions.

2) I would recommend moving the results in supp table 1 to figure 1. While negative, they are the newer results. The results shown in current figure 1 are essentially a reproduction of their previous work.

3) Need to review citations to figures. For example, no citations are made to figure 4a and 4c.

Significance

As is, the study does not provide much new insight or understanding of how the MCM mutants are driving the sex-skewed semi-lethal phenotype. It would likely take much effort (months) to reach such a goal. However, without such effort, it is unclear what the significance of the story is. It does make the observation that the placenta appears to be impacted more severely and earlier than then the embryo, and that within the placenta, certain zones and cell types are more vulnerable. The reasons for these differential impacts are unclear though.

If the authors choose not to dig deeper as suggested in the major comments, then at a minimum it would be important to soften their conclusions as raised in the summary and at least perform experiments/edits proposed in minor comments.

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Referee #1

Evidence, reproducibility and clarity

Summary:

In a previous paper (McNairn et al. 2019 "Female-biased embryonic death from inflammation induced by genomic instability" Science), the Schimenti lab demonstrated that mouse embryos with hypomorphic mutations of the heterohexameric minichromosome maintenance complex, mutations that cause increased genomic instability (GIN), show reduced embryonic viability, with greater loss of female embryos and some parent-of-origin effect. Treatment with immunosuppressants, including ibuprofen and testosterone, partially rescued the observed lethality.

In this new manuscript, the Schimenti lab demonstrates that these GIN-prone mutants feature smaller placentas with fewer cells. Mutations that interfere with the ability of the innate immune system to respond to micronuclei (a consequence of GIN) have no protective effect. Munisha and colleagues then demonstrate that MCM-mutant TSCs are harder to derive and show elevated apoptosis and a greater propensity for differentiation. The mutant TSCs show CHK1 phosphorylation, P53 phosphorylation and higher P21 levels, all consistent with a response to DNA damage. Downstream of this, they also show loss and inhibition of CDK1, which is already established to cause G2/M arrest (generally) and endoreduplication (specifically in trophoblast). The authors advance a model in which GIN results in loss of the TSC pool by apoptosis, cell cycle arrest and premature differentiation, resulting in smaller placentas and particularly fewer junctional zone cells. How this causes inflammation is less clear, but inflammation appears to be a downstream effect rather than cause of poor placentation.

Major comments:

This is a strong manuscript with few problems and all important findings well justified, indeed this is a nicely polished manuscript for something just entering peer review. There are a few unclear points textually and a couple places in the supplementary figures where better data quality would help, but generally it is a high-quality manuscript.

• I am confused as to the basis of the sex-skewing phenomenon? Is the problem that lack of maternally loaded WT Mcm4 worsens the phenotype, or is the issue that Mcm4C3/C3 dams are less able to retain pregnancies, perhaps being a more inflammatory environment? Also, while there quite consistent evidence for reduced viability of Mcm4C3/C3McmGt/+ progeny, especially for female progeny, how confident can we be that the genotype of the dam vs. sire is important? Notably on a Ddx58 background, the progeny of the Mcm4C3/C3 sire included seven live male Mcm4C3/C3McmGt/+ but no female.

• I'm not sure what Supplementary Figure 6 is showing (faster differentiation of C3 but less TGC?). Regardless, it's hard to draw too much conclusion from one not-very-pretty Western blot. This figure requires both additional replicates and a better explanation of how it fits with the other conclusions of the paper..

• Supplementary Figure 7F-G is puzzling. Half of the mESCs have gamma-H2AX at all times, including most in S or G2 phase? In Figure S7E, do the quadrants correspond to being negative or positive for gamma-H2AX? At very least, IF images showing clear gamma-H2AX foci would be much more convincing.

• The methods section is well detailed, but it would be ideal to clarify how many replicates each Western Blot or flow cytometry experiment is representative of.

The required additional experiments re: Supplementary Figure 6 and 7 could be conducted in a couple of months.

Minor comments:

• Supplementary Table 1. would be enhanced greatly showing comparable tables for Mcm4C3/C3 x Mcm4C3/+McmGt/+ in mice without the Tmem173 or Ddx58 mutations. It is fine to recycle data from McNairn 2019 here, as long as the source is indicated, but a comparison is needed.

• Is it possible that cGAS-STING and RIG pathways act redundantly to cause inflammation and lethality, or that other innate immune components are involved? I don't expect the authors to make compound mutants to test this but at least this possibility should be discussed textually.

• In Figure S3E-F, is the box above each graph supposed to show the genotype of the dam?

• "Indeed, the placenta and embryo weights of E13.5 Mcm4C3/C3 Mcm2Gt/+ Mcm3Gt/+ animals were significantly improved vs. Mcm4C3/C3 Mcm2Gt/+ animals, rendering them similar to Mcm4C3/C3 littermates (Fig. 6A-C). The JZ (but not LZ) area in Mcm4C3/C3 Mcm2Gt/+ Mcm3Gt/+ placentae also increased to the level of Mcm4C3/C3 littermates (Fig. 6D-H)." There are two problems here. First, the figure calls are wrong. Second, the description of the data is not quite right, it looks like the C3/C3 and C3/C3 M2/+ M3/+ LZs are a similar size to each and are statistically indistinguishable.

Significance

I partially discussed the above in the summary, but this paper makes a major breakthrough, showing that cell autonomous defects in hTSCs are very likely at the heart of the pathology observed in GIN-prone murine mutants.

Some questions go unsolved. Why are TSCs more prone to die in response to GIN than mESCs, particularly in light of the general observation that karyotypic abnormality is more common in placental lineage? How does the placental abnormality give rise to inflammation? No manuscript can answer every question, and I think this is a mature manuscript that can be published in a good journal with limited modifications.

I am an expert on gene regulation in placental development, with somewhat less expertise in the DNA damage field. The placenta field will find this paper interesting, as will the DNA damage field. There are also ramifications for cancer research. The question of why some cells tolerate high levels of DNA damage and others die is very relevant to cancer.

Proposition : Les sitographies proposées présentent d’autres sites du même univers thématique, mais elles fonctionnent plutôt comme des bibliographies web fermées sur elles-mêmes. Là où l'entrée du numérique au musée s'est articulé à un idéal de participation des visiteurs à travers une offre interactive (Vidal, 2021), le projet ethno, proche dans sa structure du CD-ROM, ne s'inscrit pas encore tout à fait dans cette logique.

Reviewer #1 (Public review):

This paper by Poverlein et al reports the substantial membrane deformation around the oxidative phosphorylation super complex, proposing that this deformation is a key part of super complex formation. I found the paper interesting and well-written.

* Analysis of the bilayer curvature is challenging on the fine lengthscales they have used and produces unexpectedly large energies (Table 1). Additionally, the authors use the mean curvature (Eq. S5) as input to the (uncited, but it seems clear that this is Helfrich) Helfrich Hamiltonian (Eq. S7). If an errant factor of one half has been included with curvature, this would quarter the curvature energy compared to the real energy, due to the squared curvature. The bending modulus used (ca. 5 kcal/mol) is small on the scale of typically observed biological bending moduli. This suggests the curvature energies are indeed much higher even than the high values reported. Some of this may be due to the spontaneous curvature of the lipids and perhaps the effect of the protein modifying the nearby lipids properties.

* It is unclear how CDL is supporting SC formation if its effect stabilizing the membrane deformation is strong or if it is acting as an electrostatic glue. While this is a weakenss for a definite quantification of the effect of CDL on SC formation, the study presents an interesting observation of CDL redistribution and could be an interesting topic for future work.

In summary, the qualitative data presented are interesting (especially the combination of molecular modeling with simpler Monte Carlo modeling aiding broader interpretation of the results). The energies of the membrane deformations are quite large. This might reflect the roles of specific lipids stabilizing those deformations, or the inherent difficulty in characterizing nanometer-scale curvature.

Maar als dit wel duidelijk uit de casus blijkt ga daan niet zelf de relevante markt uitwerken op de tentamen dit is zonde van je tijd die je beter kan besteden aan andere vragen.

Suis-je le seul à trouver "CSS Grids" plus intuitif/pratique que "Flexbox" ? En effet, avec CSS Grids, tu lui précises le nombre de rangées et de colonnes à avoir et basta, alors qu'avec Flexbox, tu dois réfléchir aux axes (qui est "principal", qui est "secondaire" ?), tu ne peux jamais prévoir le résultat car même en utilisant "lfex-wrap: wrap;" tu ne sais pas après quel élément le navigateur va aller à la ligne … bref, ma phobie !

Après, peut-être que les "pro" du dév préfèrent Flexbox, mais à ce stade, je préfère CSS Grids.

Qu'en pensez-vous ?

Reviewer #3 (Public review):

The goal of this work is to understand the regulation of double-strand break formation during meiosis in C. elegans. The authors have analyzed physical and genetic interactions among a subset of factors that have been previously implicated in DSB formation or the number of timing of DSBs: CEP-1, DSB-1, DSB-2, DSB-3, HIM-5, HIM-17, MRE-11, REC-1, PARG-1, and XND-1.

The 10 proteins that are analyzed here include a diverse set of factors with different functions, based on prior analyses in many published studies. The term "Spo11 accessory factors" has been used in the meiosis literature to describe proteins that directly promote Spo11 cleavage activity, rather than factors that are important for the expression of meiotic proteins or that influence the genome-wide distribution or timing of DSBs. Based on this definition, the known SPO-11 accessory factors in C. elegans include DSB-1, DSB-2, DSB-3, and the MRN complex (at least MRE-11 and RAD-50). These are all homologs of proteins that have been studied biochemically and structurally in other organisms. DSB-1 & DSB-2 are homologs of Rec114, while DSB-3 is a homolog of Mei4. Biochemical and structural studies have shown that Rec114 and Mei4 directly modulate Spo11 activity by recruiting Spo11 to chromatin and promoting its dimerization, which is essential for cleavage. The other factors analyzed in this study affect the timing, distribution, or number of RAD-51 foci, but they likely do so indirectly. As elaborated below, XND-1 and HIM-17 are transcription factors that modulate the expression of other meiotic genes, and their role in DSB formation is parsimoniously explained by this regulatory activity. The roles of HIM-5 and REC-1 remain unclear; the reported localization of HIM-5 to autosomes is consistent with a role in transcription (the autosomes are transcriptionally active in the germline, while the X chromosome is largely silent), but its loss-of-function phenotypes are much more limited than those of HIM-17 and XND-1, so it may play a more direct role in DSB formation. The roles of CEP-1 (a Rad53 homolog) and PARG-1 are also ambiguous, but their homologs in other organisms contribute to DNA repair rather than DSB formation.

An additional significant limitation of the study, as stated in my initial review, is that much of the analysis here relies on cytological visualization of RAD-51 foci as a proxy for DSBs. RAD-51 associates transiently with DSB sites as they undergo repair and is thus limited in its ability to reveal details about the timing or abundance of DSBs since its loading and removal involve additional steps that may be influenced by the factors being analyzed.

The paper focuses extensively on HIM-5, which was previously shown through genetic and cytological analysis to be important for breaks on the X chromosome. The revised manuscript still claims that "HIM-5 mediates interactions with the different accessory factors sub-groups, providing insights into how components on the DNA loops may interact with the chromosome axis." The weak interactions between HIM-5 and DSB-1/2 detected in the Y2H assay do not convincingly support such a role. The idea that HIM-5 directly promotes break formation is also inconsistent with genetic data showing that him-5 mutants lack breaks on the X chromosomes, while HIM-5 has been shown to be is enriched on autosomes. Additionally, as noted in my comment to the authors, the localization data for HIM-5 shown in this paper are discordant with prior studies; this discrepancy should be addressed experimentally.

This paper describes REC-1 and HIM-5 as paralogs, based on prior analysis in a paper that included some of the same authors (Chung et al., 2015; DOI 10.1101/gad.266056.115). In my initial review I mentioned that this earlier conclusion was likely incorrect and should not be propagated uncritically here. Since the authors have rebutted this comment rather than amending it, I feel it is important to explain my concerns about the conclusions of previous study. Chung et al. found a small region of potential homology between the C. elegans rec-1 and him-5 genes and also reported that him-5; rec-1 double mutants have more severe defects than either single mutant, indicative of a stronger reduction in DSBs. Based on these observations and an additional argument based on microsynteny, they concluded that these two genes arose through recent duplication and divergence. However, as they noted, genes resembling rec-1 are absent from all other Caenorhabditis species, even those most closely related to C. elegans. The hypothesis that two genes are paralogs that arose through duplication and divergence is thus based on their presence in a single species, in the absence of extensive homology or evidence for conserved molecular function. Further, the hypothesis that gene duplication and divergence has given rise to two paralogs that share no evident structural similarity or common interaction partners in the few million years since C. elegans diverged from its closest known relatives is implausible. In contrast, DSB-1 and DSB-2 are both homologs of Rec114 that clearly arose through duplication and divergence within the Caenorhabditis lineage, but much earlier than the proposed split between REC-1 and HIM-5. Two genes that can be unambiguously identified as dsb-1 and dsb-2 are present in genomes throughout the Elegans supergroup and absent in the Angaria supergroup, placing the duplication event at around 18-30 MYA, yet DSB-1 and DSB-2 share much greater similarity in their amino acid sequence, predicted structure, and function than HIM-5 and REC-1. Further, Raices place HIM-5 and REC-1 in different functional complexes (Figure 3B).

The authors acknowledge that HIM-17 is a transcription factor that regulates many meiotic genes. Like HIM-17, XND-1 is cytologically enriched along the autosomes in germline nuclei, suggestive of a role in transcription. The Reinke lab performed ChIP-seq in a strain expressing an XND-1::GFP fusion protein and showed that it binds to promoter regions, many of which overlap with the HIM-17-regulated promoters characterized by the Ahringer lab (doi: 10.1126/sciadv.abo4082). Work from the Yanowitz lab has shown that XND-1 influences the transcription of many other genes involved in meiosis (doi: 10.1534/g3.116.035725) and work from the Colaiacovo lab has shown that XND-1 regulates the expression of CRA-1 (doi: 10.1371/journal.pgen.1005029). Additionally, loss of HIM-17 or XND-1 causes pleiotropic phenotypes, consistent with a broad role in gene regulation. Collectively, these data indicate that XND-1 and HIM-17 are transcription factors that are important for the proper expression of many germline-expressed genes. Thus, as stated above, the roles of HIM-17 and XND-1 in DSB formation, as well as their effects on histone modification, are parsimoniously explained by their regulation of the expression of factors that contribute more directly to DSB formation and chromatin modification. I feel strongly that transcription factors should not be described as "SPO-11 accessory factors."

Author response:

The following is the authors’ response to the original reviews

Public Reviews:

Reviewer #1 (Public Review):

Summary:

The manuscript by Raices et al., provides novel insights into the role and interactions between SPO-11 accessory proteins in C. elegans. The authors propose a model of meiotic DSBs regulation, critical to our understanding of DSB formation and ultimately crossover regulation and accurate chromosome segregation. The work also emphasizes the commonalities and species-specific aspects of DSB regulation.

Strengths:

This study capitalizes on the strengths of the C. elegans system to uncover genetic interactions between a large number of SPO-11 accessory proteins. In combination with physical interactions, the authors synthesize their findings into a model, which will serve as the basis for future work, to determine mechanisms of DSB regulation.

Weaknesses:

The methodology, although standard, lacks quantification. This includes the mass spectrometry data , along with the cytology. The work would also benefit from clarifying the role of the DSB machinery on the X chromosome versus the autosomes.

• We have uploaded the MS data and added a summary table with the number of peptides and coverage.

• We have added statistics to the comparisons of DAPI body counts.

• We have provided additional images of the change in HIM-5 localization

• We have quantified the overlap (or lack thereof) between XND-1 and HIM-17 and the DNA axis

Reviewer #2 (Public Review):

Summary:

Meiotic recombination initiates with the formation of DNA double-strand break (DSB) formation, catalyzed by the conserved topoisomerase-like enzyme Spo11. Spo11 requires accessory factors that are poorly conserved across eukaryotes. Previous genetic studies have identified several proteins required for DSB formation in C. elegans to varying degrees; however, how these proteins interact with each other to recruit the DSB-forming machinery to chromosome axes remains unclear.

In this study, Raices et al. characterized the biochemical and genetic interactions among proteins that are known to promote DSB formation during C. elegans meiosis. The authors examined pairwise interactions using yeast two-hybrid (Y2H) and co-immunoprecipitation and revealed an interaction between a chromatin-associated protein HIM-17 and a transcription factor XND-1. They further confirmed the previously known interaction between DSB-1 and SPO-11 and showed that DSB-1 also interacts with a nematodespecific HIM-5, which is essential for DSB formation on the X chromosome. They also assessed genetic interactions among these proteins, categorizing them into four epistasis groups by comparing phenotypes in double vs. single mutants. Combining these results, the authors proposed a model of how these proteins interact with chromatin loops and are recruited to chromosome axes, offering insights into the process in C. elegans compared to other organisms.

Weaknesses:

This work relies heavily on Y2H, which is notorious for having high rates of false positives and false negatives. Although the interactions between HIM-17 and XND-1 and between DSB-1 and HIM-5 were validated by co-IP, the significance of these interactions was not tested, and cataloging Y2H interactions does not yield much more insight.

We appreciate that the reviewer recognized the value of our IP data, but we beg to differ that we rely too heavily on the Y2H. We also provide genetic analysis on bivalent formation to support the physical interaction data. We do acknowledge that there are caveats with Y2H, however, including that a subset of the interactions can only be examined with proteins in one orientation due to auto-activation. While we acknowledge that it would be nice to have IP data for all of the proteins using CRISPR-tagged, functional alleles, these strains are not all feasible (e.g. no functional rec-1 tag has been made) and are beyond the scope of the current work.

Moreover, most experiments lack rigor, which raises serious concerns about whether the data convincingly supports the conclusions of this paper. For instance, the XND-1 antibody appears to detect a band in the control IP; however, there was no mention of the specificity of this antibody.

We previously showed the specificity of this antibody in its original publication showing lack of staining in the xnd-1 mutant by IF (Wagner et al., 2010). To further address this, however, we have now included a new supplementary figure (Figure S1) demonstrating the specificity of the XND-1 antibody by Western blot. The antibody detects a distinct band in extracts from wild-type (N2) worms, but this band is absent in two independent xnd-1 mutant strains. This confirms that the antibody specifically recognizes XND-1, supporting the validity of the IP results shown in the main figures.

Additionally, epistasis analysis of various genetic mutants is based on the quantification of DAPI bodies in diakinesis oocytes, but the comparisons were made without statistical analyses.

We have added statistical analysis to all datasets where quantification was possible, strengthening the rigor and interpretation of our findings.

For cytological data, a single representative nucleus was shown without quantification and rigorous analysis. The rationale for some experiments is also questionable (e.g. the rescue by dsb-2 mutants by him-5 transgenes in Figure 2), making the interpretation of the data unclear. Overall, while this paper claims to present "the first comprehensive model of DSB regulation in a metazoan", cataloging Y2H and genetic interactions did not yield any new insights into DSB formation without rigorous testing of their significance in vivo. The model proposed in Figure 4 is also highly speculative.

Regarding the cytology, we provide new images and quantification of HIM-17 and XND-1 overlap with the DNA axes. We also added full germ line images showing HIM-5 localization in wild type and dsb-1 mutants, to provide a more complete and representative view of the observed phenotype. To further support our findings, we’ve also included images demonstrating that this phenotype is consistently observed with both in live worm with the the him-5::GFP transgene and in fixed worms with an endogenously tagged version of HIM-5.

Reviewer #3 (Public Review):

During meiosis in sexually reproducing organisms, double-strand breaks are induced by a topoisomerase-related enzyme, Spo11, which is essential for homologous recombination, which in turn is required for accurate chromosome segregation. Additional factors control the number and genome-wide distribution of breaks, but the mechanisms that determine both the frequency and preferred location of meiotic DSBs remain only partially understood in any organism.

The manuscript presents a variety of different analyses that include variable subsets of putative DSB factors. It would be much easier to follow if the analyses had been more systematically applied. It is perplexing that several factors known to be essential for DSB formation (e.g., cohesins, HORMA proteins) are excluded from this analysis, while it includes several others that probably do not directly contribute to DSB formation (XND-1, HIM-17, CEP-1, and PARG-1).

We respectfully disagree with the reviewer’s statement regarding the selection of factors included in our analysis. In this work, our focus was specifically on SPO-11 accessory factors — proteins that directly interact with or regulate SPO-11 activity during doublestrand break formation. Cohesins and chromosome axis proteins (such as the HORMA domain proteins) are essential for establishing the correct chromosome architecture that supports DSB formation, but there is no evidence that they are direct accessory factors of SPO-11. Therefore, they were intentionally excluded from this study to maintain a clear and focused scope on proteins that more directly modulate SPO-11 function.

Conversely, XND-1, HIM-17, CEP-1, and PARG-1 have all been implicated in regulating aspects of SPO-11-mediated DSB formation or its immediate environment. Although their contributions mayinvolve broader chromatin or DNA damage response regulation, prior literature supports their inclusion as relevant modulators of SPO-11 activity, justifying their analysis within the context of this work.

The strongest claims seem to be that "HIM-5 is the determinant of X-chromosome-specific crossovers" and "HIM-5 coordinates the actions of the different accessory factors subgroups." Prior work had already shown that mutations in him-5 preferentially reduce meiotic DSBs on the X chromosome. While it is possible that HIM-5 plays a direct role in DSB induction on the X chromosome, the evidence presented here does not strongly support this conclusion. It is also difficult to reconcile this idea with evidence from prior studies that him-5 mutations predominantly prevent DSB formation on the sex chromosomes, while the protein localizes to autosomes.

HIM-5 is not the only protein that is autosomally enriched but preferentially affects the X chromosome: MES-4 and MRG-1 are both autosomally-enriched but influence silencing of the X chromosome. While HIM-5 appears autosomally-enriched, it does not appear to be autosomal-exclusive. While we would ideally perform ChIP to determine its localization on chromatin, this method for assaying DSB sites is likely insufficient to identify DSB sites which differ in each nucleus and for which there are no known hotspots in the worm.

him-5 mutants confer an ~50% reduction in total number of breaks and a very profound change in break dynamics (seen by RAD-51 foci (Meneely et al., 2012)). Since the autosomes receives sufficient breaks in this context to attain a crossover in >98% of nuclei, this indicates that the autosomes are much less profoundly impacted by loss of DSB functions than is the X chromosome. Indeed, prior data from co-author, Monica Colaiacovo, showed that fewer breaks occur on the X (Gao, 2015) likely resulting from differences in the chromatin composition of the X and autosome resulting from X chromosome silencing.

The conclusion that HIM-5 must be required for breaks on the X comes from the examination of DSB levels and their localization in different mutants that impair but do not completely abrogate breaks. In any situation where HIM-5 protein expression is affected (xnd-1, him-17, and him-5 null alleles), breaks on the X are reduced/ eliminated. By contrast, in dsb-2 mutants, where HIM-5 expression is unaffected, both X and autosomal breaks are impacted equally. As discussed above, in the absence of HIM-5 function, there are ~15 breaks/ nucleus. The Ppie1::him-5 transgene is expressed to lower levels than Phim-5::him-5, but in the best case, the ectopic expression of this protein should give a maximum of ~15 breaks (the total # of breaks is thought to be ~30/nucleus). By these estimates, Ppie-1::him-5; him-17 and him-5 null mutants have the same number of breaks. Yet, in the former case, breaks occur on the X; whereas in the latter they do not. The best explanation for this discrepancy is that HIM-5 is sufficient to recruits the DSB machinery to the X chromosome.

The one experiment that seems to elicit the conclusion that HIM-5 expression is sufficient for breaks on the X chromosome is flawed (see below). The conclusion that HIM-5 "coordinates the activities of the different accessory sub-groups" is not supported by data presented here or elsewhere.

We have reorganized the discussion to more directly address the reviewers’ concerns. We raise the possibility that HIM-5 has an important role in bringing together the SPO-11 and its interacting components (DSB-1/2/3) with the other DSB inducing factors, including those factors that regulating DSB timing (XND-1), coordination with the cell cycle (REC-1), association with the chromosome axis (PARG-1, MRE-11), and coupling to downstream resection and repair (MRE-11, CEP-1).  

This raises a natural question: if HIM-5 has such a central role, why are the phenotypes of HIM-5 so mild? We propose that while the loss of DSBs on the X appears mild, more profound effects are seen in the total number, timing, and placement of the DSBs across the genome- all of which are diminished or altered in the absence of HIM-5. The phenotypes of him-5 loss reminiscent of those observed in Prdm9-/- in mice where breaks are relocated to transcriptional start sites and show significant delay in formation. As with PRDM9, the comparatively subtle phenotypes of HIM-5 loss do not diminish its critical role in promoting proper DSB formation in most mammals.

Like most other studies that have examined DSB formation in C. elegans, this work relies on indirect assays, here limited to the cytological appearance of RAD-51 foci and bivalent chromosomes, as evidence of break formation or lack thereof. Unfortunately, neither of these assays has the power to reveal the genome-wide distribution or number of breaks. These assays have additional caveats, due to the fact that RAD-51 association with recombination intermediates and successful crossover formation both require multiple steps downstream of DSB induction, some of which are likely impaired in some of the mutants analyzed here. This severely limits the conclusions that can be drawn. Given that the goal of the work is to understand the effects of individual factors on DSB induction, direct physical assays for DSBs should be applied; many such assays have been developed and used successfully in other organisms.

We appreciate the reviewer’s thoughtful comments. We agree that RAD-51 foci are an indirect readout of DSB formation and that their dynamics can be influenced by defects in downstream repair processes. However, in C. elegans, the available methods for directly detecting DSBs are limited. Unlike other organisms, C. elegans lacks γH2AX, eliminating the possibility of using γH2AX as a DSB marker. TUNEL assays, while conceptually appealing, have proven unreliable and poorly reproducible in the germline context. Similarly, RPA foci do not consistently correlate with the number of DSBs and are influenced by additional processing steps.

Given these limitations, RAD-51 foci remain the most widely accepted surrogate for monitoring DSB formation in C. elegans. While we fully acknowledge the caveats associated with this approach — particularly the potential effects of downstream repair defects — RAD-51 analysis continues to provide valuable insight into DSB dynamics and regulation, especially when interpreted in combination with other phenotypic assessments.

Throughout the manuscript, the writing conflates the roles played by different factors that affect DSB formation in very different ways. XND-1 and HIM-17 have previously been shown to be transcription factors that promote the expression of many germline genes, including genes encoding proteins that directly promote DSBs. Mutations in either xnd-1 or him-17 result in dysregulation of germline gene expression and pleiotropic defects in meiosis and fertility, including changes in chromatin structure, dysregulation of meiotic progression, and (for xnd-1) progressive loss of germline immortality. It is thus misleading to refer to HIM-17 and XND-1 as DSB "accessory factors" or to lump their activities with those of other proteins that are likely to play more direct roles in DSB induction.

It is clear that we will not reach agreement about the direct vs indirect roles here of chromatin remodelers/transcription factors in break formation. In yeast, there is a precedent for SPP1 and in mouse for Prdm9, both of which could be described as transcription factors as well, as having roles in break formation by creating an open chromatin environment for the break machinery. We envision that these proteins function in the same fashion. The changes in histone acetylation in the xnd-1 mutants supports such a claim.

We do not know what the reviewer is referring to in statement that “XND-1 and HIM-17 have previously been shown to be transcription factors that promote the expression of many germline genes.” While the Carelli et al paper indeed shows a role for HIM-17 in expression of many germline genes, there is only one reference to XND-1 in this manuscript (Figure S3A) which shows that half of XND-1 binding sites overlap with the co-opted germline promoters. There is no transcriptional data at all on xnd-1 mutants, save our studies (referenced herein) that XND-1 regulates him-5 expression.

For example, statements such as the following sentence in the Introduction should be omitted or explained more clearly: "xnd-1 is also unique among the accessory factors in influencing the timing of DSBs; in the absence of xnd-1, there is precocious and rapid accumulation of DSBs as monitored by the accumulation of the HR strand-exchange protein RAD-51.

We are not sure what is confusing here. The distribution of RAD-51 foci is significantly altered in xnd-1 mutants and peak levels of breaks are achieved as nuclei leave the transition zone (Wagner et al., 2010; McClendon et al., 2016). There is no other mutation that causes this type of change in RAD-51 distribution.

"The evidence that HIM-17 promotes the expression of him-5 presented here corroborates data from other publications, notably the recent work of Carelli et al. (2022), but this conclusion should not be presented as novel here.

We have clarified this in the text. We note that this paper showed alterations in him-5 levels by RNA-Seq but they did not validate these results with quantitative RT-PCR. Thus, our studies do provide an important validation of their prior results.

The other factors also fall into several different functional classes, some of which are relatively well understood, based largely on studies in other organisms. The roles of RAD50 and MRE-11 in DSB induction have been investigated in yeast and other organisms as well as in several prior studies in C. elegans. DSB-1, DSB-2, and DSB-3 are homologs of relatively well-studied meiotic proteins in other organisms (Rec114 and Mei4) that directly promote the activity of Spo11, although the mechanism by which they do so is still unclear.

Whilst we agree that we understand some of the functions of the homologs, there are clearly examples in other processes of conserved proteins adopting unique regulatory function. We should not presume evolutionary conservation until proven. Indeed the comparison between the Mer2 proteins becomes particularly relevant here. For example, the RMM complex in plants does not contain PRD3, although this protein is thought to have function in DSB formation and repair (Lambing et al, 2022; Vrielynck et al., 2021; Thangavel et al., 2023). In Sordaria, as well, the Mer2 homolog has distinct functions (Tesse et al., 2017).  

Mutations in PARG-1 (a Poly-ADP ribose glycohydrolase) likely affect the regulation of polyADP-ribose addition and removal at sites of DSBs, which in turn are thought to regulate chromatin structure and recruitment of repair factors; however, there is no convincing evidence that PARG-1 directly affects break formation.

Our prior collaborative studies on PARG-1 showed that is has a non-catalytic function that promote DSBs that is independent of accumulation of PAR (Janisiw et al., 2020; Trivedi et al., 2022)

CEP-1 is a homolog of p53 and is involved in the DNA damage response in the germline, but again is unlikely to directly contribute to DSB induction.

We respectfully disagree with the reviewer’s statement. While CEP-1 is indeed a homolog of p53 and plays a major role in the DNA damage response, prior work from Brent Derry’s lab and from our group (Mateo et al., 2016) demonstrated that specific cep-1 separationof-function alleles affect DSB induction and/or repair pathway choice independently of canonical DNA damage checkpoint activation. In particular, defects in DSB formation observed in certain cep-1 mutants can be rescued by exogenous irradiation, supporting a direct or closely linked role in promoting DSB formation rather than merely responding to damage. Thus, based on these functional data, we considered CEP-1 a relevant factor to include in our analysis. We have now clarified this rationale in the revised manuscript.

HIM-5 and REC-1 do not have apparent homologs in other organisms and play poorly understood roles in promoting DSB induction. A mechanistic understanding of their functions would be of value to the field, but the current work does not shed light on this. A previous paper (Chung et al. G&D 2015) concluded that HIM-5 and REC-1 are paralogs arising from a recent gene duplication, based on genetic evidence for a partially overlapping role in DSB induction, as well as an argument based on the genomic location of these genes in different species; however, these proteins lack any detectable sequence homology and their predicted structures are also dissimilar (both are largely unstructured but REC-1 contains a predicted helical bundle lacking in HIM-5). Moreover, the data presented here do not reveal overlapping sets of genetic or physical interactions for the two genes/proteins. Thus, this earlier conclusion was likely incorrect, and this idea should not be restated uncritically here or used as a basis to interpret phenotypes.

Actually, there is quite good bioinformatic analysis that the rec-1 and him-5 loci evolved from a gene duplication and that each share features of the ancestral protein (Chung et al., 2015). We are sorry if the reviewer casts aspersions on the prior literature and analyses. The homology between these genes with the ancestral protein is near the same degree as dsb-1, dsb-2, or dsb-3 to their ancestral homologs (<17%).

DSB-1 was previously reported to be strictly required for all DSB and CO formation in C. elegans. Here the authors test whether the expression of HIM-5 from the pie-1 promoter can rescue DSB formation in dsb-1 mutants, and claim to see some rescue, based on an increase in the number of nuclei with one apparent bivalent (Figure 2C). This result seems to be the basis for the claim that HIM-5 coordinates the activities of other DSB proteins. However, this assay is not informative, and the conclusion is almost certainly incorrect. Notably, a substantial number of nuclei in the dsb-1 mutant (without Ppie-1::him-5) are reported as displaying a single bivalent (11 DAPI staining bodies) despite prior evidence that DSBs are absent in dsb-1 mutants; this suggests that the way the assay was performed resulted in false positives (bivalents that are not actually bivalents), likely due to inclusion of nuclei in which univalents could not be unambiguously resolved in the microscope. A slightly higher level of nuclei with a single unresolved pair of chromosomes in the dsb-1; Ppie-1::him-5 strain is thus not convincing evidence for rescue of DSBs/CO formation, and no evidence is presented that these putative COs are X-specific. The authors should provide additional experimental evidence - e.g., detection of RAD-51 and/or COSA-1 foci or genetic evidence of recombination - or remove this claim. The evidence that expression of Ppie-1::him-5 may partially rescue DSB abundance in dsb-2 mutants is hard to interpret since it is currently unknown why C. elegans expresses 2 paralogs of Rec114 (DSB-1 and DSB-2), and the age-dependent reduction of DSBs in dsb-2 mutants is not understood.

We have removed this claim in part because we have been unable to create the triple mutants strains to analyze COSA-1 foci.

To the point about 11 vs 12 DAPI bodies: the literature is actually replete with examples of 11 DAPI bodies vs 12 in mutants with no breaks:

Hinman al., 2021: null allele of dsb-3 has an average of 11.6 +/- 0.6 breaks;

Stamper et al, 2013, show just over 60% of dsb-1 nuclei with 12 DAPI bodies and 5-10% with 10 DAPI bodies. (Figure 1);

In addition, we also previously showed (Machovina et al., 2016) that a subset of meiotic nuclei have a single RAD-51 focus and can achieve a crossover. RAD-51 foci in spo-11 were also reported in Colaiacovo et al., 2003.

Several of the factors analyzed here, including XND-1, HIM-17, HIM-5, DSB-1, DSB-2, and DSB-3, have been shown to localize broadly to chromatin in meiotic cells. Coimmunoprecipitation of pairs of these factors, even following benzonase digestion, is not strong evidence to support a direct physical interaction between proteins.

Similarly, the super-resolution analysis of XND-1 and HIM-17 (Figure 1EF) does not reveal whether these proteins physically interact with each other, and does not add to our understanding of these proteins functions, since they are already known to bind to many of the same promoters. Promoters are also likely to be located in chromatin loops away from the chromosome axis, so in this respect, the localization data are also confirmatory rather than novel.

While the binding to promoters would be expected to be on DNA loops, that has not been definitively shown in the worm germ line. The supplemental data of the Carelli paper suggests that there are ~250 binding sites for each protein at these coopted promoters. This could not account for crossover map seen in C. elegans.

The reviewer states correct that we do not reveal that these proteins interact, but we have shown that the two proteins co-IP and have a Y2H interaction. This interaction is supporedt by a recent publication (Blazickova et al., 2025) corroborating this conclusion and identifies XND-1 in HIM-17 co-IPs also in the presence of benzonase. We do now show, however, by immuno-localization that the two proteins appear to be adjacent, but nonoverlapping. As now described in the text, AlphaFold 3 modeling and structural analysis suggests that the two proteins do interact directly and that the tagged 5’ end of HIM-17 used in our studies is likely to be at least 200nm from the putative XND-1 binding interface, a distance that is consistent with our confocal images showing frequent juxtaposition of the two proteins.

The phenotypic analysis of double mutant combinations does not seem informative. A major problem is that these different strains were only assayed for bivalent formation, which (as mentioned above) requires several steps downstream of DSB induction. Additionally, the basis for many of the single mutant phenotypes is not well understood, making it particularly challenging to interpret the effects of double mutants. Further, some of the interactions described as "synergistic" appear to be additive, not synergistic. While additive effects can be used as evidence that two genes work in different pathways, this can also be very misleading, especially when the function of individual proteins is unknown. I find that the classification of genes into "epistastasis groups" based on this analysis does not shed light on their functions and indeed seems in some cases to contradict what is known about their functions. ‘

As described above, each of the proteins analyzed is thought to have a direct role in regulating meiotic DSB formation and single mutant phenotypes are consistent with this interpretation. In almost all-if not all- of these cases, IR induced breaks suppress univalent phenotypes (or uncover a downstream repair defect (e.g. in mre-11)) supporting this conclusion. We have changed the terminology from “epistasis groups” since this is not strict epistasis, but rather, “functional groups”.  

The yeast two-hybrid (Y2H) data are only presented as a single colony. While it is understandable to use a 'representative' colony, it is ideal to include a dilution series for the various interactions, which is how Y2H data are typically shown.

The Y2H data are presented as spots on a plate and are from three to four individual transformants per interaction tested, and are not individual colonies. The experiment was repeated in triplicate from different transformations. We have now made this clearer in the materials and methods section. This approach has been successfully used to examine protein interactions in our prior manuscripts of yeast and human proteins [Gaines et al (2015) Nat. Comms 6:7834; Kondrashova et al (2017) Cancer Discovery 7:984; Garcin et al (2019) PLoS Genetics 15:e1008355; Bonilla et al (2021) eLife 1: e68080) Prakash et al (2022) PNAS 119: e2202727119, etc]

Additional (relatively minor) concerns about these data:

(1) Several interactions reported here seem to be detected in only one direction - e.g., MRE-11-AD/HIM-5-BD, REC-1-AD/XND-1-BD, and XND-1-AD/HIM-17-BD - while no interactions are seen with the reciprocal pairs of fusion proteins. I'm not sure if some of this is due to pasting "positive" colony images into the wrong position in the grid, but this should be addressed.

The asymmetry in the interactions observed is due to the well-known phenomenon in yeast two-hybrid (Y2H) assays where certain plasmids exhibit self-activation when fused in one orientation, making interpretation of reciprocal interactions challenging. In our experiment, some of the plasmids indeed showed self-activation in one direction, which likely accounts for the lack of interaction seen with the reciprocal pairs of fusion proteins. We have clarified this point in the Methods.

(2) DSB-3 was only assayed in pairwise combinations with a subset of other proteins; this should be explained; it is also unclear why the interaction grids are not symmetrical about the diagonal.

We have now completed the analysis by adding the interactions of DSB-3 with the remaining proteins that were missing from the initial set.

(3) I don't understand why the graphic summaries of Y2H data are split among 3 different figures (1, 2, and 3).

We chose to split the graphic summaries of the Y2H data across Figures 1, 2, and 3 because we felt this organization better aligns with the flow of the results presented in each figure. Each set of interactions is shown in the context of the specific experiments and findings discussed in those sections, which we believe helps provide a clearer and more logical presentation of the data.

Recommendations for the authors:

Reviewer #1 (Recommendations For The Authors):

Figure 1: B) The IP is difficult to interpret - there is a band of the corresponding size to XND-1 in the control lane calling into question the specificity of the IP/Western.

We added a supplemental figure with the specificity of the antibody showing that there is a background non-specific band.

C) More information about the mass spectrometry should be included. No indication of the number of times a peptide was identified, or the overall coverage of the identified proteins.

Done

This is important as in the results section (line 114) the authors indicate that there was "strong" interaction yet there is no way to assess this.

D) Why wasn't hatching measured in the him-5p::him-5; him-17(ok424) strain?

Great question. I guess we need to do this while back out for review. If anyone has suggestions of what to say here. Clearly we overlooked this point but do have the strain.

E) Quantification of the cytology should be included.

We have now quantified overlap between XND-1 and HIM-17

Figure 2: C) Statistics should be included.

Done

E) Quantification should be included for the cytology. I recommend changing the eals15 to HIM-5.

We included better images showing whole gonads instead of one or two nuclei. We were not sure what the reviewers want us to quantify here since the relocalization of the protein to the cytoplasm is very clear.

I have a general issue with the use of the term epistasis - this is used to order gene function based on different mutant phenotypes, usually with null alleles. While I think the authors have valid points with how they group the different SPO-11 accessory proteins, I do not think they should use the word epistasis, but rather genetic interactions.

We appreciate the reviewers thoughts on this matter and have removed the term epistasis and use functional groups or genetic interactions throughout the text.

Figure 4 and the nature of the X chromosome: First, I think it would help the non-C. elegans reader to include a little more information on the X chromosome with respect to its differences compared to the autosomes. I also think that, if possible, it would be beneficial to include a model of the X in Figure 4.

We have added more about X/autosome differences in the intro and during the discussion of HIM-5 function and have added a figure showing difference in the behavior of the X/autosomes during DSB/crossover formation.

Minor points:

Abstract: Given the findings of Silva and Smolikove on SPO-11 breaks, I recommend removing "early" from line 28 in the Abstract.

Done

Introduction (line 93): I think "biochemical studies" is a stretch here - I recommend "interaction studies".

Done

Results: (lines 160-161): mutations are not required for breaks. Line 172, there is a problem with the sentence.

Corrected

Reviewer #2 (Recommendations For The Authors):

Major comments:

(1) Figure 1B- The signal for XND-1 seems to appear both in the control and him-17::HA IP. Do the authors have tested the specificity of the XND-1 antibody?

We included a supplementary figure demonstrating the specificity of the XND-1 antibody by Western blot. This was also previously published (Wagner et al., 2010)

(2) Figure 1D - can the authors provide an explanation why the him-5p::him-5 transgene that drives a higher expression than pie-1p::him-5 fails to suppress the Him phenotype seen in him-17? What are the HIM-5 levels like in these two strains compared to N2 and him-17 null mutants? Can this information provide explanation for the differential effect of the him-5 transgenes?

We previously reported that him-5p::him-5 drives higher expression than pie-1p::him-5 (McClendon et al, 2016).

The reason that him-5p::him-5 does not rescue, despite higher wild type expression is that HIM-17 directly regulates expression of him-5. Since HIM-17 does not regulate the pie-1 promoter, the pie-1p::him-5 construct can at least partially suppress the him-17 mutation.

We have (hopefully) explained this better in the text.  

(3) Line 102- the subheading "HIM-5 is the essential factor for meiotic breaks in the Xchromosome" may not be appropriate for this section. This is what has previously been known. However, the results in Figure 1 demonstrate that a him-5 transgene can partially rescue the him-17 and ¬xnd-1 phenotype, but not that it is essential for meiotic DSB formation on X chromosomes.

We think some of the concern here is sematic and have changed the phraseology to say that HIM-5 is SUFFICIENT for DSBs on the X… which had not previously been shown.

Vis-à-vis the X chromosome, in all genetic backgrounds examined, the absence of HIM-5 consistently results in a complete lack of DSBs on the X. For instance, in dsb-2 mutants— where HIM-5 is still expressed—DSBs are reduced genome-wide, but the X chromosome occasionally retains breaks. In contrast, even a weak allele of him-17 results specifically in the loss of X chromosome breaks, underscoring a unique requirement for HIM-5 in promoting DSBs on the X. While Figure 1 shows that a him-5 transgene can partially rescue him-17 and xnd-1 phenotypes, the consistent observation that X breaks are absent without HIM-5 supports its classification as sufficient for DSB formation on the X chromosome.

(4) Figure 1E - please consider enlarging the images and showing multiple examples.

Done.

I also suggest that the authors perform a more rigorous analysis to support the conclusion that XND-1 and HIM-17 localize away from the axis by quantifying multiple images and doing line-scan analysis.

Provided. New images are provided in both, the main and supplemental figures, and quantification is included. There is no detectable overlap of the two protein with one another or the DNA axes (see quantification of overlap in Fig. 1).

(5) Line 162 - This is the first mention of DSB-1, DSB-2, and DSB-3 in the paper. DSB-1 and DSB-2 are Rec114 homologs in C. elegans (Tesse et al., 2017), while DSB-3 is a homolog of Mei4 (Hinman et al., 2021). These proteins should be properly introduced in the introduction with appropriate citations.

Done. We appreciate the reviewer pointing out that this was the first reference to these genes.

(6) Line 169 - the rationale for this experiment is unclear. Why did the Y2H interaction between HIM-5 and DSB-1 prompt the authors to test the rescue of dsb-1 or dsb-2 phenotypes by the ectopic expression of him-5? Do the authors have evidence that HIM-5 level is reduced in dsb-1 or dsb-2 mutants?

We have reorganized this section to better explain the motivation for looking at these interactions. We did see a difference in the localization in HIM-5 in the dsb-1 mutant animals and we did have a sense that HIM-5 was critical for breaks on the X. We reasoned that it could have independent functions in promoting breaks that were not yet appreciated so wanted to do this experiment.

(7) Line 172 - "very slightly reduced". This claim requires statistical analysis.

We added statistical analysis, but we also removed this claim.

(8) Figures 2C and 2D - Can the authors provide an explanation why the pie-1p::him-5 transgene fails to suppress the phenotypes in dsb-1, while the him-5p::him-5 trasgene can? Again, the rationale for these experiments is unclear. Because of this, the interpretation is also unclear.

The difference in rescue between the pie-1p::him-5 and him-5p::him-5 transgenes likely reflects differences in expression levels. As previously shown (McClendon et al., 2016), the him-5p::him-5 construct results in significantly higher expression of HIM-5 protein compared to pie-1p::him-5. This elevated expression likely explains its ability to partially rescue the dsb-1 phenotype. In contrast, the lower expression driven by the pie-1 promoter is insufficient to compensate for the absence of dsb-1 function. We have clarified the rationale and interpretation of these experiments in the revised manuscript to better reflect this point.

(9) Lines 184-185 - the data for endogenously tagged HIM-5::3xHA are not shown anywhere in the paper. This must be shown.

We have added this in the supplemental figures.

(10) Figure 2D and 2E - what does the localization of pie-1p::him-5::GFP (eaIs15) and him5p::him-5::GFP (eaIs4) look like in wild-type and dsb-1 mutants? Are the cytoplasmic aggregates caused by increased levels of HIM-5 expression? Can the differential behavior of him-5 transgenes provide explanation for differential rescues?

We now show both live and fixed images of Phim-5::him-5::gfp transgenes, as well as the localization of the endogenously HA-tagged HIM-5 locus (Figure 2 and S3). In all cases, the protein is initially nuclear and then absent from meiotic nuclei with similar timing. The Ppie1::him-5 transgene was very difficult to image due to low expression (even in wild type) so it not shown here. We presume it is the slightly elevated level of expression of the Phim5::him-5::gfp that can explain the differential rescue.

(11) Lines 221-222, where are the results shown? Please refer to Figure S3.

Done

(12) Figure S3 - these need statistical analyses.

Done

(13) Lines 230-231 - what about the rec-1; parg-1; cep-1 triple mutant?

This is an excellent suggestion and not one we have not yet pursued. Given the lack of strong phenotypes in all combination of double mutants, we prioritized other experiments . However, we agree that examining the rec-1; parg-1; cep-1 triple mutant would provide a valuable test of whether these factors act in the same pathway, and we appreciate the reviewer highlighting this potential future direction.

(14) Line 298 - I suggest the authors take a look at the Alphafold prediction of DSB-1/DSB-2/DSB-3 and the comparison to human and budding yeast Rec114/Mei4 complex in Guo et al., 2022 eLife, which could provide insights into the Y2H results.

We thank the reviewer for these comments and have indeed used these interactions and predicted homologies to zero in a region of interaction between these proteins that resembles what is seen in humans and yeast with a dimer of REC114 like proteins wraps stabilizing a central Mei4 helix . This is now shown in Figure 3H, I. Satisfyingly, this modeling predicts that a trimer comprised of 2 DSB-1 proteins with DSB-3 is more stable than a DSB1-DSB-2-DSB-3 trimer. This might explain why DSB-2 is not required in young adults and only becomes essential as DSB-1 levels drop in older animals (Rosu et al., 2013)

(15) Can the authors introduce mutations within the DSB-1 interfaces that disrupt the interaction to either SPO-11 or DSB-2?

We have begun to address this question by introducing targeted mutations within DSB-1. As shown in Figure 3E and 3F, mutations in the C-terminal region of DSB-1—which includes a core of four α-helices—disrupt its interaction with DSB-2 and DSB-3, but not with SPO-11. These findings suggest that the C-terminus mediates interactions specifically with DSB2 and DSB-3

(16) Line 323 - The him-5 phenotypes are too weak to support the idea that it serves as the linchpin for the whole DSB complex. Do the authors have an explanation for why him-5 mutants exhibit X-chromosome-specific DSB defects?

In response to the reviewer, above, and in the text, we have included a more detailed explanation of why we think HIM-5 has a key role in coordinating meiotic break formation. Although, identified for its role on the X, the phenotypes associated with DSB formation in the mutant are really quite pleiotropic and severe.

(17) Line 436 - C. elegans lacks DSB hotspots.

Removed

Minor comments:

(1) Figure 1A - please show the raw data for the yeast two-hybrid.

We show representative yeast colonies in Figure S3.

(2) It looks like the labeling for Figure 1B and 1C are switched.

Fixed.

(3) Figure 1B - what does the red box indicate? Please explain it in the legend.

It indicates the XND-1 band. We added that information in the legend.

(4) Figure 1C - in the legend, it was noted that the results are from GFP pulldowns of HIM17::GFP. However, the method for Figure 1B and the method section noted that HIM-17 was tagged with 3xHA, and the pull-down was performed using anti-HA affinity matrix. Please reconcile this discrepancy.

That’s because they were done in two different sets of experiments. For the IPs we used a HIM-17::HA strain and for the MS, a HIM-17::GFP strain.

(5) Also in Figure 1C - please call Table S2 in the main text when discussing the mass spec results. Also, it is not clear what HIM-17 and GFP indicate in the table. What makes CKU80 different from the other proteins listed under GFP? Please explain more clearly in the legend.

We have move the table to supplemental data where we have included all of the peptide counts and gene coverage. We have included in the revised method rationale for inclusion in this table which explains why CKU-80 differs.

(6) Line 527 - it is unclear what experiment was done for HIM-17. Please revise it to indicate that this is for "HIM-17 immunoprecipitation". Also please indicate the strain used for HIM17 pull-down (AV280?).

(7) Line 113- please be specific about how the HIM-17 IP was performed. Which epitope and strains are used for pull-downs?

This indeed was AV280. This has been added to the text and methods.

(8) Figure 1D- What does ND mean? In the text, it was stated that there was only a minor suppression of hatching rates. The hatching rate for him-5p::him-5; him-17 must have been measured, and the data must be presented.

ND does mean not determined. We have removed the statement about “minor suppression”. We only tested the overall population dynamics in the Phim-5::him-5;him17(ok424) and the DAPI body counts. The failure to suppress the latter suggests there would be no enect on hatching rates, although we did not test this directly. Since we had done this for the Ppie-1::him-5;him-17 strain, we provided this information to further support the claims of genetic rescue by ectopic expression.

(9) Line 151 - please specify that STED was used.

We have removed the STED images, and just show the confocal images with Lightning Processing.

(10) Figure 1E- the authors suggested that HIM-17 and XND-1 mainly localize to autosomes but not the X chromosome. However, there is not enough evidence that the chromosome excluded from HIM-17 staining is indeed an X chromosome.

(11) Figure 1E (Line 154) - what are the active chromatin markers examined? Where are the data?

We have previously shown that the chromosome lacking XND-1 staining is the X (Wagner et al., 2010). The X is heterochromatic and chromatin marks associated with active transcription, including H3K4me3 and HTZ-1 (a variant H2A), preferentially localize to autosomes, effectively anti-marking the X chromosome. As shown in the new Figure 1E, a single chromosome has very little XND-1 and HIM-17 associated proteins. This is the X chromosome.

(12) Line 172 - It should be a comma instead of the period after "In dsb-1 mutants".

Fixed

(13) Figure S3H-K - I suggest the authors indicate the alleles of mre-11 (null vs. iow1) on the graph, similarly to him-5(e1490) to avoid confusion.

Done

(14) Lines 294 and 600 - Guo et al. 2022 is now published in eLife. The authors must cite the published paper, not the preprint.

Fixed

(15) Line 407 - the reference Carelli et al., 2022 is missing.

Added

(16) Line 766 - please remove "is" before nuclear.

Done

Reviewer #3 (Recommendations For The Authors):

Major issues:

In my view, the most interesting mechanistic finding in the paper is the evidence that HIM-5 may not bind to chromatin in the absence of DSB-1. If validated, this would suggest that HIM-5 is likely to be directly involved in a process that promotes break formation, in contrast to factors such as HIM-17 and XND-1. It does not, however, support the idea that HIM-5 is at the top of a hierarchy of DSB factors, as it is interpreted here. More importantly, the data supporting this claim are unconvincing; only a single image of an unfixed gonad from an animal expressing HIM-5::GFP is shown. Immunofluorescence should be performed and the results must be quantified.

We have provided additional images of the HIM-5 relocalization to show that we observed this in both fixed and live worms with two different tagged strains. The exclusion from the nucleus is seen in all scenarios. Whether the protein now accumulates exclusively in the cytoplasm/ is destabilized is challenging to address with the fixed images due to the arbitrariness of defining “background” staining.

More generally, this type of analysis, looking at the interdependence of different factors for their association with chromosomes, is much more informative than the genetic interaction data presented in the paper, which does not seem to provide any mechanistic insights into the functions of the factors analyzed. The paper could potentially be greatly improved through a more extensive, systematic analysis of the interdependence of DSBpromoting factors for their localization to chromosomes.

We have at least added this for XND-1 and HIM-17 and show they are not interdependent for chromosome association. We also provide for the first time data on the localization of HIM-5 in the dsb-1 mutant. Many of the other interactions have already been shown in the literature and/or were not warranted base on the lack of genetic interaction we present here.

Minor issues:

The title is vague and inconclusive. A more concrete title summarizing the major findings would help readers to assess whether the work is of interest.

We have discussed the title extensively with all authors and all would like to keep the current title.

The authors claim that the expression of HIM-5 from a different promoter (Ppie-1::him-5) but not its endogenous promoter (Phim-5::him-5) can partially rescue the DSB defect in him-17 mutants. To support this claim, they should really quantify the germline expression of HIM-5 in wild-type, him-17, him-17; Ppie-1::him-5, and Phim-5::him-5; him-17.

We had previously reported the expression in the N2 background of both transgenes (McClendon et al., 2016)

Panel O appears to be missing from Figure S3.

Fixed

The evidence for chromosome fusions in cep-1; mre-11 mutants shown in S4D is not convincing and the claim should be removed unless stronger evidence can be obtained.

A clearer image has been added

The basis of the following statement is unclear: "Furthermore, rec-1;him-5 double mutants give an age-dependent severe loss of DSBs (like dsb-2 mutants) suggesting that the ancestral function of the protein may have a more profound effect on break formation." The manuscript does not seem to include data regarding age-dependent loss of DSBs and no other publication is cited to support this claim. The interpretation is also perplexing; I think that it may be predicated on the idea that REC-1 and HIM-5 are paralogs, but as stated above, this claim is not well supported and is likely specious.

We have added the reference. This was shown in Chung et al., 2013 – the paper that presented the cloning of the rec-1 locus.

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Dossier d'Information : La Méthode Réconciliations

Résumé

La méthode "Réconciliations" est une approche pédagogique innovante, conçue par Jérémie Fontanieu, professeur de sciences économiques et sociales (SES), et son ancien collègue David Benoit, professeur de mathématiques au lycée de Drancy.

Née en 2012 du constat de la démotivation des élèves, de l'épuisement des enseignants et de la rupture de communication entre l'école et les familles, cette méthode repose sur un principe fondamental : la création d'une alliance solide et proactive entre les professeurs et les parents.

Le protocole s'articule autour de deux piliers : un appel téléphonique à chaque famille avant même la rentrée scolaire pour établir un contact de confiance, suivi de l'envoi d'un SMS individualisé et hebdomadaire pour maintenir un dialogue constant tout au long de l'année.

En transformant les parents en "alliés indéfectibles", la méthode change la dynamique de la classe.

Les élèves, conscients de cette communication permanente, deviennent plus engagés et responsables, ce qui enclenche un cercle vertueux de progrès, d'encouragements et de réussite.

Les résultats sont probants : la classe de Jérémie Fontanieu affiche 100% de réussite au baccalauréat depuis l'année scolaire 2017-2018.

Au-delà des performances académiques, la méthode réduit considérablement le temps consacré à la discipline, diminue le sentiment d'isolement des professeurs et réconcilie les enseignants avec leur métier.

Développée de manière indépendante, sans soutien institutionnel, la méthode se diffuse via un collectif d'enseignants qui comptait 350 membres pour l'année 2023/2024, avec un objectif de 1000 participants.

Flexible, elle est appliquée avec succès de l'école primaire au lycée, dans des contextes socio-économiques variés, des zones prioritaires aux centres-villes et zones rurales.

1. Genèse et Contexte de la Méthode

La méthode Réconciliations est née d'une série de constats alarmants sur l'état du système éducatif, particulièrement exacerbés dans des contextes socio-économiques difficiles comme la Seine-Saint-Denis.

A. Les constats initiaux

Jérémie Fontanieu identifie plusieurs sources de frustration et d'échec qui ont motivé le développement de son approche :

• L'épuisement et le désespoir des enseignants : Particulièrement chez les plus jeunes, un sentiment d'abandon par l'institution face à la "violence de ce métier" et une impuissance face à des adolescents qui "gâchent leur potentiel".

Les professeurs se sentent seuls à porter toutes les responsabilités.

• La démotivation des élèves : Souvent "accros aux écrans et aux réseaux sociaux", les élèves manquent d'implication dans leur scolarité, ce qui accroît la frustration de leurs professeurs.

Ils ont "la flemme" ou manquent de confiance en eux.

• La rupture entre parents et enseignants : Une distance, voire une confrontation, entre ces deux pôles éducatifs, marquée par des "quiproquos et des failles" que les élèves exploitent.

Les parents, souvent tenus à l'écart, reçoivent des informations partielles de leurs enfants.

Les appels de l'école sont quasi systématiquement perçus comme des annonces de mauvaises nouvelles.

• Le sentiment d'abandon généralisé : En Seine-Saint-Denis, élèves et parents se sentent délaissés par l'Éducation nationale et la République, percevant l'école comme une "machine à broyer" incapable de les intégrer.

Ce sentiment est également partagé par les enseignants face à la pénurie structurelle, les faibles salaires et la dégradation des conditions de travail.

B. La déconstruction du "Mythe du prof héros"

Jérémie Fontanieu, dans son livre Le Mythe du prof héros, analyse une construction culturelle qu'il juge toxique.

Ce mythe, hérité des "hussards noirs de la République" du XIXe siècle, place l'enseignant sur un piédestal et lui attribue des capacités extraordinaires.

• Un mythe à double tranchant : Si l'idée de valoriser les professeurs est belle en apparence, elle conduit les parents à se décharger entièrement sur l'enseignant ("les laisser gérer").

• Une source de culpabilité : Pour les professeurs, cette attente irréaliste engendre un "sentiment de culpabilité de ne pas réussir à être à la hauteur du mythe".

• Un frein à l'implication parentale : Ce mythe dissuade les parents de s'impliquer, alors même qu'ils ont un rôle crucial à jouer.

Fontanieu insiste sur le fait que l'implication parentale n'est pas forcément intellectuelle mais relève de "l'attention morale", du soutien aux valeurs d'honnêteté et de courage, communes à l'éducation parentale et scolaire.

2. Principes Fondamentaux et Mécanisme Opérationnel

La méthode Réconciliations repose sur une stratégie de co-éducation proactive, simple et structurée, visant à faire des parents des partenaires centraux du processus éducatif.

A. Le socle : l'alliance parents-professeurs

L'idée centrale est de "nouer le dialogue" entre professeurs et parents pour créer un binôme solide.

En informant systématiquement les parents, l'enseignant change de statut aux yeux des élèves.

Ces derniers, réalisant que leurs parents et professeurs "sont devenus des amis", ne peuvent plus exploiter le manque de communication.

B. Le mécanisme en deux temps

La méthode s'appuie sur deux actions clés, mises en œuvre dès le début de l'année scolaire.

Étape

Description

Objectifs

1. L'appel téléphonique initial

L'enseignant contacte chaque famille personnellement "le 31 août ou le 1er septembre", avant même qu'un problème ne survienne.

• - Établir la confiance : Les parents, "positivement surpris", apprécient cette attention et deviennent rapidement des alliés.<br>\
• • Présenter la démarche : L'enseignant explique sa méthode et son intention de collaborer.<br>\
• • Dédramatiser la communication : L'appel n'est pas lié à une sanction, ce qui change la perception de l'école.

2. Les SMS hebdomadaires

Chaque semaine, un SMS individualisé est envoyé à chaque famille pour l'informer du comportement et du travail de l'enfant, "y compris lorsqu’il n’y a pas de problème".

• - Maintenir un dialogue constant : Assurer un suivi régulier et éviter les ruptures de communication.<br>
• - Valoriser et encourager : Les SMS permettent de féliciter les efforts et les progrès, renforçant la motivation.<br>\
• • Assurer la cohésion : Le fait que tous les élèves soient concernés, qu'ils soient en difficulté ou non, évite la stigmatisation et favorise la solidarité.

Jérémie Fontanieu souligne que cette approche est "contre-intuitive" car elle demande un investissement de travail supplémentaire en début d'année, mais que ce temps est "largement rentabilisé" par la suite.

3. Impacts et Résultats Observés

La mise en place de la méthode Réconciliations génère des effets positifs et mesurables sur l'ensemble des acteurs du système éducatif : élèves, enseignants et parents.

A. Sur les élèves

• Engagement accru : Constatant l'alliance entre parents et professeurs, les élèves deviennent "moins passifs et plus engagés" et prennent leurs responsabilités.

• Cercle vertueux de la réussite : L'investissement croissant des élèves entraîne des progrès, qui sont salués par les adultes (parents et professeurs).

Ces encouragements renforcent à leur tour l'implication, créant "une dynamique de réussite, de confiance et d'espoir pour tous".

• Amélioration des résultats scolaires : Depuis l'année scolaire 2017-2018, la classe de terminale de Jérémie Fontanieu affiche un taux de 100% de réussite au baccalauréat.

Les élèves terminent le programme en avance, ce qui leur laisse "beaucoup de temps pour réviser".

• Gain de confiance : La méthode permet aux élèves de réussir "là où ils pensaient ne pas en être capable", ce qui les encourage à poursuivre des études supérieures.

B. Sur les enseignants

• Réduction de la charge disciplinaire : Le partenariat avec les parents diminue les comportements perturbateurs. C'est "de l'énergie dépenser en moins à faire sa discipline".

• Fin de l'isolement : Les professeurs ne se sentent plus seuls à tout porter sur leurs épaules.

Ils trouvent un soutien précieux chez les parents, qui deviennent des "alliés indéfectibles" les protégeant des "violences du métier".

• Réconciliation avec le métier : La méthode permet aux enseignants de se consacrer à leur cœur de métier : l'enseignement. Jérémie Fontanieu évoque "une réconciliation entre nous, enseignants, et notre métier".

• Gestion du temps optimisée : Bien que l'approche puisse sembler chronophage, elle fait en réalité gagner "beaucoup de temps" en réduisant les conflits et en augmentant l'implication des élèves.

C. Sur les parents

• Partenaires actifs : Les parents deviennent des "acteurs clés" et des partenaires fiables, intégrés au processus éducatif.

• Influence positive : Ils réalisent l'influence qu'ils peuvent avoir, même sans compétences académiques spécifiques. Leur rôle est un levier d'attention morale et de soutien.

• Relation apaisée avec l'école : La communication régulière et positive transforme la relation, qui n'est plus basée sur la crainte des mauvaises nouvelles.

4. Le Collectif "Réconciliations" : Diffusion et Organisation

La méthode, initialement expérimentale, est aujourd'hui portée par un collectif d'enseignants en pleine croissance, qui fonctionne sur un modèle horizontal et indépendant.

A. Historique et croissance

• Développement : La méthode a été développée à partir de 2012 au lycée Eugène Delacroix de Drancy.

• Création du collectif : Après avoir constaté des résultats "suffisamment forts", le collectif est créé en 2021 pour partager la méthode.

• Expansion rapide : Le collectif est passé de 200 enseignants à 350 pour l'année 2023-2024, avec des projections autour de 500 pour 2024-2025.

• Objectif : Atteindre une masse critique de 1000 enseignants pour passer à une phase de diffusion à plus grande échelle via un site internet et un manuel.

B. Philosophie et indépendance

Le collectif revendique une indépendance totale et refuse "aucun soutien institutionnel". Jérémie Fontanieu explique ce choix : "Nous utilisons notre liberté pédagogique.

Nous sommes indépendants, et nous sommes très attachés à la diffusion horizontale de cette méthode, de professeur à professeur.

Nous grandissons plus lentement sans l’aide de l’État, mais de manière plus saine". La diffusion se fait principalement par le bouche-à-oreille.

C. Portée et applicabilité

La méthode Réconciliations démontre une grande flexibilité et s'adapte à divers contextes :

• Niveaux scolaires : Elle est appliquée de l'école primaire (CM2) jusqu'au lycée.

• Contextes géographiques et sociaux : Si elle est née en "quartier populaire", environ la moitié des enseignants qui l'utilisent travaillent en zones rurales ou dans des établissements de centre-ville, prouvant sa pertinence au-delà des zones d'éducation prioritaire.

5. Accès à la Méthode et Ressources Disponibles

Pour préserver la qualité de l'accompagnement, l'accès à la méthode est actuellement contrôlé par son fondateur en attendant que le collectif atteigne sa taille cible.

• Comment participer : Les enseignants intéressés doivent contacter directement Jérémie Fontanieu par email à l'adresse projet.reconciliations@gmail.com.

Les détails de la méthode restent "assez secrets" et ne sont pas communiqués publiquement pour le moment.

• Outils de soutien pour les membres : Les professeurs qui rejoignent le collectif ont accès à un ensemble d'outils pratiques :

• ◦ Vidéos et tutoriels (notamment pour la rédaction des SMS).   
• ◦ Groupes de discussion en ligne.   
• ◦ Visioconférences hebdomadaires.   
• ◦ Une rencontre annuelle pour un suivi et une formation continue.

• Ressources publiques : Pour en savoir plus sur la philosophie de la méthode, le public peut consulter :

• ◦ Le livre de Jérémie Fontanieu, "Le Mythe du prof héros".   
• ◦ Le film documentaire "Le Monde est à eux", sorti au cinéma en mars 2024.   
• ◦ Un deuxième documentaire disponible en ligne, montrant l'application de la méthode en écoles primaires et au collège.

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Santé Mentale et Handicap : Synthèse de l'Audition de la Défenseure des droits

Résumé Exécutif

Ce document de synthèse présente les constats et analyses clés issus de l'audition de Claire Hédon, Défenseure des droits, devant la commission d'enquête sur les défaillances des politiques publiques en matière de santé mentale et de handicap. L'audition révèle une divergence critique entre les droits proclamés par la loi et leur application effective sur le terrain. Le handicap demeure le premier motif de saisine pour discrimination, signalant des failles systémiques dans des domaines essentiels tels que l'éducation, l'emploi et l'accessibilité. La situation de la santé mentale est jugée particulièrement alarmante, avec un système de soins insuffisant et cloisonné pour les adultes, et des conditions critiques pour les mineurs marqués par des délais d'attente insoutenables et des pratiques d'hospitalisation inadaptées. La Défenseure des droits soutient que le non-respect des droits fondamentaux, loin d'être une économie, engendre un coût social et financier élevé à long terme. La collecte de données fiables, l'application rigoureuse des textes existants et une approche décloisonnée sont identifiées comme des leviers indispensables pour remédier à ces défaillances.

1. Le Défenseur des droits : Un Observatoire des Défaillances Systémiques

L'institution du Défenseur des droits, par ses cinq domaines de compétence (droits des usagers des services publics, lutte contre les discriminations, droits de l'enfant, déontologie de la sécurité, protection des lanceurs d'alerte), constitue un observateur privilégié des carences des politiques publiques relatives au handicap et à la santé mentale.

Le Handicap comme Premier Motif de Discrimination

Claire Hédon souligne que le handicap est, depuis plusieurs années, le premier motif de saisine en matière de discrimination, ce qui témoigne de difficultés persistantes et généralisées.

• Statistiques Clés (2024) :

◦ Total des saisines pour discrimination : 5 679    ◦ Part concernant le handicap : 22 % (soit 1 249 réclamations)

Ces discriminations s'exercent dans de multiples domaines : emploi, scolarisation, accès à la santé, à la justice, aux loisirs, au sport et à la culture.

Le Coût du Non-Respect des Droits

La Défenseure des droits conteste l'idée selon laquelle l'application des droits fondamentaux représenterait un coût financier excessif. Elle affirme sa conviction que "c'est le non-respect des droits fondamentaux qui entraînera à terme un coût élevé pour la société". L'approche de l'institution se concentre sur "l'écart entre le droit annoncé et son effectivité", soulignant que les défaillances actuelles génèrent un coût social majeur.

2. La Santé Mentale : Une Crise des Droits Fondamentaux

L'audition met en lumière une crise profonde dans la prise en charge de la santé mentale en France, exacerbée par la crise sanitaire du Covid-19. Les politiques publiques sont jugées insuffisantes tant en quantité qu'en organisation.

2.1. Prise en Charge des Adultes : Un Système Insuffisant et Cloisonné

Le système de soins pour adultes souffre de faiblesses structurelles majeures :

• Offre de soins : Des offres trop faibles, des capacités d'hospitalisation limitées et des déserts médicaux.

• Organisation : Un système mal organisé et cloisonné entre les secteurs sanitaire et médico-social.

• Ressources : Des moyens qui stagnent alors que les besoins augmentent, rendant les conditions d'exercice indignes pour les soignants et les patients.

Conséquences pour les patients :

• Délais d'attente excessifs.

• Ruptures de soins fréquentes et errance sanitaire.

• Inégalités territoriales criantes, pénalisant particulièrement les personnes précaires.

Focus : La Situation Critique des Personnes Détenues

La santé mentale des personnes détenues est une préoccupation majeure, avec une surreprésentation des pathologies et troubles mentaux en milieu carcéral.

• Appels à la plateforme (3141) de juillet 2024 à juillet 2025 :

◦ 7,6 % des appels concernaient des difficultés d'accès aux soins (1 065 appels).    ◦ 106 appels portaient spécifiquement sur un risque suicidaire.

Causes identifiées :

1. La politique de désinstitutionnalisation : Menée sans un développement suffisant des services de proximité pour prendre le relais des services hospitaliers psychiatriques.

2. La diminution des déclarations d'irresponsabilité pénale : Conduisant au maintien en détention de personnes dont l'état de santé nécessiterait une prise en charge dans une structure de soins.

La Cour européenne des droits de l'homme (arrêt GC c. France, 2012) a qualifié cette situation de "traitement inhumain". Le manque de continuité des soins à la sortie de prison augmente par ailleurs le risque de récidive.

2.2. Santé Mentale des Mineurs : Une Situation Alarmante

Les données concernant la santé mentale des jeunes sont particulièrement inquiétantes. Une étude de 2025 (Institut Montaigne, Mutualité française, Institut Terram) révèle que 25 % des jeunes de 15 à 29 ans souffrent de dépression, un chiffre atteignant 39 % en outre-mer.

Carences Structurelles de la Pédopsychiatrie

• Absence de données fiables : Le manque de données agrégées sur le nombre d'enfants en attente de prise en charge "fragilise le pilotage de nos politiques publiques". Le rapport 2023 de la Cour des comptes estime que sur 1,6 million d'enfants souffrant d'un trouble psychique, seuls 50 à 53 % bénéficient de soins.

• Pénurie de médecins et inégalités territoriales : Malgré des infrastructures dans la moyenne européenne, le secteur est saturé. Les Centres Médico-Psychologiques (CMP) sont inégalement répartis, et les délais pour obtenir un premier rendez-vous dépassent souvent un an.

Pratiques Inadaptées et Atteintes aux Libertés

Des pratiques préoccupantes sont régulièrement signalées :

• Hospitalisation en services pour adultes : Des enfants et adolescents sont hospitalisés dans des services de psychiatrie adulte, une situation qui "ne fait que s'aggraver".

• Maintien par défaut : Des jeunes en situation de handicap sont maintenus en structure psychiatrique faute de places dans le secteur médico-social ou en protection de l'enfance.

• Recours à l'isolement et à la contention : Ces mesures de dernier recours sont utilisées de manière trop fréquente, souvent motivées par un manque de personnel. Pour les mineurs hospitalisés en "soins libres" (à la demande des parents mais sans leur propre consentement), il n'existe aucun contrôle systématique par un juge des libertés et de la détention (JLD), contrairement aux adultes.

Exemple emblématique : Une adolescente de 15 ans, atteinte d'autisme sévère, a été hospitalisée pendant plus de deux ans dans un service psychiatrique pour adultes, sans justification médicale. Elle était confinée dans une chambre d'isolement "plus de 20 heures par jour", déscolarisée et privée de soins somatiques essentiels.

3. Politiques du Handicap : Des Droits Proclamés mais Non Effectifs

Vingt ans après la loi de 2005, son application reste partielle et les obstacles à l'inclusion demeurent nombreux.

3.1. Éducation : Une Inclusion Inachevée

Bien que la loi de 2005 ait permis une augmentation du nombre d'enfants handicapés scolarisés, l'accès à une éducation de qualité reste difficile.

Catégorie de réclamation (2024)

Chiffres et pourcentages

Discrimination liée à l'éducation/formation

7 % des 5 679 saisines

Droits de l'enfant (majorité liée à la scolarisation)

30 % des 3 073 saisines

Obstacles persistants :

• Manque d'AESH : Malgré les créations de postes, les besoins ne sont pas couverts.

• Pause méridienne : La loi du 27 mai 2024 prévoyant la prise en charge par l'État de l'accompagnement sur le temps de la pause méridienne est "très loin d'être effective" en raison de blocages administratifs.

• Aménagement des examens : Une augmentation inquiétante des refus d'aménagement pour des élèves ou étudiants handicapés, parfois sous le prétexte paradoxal que "leurs résultats étaient bons".

3.2. Emploi : Premier Domaine de Discrimination

L'emploi est le principal secteur où s'exercent les discriminations liées au handicap. Sur les réclamations pour handicap en 2024, 21 % concernent l'emploi privé et 24 % l'emploi public. L'obligation d'emploi de 6 % ne suffit pas à garantir l'égalité de traitement.

Difficultés récurrentes :

• Aménagement tardif du poste de travail.

• Non-respect des préconisations du médecin du travail.

• Difficultés accrues dans le maintien dans l'emploi pour les personnes dont le handicap ou la maladie survient en cours de carrière.

3.3. Accessibilité : Un Retard Persistant

L'accessibilité, condition essentielle à la participation sociale, reste un point faible majeur.

• Transports : L'objectif de mise en accessibilité n'est pas atteint, la loi s'étant limitée aux "points d'arrêt prioritaires".

• Logement : Inquiétude face à l'assouplissement des règles d'accessibilité (loi ELAN).

• Numérique : La dématérialisation produit des effets ambivalents. Selon l'ARCOM, peu de sites publics atteignent 50 % d'accessibilité et seulement 5 % sont totalement conformes.

3.4. Aides à l'autonomie : Une Compensation Insuffisante et Inégale

Le droit à la compensation instauré par la loi de 2005 présente des limites flagrantes.

• La barrière des 60 ans : Une différence de traitement persiste selon que le handicap survient avant ou après 60 ans, la fusion des régimes prévue pour 2010 n'ayant jamais eu lieu.

• Limites de la PCH (Prestation de Compensation du Handicap) :

◦ L'aide humaine est limitée aux besoins essentiels.    ◦ Les aides techniques sont sous-financées.    ◦ La PCH parentalité est critiquée pour ses critères restrictifs.

4. Recommandations et Perspectives

L'audition se conclut sur plusieurs axes d'action prioritaires pour remédier aux défaillances constatées.

• Application des textes : L'urgence est "l'application pure et simple des textes votés par le Parlement", dont beaucoup sont en attente de décrets d'application.

• Données statistiques : Il est impératif de disposer de données fiables et agrégées (ex : nombre d'heures de scolarisation effectives, nombre de places manquantes en IME) pour piloter les politiques publiques.

• Décloisonnement : Renforcer la coordination entre les secteurs sanitaire, médico-social, éducatif et judiciaire est crucial pour assurer la fluidité des parcours.

• Priorité à la jeunesse : La santé mentale des jeunes, érigée en grande cause nationale 2025, nécessite une "véritable prise de conscience collective" et des moyens financiers adéquats, notamment pour les CMP.

• Formation : L'amélioration de la formation des professionnels (enseignants, AESH, employeurs, soignants) est essentielle pour faire évoluer les pratiques et les cultures professionnelles.

• Lutte contre la complexité administrative : Le "mille-feuille" des dispositifs doit être simplifié pour améliorer la lisibilité et l'accès aux droits pour les familles.

technical problems

• Tema: 950
• Processo(s): RE 632.115
• Relator: Min. Luís Roberto Barroso
• Título: Responsabilidade civil objetiva do Estado por atos protegidos por imunidade parlamentar.

O Tribunal fixou a seguinte tese: - 1. A imunidade material parlamentar (art. 53, caput, c/c art. 27, § 1º, e art. 29, VIII, CF/1988) configura excludente da responsabilidade civil objetiva do Estado (art. 37, § 6º, CF/1988), afastando qualquer pretensão indenizatória em face do ente público por opiniões, palavras e votos cobertos por essa garantia.

• 2. Nas hipóteses em que a conduta do parlamentar extrapolar os limites da imunidade material, eventual responsabilização recairá de forma pessoal, direta e exclusiva sobre o próprio parlamentar, sob o regime de responsabilidade civil subjetiva.

<u>HEMENÊUTICA CONSTITUCIONAL</u>

MÉTODO TÓPICO-PROBLEMÁTICO - Fonte: A Tópica e a Argumentação Jurídica, por Thomas da Rosa de Bustamante

Resumo: A Tópica Jurídica de Theodor Viehweg

I. Definição, Contexto e Propósito

Marco no Pensamento Jurídico: A obra Tópica e Jurisprudência (1953) rompeu com o positivismo dominante, que via o jurista como um mero aplicador da lei.

Crítica ao Positivismo: Em um contexto pós-guerra, a Tópica surgiu como resposta à incapacidade do positivismo de lidar com juízos de valor de forma racional. Viehweg buscou recuperar a razão prática para controlar a racionalidade das decisões.

II. Os Três Pilares Conceituais

1. A Aporia (O Problema)
   • Definição: Uma "questão estimulante e ineludível" que admite mais de uma resposta.
   • Aporia Fundamental do Direito: "O que é justo aqui e agora".
   • Função: É o ponto de partida do pensamento, estimulando a busca por uma solução.
2. A Tópica (O Método)
   • Definição: Uma técnica de pensamento orientada pelo problema (techne), não uma ciência com verdades absolutas (episteme).
   • Função Principal: É uma "arte de invenção" (ars inveniendi) para buscar e encontrar as premissas do raciocínio.
   • Natureza: Dialética, partindo de opiniões verossímeis e aceitas (endoxa).
3. O Topos (A Ferramenta)
   • Definição: Os topoi (plural) são "pontos de vista utilizáveis e aceitáveis" que servem como "fórmulas de procura" para argumentos.
   • Tipos: A Tópica pode ser de primeiro grau (busca casual de topoi) ou de segundo grau (uso de catálogos de topoi já consolidados).

III. Tópica vs. Pensamento Sistemático

Pensamento Sistemático: Parte de um sistema fechado para deduzir soluções. A prioridade é o sistema.

Pensamento Tópico: Parte do problema concreto (aporia) para buscar, em vários sistemas, a melhor solução. A prioridade é o problema.

IV. Legado e Críticas

Legado:

• Ponto de partida das teorias modernas da argumentação jurídica.
• Revelou o raciocínio jurídico como um processo dialógico e discursivo.
• Mudou o foco da linguagem jurídica para sua dimensão pragmática.

Críticas:

• Não estabelece hierarquia ou regras de preferência entre topoi conflitantes.
• Não deixa claro o papel da lei, que poderia ser vista como apenas mais um topos.
• Partiu de um conceito restrito de "sistema", que o próprio Viehweg reviu posteriormente.

• Informativo 1110
• RE 1017365 / SC - Tema nº 1031
• Órgão julgador: Tribunal Pleno
• Relator(a): Min. EDSON FACHIN
• Julgamento: 27/09/2023 (Presencial)
• Ramo do Direito: Constitucional, Administrativo
• Matéria: Ordem Social; Índios; Demarcação de Terras; Posse Tradicional; Direito Originário Territorial/Domínio Público; Terras Indígenas; Procedimento Declaratório de Direito Originário

Demarcação de terras tradicionalmente indígenas: desnecessidade de um marco temporal como parâmetro à declaração do direito originário territorial

Tese fixada - I - A demarcação consiste em procedimento declaratório do direito originário territorial à posse das terras ocupadas tradicionalmente por comunidade indígena;

• II - <u>A posse tradicional indígena é distinta da posse civil</u>, consistindo na ocupação das terras habitadas em caráter permanente pelos indígenas, nas utilizadas para suas atividades produtivas, nas imprescindíveis à preservação dos recursos ambientais necessários a seu bem-estar e nas necessárias a sua reprodução física e cultural, segundo seus usos, costumes e tradições, nos termos do § 1º do artigo 231 do texto constitucional;

• III - A proteção constitucional aos direitos originários sobre as terras que tradicionalmente ocupam independe da existência de um marco temporal em 05 de outubro de 1988 ou da configuração do renitente esbulho, como conflito físico ou controvérsia judicial persistente à data da promulgação da Constituição;

• IV – Existindo ocupação tradicional indígena ou renitente esbulho contemporâneo à promulgação da Constituição Federal, aplica-se o regime indenizatório relativo às benfeitorias úteis e necessárias, previsto no § 6º do art. 231 da CF/88;

• V – Ausente ocupação tradicional indígena ao tempo da promulgação da Constituição Federal ou renitente esbulho na data da promulgação da Constituição, são válidos e eficazes, produzindo todos os seus efeitos, os atos e negócios jurídicos perfeitos e a coisa julgada relativos a justo título ou posse de boa-fé das terras de ocupação tradicional indígena, assistindo ao particular direito à justa e prévia indenização das benfeitorias necessárias e úteis, pela União; e, quando inviável o reassentamento dos particulares, caberá a eles indenização pela União (com direito de regresso em face do ente federativo que titulou a área) correspondente ao valor da terra nua, paga em dinheiro ou em títulos da dívida agrária, se for do interesse do beneficiário, e processada em autos apartados do procedimento de demarcação, com pagamento imediato da parte incontroversa, garantido o direito de retenção até o pagamento do valor incontroverso, permitidos a autocomposição e o regime do § 6º do art. 37 da CF;

• VI – Descabe indenização em casos já pacificados, decorrentes de terras indígenas já reconhecidas e declaradas em procedimento demarcatório, ressalvados os casos judicializados e em andamento;

• VII – É dever da União efetivar o procedimento demarcatório das terras indígenas, sendo admitida a formação de áreas reservadas somente diante da absoluta impossibilidade de concretização da ordem constitucional de demarcação, devendo ser ouvida, em todo caso, a comunidade indígena, buscando-se, se necessário, a autocomposição entre os respectivos entes federativos para a identificação das terras necessárias à formação das áreas reservadas, tendo sempre em vista a busca do interesse público e a paz social, bem como a proporcional compensação às comunidades indígenas (art. 16.4 da Convenção 169 OIT);

• VIII – A instauração de procedimento de redimensionamento de terra indígena não é vedada em caso de descumprimento dos elementos contidos no artigo 231 da Constituição da República, por meio de pedido de revisão do procedimento demarcatório apresentado até o prazo de cinco anos da demarcação anterior, sendo necessário comprovar grave e insanável erro na condução do procedimento administrativo ou na definição dos limites da terra indígena, ressalvadas as ações judiciais em curso e os pedidos de revisão já instaurados até a data de conclusão deste julgamento;

• IX - O laudo antropológico realizado nos termos do Decreto nº 1.775/1996 é um dos elementos fundamentais para a demonstração da tradicionalidade da ocupação de comunidade indígena determinada, de acordo com seus usos, costumes e tradições, na forma do instrumento normativo citado;

• X - As terras de ocupação tradicional indígena são de posse permanente da comunidade, cabendo aos indígenas o usufruto exclusivo das riquezas do solo, dos rios e lagos nelas existentes;

• XI - As terras de ocupação tradicional indígena, na qualidade de terras públicas, são inalienáveis, indisponíveis e os direitos sobre elas imprescritíveis;

• XII – A ocupação tradicional das terras indígenas é compatível com a tutela constitucional do meio ambiente, sendo assegurado o exercício das atividades tradicionais dos povos indígenas;

• XIII – Os povos indígenas possuem capacidade civil e postulatória, sendo partes legítimas nos processos em que discutidos seus interesses, sem prejuízo, nos termos da lei, da legitimidade concorrente da FUNAI e da intervenção do Ministério Público como fiscal da lei.”

Resumo - O reconhecimento do direito às terras tradicionalmente ocupadas pelos indígenas não se sujeita ao marco temporal da promulgação da Constituição Federal (5/10/1988) nem à presença de conflito físico ou controvérsia judicial existentes nessa mesma data.

• Em mudança de posicionamento jurisprudencial, esta Corte concluiu pela inaplicabilidade da teoria do fato indígena e pela prevalência da teoria do indigenato, segundo a qual a posse dos indígenas sobre as terras configura um direito próprio dos povos originários e cuja tradicionalidade da ocupação deve ser considerada conforme os parâmetros expressamente previstos no texto constitucional (CF/1988, art. 231, §§ 1º e 2º).

• Se houver ocupação tradicional indígena ou renitente esbulho contemporâneo à data de promulgação da Constituição Federal de 1988, são assegurados aos não índios o direito à indenização pelas benfeitorias úteis e necessárias (CF/1988, art. 231, § 6º). Porém, na hipótese de inexistir quaisquer dessas situações, consideram-se válidos e eficazes os atos e negócios jurídicos perfeitos e a coisa julgada relativos a justo título ou posse de boa-fé das terras de ocupação tradicional indígena. Neste caso, o particular tem direito a ser previamente indenizado pela União ao valor correspondente às benfeitorias necessárias e úteis, ou, quando inviável o seu reassentamento, ao valor da terra nua (1).

• Com base nesses e em outros entendimentos, o Plenário, por maioria, ao apreciar o Tema 1.031 da repercussão geral, deu provimento ao recurso extraordinário para anular o acórdão recorrido e reformar a sentença de primeiro grau, julgando, por conseguinte, improcedentes os pedidos deduzidos na petição inicial.

A Constituição expressamente declarou a nulidade absoluta de títulos de propriedade ou de exploração de riquezas em terras tradicionalmente ocupados pelos índios.

Veja que, conforme art. 68 ADCT e art. 13 do Decreto nº 4.887/2003, essa proteção não abarca terras ocupadas por quilombolas e demais populações tradicionais. Acaso haja domínio particular sobre essas áreas, deve-se proceder com a desapropriação da área.

• ADI 4269
• Órgão julgador: Tribunal Pleno
• Relator(a): Min. EDSON FACHIN
• Julgamento: 18/10/2017
• Publicação: 01/02/2019

AÇÃO DIRETA DE INCONSTITUCIONALIDADE. DIREITO CONSTITUCIONAL E ADMINISTRATIVO. REGULARIZAÇÃO FUNDIÁRIA DAS TERRAS DE DOMÍNIO DA UNIÃO NA AMAZÔNIA LEGAL. IMPUGNAÇÃO AOS ARTIGOS 4º, §2º, 13, 15, INCISO I, §§ 2º, 4º E 5º, DA LEI Nº 11.952/2009. PREJUÍZO PARCIAL DA AÇÃO. ALTERAÇÃO SUBSTANCIAL E REVOGAÇÃO DE DISPOSITIVOS PROMOVIDA POR LEI SUPERVENIENTE. ADEQUADA PROTEÇÃO ÀS TERRAS QUILOMBOLAS E DE OUTRAS COMUNIDADES TRADICIONAIS AMAZÔNICAS. INCONSTITUCIONALIDADE DA INTERPRETAÇÃO QUE CONCEDE ESSAS TERRAS A TERCEIROS. INTERPRETAÇÃO CONFORME À CONSTITUIÇÃO. ARTIGOS 216, INCISO II, DO TEXTO CONSTITUCIONAL E 68 DO ADCT. AUSÊNCIA DE VISTORIA PRÉVIA NA REGULARIZAÇÃO DE IMÓVEIS DE ATÉ QUATRO MÓDULOS FISCAIS. PROTEÇÃO DEFICIENTE AO MEIO AMBIENTE SE DESACOMPANHADA DE MEIOS EFICAZES PARA FISCALIZAÇÃO DOS REQUISITOS DE INGRESSO NO PROGRAMA TERRA LEGAL. INTERPRETAÇÃO CONFORME À CONSTITUIÇÃO. RESPEITO AO ARTIGO 225, CAPUT, DA CONSTITUIÇÃO. - 1. Há prejuízo parcial da ação direta de inconstitucionalidade quando lei superveniente promova alteração substancial ou revogue dispositivo impugnado em demanda de controle concentrado, conforme jurisprudência pacífica desta Corte. No caso, a superveniência da Lei nº 13.465, de 11 de julho de 2017, alterou a redação do artigo 15, inciso I e §2º, bem como revogou expressamente seus §§ 4º e 5º, circunstância que impede o conhecimento da ação, no ponto. - 2. O direito ao meio ambiente equilibrado foi assegurado pela Constituição da República, em seu artigo 225, bem como em diversos compromissos internacionais do Estado Brasileiro. A região amazônica, dada a diversidade biológica, cultural, etnográfica e geológica, mereceu tutela especial do constituinte, tornando-se imperiosa a observância do desenvolvimento sustentável na região, conjugando a proteção à natureza e a sobrevivência humana nas áreas objeto de regularização fundiária.

• 3. Revela-se de importância ímpar a promoção de regularização fundiária nas terras ocupadas de domínio da União na Amazônia Legal, de modo a assegurar a inclusão social das comunidades que ali vivem, por meio da concessão de títulos de propriedade ou concessão de direito real de uso às áreas habitadas, redução da pobreza, acesso aos programas sociais de incentivo à produção sustentável, bem como melhorando as condições de fiscalização ambiental e responsabilização pelas lesões causadas à Floresta Amazônica.

• 4. O artigo 4º, §2º da Lei nº 11.952/2009 vai de encontro à proteção adequada das terras dos remanescentes de comunidades quilombolas e das demais comunidades tradicionais amazônicas, ao permitir interpretação que possibilite a regularização dessas áreas em desfavor do modo de apropriação de território por esses grupos, sendo necessária interpretação conforme aos artigos 216, I da Constituição e 68 do ADCT, para assegurar a relação específica entre comunidade, identidade e terra que caracteriza os povos tradicionais.

• 5. Exige interpretação conforme à Constituição a previsão do artigo 13 da Lei nº 11.952/2009, ao dispensar a vistoria prévia nos imóveis rurais de até quatro módulos fiscais, a fim de que essa medida de desburocratização do procedimento seja somada à utilização de todos os meios eficazes de fiscalização do meio ambiente, como forma de tutela à biodiversidade e inclusão social dos pequenos proprietários que exercem cultura efetiva na área.

• 6. Ação Direta de Inconstitucionalidade conhecida parcialmente e, na parte conhecida, julgada parcialmente procedente.

Legislação LEG-FED ADCT ANO-1988 ART-00068 ATO DAS DISPOSIÇÕES CONSTITUCIONAIS TRANSITÓRIAS

Outras ocorrências Doutrina (1)

• ADI 3239
• Órgão julgador: Tribunal Pleno
• Relator(a): Min. CEZAR PELUSO
• Redator(a) do acórdão: Min. ROSA WEBER
• Julgamento: 08/02/2018
• Publicação: 01/02/2019

AÇÃO DIRETA DE INCONSTITUCIONALIDADE. DECRETO Nº 4.887/2003. PROCEDIMENTO PARA IDENTIFICAÇÃO, RECONHECIMENTO, DELIMITAÇÃO, DEMARCAÇÃO E TITULAÇÃO DAS TERRAS OCUPADAS POR REMANESCENTES DAS COMUNIDADES DOS QUILOMBOS. ATO NORMATIVO AUTÔNOMO. ART. 68 DO ADCT. DIREITO FUNDAMENTAL. EFICÁCIA PLENA E IMEDIATA. INVASÃO DA ESFERA RESERVADA A LEI. ART. 84, IV E VI, "A", DA CF. INCONSTITUCIONALIDADE FORMAL. INOCORRÊNCIA. CRITÉRIO DE IDENTIFICAÇÃO. AUTOATRIBUIÇÃO. TERRAS OCUPADAS. DESAPROPRIAÇÃO. ART. 2º, CAPUT E §§ 1º, 2º E 3º, E ART. 13, CAPUT E § 2º, DO DECRETO Nº 4.887/2003. INCONSTITUCIONALIDADE MATERIAL. INOCORRÊNCIA. IMPROCEDÊNCIA DA AÇÃO. - 1. Ato normativo autônomo, a retirar diretamente da Constituição da República o seu fundamento de validade, o Decreto nº 4.887/2003 apresenta densidade normativa suficiente a credenciá-lo ao controle abstrato de constitucionalidade. - 2. Inocorrente a invocada ausência de cotejo analítico na petição inicial entre o ato normativo atacado e os preceitos da Constituição tidos como malferidos, uma vez expressamente indicados e esgrimidas as razões da insurgência. - 3. Não obsta a cognição da ação direta a falta de impugnação de ato jurídico revogado pela norma tida como inconstitucional, supostamente padecente do mesmo vício, que se teria por repristinada. Cabe à Corte, ao delimitar a eficácia da sua decisão, se o caso, excluir dos efeitos da decisão declaratória eventual efeito repristinatório quando constatada incompatibilidade com a ordem constitucional. - 4. O art. 68 do ADCT assegura o direito dos remanescentes das comunidades dos quilombos de ver reconhecida pelo Estado a propriedade sobre as terras que histórica e tradicionalmente ocupam – direito fundamental de grupo étnico-racial minoritário dotado de eficácia plena e aplicação imediata. Nele definidos o titular (remanescentes das comunidades dos quilombos), o objeto (terras por eles ocupadas), o conteúdo (direito de propriedade), a condição (ocupação tradicional), o sujeito passivo (Estado) e a obrigação específica (emissão de títulos), mostra-se apto o art. 68 do ADCT a produzir todos os seus efeitos, independentemente de integração legislativa. - 5. Disponíveis à atuação integradora tão-somente os aspectos do art. 68 do ADCT que dizem com a regulamentação do comportamento do Estado na implementação do comando constitucional, não se identifica, na edição do Decreto 4.887/2003 pelo Poder Executivo, mácula aos postulados da legalidade e da reserva de lei. Improcedência do pedido de declaração de inconstitucionalidade formal por ofensa ao art. 84, IV e VI, da Constituição da República. - 6. O compromisso do Constituinte com a construção de uma sociedade livre, justa e solidária e com a redução das desigualdades sociais (art. 3º, I e III, da CF) conduz, no tocante ao reconhecimento da propriedade das terras ocupadas pelos remanescentes das comunidades dos quilombos, à convergência das dimensões da luta pelo reconhecimento – expressa no fator de determinação da identidade distintiva de grupo étnico-cultural – e da demanda por justiça socioeconômica, de caráter redistributivo – compreendida no fator de medição e demarcação das terras. - 7. Incorporada ao direito interno brasileiro, a Convenção 169 da Organização Internacional do Trabalho – OIT sobre Povos Indígenas e Tribais, consagra a "consciência da própria identidade" como critério para determinar os grupos tradicionais aos quais aplicável, enunciando que Estado algum tem o direito de negar a identidade de um povo que se reconheça como tal. - 8. Constitucionalmente legítima, a adoção da autoatribuição como critério de determinação da identidade quilombola, além de consistir em método autorizado pela antropologia contemporânea, cumpre adequadamente a tarefa de trazer à luz os destinatários do art. 68 do ADCT, em absoluto se prestando a inventar novos destinatários ou ampliar indevidamente o universo daqueles a quem a norma é dirigida. O conceito vertido no art. 68 do ADCT não se aparta do fenômeno objetivo nele referido, a alcançar todas as comunidades historicamente vinculadas ao uso linguístico do vocábulo quilombo. Adequação do emprego do termo “quilombo” realizado pela Administração Pública às balizas linguísticas e hermenêuticas impostas pelo texto-norma do art. 68 do ADCT. Improcedência do pedido de declaração de inconstitucionalidade do art. 2°, § 1°, do Decreto 4.887/2003. - 9. Nos casos Moiwana v. Suriname (2005) e Saramaka v. Suriname (2007), a Corte Interamericana de Direitos Humanos reconheceu o direito de propriedade de comunidades formadas por descendentes de escravos fugitivos sobre as terras tradicionais com as quais mantêm relações territoriais, ressaltando o compromisso dos Estados partes (Pacto de San José da Costa Rica, art. 21) de adotar medidas para garantir o seu pleno exercício. - 10. O comando para que sejam levados em consideração, na medição e demarcação das terras, os critérios de territorialidade indicados pelos remanescentes das comunidades quilombolas, longe de submeter o procedimento demarcatório ao arbítrio dos próprios interessados, positiva o devido processo legal na garantia de que as comunidades tenham voz e sejam ouvidas. Improcedência do pedido de declaração de inconstitucionalidade do art. 2º, §§ 2º e 3º, do Decreto 4.887/2003. - 11. Diverso do que ocorre no tocante às terras tradicionalmente ocupadas pelos índios – art. 231, § 6º – a Constituição não reputa nulos ou extintos os títulos de terceiros eventualmente incidentes sobre as terras ocupadas por remanescentes das comunidades dos quilombos, de modo que a regularização do registro <u>exige o necessário o procedimento expropriatório</u>. A exegese sistemática dos arts. 5º, XXIV, 215 e 216 da Carta Política e art. 68 do ADCT impõe, quando incidente título de propriedade particular legítimo sobre as terras ocupadas por quilombolas, seja o processo de transferência da propriedade mediado por regular procedimento de desapropriação. Improcedência do pedido de declaração de inconstitucionalidade material do art. 13 do Decreto 4.887/2003. Ação direta de inconstitucionalidade julgada improcedente.

• ADI 7008
• Órgão julgador: Tribunal Pleno
• Relator(a): Min. ROBERTO BARROSO
• Julgamento: 22/05/2023
• Publicação: 06/06/2023

Direito constitucional e administrativo. Ação direta de inconstitucionalidade. Lei nº 16.260/2016, do Estado de São Paulo. Concessão de áreas estaduais para exploração de atividades de ecoturismo e extração comercial de madeira e subprodutos florestais. - 1. Ação direta de inconstitucionalidade contra a Lei nº 16.260/2016, do Estado de São Paulo, que autoriza a concessão à iniciativa privada de áreas estaduais para exploração de atividades de ecoturismo e extração comercial de madeira e subprodutos florestais. - 2. O ato normativo veicula autorização legislativa dada ao Poder Executivo estadual para a concessão da exploração de serviços ou do uso, total ou parcial, de áreas em próprios estaduais. Ato normativo de caráter genérico que não afasta a incidência de normas editadas pela União em matéria ambiental ou o dever de consulta prévia às comunidades indígenas e tradicionais eventualmente afetadas. Sendo evidente o sentido da norma, revela-se incabível a interpretação conforme à Constituição para essa finalidade. - 3. O art. 231 da Constituição consagrou o caráter originário do direito dos índios às terras por eles “tradicionalmente ocupadas”, reservando-lhes, com exclusividade, o usufruto das riquezas do solo, dos rios e dos lagos nelas existentes. Além disso, essas terras foram incluídas entre os bens da União (art. 20, XI, da CF/88). Trata-se, portanto, de território pertencente à União e de usufruto exclusivo dos povos indígenas, sendo inconstitucional a sua concessão pelo Estado à iniciativa privada. - 4. Também a proteção às terras ocupadas por comunidades tradicionais e de remanescentes quilombolas é essencial à preservação de sua identidade e seus “modos de criar, fazer e viver” (arts. 215 e 216 da Constituição; art. 68 do ADCT e Convenção nº 169 da OIT). É inconstitucional a concessão dessas áreas, pelo Estado, à iniciativa privada, para exploração florestal madeireira e do ecoturismo, independentemente do <u>status de regularização fundiária</u> e da <u>morosidade</u> do Estado em efetivar seu dever de demarcá-las e protegê-las. - 5. Pedido julgado parcialmente procedente, para conferir interpretação conforme a Constituição à Lei nº 16.260/2016, do Estado de São Paulo, de modo a afastar sua incidência relativamente às terras tradicionalmente ocupadas por comunidades indígenas, remanescentes quilombolas e demais comunidades tradicionais. - 6. Fixação da seguinte tese de julgamento: “1.* É constitucional norma estadual que, sem afastar a aplicação da legislação nacional em matéria ambiental (inclusive relatório de impacto ambiental) e o dever de consulta prévia às comunidades indígenas e tradicionais, quando diretamente atingidas por ocuparem zonas contíguas, autoriza a concessão à iniciativa privada da exploração de serviços ou do uso de bens imóveis do Estado; 2.* A concessão pelo Estado não pode incidir sobre áreas tradicionalmente ocupadas por povos indígenas, remanescentes quilombolas e demais comunidades tradicionais”.

Tese - 1. É constitucional norma estadual que, sem afastar a aplicação da legislação nacional em matéria ambiental (inclusive relatório de impacto ambiental) e o dever de consulta prévia às comunidades indígenas e tradicionais, quando diretamente atingidas por ocuparem <u>zonas contíguas</u>, autoriza a concessão à iniciativa privada da exploração de serviços ou do uso de bens imóveis do Estado;

• 2. A concessão pelo Estado não pode incidir sobre áreas tradicionalmente ocupadas por povos indígenas, remanescentes quilombolas e demais comunidades tradicionais.

• Tema: 1.196
• Processo(s): RE 1.347.526
• Relator: Min. Cristiano Zanin
• Título: Constitucionalidade da Medida Provisória 739/2016, substituída pela Medida Provisória 767/2017 e convertida na Lei 13.457/2017, as quais alteraram a Lei 8.213/1991, inserindo preceito sobre prazo estimado para a duração do benefício.

O Tribunal fixou a seguinte tese: - Não viola os artigos 62, caput e § 1º, e 246 da Constituição Federal a estipulação de prazo estimado para a duração de benefício de auxílio-doença, conforme estabelecido nos §§ 8º e 9º do art. 60 da Lei 8.213/1991, com redação dada pelas medidas provisórias 739/2016 e 767/2017, esta última convertida na Lei 13.457/2017.

Document d'information : Enjeux et Défis de la Santé Mentale en France

Synthèse

L'audition devant la commission d'enquête de l'Assemblée nationale met en lumière une crise profonde et multidimensionnelle du système de santé mentale en France.

Les analyses des experts révèlent un fardeau économique et social colossal, estimé à 163 milliards d'euros, plaçant les maladies mentales au premier rang des dépenses de l'Assurance Maladie.

Ce coût est principalement tiré par les hospitalisations, qui représentent jusqu'à 85 % des dépenses directes pour des pathologies comme la schizophrénie, tandis que les coûts des médicaments, majoritairement génériqués, restent faibles.

Le système de soins psychiatriques est caractérisé par des défaillances systémiques majeures. La prévention est quasi inexistante, entraînant des retards de diagnostic dramatiques (plus de 10 ans pour les troubles bipolaires).

L'organisation des soins, jugée obsolète, reste hospitalo-centrée, inégalitaire sur le territoire et cloisonnée, notamment entre les soins somatiques et psychiatriques.

Ce cloisonnement a des conséquences mortelles, réduisant l'espérance de vie des patients de 15 à 20 ans, principalement à cause de maladies cardiovasculaires et de cancers non ou mal soignés.

Malgré ce tableau sombre, des innovations organisationnelles et technologiques ont prouvé leur efficacité.

Les "Centres Experts", par des bilans complets, réduisent significativement les hospitalisations et améliorent le pronostic des patients.

De même, des projets pilotes utilisant des outils numériques (expérimentation "Article 51") ont divisé par deux les tentatives de suicide et généré des économies substantielles.

Cependant, ces innovations peinent à être déployées à grande échelle en raison de freins structurels, d'un manque de vision stratégique et d'un sous-investissement chronique dans la recherche et le développement.

La psychiatrie souffre en parallèle d'une grave crise d'attractivité, exacerbant les pénuries de personnel et la saturation du système.

Enfin, la recherche et le pilotage des politiques publiques sont handicapés par un manque criant de données structurées, notamment sur le volet du handicap.

1. Le Fardeau Économique et Social des Maladies Mentales

L'analyse économique présentée par Isabelle Duranzaleski, professeur de médecine et docteur en économie, révèle l'empreinte considérable des pathologies psychiatriques sur la société française.

L'étude, qui reproduit des méthodologies internationales pour permettre les comparaisons, agrège plusieurs types de coûts pour obtenir un chiffre global.

1.1. Une Estimation Globale de 163 Milliards d'Euros

En combinant l'ensemble des coûts, l'étude arrive à un total de 163 milliards d'euros.

Ce chiffre, bien que sujet à des risques de double compte, a pour objectif principal d'alerter les décideurs publics sur l'ampleur du fardeau.

Il se décompose en quatre catégories principales :

1. Dépenses de l'Assurance Maladie : Les coûts directs des soins médicaux, qui placent les maladies mentales comme le premier ou deuxième poste de dépense avec le cancer.

2. Dépenses du secteur médico-social : Les coûts réels engagés pour l'accompagnement.

3. Pertes de production : Le "manque à gagner" pour la société lié à la morbidité et à la mortalité prématurée.

4. Perte de santé valorisée : Une estimation monétaire de la perte d'années de vie en bonne santé, calculée selon des standards internationaux.

1.2. La Prépondérance des Coûts d'Hospitalisation

Une analyse détaillée des dépenses directes pour les patients atteints de schizophrénie et de troubles bipolaires, menée via les Centres Experts, démontre que l'hospitalisation constitue la source principale des coûts.

• Pour la schizophrénie, 85 % des coûts directs sont liés aux hospitalisations.

• Pour les troubles bipolaires, ce chiffre s'élève à 78 %.

En comparaison, la part des médicaments est très faible, en raison de l'accès quasi-exclusif à des traitements génériqués et du manque d'accès aux innovations thérapeutiques.

Pathologie

Part des Hospitalisations

Part des Médicaments

Part des Consultations

Schizophrénie

85 %

9 %

6-7 %

Troubles Bipolaires

78 %

18 %

6-7 %

1.3. Le Coût Spécifique du Suicide

Une étude distincte, utilisant la même méthodologie, a évalué le coût du suicide et des tentatives de suicide, en incluant les coûts directs des soins, la perte de production et la perte d'années de vie valorisée.

• Coût du suicide : 18 milliards d'euros.

• Coût des tentatives de suicide : 5 milliards d'euros.

2. Défaillances Systémiques et Organisation des Soins

Les experts s'accordent sur un constat sévère : l'organisation actuelle des soins psychiatriques en France est en échec. Elle est marquée par un retard structurel, une inégalité d'accès et un cloisonnement préjudiciable.

2.1. L'Échec de la Prévention

Selon Marion Leboyer, professeur de psychiatrie, et Coralie Gandré, maîtresse de recherche à l'IRDES, le système de soins français présente des défaillances majeures aux trois niveaux de la prévention.

• Prévention primaire : Elle est quasi-inexistante, marquée par une méconnaissance profonde des maladies mentales dans la société et une méfiance envers la psychiatrie, ce qui entraîne une perte de chance considérable.

La France accuse un retard de 20 ans par rapport aux pays anglo-saxons dans la mise en place de mesures de prévention et de lutte contre la stigmatisation.

• Prévention secondaire : Elle se traduit par un retard au diagnostic catastrophique.

◦ Troubles bipolaires : Plus de 10 ans en moyenne entre les premiers symptômes et le diagnostic.    ◦ Schizophrénie : Une "durée de psychose non traitée" de 2 à 5 ans, alors que les cinq premières années sont cruciales pour la réponse au traitement.

Ce retard est attribué à un déficit de formation des médecins de première ligne et à un manque d'information du grand public.

• Prévention tertiaire : L'arrivée tardive dans le soin se fait majoritairement par les urgences, qui sont engorgées par des patients de plus en plus sévères, chroniques et polypathologiques.

Un patient sur quatre hospitalisé en psychiatrie y entre via les urgences, un indicateur international de mauvaise qualité de l'accès aux soins.

2.2. Un Modèle de Soins Obsolète, Inégal et Cloisonné

Le système français est décrit comme :

• Hospitalo-centré : L'approche reste centrée sur l'hôpital, malgré un virage ambulatoire précoce (80 % des prises en charge).

Un quart des lits en psychiatrie est occupé au long cours sans indication thérapeutique, souvent par défaut d'offre d'hébergement non médicalisé.

• Inégalitaire sur le territoire : L'accès aux soins varie considérablement d'une région à l'autre.

La prévalence de la schizophrénie et des troubles bipolaires est deux fois plus élevée dans les villes, suggérant la nécessité de politiques de soins adaptées aux facteurs de risque environnementaux (urbanicité, pollution, stress).

• Peu lisible et insuffisamment spécialisé : L'offre de soins est confuse pour les usagers et manque de spécialisation par pathologie, contrairement aux pratiques internationales.

• Manquant de vision stratégique : Les experts déplorent une absence de stratégie claire et de politique d'évaluation de l'organisation des soins.

2.3. La Fracture entre Soins Somatiques et Psychiatriques

Un des points les plus critiques soulevés est le cloisonnement total entre la psychiatrie et les autres spécialités médicales.

Les conséquences pour les patients sont dramatiques :

• Surmortalité massive : La première cause de mortalité n'est pas le suicide, mais les maladies cardiovasculaires et les cancers.

L'espérance de vie est réduite de 20 ans pour les femmes et 15 ans pour les hommes (données de M. Leboyer) ou de 13 ans pour les femmes et 16 ans pour les hommes (étude IRDES).

Le taux de mortalité est 2 à 3 fois supérieur à celui de la population générale.

• Sous-dépistage des comorbidités : Des pathologies comme le syndrome métabolique (hypertension, obésité, etc.) sont très fréquentes (24 % pour la schizophrénie, 38 % pour la dépression résistante, contre 10 % en population générale), mais 70 % à 90 % des patients ne sont ni dépistés, ni soignés.

• Moindre recours aux soins préventifs : Les patients ont moins accès au dépistage des cancers, à la vaccination, aux dentistes, ophtalmologues ou gynécologues.

• Retard au diagnostic pour le cancer : Les patients atteints de troubles psychiques sont diagnostiqués plus tardivement pour les cancers, reçoivent des prises en charge plus invasives mais moins intensives, ce qui augmente les pertes de chance.

3. Innovations et Levier d'Amélioration : Un Potentiel Sous-exploité

Face à ces défaillances, des innovations organisationnelles, numériques et thérapeutiques ont démontré leur efficacité, mais leur déploiement reste limité par de nombreux freins.

3.1. Les Centres Experts : Un Modèle d'Évaluation Efficace

Inspirés des modèles existants pour le cancer ou les maladies rares, les Centres Experts proposent un bilan complet (psychiatrique, cognitif, social, somatique) sur une journée en hôpital de jour.

• Impact démontré : Les études menées avant et après passage dans ces centres montrent une diminution significative du nombre de journées d'hospitalisation, une amélioration du pronostic, une meilleure adhérence au traitement et un meilleur dépistage des comorbidités somatiques.

• Objectif : L'objectif est de déployer ce dispositif sur tout le territoire national et de l'inscrire dans la liste des activités spécifiques nationales pour garantir un accès équitable à tous les patients.

3.2. Le Numérique au Service du Suivi (Expérimentation Article 51)

Un projet pilote a testé une innovation organisationnelle combinant un suivi par une infirmière de pratique avancée ("case manager") et des outils digitaux pour des patients bipolaires.

• Résultats positifs : L'évaluation par le ministère de la Santé a montré :

• ◦ Tentatives de suicide divisées par deux (de 7,6 % à 3,9 %).  
• ◦ Journées d'hospitalisation réduites (de 42 % à 24 %).  
• ◦ Impact économique démontré : un gain estimé à 3 500 € par patient et par an, grâce à la baisse des hospitalisations.

• Déploiement en attente : Malgré ces résultats, la décision de généraliser le dispositif est toujours en attente, suscitant l'inquiétude des patients et des soignants.

3.3. Freins à l'Innovation et à la Recherche

Plusieurs obstacles entravent la modernisation de la psychiatrie :

• Sous-investissement dans la recherche : La France ne consacre que 2 à 4 % de son budget de recherche biomédicale à la psychiatrie, l'un des taux les plus faibles des pays développés.

• Faible translation des découvertes : De nombreuses innovations (biomarqueurs sanguins, imagerie cérébrale, outils numériques) issues de la recherche peinent à être appliquées dans les soins courants.

• Accès limité aux nouvelles thérapies : Les patients français ont un accès moindre aux innovations thérapeutiques, qu'elles soient médicamenteuses (ex: antipsychotiques de 2e génération disponibles ailleurs en Europe mais pas en France) ou psychosociales.

4. Enjeux Transversaux et Difficultés Spécifiques

4.1. Crise d'Attractivité et Pénurie de Personnel

La psychiatrie fait face à une crise d'attractivité majeure, constituant un frein structurel à toute amélioration.

• Désaffection des jeunes médecins : La psychiatrie est choisie parmi les dernières disciplines par les internes, contrairement à des pays comme le Canada où elle est devenue un premier choix suite à des investissements massifs.

• Pénurie de personnel : La FHF (Fédération Hospitalière de France) estime qu'un quart des postes de psychiatres sont vacants dans plus de la moitié des établissements publics.

• Conséquences directes : Cette pénurie entraîne une fermeture massive de lits d'hospitalisation et une saturation de l'ensemble du système de soins (CMP surchargés, urgences engorgées).

4.2. Les Pratiques Coercitives et les Droits des Patients

La France se distingue par un recours élevé à des pratiques restrictives de liberté, avec des variations très importantes entre établissements qui interrogent l'équité des prises en charge.

• Soins sans consentement : Près de 100 000 personnes par an (soit 5% de la file active).

• Isolement : Près de 30 000 personnes par an.

• Contention mécanique : Près de 10 000 personnes par an. Ces chiffres placent la France dans une situation défavorable par rapport aux autres pays développés, avec une tendance à l'augmentation.

4.3. Le Manque Crucial de Données sur le Handicap

Maude Espagiac, spécialiste du handicap, souligne une difficulté majeure pour la recherche et le pilotage des politiques : l'accès aux données.

• Cloisonnement des données : Les systèmes d'information des secteurs médical, social et médico-social ne communiquent pas, ce qui empêche d'avoir une vision complète des parcours et des coûts.

• Identification des personnes : Il est très difficile d'identifier les personnes en situation de handicap dans les bases de données de santé existantes, et de mesurer les coûts non publics (reste à charge pour les familles, les aidants).

• Perspective d'amélioration : L'intégration annoncée des données des MDPH (Maisons Départementales des Personnes Handicapées) dans le Système National des Données de Santé (SNDS) d'ici 2026 est une avancée attendue depuis une décennie.

Buat kan makalah nya

Author response:

Joint Public Review

This manuscript puts forward the provocative idea that a posttranslational feedback loop regulates daily and ultradian rhythms in neuronal excitability. The authors used in vivo long-term tip recordings of the long trichoid sensilla of male hawkmoths to analyze spontaneous spiking activity indicative of the ORNs' endogenous membrane potential oscillations. This firing pattern was disrupted by pharmacological blockade of the Orco receptor. They then use these recordings together with computational modeling to predict that Orco receptor neuron (ORN) activity is required for circadian, not ultradian, firing patterns. Orco did not show a circadian expression pattern in a qPCR experiment, and its conductance was proposed to be regulated by cyclic nucleotide levels. This evidence led the authors to conclude that a post-translational feedback loop (PTFL) clockwork, associated with the ORN plasma membrane, allows for temporal control of pheromone detection via the generation of multi-scale endogenous membrane potential oscillations. The findings will interest researchers in neurophysiology, circadian rhythms, and sensory biology. However, the manuscript has limited experimental evidence to support its central hypothesis and is undermined by several questionable assumptions that underlie their data analysis and model builds, as well as insufficient biological data, including critical controls to validate and/or fully justify the model the authors are proposing.

We thank the reviewers for their thorough and thoughtful comments and believe that the manuscript will be much stronger once we incorporate the requested changes.

Please note that we used ORN as acronym for “olfactory receptor neuron” throughout the manuscript. ORNs contain odorant receptors (ORs), and in insects these ORs have to associate with the olfactory receptor co-receptor (Orco) in the cilium of the neuron to form functional OR-Orco complexes for odorant detection. Besides this chaperone function, Orco can form homomers with the potential to act as ionic pacemaker channels; a role which we explore in this study.

Strengths:

The study is notable for its combination of long-term in vivo tip recordings with computational modeling, which is technically challenging and adds weight to the authors' claims. The link between Orco, cyclic nucleotides, and circadian regulation is potentially important for sensory neuroscience, and the modeling framework itself - a stochastic Hodgkin-Huxley formulation that explicitly incorporates channel noise - is a solid and forward-looking contribution. Together, these elements make the study conceptually bold and of clear interest to circadian and olfactory biologists.

Major weaknesses:

At the same time, several limitations temper the conclusions. The pharmacological evidence relies on a single antagonist and concentration, without key controls. The circadian analysis is based on relatively small numbers of neurons, with rhythms detected only in subsets, and the alignment procedure used in constant darkness raises concerns of bias. The molecular evidence is sparse, with only three qPCR timepoints, and the model, while creative, rests on assumptions that are not yet fully supported by in vivo data.

Please see our responses to the detailed comments.

Detailed comments are provided below:

(1) The role for Orco proposed in the authors' model largely stems from the effects seen following the administration of (a single dose) of the Orco antagonist, OLC15. However, this hypothesis is undercut by the lack of adequate pharmacological controls, including a basic multipoint OLC15 dose-response series in addition to the administration of blockers for the other channels that are embedded in their model, but which were ruled out as being involved in the modulation of biological rhythms. In addition, these studies would (ideally) also benefit from the inclusion of the same concentration (series) of an inactive OLC15 analog to better control for off-target effects.

The Orco agonist VUAA1 (Jones et al., 2011) binds directly to Orco and increases the channel open time probability. In M. sexta hawkmoths, we have already published that VUAA 1 increases the low spontaneous activity of ORNs in a dose-dependent fashion (Nolte et al., 2016). Chen and Luetje (2012) systematically varied the chemical structure of VUAA1 to identify new Orco ligands and discovered 22 Orco Ligand Candidates (OLC) that either activated or inhibited Orco. In their heterologous expression system, Orco was most sensitive to inhibition by OLC15. Based on these results, we published a dose-response curve of OLC15 inhibition (1-100 µM) using in vivo tip recordings of pheromone-sensitive long trichoid sensilla of M. sexta (Nolte et al., 2016). In that study, we could also demonstrate that OLC15 antagonizes the VUAA1 activation of Orco.

Furthermore, we tested other published Orco antagonists in in vivo assays in intact hawkmoths, focusing on amiloride-derived antagonists, because we previously identified an amiloride-sensitive cation channel in hawkmoth ORNs. We found that, in contrast to OLC15, the amilorides HMA and MIA were not Orco-specific but instead affected different targets depending on time-of-day (Nolte et al., 2016). Based on those experiments and the dose-response curves we determined that the Orco agonist VUAA1 (Jones et al., 2011) and the Orco antagonist OLC15 (Chen and Luetje, 2012) worked best in hawkmoth ORNs to target Orco pharmacologically. Based on comparative tests with other published Orco antagonists we settled since then in all further experiments on a dose of 50 µM OLC15.

We will clarify the Methods section accordingly.

(2) The expression pattern of Orco was assessed using qPCR at only three timepoints. Rhythmic transcripts can easily be missed with such sparse sampling (Hughes et al., 2017). A minimum of six evenly spaced timepoints across a 24-hour cycle would be required to confidently rule out circadian transcriptional regulation. In addition, the use of the timeless mRNA control from another study is not acceptable. Furthermore, qPCR analysis measures transcript abundance, not transcription, as the authors repeatedly state. Transcriptional studies would require nuclear run-off or, more recently, can be done with snRNAseq analysis. Taken together, these concerns undermine the authors' desire to rule out TTFL-based control that directly led them to implicate a PTTF-based model.

We agree with the referees that more time points and a direct comparison between timeless and Orco mRNA levels should be included in this manuscript. We will include these additional qPCR experiments and edit the manuscript to make clear that we measure transcript abundance, but we will not perform snRNAseq analysis due to time- and financial constraints. We are currently working on the transcriptional control of Orco, both during ontogeny and throughout the day but this work in progress is beyond the scope of this manuscript.

(3) The modelling presented is based on Orco as a ZT-dependent conductance tied to the cAMP oscillations that were reported by this group in the cockroach and from the presence and functionality in Manduca of homomeric Orco complexes that are devoid of tuning ORs. While these complexes have been generated in cell culture and other heterologous expression systems, as well as presumably exist in vivo in the Drosophila empty neuron and other tuning OR mutants, there is no evidence that these complexes exist in wild-type Manduca ORNs. While this doesn't necessarily undermine every aspect of their models, the authors should note the presence of Orco/OR complexes rather than Orco homomeric complexes.

Our ELISAs found circadian oscillations in cAMP levels not only in antennae of the Madeira cockroach (Schendzielorz et al., 2014, 2012), but also in hawkmoth antennae (Schendzielorz et al., 2015). We will add the 2015 citation to the Modeling chapter in the Methods section to clarify this.

We agree with the referees that we cannot distinguish between Orco homo- and heteromers in the different compartments of our hawkmoth ORNs. Thus, as the referee suggests, we will add text regarding the presence and localization of OR-Orco heteromers. However, we have indications that Orco homomers could indeed be present in the hawkmoth ORNs. In a heterologous expression system, MsexOrco expression alone was sufficient to increase intracellular Ca²⁺ levels in response to VUAA1 application (Nolte et al., 2013). In differentiating primary cell cultures of hawkmoth antennae, Orco expression started during a developmental time window where ORNs did not yet express pheromone receptors, and Orco affected spontaneous activity (Nolte et al., 2016). Thus, Orco homomers are present in developing hawkmoth ORNs during a time window where ORNs already express spontaneous activity but cannot heteromerize with pheromone receptors. However, we do not know whether and in what ratio homo- and heteromers of Orco and ORs are present in the respective sensillum compartments of adult hawkmoths (Nolte et al., 2013; Stengl, 1994; Stengl and Hildebrand, 1990).

We will clarify our manuscript accordingly.

(4) Some aspects of the authors' models, most notably the decision to phase align/optimize their DD and OLC15 recordings, are likely to bias their interpretations.

It is consensus that insects display daily and circadian rhythms in pheromone-dependent mating, odor-gated feeding, and egg-laying behavior that phase-locks to environmental rhythms, corresponding with daily/circadian rhythms of sensory neuron physiology (e.g., Merlin et al., 2007; Rymer et al., 2007; Schendzielorz et al., 2015, 2012). However, circadian rhythms can be easily masked by stress, like the disturbances during a very challenging long-term recording experiment over several days. In addition, we observed in our animal raising facility that in LD 17:7 light-dark cycles the originally nocturnal hawkmoths M. sexta distribute their activity patterns over the course of the day, finding nocturnal as well as diurnal hawkmoths. Thus, light-dark cycles were not enough to ensure phase-synchronized behavioral rhythms, and it is very likely that the nocturnal hawkmoths rely heavily on pheromone/odor dependent synchronization as also found in other moth species (Ghosh et al., 2024). Here, we used isolated males that were never exposed to the female pheromones so that their circadian activity patterns readily disperse. Therefore, it became necessary in free-running conditions to first determine the respective behavioral rhythm for each animal, and then to phase-align their activity patterns to allow for statistical analysis. Otherwise, circadian differences would average out in a free-running population. As requested by the referees in point (7), we will use additional tests for rhythmicity in each of our recordings and revise the manuscript accordingly.

Assuming that hawkmoths need pheromone presence as additional Zeitgeber, we are currently working on a new set of experiments where we attempt to improve synchronization by exposure to LD cycles and pheromone before DD and OLC15 recordings. We will add these experiments to the manuscript.

(5) The tip recordings from long trichoid sensilla are critical aspects of this study. These recordings were carried out on upper sensillar tips located on the distal-most second annulus. Since there are approximately 80 annuli on the Manduca antennae, it is unclear whether the recordings are representative of the antennal response.

We think the reviewers might have misinterpreted our description of the recording site. In the Methods, we state that we clip off the 20 most distal annuli (leaving a stump of about 60 annuli) and insert the reference electrode into the flagellum up to the second annulus from the cut end, i.e., the recording site is located at 2/3 – 3/4 of the antenna length as seen from the head of the animal. We will make this more clear in the Methods section.

In addition, our lab did show with antibody stainings against Orco that apparently all ORNs that innervate long and short trichoid sensilla along the whole flagellum express the same staining pattern (Nolte et al., 2016). Furthermore, our patch clamp recordings of primary cell cultures of whole male antennae found largely overlapping ion channel populations across ORNs. This would indicate that all ORNs, whether they express pheromone- or general odorant receptors, could potentially share the same Orco-dependent spontaneous activity rhythms. In our lab, different experimenters from different years that recorded from long trichoid sensilla on different annuli did not detect obvious differences in neither the spontaneous activity nor the pheromone responses (c.f., Dolzer et al., 2003; Gawalek and Stengl, 2018; Schneider et al., 2025). Thus, it is very likely that we are reporting a general encoding mechanism that is not locally restricted along the antennal flagellum.

(5.1) The authors do not provide any data in support of their cAMP/cGMP-based Orco gating…

There are publications supporting cyclic nucleotide gating of Orco in Drosophila, but only after previous phosphorylation via protein kinase C (PKC; review: (Wicher and Miazzi, 2021)). Since Orco is very conserved among insect species, it is likely that these PKC and cGMP/cAMP-dependent regulations are present in other insect species. We are currently running thorough tip-recording experiments on the regulation of Orco gating, which are beyond the scope of this manuscript. However, we will add a set of experiments to this manuscript that demonstrates cAMP gating of Orco.

(5.2)… and the PTTF model proposed is somewhat disappointing.

For a detailed introduction of our PTFL membrane clock hypothesis please see our opinion paper (Stengl and Schneider, 2024).

(5.3) The model seems to be influenced by their long-held proposal that insect olfactory signaling has a critical metabotropic component involving cyclic nucleotides, PKC, etc, a view that may be influenced by the use of Orco homomeric complexes generated in HEK cells.

Indeed, we propose a metabotropic pheromone-transduction cascade, which in moths and cockroaches is based on G-protein-mediated activation of phospholipase C but not on adenylyl cyclase activation. Our hypothesis is not influenced by HEK cell heterologous expression studies of Orco but is supported by our own work comparing in vivo tip recordings of intact hawkmoths with patch clamp experiments on hawkmoth primary cell cultures of olfactory receptor neurons, which are able to respond to their species-specific pheromones in vitro ((Schneider et al., 2025; Stengl, 2010; Stengl and Funk, 2013; Wicher and Miazzi, 2021). In addition, a multitude of publications by other laboratories with in vivo and in vitro studies using physiological, genetic, and immunocytochemical assays all support a metabotropic signal transduction cascade in insect olfaction (reviews: Stengl, 2010; Stengl and Funk, 2013; Wicher and Miazzi, 2021). In contrast, the hypothesis suggesting a solely ionotropic pheromone- and general odor-dependent transduction cascade for all insect species is based on very sparse experimental evidence, based primarily on heterologous expression studies such as HEK cells that lack the insect’s WT molecular surroundings, and thus, cannot predict OR-Orco function in vivo. Furthermore, the ionotropic hypothesis is heavily based upon the argument that an inverse 7TM receptor cannot couple to G-proteins, which lacks careful backup via biochemical and structural studies. In addition, the ionotropic hypothesis lacks support via carefully performed physiological in vivo studies in different insect species that paid attention to analysis of the distinct kinetic components of ORN´s odor/pheromone responses and that employ physiological concentrations and durations of odor/pheromone stimuli (please see our most recent publication by Schneider et al. (2025)).

(5.4) Nevertheless, structural studies on Orco do not support a cyclic nucleotide binding site, although PKC-based phosphorylation has been implicated in the fine-tuning/adaptation of olfactory signaling.

While structural studies did not find evidence for conserved known cyclic nucleotide binding sites on Orco, this does not exclude the presence of so far unknown binding sites, or via sites that fold out only after a specific sequence of previous phosphorylations of the many phosphorylation sites on Orco. Indeed, physiological studies in Drosophila presented evidence for cyclic nucleotide dependence of Orco after previous PKC-dependent phosphorylation (Getahun et al., 2013). Our ongoing in vivo experiments in hawkmoths further corroborate a PKC- and cAMP-dependent modulation of Orco. These studies will be published in a follow-up publication.

(6) Because only 5/11 LD and 7/10 DD animals showed daily rhythms, with averages lacking clear daily modulation, the methods are not sufficiently reliable enough to reveal novel underlying mechanisms of circadian rhythm generation. The reported results are therefore not yet reliable or quantifiable. To quantify their results, the authors should apply tests for circadian rhythmicity using methods such as RAIN, JTK CYCLE, MetaCycle, or Echo. The use of FFT and Wavelet is applauded, but these methods do not have tests of significance for rhythms and can be biased when analyzing data in which there could only be 1-3 circadian cycles. Because the conclusions appear to be based on 11-12 neurons that were recorded for 2-4 days, the reader is concerned that the methods are not yet perfected to provide strong evidence for circadian regulation of spontaneous firing of ORNs. The average data (e.g., Figure 3Bii and 3Cii) highlight the apparent lack of daily rhythms. In summary, the results would be more compelling if more than 50% of the recordings had significant circadian amplitudes and with similar periods and phases.

The long-term tip-recordings of intact hawkmoths are very challenging and take a very long time to accomplish, thus, we are very happy that we succeeded in obtaining so many of them (N=34). Since 5/11 LD recordings and 7/10 DD recordings revealed daily/circadian rhythmicity and since many other physiological recordings at different ZTs of different members of our laboratory all revealed ZT-dependent pheromone-transduction we can be certain that the physiology of hawkmoth antennae is under strict circadian control. Please see also our response to (4) above commenting the phase-dispersal of activity rhythms observed in our experiments, as well as in the behavior of hawkmoth males in the mating cage.

Nevertheless, we will follow the advice of the referees to apply additional tests for significance of rhythms in spontaneous activity, and we are thankful for the tests suggested that we were not aware of.

(7) The statement that circadian patterns of ORN firing are lost with the Orco antagonist (OLC15) is not strongly supported. The manuscript should be revised to quantify how Orco changed circadian amplitude in the 12 recorded neurons. Measures of circadian amplitude can avoid confusing/vague statements like Line 394 “low and high frequency bands appeared to merge during the activity phase around ZT 0 in the animals that showed clear circadian rhythms (N = 5 of 11 in LD)”. The conclusion that Orco blocks circadian firing appears to be contradicted by Figure 6, which indicates that ~6 of these neurons had circadian periods detected by wavelet. The manuscript would be strengthened with details about the specificity and reproducibility of the Orco antagonist. The authors quantify the gradual decrease in firing with the slope of a linear fit to estimate how the “effectiveness [of OLC15] increased over time.” They conclude that the drug “obliterated circadian rhythms and attenuated the spontaneous activity in several, but not all experiments (N = 8 of 12).” The report would be greatly strengthened with corroborating data from additional Orco antagonists and additional doses of OLC15 (the authors use only 50 uM OLC15).

We will revise our data analysis, according to the valuable suggestions of the referees.

However, based upon our previous studies with other Orco antagonists and different doses of OLC15 (Nolte et al., 2016) we found that 50 µM OLC15 is the best Orco antagonist dose in M. sexta to target Orco-dependent modulation of spontaneous action potential activity of hawkmoth olfactory receptor neurons. Please see also our response to (1).

(8) The manuscript includes several statements that are more speculation than conclusion. For example, there is no evidence for tuning or plasticity in this report. Statements like the following should be removed or addressed with experiments that show changes in odor response specificity or sensitivity: "ORN signalosomes are highly plastic endogenous PTFL clocks comprising receptors for circadian and ultradian Zeitgebers that allow to tune into internal physiological and external environmental rhythms as basis for active sensing." (Discussion Line 622). The paper concludes that (line 380) "mean frequency of spontaneous spiking and the frequency of bursting expressed daily modulation, and are both most likely controlled via a circadian clock that targets the leak channel Orco." This is too bold given the available results.

We will revise the discussion accordingly and clarify which statements are supported via published evidence and which are predictions based upon our novel hypothesis published in our opinion paper (Stengl and Schneider, 2024).

(9.1) Because Orco conductance is modulated by cyclic nucleotides, it remains highly plausible that circadian regulation occurs upstream at the level of signaling pathways (e.g., calcium, calcium-binding proteins, GPCRs, cyclases, phosphodiesterases).

We agree with the referees that it is very likely that there are multiple layers of interconnected feedback cycles that control Orco localization and activity. Our novel hypothesis suggests interlocked TTFL and PTFL control of physiological circadian rhythms, not strictly hierarchical TTFL control, which would require a daily turnover of membrane proteins and transcriptional control via the established TTFL clock in insect ORNs. We currently search for TTFL control at all levels of odor/pheromone transduction using ZT-dependent transcriptomics in combination with qPCR and single nuclear transcriptomics, involving also all the molecules suggested by the referees. These studies are ongoing, are very time- and money-consuming, and are beyond the scope of this manuscript.

(9.2) The possibility that circadian oscillations of cyclic nucleotides are generated by the canonical TTFL mechanism has not been excluded. In fact, extensive work in Drosophila has demonstrated that the TTFL-based molecular clock proteins are required for circadian rhythms in olfaction.

Our experiments that test circadian TTFL control at different levels of the cAMP transduction cascade in hawkmoth antennae are on the way and are part of another publication. We will revise our discussion accordingly.

The experiments published for TTFL dependent control of Drosophila olfaction that we are aware of (Krishnan et al., 1999; Tanoue et al., 2004) do not exclude interlinked PTFL and TTFL clocks. Krishnan et al. (1999) demonstrate that the TTFL clock in antennal olfactory receptor neurons correlates with circadian rhythms in odor responses measured in electroantennogram (EAG) recordings, not in single sensillum recordings as in our experiments. EAG recordings comprise not only voltage responses of the olfactory sensory neurons but also voltage changes generated in non-neuronal antennal cells such as trichogen and tormogen cells that built the transepithelial potential gradient via vATPases that generates the high K⁺ concentration in the sensillum lymph (Jain et al., 2024; Klein, 1992; Thurm and Küppers, 1980). In addition, EAG recordings most likely contain responses of afferent neurons originating from somata in the brain that maintain central control of the antennae. Thus, EAG recordings are difficult to interpret.

(11) A defining feature of circadian oscillators is the feedback mechanism that generates a time delay (e.g., PERIOD/TIMELESS repressing their own transcription). While the authors describe how cyclic nucleotides can regulate Orco conductance, they do not provide a convincing explanation of how Orco activity could, in turn, feed back into the proposed PTFL to sustain oscillations. For these reasons, the authors should consider:

a) Providing a broader discussion of non-TTFL models of circadian rhythms (e.g., redox cycles, post-translational modifications).

We will revise the discussion accordingly.

b) Reassessing Orco expression using a higher-resolution temporal sampling ({greater than or equal to}6 timepoints per 24 h).

We will add those experiments to the revised version of the manuscript (see our response to (2)).

c) Clarifying or revising the PTFL model to explicitly address how feedback would be achieved. Alternatively, the data may be more consistent with Orco conductance rhythms being regulated by post-translational mechanisms downstream of the canonical TTFL oscillator, as suggested by the Drosophila olfactory system literature.

We will revise the manuscript accordingly.

Minor weaknesses:

(1) The authors should compare the firing patterns of ORN neurons to the bursts, clusters, and packets of retinal efferent spikes reported in Liu JS and Passaglia CL (2011; JBR). By comparing measures in moths to measures in Limulus, the authors might be able to address the question: Is the daily firing pattern of ORN neurons likely a conserved feature of circadian control of sensory sensitivity?

We will revise the discussion accordingly.

(2) The methods need further details. For example, it is unclear if or how single neuron activity was discriminated and whether the results were compromised by the relatively large environmental fluctuations in temperature (21-27oC), humidity (35-60%), or other cues known to modulate spontaneous firing.

We will clarify the Methods section.

References

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Gawalek P, Stengl M. 2018. The Diacylglycerol Analogs OAG and DOG Differentially Affect Primary Events of Pheromone Transduction in the Hawkmoth Manduca sexta in a Zeitgebertime-Dependent Manner Apparently Targeting TRP Channels. Front Cell Neurosci 12:218. doi:10.3389/fncel.2018.00218

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Ghosh S, Suray C, Bozzolan F, Palazzo A, Monsempès C, Lecouvreur F, Chatterjee A. 2024. Pheromone-mediated command from the female to male clock induces and synchronizes circadian rhythms of the moth Spodoptera littoralis. Curr Biol 34:1414-1425.e5. doi:10.1016/j.cub.2024.02.042

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Nolte A, Funk NW, Mukunda L, Gawalek P, Werckenthin A, Hansson BS, Wicher D, Stengl M. 2013. In situ Tip-Recordings Found No Evidence for an Orco-Based Ionotropic Mechanism of Pheromone-Transduction in Manduca sexta. PLOS ONE 8:e62648. doi:10.1371/journal.pone.0062648

Nolte A, Gawalek P, Koerte S, Wei H, Schumann R, Werckenthin A, Krieger J, Stengl M. 2016. No Evidence for Ionotropic Pheromone Transduction in the Hawkmoth Manduca sexta. PLOS ONE 11:e0166060. doi:10.1371/journal.pone.0166060

Rymer J, Bauernfeind AL, Brown S, Page TL. 2007. Circadian rhythms in the mating behavior of the cockroach, Leucophaea maderae. J Biol Rhythms 22:43–57. doi:10.1177/0748730406295462

Schendzielorz J, Schendzielorz T, Arendt A, Stengl M. 2014. Bimodal Oscillations of Cyclic Nucleotide Concentrations in the Circadian System of the Madeira Cockroach Rhyparobia maderae. J Biol Rhythms 29:318–331. doi:10.1177/0748730414546133

Schendzielorz T, Peters W, Boekhoff I, Stengl M. 2012. Time of Day Changes in Cyclic Nucleotides Are Modified via Octopamine and Pheromone in Antennae of the Madeira Cockroach. J Biol Rhythms 27:388–397. doi:10.1177/0748730412456265

Schendzielorz T, Schirmer K, Stolte P, Stengl M. 2015. Octopamine Regulates Antennal Sensory Neurons via Daytime-Dependent Changes in cAMP and IP3 Levels in the Hawkmoth Manduca sexta. PLOS ONE 10:e0121230. doi:10.1371/journal.pone.0121230

Schneider AC, Schröder K, Chang Y, Nolte A, Gawalek P, Stengl M. 2025. Hawkmoth Pheromone Transduction Involves G-Protein–Dependent Phospholipase Cβ Signaling. eNeuro 12:ENEURO.0376-24.2024. doi:10.1523/ENEURO.0376-24.2024

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Thurm U, Küppers J. 1980. Epithelial physiology of insect sensilla In: Locke M, Smith DS, editors. Insect Biology in the Future. Academic Press. pp. 735–763. doi:10.1016/B978-0-12-454340-9.50039-2

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Synthèse de l'Audition sur l'État de la Santé Mentale en France

Résuméf

L'audition à la commission d'enquête de l'Assemblée nationale a mis en lumière un consensus alarmant sur l'état désastreux de la psychiatrie en France, particulièrement en pédopsychiatrie, qualifiée de "désastre absolu".

Les experts, un pédopsychiatre-épidémiologiste et un psychanalyste-chercheur, s'accordent sur plusieurs points critiques : une dégradation continue du bien-être psychique de la population depuis 20 ans, une inversion préoccupante de la tendance à la baisse des suicides chez les jeunes depuis 2017, et une offre de soins totalement inadaptée face à une demande croissante, créant un "effet ciseau" dévastateur.

Les défaillances du système sont jugées systémiques et profondes, impliquant une responsabilité partagée entre les psychiatres (pour leurs certitudes passées), les administrations ("il nous flingue"), les directeurs d'hôpitaux (gestion par "tableau Excel") et des politiques publiques inadaptées.

La critique vise particulièrement le "New Public Management", qui applique des logiques de rentabilité au soin, et l'hégémonie d'une approche "scientiste" de l'Evidence-Based Medicine, jugée inefficace et inconsistante dans le champ de la santé mentale de l'enfant.

Des dispositifs comme "Mon Soutien Psy" sont cités comme des exemples de "leviers qu'il ne fallait pas activer".

Face à ce constat, les experts appellent à une réorientation radicale. Les leviers d'action prioritaires incluent la prévention, notamment la lutte contre la maltraitance infantile qui explique 50% des troubles futurs, et le renforcement des dispositifs institutionnels existants (CMP, CMPP, hôpitaux) plutôt que la création de nouvelles structures complexes.

La formation de thérapeutes qualifiés et la revalorisation des pratiques cliniques pluridisciplinaires sont essentielles.

Enfin, bien que le coût de l'inaction se chiffre en milliards d'euros, les experts soulignent que la solution n'est pas uniquement budgétaire mais réside dans une meilleure organisation des ressources existantes et dans des choix politiques courageux qui replacent la relation humaine et la complexité clinique au cœur du système de soin.

1. État des Lieux : Un Constat Alarmant

Les deux intervenants dressent un tableau extrêmement sombre de la situation psychiatrique en France, soulignant la nécessité de distinguer le "vécu anxio-dépressif" des pathologies cliniques et de se méfier des chiffres de prévalence bruts qui, pour des troubles dimensionnels comme la dépression, "ne veulent rien dire".

1.1. Tendances Épidémiologiques Inquiétantes

Le professeur Falissard, épidémiologiste, identifie une "quadruple interaction entre le temps, l'âge, le genre et la pathologie".

• Suicide et tentatives de suicide : Si la tendance globale sur 30 ans est à l'amélioration, une rupture nette est observée depuis 2017 chez les jeunes.

• ◦ L'amélioration s'est stoppée pour les suicides chez les jeunes.  
• ◦ Les suicides augmentent légèrement chez les jeunes filles.  
• ◦ Les tentatives de suicide montent de "façon spectaculaire" chez les jeunes filles depuis 2017.

• Vécu anxio-dépressif : Le ressenti subclinique mesuré par Santé publique France se dégrade "de façon homogène" depuis 20 ans, touchant toutes les tranches d'âge et tous les genres.

• Pédopsychiatrie : La situation est décrite comme un "désastre absolu". Certains départements n'ont plus de pédopsychiatres, rendant la permanence des soins impossible.

1.2. L'Effet Ciseau : Une Offre de Soins Débordée

M. Tonou met en évidence l'écart croissant entre l'augmentation de la demande et le déficit de l'offre de soins, créant un "effet ciseau" aux conséquences désastreuses.

• Délais d'attente : Les délais pour une consultation spécialisée sont "insupportables", allant de 6 à 18 mois.

À l'échelle d'un enfant de 3 à 6 ans, cela équivaut à un délai de 5 à 10 ans pour un adulte.

• Conséquences cliniques :

◦ Augmentation des hospitalisations en urgence.    ◦ Augmentation des passages à l'acte suicidaire.     ◦ Consommation accrue de psychotropes en pédiatrie, souvent hors autorisation de mise sur le marché (AMM).     ◦ Substitution des psychothérapies recommandées par le seul médicament, faute de moyens.

Selon les estimations, 13% de la population française serait concernée par un trouble mental, soit 1,5 million d'enfants et 9 millions de personnes au total.

2. Défaillances Systémiques et Critiques de la Gouvernance

Les experts s'accordent sur le fait que la crise actuelle est le résultat d'une série de défaillances à tous les niveaux du système. La responsabilité est "partagée" et les erreurs stratégiques des pouvoirs publics sont pointées du doigt.

2.1. Une Responsabilité Partagée

Le professeur Falissard insiste : "tout le monde est responsable du fait qu'aujourd'hui c'est une catastrophe".

Acteur

Critique

Les psychiatres

Ont eu le tort au 20e siècle de croire détenir une vérité unique (la psychanalyse), ce qui a nui aux patients, notamment dans l'autisme. Ce n'est plus le cas pour 90% des praticiens aujourd'hui.

L'Administration et la Tutelle

"Il ne nous aide pas, il nous flingue". Des réglementations absurdes (ex: conventions pour les orthophonistes en CMP) bloquent concrètement la prise en charge des enfants.

Le Délégué Interministériel (TND)

Est qualifié d'"antipsychiatre", accusé d'empêcher la construction de soins avec une "lubie scientiste" et une recherche de solutions simplistes à des problèmes complexes.

Les Directeurs d'Hôpitaux

Privilégient une gestion comptable ("Le tableau Excel il est bien rempli") au détriment de la qualité des soins, menant à des catastrophes (ex: aide-soignant d'orthopédie remplaçant une infirmière psy, conduisant à des abus sexuels).

Les Parents

Sont souvent "partie du problème", plaçant les soignants dans une situation complexe entre le devoir de protection de l'enfant et l'impératif d'inclure les parents dans le soin.

2.2. Erreurs Stratégiques de Gouvernance

M. Tonou identifie deux phénomènes majeurs qui ont sapé les fondements du soin psychique :

1. Le New Public Management : La gestion des structures publiques comme des entreprises, substituant "la rentabilité et le profit au principe fondateur des missions de services publics".

2. L'Evidence-Based Medicine (EBM) : Son déploiement pour évaluer la psychiatrie s'est révélé "tout à fait inconsistant dans le domaine de la santé mentale de l'enfant", avec "aucune avancée en terme de diagnostic, aucune avancée en terme de traitement".

Plusieurs initiatives sont citées comme des "archétypes de ce qu'il ne faudrait pas faire" :

• Le dispositif Mon Soutien Psy.

• La stratégie TND 2023-2027.

• Le cas des centres experts et de la Fondation FondaMental, critiqués pour leur approche qui dissocie le diagnostic du soin, leur absence de résultats concrets (zéro marqueur biologique trouvé) et les biais scientifiques de leurs études d'efficacité.

3. Prévention et Pistes d'Amélioration

Plutôt que de chercher des solutions simplistes, les experts appellent à revenir aux fondamentaux du soin, de la prévention et à mieux organiser les ressources existantes.

3.1. La Prévention comme Levier Principal

• Lutte contre la maltraitance : La prévention primaire, c'est "éviter les abus sur les enfants".

Cela "explique 50 % de la variance des problèmes psychiatriques des adolescents et des adultes après".

L'Aide Sociale à l'Enfance (ASE), qui devrait être le bras armé de cette prévention, est elle-même "un désastre absolu".

• Facteurs de risque sociaux : La lutte contre la pauvreté, la précarité et l'exclusion est une politique de prévention en santé mentale.

"Lorsque je propose une aide sociale à une famille en difficulté [...] je préviens aussi un risque de santé mentale".

• Milieu scolaire : Réduire le nombre d'élèves par classe (le seuil de 17 élèves est cité comme optimal pour l'apprentissage de la lecture) est un levier puissant pour la santé mentale des enfants.

3.2. Renforcer l'Existant et Former les Acteurs

La priorité n'est pas de créer de nouveaux dispositifs, mais de soutenir les institutions et les pratiques qui ont fait leurs preuves.

• Soutenir les institutions : "S'il y avait qu'une chose à retenir, c'est celle-là".

Il faut "rouvrir des places, des lits à l'hôpital, dans les services spécialisés, les CMP, les CMPP". Il faut cesser de "déshabiller le CMP" pour "abonder les centres experts".

• Repenser la formation :

◦ La question centrale n'est pas "quelle est la bonne thérapie ?" mais "qui est un bon thérapeute ?".

L'effet du clinicien est largement supérieur à l'effet spécifique de la thérapie.    *   ◦ Il n'existe pas de formation universitaire pour les psychothérapies en France.    *  ◦ Il faut recréer des formations intermédiaires pour les infirmiers, sur le modèle d'une spécialisation locale d'un an ("infirmiers plus un"), car le modèle des Infirmières en Pratique Avancée (IPA) est trop lourd et coûteux.

• Valoriser la diversité des approches : La spécificité française réside dans une grande diversité de pratiques (psychanalyse, thérapies familiales, psychothérapie institutionnelle) qui "font leur preuve dans la clinique". Toute tentative de réduire cette diversité "va se payer par du moins de soins".

4. Enjeux Économiques et Budgétaires

Le débat sur les moyens financiers révèle une tension entre la nécessité de prouver l'efficacité économique des investissements et la conviction que le soin aux plus vulnérables relève d'un "pacte démocratique" non quantifiable.

4.1. Le Coût de l'Inaction

M. Tonou propose une méthode pour chiffrer le "coût de l'inaction", qui se calculerait en milliards d'euros.

• Exemple de calcul : Pour un coût moyen estimé de 10 000 € par an et par patient, une meilleure prise en charge permettant de réduire ces coûts de 20% générerait une économie de 3,9 milliards d'euros en population pédiatrique et de 18 milliards d'euros en population générale.

• Finalité : Démontrer que "le coût de l'inaction est beaucoup plus élevé que des politiques volontaires et cohérentes".

4.2. Une Question d'Organisation plus que de Moyens ?

Le professeur Falissard adopte une posture provocatrice : "Ça n'est pas une question de moyen".

• Gains d'efficience : "Nous pourrions faire beaucoup mieux avec la même quantité d'argent". Il pointe l'argent alloué à des dispositifs coûteux et peu efficaces (ex: hospitalisations de semaine pour bilans TDAH) alors que les urgences ne sont pas financées.

• Inefficacité des études médico-économiques : Il affirme que les études prouvant le sous-financement de la psychiatrie "n'ont servi à rien".

• Injustice de l'allocation des ressources : Il dénonce une inégalité fondamentale : "On n'a pas le même argent selon les maladies qu'on a en France".

Des traitements à 2 millions d'euros sont remboursés pour certaines maladies rares, tandis qu'il n'y a "pas 3000 € pour une tentative de suicide chez une adolescente".

La rationalité économique ne s'applique pas à la psychiatrie en France.

La conclusion partagée est que la priorité absolue est de mieux organiser le système, en se basant sur les acteurs de terrain ("pas des gens en costard-cravate") pour redéfinir les priorités et optimiser les dépenses.

Synthèse de l'Audition sur la Santé Mentale des Jeunes

Résumé Exécutif

L'audition met en lumière une crise sans précédent dans la prise en charge de la santé mentale des jeunes en France, une situation préexistante mais exacerbée de manière exponentielle par la pandémie de COVID-19.

Les experts s'accordent sur un diagnostic alarmant marqué par une pénurie critique de personnels soignants, des délais d'attente pour les soins qui engendrent des "pertes de chance" dramatiques, et une fragmentation systémique qui handicape la continuité des parcours.

Les défaillances identifiées ont des coûts individuels, familiaux et sociétaux massifs. Sur le plan individuel, elles se traduisent par une augmentation du risque suicidaire et une péjoration de la santé physique.

Pour les familles, elles représentent un fardeau émotionnel et financier considérable. À l'échelle de la société, l'absence de prise en charge précoce compromet l'avenir d'une génération et engendre des coûts à long terme bien supérieurs à ceux d'un investissement préventif.

Un goulot d'étranglement majeur est identifié entre les structures sanitaires et le secteur médico-social, où un manque criant de places d'aval conduit à une saturation des lits d'hospitalisation psychiatrique.

Face à ce constat, plusieurs axes stratégiques émergent : la nécessité absolue * d'investir dans la détection et l'intervention précoces, notamment en périnatalité et en milieu scolaire ; * l'urgence de former massivement tous les professionnels (médecins généralistes, personnels paramédicaux) et de * décloisonner les pratiques entre santé somatique et psychiatrique ; * et l'impératif d'instaurer une culture de l'évaluation systématique des dispositifs de soins pour allouer les ressources de manière plus efficiente et ciblée.

I. Diagnostic d'une Crise Systémique et Humaine

Les experts auditionnés décrivent unanimement une situation de crise aiguë dans le secteur de la psychiatrie et de la pédopsychiatrie, caractérisée par une inadéquation profonde entre les besoins de la population jeune et l'offre de soins disponible.

A. Une Pénurie Critique de Personnels Soignants

Un problème central et quotidien est le "manque criant de soignant". Il ne s'agit pas seulement d'un manque de postes budgétés, mais d'une incapacité à pourvoir les postes existants en raison d'un défaut d'attractivité majeur de l'hôpital public.

• Postes Vacants : Un service de psychiatrie adulte parisien rapporte 50 postes d'infirmiers vacants sur 200, conduisant à des unités d'hospitalisation fonctionnant avec un ou deux infirmiers titulaires, ce qui "altère de façon dramatique la qualité des soins".

• Crise des Vocations : Ce manque d'attractivité, observé dans tous les pays occidentaux, touche les infirmiers comme les médecins, y compris dans des régions autrefois préservées comme Paris intra-muros. Les écoles d'infirmières sont décrites comme "vides".

• Hétérogénéité des Ressources : Si certains services manquent de personnel pour remplir les postes, d'autres, notamment en pédopsychiatrie, manquent de postes autorisés, illustrant une rigidité dans l'allocation des ressources par les Agences Régionales de Santé (ARS).

B. Des Délais de Prise en Charge aux Conséquences Lourdes

La pénurie de soignants et la désorganisation des filières entraînent des retards de prise en charge aux conséquences graves pour les jeunes.

• Retards au Diagnostic : L'allongement des délais de consultation retarde le diagnostic.

Or, la "durée de maladie non traitée" est le facteur pronostique majeur : plus ce temps est long, plus le handicap généré sera important et la maladie difficile à soigner.

• Perte de Chance : Des jeunes en situation de risque vital, comme ceux souffrant d'anorexie mentale, peuvent attendre de trois à six mois pour une hospitalisation.

Ce retard constitue une "perte de chance" majeure, compromettant leur santé physique, psychique et leur avenir scolaire et social.

• Impact sur le Développement : Pour les enfants et adolescents, qui sont des "êtres en développement", une prise en charge tardive a des conséquences non seulement sur leur souffrance immédiate mais aussi sur leur trajectoire de vie future en tant qu'adulte.

C. L'Impact du COVID-19 comme Révélateur et Accélérateur

Bien que les difficultés soient antérieures à 2020, la crise sanitaire a agi comme un puissant accélérateur, provoquant une "décompensation" du système et une augmentation exponentielle des demandes de soins. Les experts affirment n'avoir "jamais vécu une situation comme celle-ci".

Les conséquences de cette période, notamment la perturbation du lien social et scolaire, se font encore sentir aujourd'hui sur la santé mentale de la jeune génération.

II. Les Coûts Multiples des Défaillances du Système

L'incapacité du système à répondre aux besoins génère des coûts importants et mesurables à trois niveaux : individuel, familial et sociétal.

L'objet de la commission d'enquête est précisément de démontrer que les "coûts évités" par une meilleure prise en charge sont insuffisamment appréhendés.

Niveau d'Impact

Description des Coûts

Individuel

• • Risque suicidaire augmenté et suicides effectifs. <br>
• • Santé physique menacée : les troubles mentaux péjorent la santé globale et l'espérance de vie. <br>
• • Désinsertion sociale et scolaire à un âge clé du développement.

Familial

• • Fardeau émotionnel et temporel pour les parents et la fratrie. <br>
• • Coût financier direct pour les soins non pris en charge par l'Assurance Maladie. <br>
• • Impact sur la santé et l'insertion professionnelle des parents, contraints d'accompagner leur enfant.

Sociétal

• - Perte de potentiel humain et économique pour la société. <br>
• • Augmentation des coûts à long terme liés aux complications et au handicap. <br>
• • Saturation du système de soins : des études montrent que les troubles mentaux représentent l'une des principales causes de coût pour les sociétés (mesuré par les indicateurs DALYs).

La Saturation du Système par le "Défaut d'Aval"

Une défaillance structurelle majeure est le lien entre les structures sanitaires et médico-sociales.

• Occupation Inadéquate des Lits : Il est estimé que 20 à 30 % des lits en hôpital psychiatrique sont occupés par des patients qui n'y ont "rien à faire" et devraient être dans des structures d'aval (Foyers d'Accueil Médicalisés, Maisons d'Accueil Spécialisées).

• Pénurie de Places : Le nombre de places dans ces structures est "bien trop insuffisant". Ces patients, qui ont besoin d'un accompagnement au long cours, bloquent des lits de soins aigus.

• Échec des Politiques Publiques : La décision de fermer l'accès aux structures en Belgique pour les patients français n'a pas été suivie de la création de places équivalentes en France. Aucun chantier de FAM ou de MAS n'aurait été lancé en Île-de-France depuis cinq ans.

III. Axes Stratégiques pour une Réponse Efficace

Face à ce diagnostic, les experts proposent des solutions articulées autour de la prévention, de la formation, de la coordination et de l'évaluation.

A. La Prévention et la Détection Précoce : Une Priorité Absolue

Il est crucial d'intervenir le plus tôt possible pour réduire la "durée de maladie non traitée".

• Périmètre d'Action :

◦ Prévention primaire : Agir sur les conditions de développement (bien-être familial, scolaire, lutte contre les toxiques).     ◦ Prévention secondaire : Repérer et soigner précocement les troubles émergents.     ◦ Prévention tertiaire : Éviter les rechutes par un suivi adapté et des lieux de vie protégés.

• Champs d'Intervention Clés :

◦ Périnatalité : Mieux détecter et traiter la dépression maternelle (qui touche jusqu'à 25 % des mères) pour le bien-être de la mère et du bébé.     ◦ Milieu Scolaire : Le milieu scolaire est un lieu central d'expression de la souffrance.

Il est impératif de renforcer la médecine scolaire et de créer des liens structurés (cellules mixtes, lignes téléphoniques dédiées) entre l'Éducation Nationale et les services de pédopsychiatrie.

• Le Défi : Le système a progressé sur le "repérage" mais échoue souvent à assurer la "prise en charge" intensive et pluridisciplinaire qui doit suivre.

B. Formation et Coordination : Décloisonner les Pratiques

La complexité des situations exige un partage des compétences et un décloisonnement des institutions.

• Formation des Professionnels :

◦ Médecins Généralistes : Ils sont en première ligne (25-30 % de leur patientèle concerne la santé mentale) mais manquent de formation spécifique.

La proposition d'un semestre obligatoire de psychiatrie pour les internes en médecine générale est rappelée.     *  ◦ Personnels Paramédicaux : Il est nécessaire de former plus largement à la psychiatrie (infirmiers, psychologues) et de revaloriser leurs compétences, par exemple via la supervision.   *   ◦ Pédopsychiatres : La France est en sous-dotation par rapport à ses voisins européens. Il faut créer plus de postes universitaires pour former la relève.

• Décloisonnement des Soins :

◦ Somatique et Psychiatrique : Développer une double culture et une approche globale de la santé, en intégrant le soin psychique dans les maladies chroniques et inversement.    ◦ Lisibilité de l'Offre : L'organisation de l'offre de soins est "complètement opaque" pour les usagers et même pour les professionnels. La création d'un répertoire accessible (par exemple, adossé à Pronote) est suggérée.

C. L'Innovation et l'Évaluation : Piloter par la Donnée

Le système ne pourra s'améliorer sans une culture de l'innovation et de l'évaluation rigoureuse.

• Innovation Thérapeutique : Les traitements actuels ont des limites (un tiers des patients ne répondent pas aux traitements conventionnels).

Il est essentiel de soutenir la recherche et l'innovation (neuromodulation, nouvelles molécules).

• Réforme du Financement : Le mode de financement par "enveloppe globale" en psychiatrie est jugé "illisible", rigide et un frein à l'innovation, car il ne permet pas de financer les nouvelles thérapeutiques coûteuses et ne s'adapte pas aux évolutions démographiques des secteurs.

• Culture de l'Évaluation : C'est une lacune majeure du système français. Les dispositifs de soins, notamment les initiatives innovantes comme les "équipes mobiles", sont lancés sans que leur efficacité ne soit évaluée de manière rigoureuse.

Il est impératif d'intégrer et de financer l'évaluation dès la conception de tout nouveau projet.

IV. Enjeux Spécifiques et Populations Vulnérables

• Les Addictions : Les experts alertent sur l'enjeu majeur des addictions aux toxiques (cannabis, molécules de synthèse), qui inondent le pays et constituent un facteur de risque majeur pour les troubles mentaux, un sujet jugé "un peu abandonné".

• Le Milieu Carcéral : Qualifié d' "aveu d'échec monstrueux", les prisons regorgent de malades mentaux qui échappent souvent à une prise en charge adaptée.

• Les Populations Précaires : Un effort particulier doit être fait pour assurer une continuité des soins auprès des jeunes les plus défavorisés (pris en charge par l'ASE ou la PJJ, familles migrantes), qui sont souvent les plus éloignés du système de santé.

• Le Transfert vers le Privé : Une part importante des lits de psychiatrie a été transférée du secteur public vers le secteur privé.

Or, les cliniques privées n'ont pas les mêmes missions de service public, sélectionnent leurs patients et pratiquent des tarifs qui limitent leur accessibilité.

Reviewer #2 (Public review):

Summary:

Toxoplasma gondii is an obligate intracellular parasite and the causative agent of Toxoplasmosis. Parasite invasion into host cells, intracellular replication, and then egress, which results in the destruction of the infected cell, is central to pathogenicity. This manuscript focuses on understanding how maternal resources (in this case, cellular organelles) are shared between daughter parasites during cell division. Many organelles are single copy, meaning that division and inheritance by the daughters is crucial for successful replication. The major strength of this study was the use of a Halo-based pulse chase assay to characterize patterns of organelle inheritance. The results show that both microneme and rhoptries (secretory vesicles) previously thought to be synthesized de novo are inherited by daughter parasites. Thus, this paper adds new insight to our understanding of cell division in this important parasite.

Strengths:

This study demonstrated that pulse labeling of proteins can be used to monitor protein synthesis, turnover, and movement. This approach will be of great interest to the field. Using this method, the authors demonstrate three main modes of organelle inheritance.

(1) Organelles, where there are multiple copies (such as secretory vesicles, micronemes, and rhoptries), are divided between the daughter parasites, with additional contribution of newly formed vesicles. New and old material remain as separate entities in the cell.

(2) Single-copy organelles, which are expanded to include newly synthesized material prior to division, such as the Golgi and apicoplast.

(3) Cytoskeletal structures that are synthesized anew during each round of division. These studies provide more refined insight into patterns or organelle inheritance and demonstrate that secretory organelles are not made de novo during each round of division as previously thought. The paper has a logical flow, and overall, the data is presented in a clear and organized fashion.

Weaknesses:

(1) Descriptions of methodology and statistical analysis were incomplete.

(2) There are inconsistencies between the data in Figures 1 and 5. In Figure 1, a small amount of maternal IMC is visible in stage 2 parasites. Although this is a ~90% reduction, these parasites should be quantified as parasites with material IMC. However, the graph in Figure 5C indicates that no material parasites have GAPM1a, given that graph 5C is a binary measure (present vs. absent), one would expect a non-zero percent of parasites to have maternal material.

(3) The conclusion from Figure 6 was not justified based on the data. I agree with the author's conclusion that the accumulation of micronemes and rhoptries in the residual body was time-dependent. In Figure 6A, the signal observed in the residual body at times 6:30, 13, and 14 hours is not observed in subsequent time points. However, the fate of these micronemes and rhoptries is unclear. It cannot be concluded that these vesicles are recycled back to the mother. They could also have been degraded. In fact, the graphs of microneme inheritance in Figure 2B show a decrease in maternal signal from 100% to 80% between stages 1 and 2, indicating that some microneme degradation is taking place.

(4) To convincingly demonstrate that the redistribution of micronemes and rhoptries was due to recovery of MyoF protein levels after auxin washout, a Western blot should be performed to show MyoF protein levels over time. In addition, the decrease in mMIC2 protein levels in the residual body in Figure 8F should be measured and normalized for photobleaching. Both apical and basal signals appear to be reduced over the time course of imaging.

Analyse de la Politique de Santé Mentale et de Psychiatrie en France

Synthèse

Ce document de synthèse analyse l'état actuel et les perspectives d'évolution des politiques publiques de santé mentale et de psychiatrie en France, en se basant sur les auditions de la délégation ministérielle dédiée.

Il en ressort un constat central : après plus de trente ans de négligence, où la santé mentale a été le "parent pauvre des politiques publiques", un tournant majeur a été amorcé en 2018 avec la "Feuille de route santé mentale et psychiatrie".

Cette initiative marque une rupture, symbolisant un engagement politique et financier inédit pour rattraper des décennies de défaillances structurelles.

La crise Covid-19 a agi comme un révélateur, exacerbant les vulnérabilités préexistantes du système de soins (pénurie de soignants, hospitalo-centrisme, manque de prévention) et de la population (dégradation de la santé mentale des jeunes, des femmes et des précaires).

Le système actuel est décrit comme largement "illisible", constitué d'une "multitude de particularismes" et freiné par un modèle de financement "anesthésiant" qui décourage l'innovation.

Face à ces défis, une stratégie de transformation profonde est proposée, articulée autour de plusieurs axes fondamentaux :

1. Une gouvernance refondée et interministérielle : Inspirée du modèle du handicap, elle vise à coordonner l'ensemble des politiques publiques ayant un impact sur la santé mentale, en impliquant tous les ministères concernés.

2. Une programmation pluriannuelle : Pour sortir de la logique budgétaire annuelle (PLFSS) et donner de la visibilité financière et stratégique aux réformes sur le moyen et long terme.

3. Une organisation graduée des soins : Renforcer les premières lignes (médecine générale, psychologues, Maisons des adolescents) pour mieux orienter les patients et réserver les services de psychiatrie hautement spécialisés aux cas les plus complexes.

4. Des réformes structurelles du financement et des autorisations : Introduire des mécanismes incitatifs pour encourager l'innovation, les soins ambulatoires et la coopération entre tous les acteurs d'un territoire (public, privé, associatif).

L'enjeu humain reste crucial, avec une crise d'attractivité des métiers liée non seulement à la pénurie mais aussi à une "blessure morale" des soignants due à la perte de sens.

La dynamique actuelle, portée par une mobilisation politique et sociétale sans précédent, représente un "momentum" unique pour amplifier et accélérer ces réformes.

Analyse Détaillée

Un Héritage de Négligence Structurelle

Pendant plus de 30 ans, la santé mentale a été marginalisée dans les politiques publiques, une situation illustrée par plusieurs facteurs structurels :

• Le "parent pauvre" des politiques de santé : Ce statut s'est traduit par une considération "à part" des patients, des familles et des professionnels, tant dans le système de santé que dans la société.

• Une sous-valorisation financière : L'Objectif national de dépenses d'assurance maladie (Ondam) pour la psychiatrie a systématiquement progressé moins vite que l'Ondam pour la médecine, la chirurgie et l'obstétrique (MCO).

• Un pilotage financier "anesthésiant" : Le modèle de la dotation annuelle de fonctionnement (DAF) a largement contribué à freiner l'innovation et l'adaptation de l'offre de soins face à des besoins populationnels croissants.

• Une offre de soins illisible : L'absence de pilotage stratégique fort a conduit à une "multitude de particularismes" territoriaux, rendant le système complexe et difficile à naviguer pour les usagers, les familles et même les professionnels.

Des familles en sont réduites à déménager pour accéder à un secteur de psychiatrie jugé plus performant.

• Une faible culture des données probantes : Malgré l'existence de nombreuses études validées sur les prises en charge efficaces, le secteur a peu intégré ces "données probantes" dans ses pratiques.

La Feuille de Route de 2018 : Une Rupture et un Nouvel Élan

La "Feuille de route santé mentale et psychiatrie", lancée en 2018, est présentée comme une "rupture par rapport à une aboulie de plus de 30 ans".

Elle constitue le point de départ d'une politique de rattrapage, marquée par un engagement politique et financier inédit.

• Qualité et alignement international : La feuille de route est jugée de qualité et conforme aux standards internationaux.

• Enrichissements successifs : Elle a été constamment renforcée par des jalons importants comme le Ségur de la santé, les Assises de la santé mentale et de la psychiatrie, les Assises de la pédiatrie, et les annonces dans le cadre de la grande cause nationale.

• Continuité politique : Malgré une forte instabilité ministérielle (le délégué ministériel a "survécu à 10 ministres de la santé"), la feuille de route a été systématiquement reconduite et enrichie, assurant une forme de continuité dans l'action publique.

• Premiers effets visibles : Les réformes structurelles engagées commencent à porter leurs fruits, bien que leur plein impact ne soit attendu qu'à moyen terme.

Les Vulnérabilités Révélées par la Crise Sanitaire

La crise du Covid-19 a amplifié des fragilités structurelles anciennes, sans pour autant en être la cause première.

• Vulnérabilités du système de soins :

◦ Manque de soignants et départs de l'hôpital public.    ◦ Débits de formation insuffisants.    ◦ Un "hospitalo-centrisme" persistant.    ◦ Pauvreté de la santé primaire et des politiques de prévention.    ◦ Fortes hétérogénéités territoriales.

• Vulnérabilités de la population :

◦ Une dégradation de la santé mentale des jeunes, des femmes et des personnes en situation de précarité, un phénomène observé à l'échelle européenne et mondiale.

Vers un Changement de Paradigme : Stratégie et Réformes Proposées

Pour répondre à ces défis systémiques, un changement de paradigme est préconisé, s'appuyant sur des réformes profondes de la gouvernance, de la planification et de l'organisation des soins.

Refonder la Gouvernance sur un Modèle Interministériel

L'action sur les déterminants de la santé mentale (logement, emploi, lutte contre les violences, addictions) ne relève pas du seul ministère de la Santé. Une gouvernance interministérielle est donc jugée indispensable.

Structure Proposée

Fréquence

Objectif

Comité Interministériel

Annuelle

Définir, coordonner et évaluer les politiques publiques en faveur de la santé mentale, sur le modèle du Comité Interministériel du Handicap (CIH).

Conférence Nationale

Triennale

Débattre des orientations et des moyens des politiques de santé mentale, en réunissant l'ensemble des parties prenantes.

Comité des Parties Prenantes

À définir

Formaliser un organe consultatif pour assurer la participation active des usagers, familles, professionnels et autres acteurs.

Délégation Ministérielle

Renforcée

Renforcer ses moyens (objectif de 8 agents) pour lui confier la coordination et le pilotage de la feuille de route devenue interministérielle.

Instaurer une Programmation Pluriannuelle

Le cycle budgétaire annuel du Projet de Loi de Financement de la Sécurité Sociale (PLFSS) est un obstacle à la mise en œuvre de réformes structurelles.

La nécessité d'une vision à long terme est soulignée, avec un plaidoyer pour une loi de programmation qui garantirait une visibilité financière et stratégique sur plusieurs années.

Cette approche permettrait d'investir dans des actions de prévention dont les bénéfices, notamment en termes de "coût évité", ne sont mesurables que sur la durée.

Organiser l'Offre de Soins : Gradation et Coordination

Le système actuel est marqué par un héritage où "tout allait à la psychiatrie". La stratégie proposée vise à structurer une offre de soins graduée :

1. Renforcer les premières lignes : La médecine générale, les dispositifs comme "MonSoutienPsy" et les Maisons des adolescents doivent jouer un rôle de filtre pour les troubles légers à modérés et "refroidir" un certain nombre de situations.

2. Réserver la psychiatrie spécialisée : Le secteur de psychiatrie, avec ses équipes hautement spécialisées (psychiatres, psychologues, IPA, psychomotriciens), doit se concentrer sur les cas les plus complexes et graves.

3. Coordonner tous les acteurs : La réforme des autorisations vise à obliger les différents offreurs de soins d'un territoire (public sectorisé, public non sectorisé, privé) à sortir de leurs "couloirs de nage" pour s'articuler fonctionnellement et se répartir la charge des besoins.

4. Inciter à l'innovation : La réforme du mode de financement introduit des compartiments financiers incitatifs pour encourager les pratiques orientées vers le rétablissement, l'ambulatoire et les alternatives à l'hospitalisation, notamment sans consentement.

La Nécessité d'un "Grand Texte" Clarificateur

Un texte de loi est jugé crucial pour clarifier la politique de santé mentale, remettre de l'ordre dans les "particularismes" et définir des standards de prise en charge basés sur les données probantes.

Enjeux Cruciaux : Ressources Humaines et Évaluation

L'Attractivité des Métiers : Au-delà de la Pénurie

La crise de l'attractivité en psychiatrie est multifactorielle :

• Pénurie et burnout : La pénurie de personnel génère une surcharge de travail pour les équipes en place, créant un cercle vicieux.

• "Blessure morale" : Plus profondément, les soignants expriment une perte de sens. Ils sont confrontés à des situations qui violent leur éthique professionnelle (ex: maintenir un patient attaché pendant plusieurs jours sur un brancard faute de lit), ce qui génère une "blessure morale".

• Redonner du sens : Les dispositifs innovants (ex: équipes mobiles de crise financées par le Fonds d'Innovation Organisationnelle en Psychiatrie - FIOP) rencontrent moins de difficultés de recrutement car ils s'inscrivent dans un projet clair et porteur de sens.

• Formation : La réforme du DES de psychiatrie, en instaurant un passage obligatoire en pédopsychiatrie plus tôt dans le cursus, vise à améliorer l'attractivité de cette spécialité. Pour les infirmières, un renforcement des modules de santé mentale dans la formation initiale et un meilleur accompagnement à la prise de poste ("onboarding") sont des pistes explorées.

Développer une Culture de l'Évaluation

La France est jugée en retard sur l'évaluation de ses politiques publiques.

• Le coût de l'inaction : Des études, notamment anglo-saxonnes, démontrent les coûts socio-économiques phénoménaux de la non-prise en charge des troubles mentaux (estimés à 163 milliards d'euros par an en France par la Fondation FondaMental).

• L'argument du "coût évité" : Investir dans la prévention est économiquement vertueux. Par exemple, il est démontré qu'1€ investi dans des soins psychologiques de première ligne permet d'économiser entre 1,4€ et 1,6€. Cet argument peine cependant à être pris en compte dans les arbitrages budgétaires annuels.

• Évaluation des politiques publiques : Un ensemble d'indicateurs a été mis au point pour suivre les effets de la feuille de route, ce qui constitue une exception. Il reste à développer cette culture au niveau local pour évaluer l'efficacité des dispositifs innovants financés par appels à projets.

Synthèse de l'audition de Santé publique France sur la santé mentale et le handicap

Résumé

L'audition de Santé publique France devant la commission d'enquête met en lumière une dégradation persistante de la santé mentale de la population française depuis la pandémie de Covid-19, touchant particulièrement les jeunes de 18 à 24 ans et les femmes.

Les données de surveillance révèlent une prévalence élevée des troubles dépressifs et anxieux, avec un décalage majeur entre les besoins et le recours effectif aux soins.

Près de la moitié des adultes ayant connu un épisode dépressif caractérisé n'ont eu aucun recours thérapeutique.

Les principaux freins identifiés sont le coût des consultations, la difficulté à se confier et le manque d'information.

Concernant les personnes en situation de handicap, l'agence souligne une lacune importante dans les données de surveillance, rendant difficile la caractérisation fiable de leur état de santé et de leur prise en charge.

L'accès aux données des Maisons Départementales des Personnes Handicapées (MDPH) est identifié comme un levier majeur d'amélioration.

Face à ces constats, Santé publique France insiste sur l'importance cruciale de la prévention.

Les stratégies préconisées incluent le renforcement des compétences psychosociales dès l'enfance, la lutte contre la stigmatisation via des campagnes d'information et la promotion de la santé mentale positive. Des dispositifs comme le programme "Vigilance", qui a démontré un retour sur investissement positif (€1 investi pour €2 économisés en coûts de santé), sont mis en avant comme des modèles à généraliser pour une approche économiquement vertueuse de la santé publique.

1. Rôle et Méthodes de Surveillance de Santé publique France

Santé publique France, agence de santé publique créée en 2016, fonde ses missions sur un triple objectif :

1. Anticiper et répondre aux crises sanitaires, notamment par la gestion des stocks stratégiques de produits de santé et la mobilisation de la réserve sanitaire.

2. Surveiller l'état de santé de la population sur l'ensemble du territoire, y compris ultramarin, en couvrant les maladies infectieuses, chroniques et les expositions environnementales.

3. Développer la prévention et promouvoir la santé.

Pour la surveillance de la santé mentale, l'agence s'appuie sur plusieurs sources de données complémentaires :

• Les enquêtes en population générale :

• ◦ Réalisées sur des échantillons aléatoires, elles utilisent des questionnaires et des échelles de santé mentale pour évaluer l'état de la population sans poser de diagnostic individuel.  

• ◦ Exemples notables : le Baromètre de Santé publique France (adultes), l'enquête ENABI (enfants de 3 à 11 ans, réalisée en milieu scolaire en 2022), et l'enquête EnCLASS (collégiens).   

• ◦ Pendant la crise sanitaire, l'enquête Coviprêve a permis un suivi plus rapide, bien que moins détaillé.

• Les bases de données médico-administratives :

◦ Le Système National des Données de Santé (SNDS) est une source majeure d'informations.  

◦ Les données des services d'urgence (motifs de passage) et de SOS Médecins permettent un suivi en temps réel de certains indicateurs comme les troubles anxieux ou les tentatives de suicide.

L'ensemble de ces données permet d'obtenir une "photographie en vie réelle" de la santé mentale des Français, contribuant à l'élaboration de stratégies de prévention et de campagnes d'information.

2. État des Lieux de la Santé Mentale en France

2.1. Une Dégradation Post-Covid Durable

La surveillance épidémiologique confirme une dégradation nette de la santé mentale de la population française par rapport à la période pré-Covid.

• Populations les plus touchées : Les jeunes adultes de 18 à 24 ans, les jeunes filles et les femmes en général présentent les indicateurs les plus dégradés.

• Persistance : Les différents indicateurs de santé mentale se maintiennent à un niveau élevé, sans retour aux niveaux d'avant la crise sanitaire. Les causes sont multifactorielles (éco-anxiété, système économique, mais aussi une plus grande déclaration due à une libération de la parole).

2.2. Données Clés sur la Prévalence des Troubles

Les enquêtes récentes fournissent des chiffres préoccupants :

Population Cible

Indicateur

Donnée Chiffrée

Source (Année)

Adultes (18-79 ans)

Épisode dépressif caractérisé (12 derniers mois)

1 adulte sur 6

Baromètre SPF (2024)

Adultes (18-79 ans)

Trouble anxieux (12 derniers mois)

6 % de la population

Baromètre SPF (2024)

Enfants (6-11 ans)

Trouble probable de la santé mentale

Plus d'1 enfant sur 10

ENABI (2022)

Enfants (tous âges)

Consultation d'un professionnel pour des raisons psychologiques/d'apprentissage

1 enfant sur 5

ENABI (2022)

Collégiens

Consultation d'un psychiatre au cours de leur vie

1 tiers des collégiens

EnCLASS

2.3. Le Non-Recours aux Soins : Un Enjeu Majeur

Un décalage important est observé entre les besoins exprimés ou mesurés et le recours effectif à une prise en charge.

• Épisodes dépressifs : Près de la moitié (50 %) des personnes déclarant un épisode dépressif n'ont eu "aucun recours thérapeutique" (ni professionnel, ni traitement).

• Troubles anxieux : Cette proportion est de 1 personne sur 3.

• Profils concernés : Le non-recours aux soins est plus élevé chez les hommes que chez les femmes.

• Situations critiques : Près de 40 % des personnes déclarant une tentative de suicide ne se sont pas présentées à l'hôpital et n'ont pas consulté de professionnel de santé par la suite.

2.4. Les Freins à la Consultation

L'enquête Coviprêve a permis d'identifier les principaux obstacles au recours aux soins en santé mentale :

• 1. Le prix de la consultation (cité par près de la moitié des répondants).

• 2. La difficulté à se confier ou la peur de ce qu'ils pourraient découvrir sur eux-mêmes.

• 3. Le manque d'information sur les professionnels et leur rôle.

• 4. La difficulté à obtenir un rendez-vous.

• 5. La peur que l'entourage l'apprenne (stigmatisation).

• 3. La Situation Spécifique des Personnes en Situation de Handicap

Santé publique France reconnaît un manque de données structurées concernant l'état de santé des personnes en situation de handicap.

• Limites de la surveillance : La surveillance de cette population n'entre pas "strictement" dans les missions de l'agence, bien qu'elle soit incluse dans les enquêtes générales.

• Difficultés de caractérisation : Il est difficile d'identifier et de caractériser de manière fiable ces personnes dans les bases de données. L'Allocation Adulte Handicapé (AAH) est le principal repère, mais elle ne couvre que les adultes en âge de travailler avec des handicaps reconnus comme sévères.

• Besoin crucial de données : L'agence attend avec impatience la remontée des données des Maisons Départementales des Personnes Handicapées (MDPH) dans le SNDS, ce qui constituerait un "saut qualitatif et quantitatif" pour mieux orienter les politiques publiques.

• Vulnérabilités observées : Les données existantes montrent que les bénéficiaires de l'AAH sont "proportionnellement plus concernés par des événements cardiovasculaires graves".

4. Stratégies de Prévention et Pistes d'Amélioration

Face à ces constats, Santé publique France place la prévention au cœur de sa stratégie.

4.1. Axes de Prévention

• Prévention primaire :

◦ Compétences psychosociales (CPS) : Développer dès le plus jeune âge (école, associations sportives) des capacités à gérer le stress, communiquer, résoudre des problèmes.

Cette approche, inspirée des modèles anglo-saxons, est de plus en plus acceptée et intégrée, notamment par l'Éducation Nationale.  

◦ Promotion de la santé mentale positive : Informer sur les comportements protecteurs (activité physique, sommeil, altruisme, pensée positive) au même titre que la santé physique.

• Lutte contre la stigmatisation :

• ◦ Mener des campagnes d'information pour dédramatiser les troubles psychiques.  

• ◦ Mettre à disposition des ressources grand public comme le site santémentaleinfoservice.fr.

• Prévention tertiaire (prévention de la récidive) :

◦ Le dispositif Vigilance, qui consiste à rappeler les personnes ayant fait une tentative de suicide six mois après leur passage aux urgences, a fait l'objet d'une évaluation médico-économique très positive. Il est en cours de déploiement dans toutes les régions.

4.2. Pistes d'Amélioration

Santé publique France identifie plusieurs axes pour améliorer la connaissance et l'action :

• Mieux caractériser les personnes en situation de handicap dans les bases médico-administratives et médico-sociales.

• Mieux documenter la santé et le rôle des aidants.

• Poursuivre et développer les enquêtes en milieu scolaire pour un dépistage précoce.

• Renforcer l'information sur les signes de souffrance psychique et les parcours de soins gradués.

5. Enjeux Économiques et Décisionnels

L'audition a souligné la dimension économique de la santé mentale et l'importance de convaincre les décideurs publics d'investir dans la prévention.

• Coût des troubles psychiques : Estimé à 109 milliards d'euros pour la société française, dont près de la moitié en perte de productivité.

• Retour sur investissement de la prévention :

• ◦ L'évaluation du dispositif Vigilance montre que 1 € investi permet d'économiser 2 € de coûts de santé, avec un coût moyen évité de 248 € par patient.  
• ◦ Santé publique France s'engage à évaluer de plus en plus le retour sur investissement de ses actions.

• Nécessité d'un plaidoyer : L'agence travaille au développement d'indicateurs sur le "fardeau de la maladie" (Global Burden of Disease) pour objectiver le poids des troubles sur la société et justifier les investissements en prévention.

Le manque de données fiables, notamment à un niveau territorial fin, reste un obstacle pour convaincre les acteurs locaux.

Processo de Responsabilização - Comissão de 2 ou + servidores estáveis conduzem o processo. Se empregados, devem pertencer ao quadro permanente com pelo menos 3 anos de tempo de serviço; - Prazo de 15 dias úteis para contestação; - Prazo de 15 dias úteis para alegações finais; - Se houver atos ilícitos previstos na Lei Anticorrupção, deverá haver apuração conjunta no mesmo processo. - Aplicação de sanção de declaração de inidoneidade para contratar e licitar é de competência exclusiva de Ministro de Estado/Secretário do Estado; - Contra aplicação de declaração de inidoneidade para contratar e licitar somente cabe pedido de reconsideração no prazo de 15 dias úteis; - Prazo recursal é de 3 dias úteis; - Tanto recurso, quanto pedido de reconsideração terão efeito suspensivo.

Regra Geral (Art. 14, I): A vedação à participação do autor do anteprojeto, projeto básico ou executivo na licitação é a regra geral. O objetivo é proteger os princípios da isonomia, moralidade e impessoalidade, evitando direcionamento e conflito de interesses.

Exceção Principal - Concessões e Permissões: Esta vedação NÃO se aplica aos processos de licitação para concessões e permissões de serviços públicos.

• Fundamento Legal Expresso: A permissão é garantida pelo Art. 31 da Lei nº 9.074/1995, que autoriza expressamente a participação dos autores dos projetos nesses certames.

• Justificativa: No modelo de concessão, o risco é transferido ao particular, e o foco está na eficiência da prestação do serviço, o que mitiga os riscos de direcionamento do projeto da obra em si.

Exceção Decorrente - Procedimento de Manifestação de Interesse (PMI): A participação do autor dos estudos também é permitida na licitação subsequente.

• Justificativa: A proibição inviabilizaria o próprio instituto do PMI, cujo objetivo é justamente atrair a expertise do setor privado para desenvolver projetos para a Administração. O vencedor da licitação, caso não seja o autor dos estudos, geralmente o ressarcirá.

Aplicação em Estatais (Lei 13.303/2016): Importante notar que a Lei das Estatais (Art. 44, I) segue a regra geral de vedação, aplicando a mesma proibição deste Art. 14.

Document d'Information : Prise en Charge de la Santé Mentale et du Handicap par l'Assurance Maladie

Résumé

Ce document synthétise les stratégies, les actions et les défis de l'Assurance Maladie (CNAM) concernant la prise en charge de la santé mentale et du handicap, tels que présentés lors d'une audition devant une commission d'enquête de l'Assemblée nationale.

La santé mentale représente le premier poste de dépenses de l'Assurance Maladie, avec près de 28 milliards d'euros annuels, dans un contexte de dégradation des indicateurs, notamment une augmentation de plus de 60 % de la consommation d'antidépresseurs chez les jeunes entre 2019 et 2023.

Face à cet enjeu, la CNAM déploie une stratégie axée sur la prévention, la détection précoce et l'organisation de nouvelles filières de soins, incarnée par le dispositif "Mon Soutien Psy" qui a déjà bénéficié à plus de 900 000 assurés.

Concernant le handicap, l'action se concentre sur l'amélioration de l'accès aux soins, une difficulté majeure confirmée par le baromètre Handifaction qui révèle que près de 30 % des personnes concernées rencontrent des obstacles (refus de soins, renoncement).

Les leviers mobilisés incluent l'intégration de mesures spécifiques dans les conventions avec les professionnels de santé (ex: "consultations blanches") et le soutien à des modèles innovants comme les centres "Handiconsulte".

Deux enjeux transversaux majeurs émergent : la conviction que l'investissement dans la prévention génère un retour médico-économique significatif (un euro investi en prévention en santé mentale en rapporterait quatre) et la nécessité de développer des modèles de remboursement pour des professionnels non conventionnés au niveau national (psychomotriciens, ergothérapeutes), ce que la CNAM se dit prête à mettre en œuvre.

Enfin, une alerte forte est lancée sur les pénuries de médicaments, dont certaines sont attribuées non pas à des difficultés d'approvisionnement, mais à des stratégies commerciales de laboratoires qui cessent de livrer la France suite à des négociations sur les prix, qualifiées de "chantage".

Axe 1 : Amélioration de l'Accès aux Soins pour les Personnes en Situation de Handicap

Diagnostic : Difficultés d'Accès et Manque de Données

L'Assurance Maladie identifie l'accès aux soins des personnes en situation de handicap comme un axe prioritaire.

Le diagnostic s'appuie notamment sur le baromètre Handifaction, dont la gestion a été internalisée par la CNAM pour lui donner une plus grande ampleur.

Les résultats de ce baromètre sont clairs :

• Près de 30 % des personnes interrogées déclarent des difficultés d'accès aux soins.

• Ces difficultés incluent des situations de refus de soins, de renoncement ou la nécessité de contacter plusieurs professionnels avant d'obtenir une prise en charge.

Un défi technique majeur demeure : les systèmes d'information de l'Assurance Maladie ne permettent pas d'identifier une personne par sa situation de handicap.

Pour pallier ce manque, la CNAM utilise des indicateurs indirects, comme le statut d'Affection de Longue Durée (ALD) ou le bénéfice de la Complémentaire Santé Solidaire (C2S), considérant qu'une part importante de ces populations est également en situation de handicap.

Leviers d'Action de l'Assurance Maladie

Pour répondre à ces enjeux, la CNAM mobilise plusieurs leviers d'action structurés, notamment dans le cadre de la Charte Romain Jacob, signée et déployée sur l'ensemble du réseau.

Levier d'Action

Description

Engagements Conventionnels

Intégration systématique du handicap dans les négociations avec les professionnels de santé (médecins, dentistes, masseurs-kinésithérapeutes).

Mise en place de mesures spécifiques comme les "consultations blanches" (consultations préparatoires non soignantes pour familiariser le patient et le praticien) qui bénéficient d'une rémunération dédiée.

Offre de Soins Propre

La CNAM gère un réseau de plus de 200 établissements de soins non lucratifs (15 000 salariés) fortement orienté vers la prise en charge du handicap et engagé dans le "virage inclusif".

Accessibilité des Services

Travail systématique sur l'accessibilité physique, téléphonique et numérique des services de l'Assurance Maladie (site ameli.fr, compte Ameli, Mon Espace Santé).

Innovation Organisationnelle

Soutien aux expérimentations (via l'article 51) comme Handiconsulte, qui propose un modèle de rémunération au forfait pour des centres dédiés à la prise en charge somatique (gynécologie, dentaire, radiologie) des personnes handicapées. Un déploiement plus large est à l'étude.

Coordination (PCO)

Participation active au déploiement des Plateformes de Coordination et d'Orientation (PCO), notamment pour les troubles du neurodéveloppement (TND) et l'autisme, qui visent à organiser et solvabiliser une réponse rapide pour les enfants et leurs familles.

Axe 2 : La Santé Mentale, Priorité de Santé Publique et Enjeu Financier Majeur

Constat : Des Indicateurs Alarmants et un Coût Élevé

La santé mentale est un enjeu de santé publique majeur, comme en témoignent les chiffres clés partagés par la CNAM.

Indicateur

Donnée Clé

Dépenses Annuelles

Près de 28 milliards d'euros, ce qui en fait le premier poste de dépenses de l'Assurance Maladie.

Population Affectée

1 Français sur 5 est concerné par des difficultés de santé mentale.

Médication chez les Jeunes

+60 % d'augmentation des prescriptions d'antidépresseurs chez les jeunes entre 2019 et 2023.

Arrêts de Travail

Un tiers des journées d'arrêt de travail sont liées à des troubles de santé mentale.

La tendance épidémiologique générale est jugée "pas bonne", soulignant l'urgence d'agir contre une dégradation continue de la santé mentale de la population, particulièrement depuis la crise du Covid.

Stratégie de l'Assurance Maladie : Prévention et Organisation des Soins

La réponse de la CNAM s'articule autour de deux axes principaux : la prévention et la structuration d'une offre de soins graduée pour éviter le recours systématique au médicament ou à l'hospitalisation.

1. Prévention et Détection Précoce :

• Soutien au programme "Premier Secours en Santé Mentale", notamment auprès des jeunes (universités, missions locales) et en cours de déploiement dans le monde de l'entreprise.

• Relai des campagnes de prévention sur les facteurs de risque, comme l'exposition aux écrans chez les jeunes enfants.

• Détection précoce des troubles du langage à l'école avec des programmes impliquant des orthophonistes pour organiser un "fast track" vers la prise en charge.

2. Organisation du Système de Soins :

• Équiper le médecin généraliste : Reconnu comme la porte d'entrée du système, la CNAM développe des outils et un accompagnement pour aider les généralistes, souvent démunis, à aller au-delà de la prescription de médicaments ou d'arrêts de travail.

• Favoriser la coopération : Soutien aux binômes médecin-infirmier (notamment via l'expérimentation "Sésame") et aux Infirmiers en Pratique Avancée (IPA).

• Structurer des équipes de soins spécialisées de psychiatres pour organiser une offre de téléconsultation coordonnée avec les médecins traitants.

• Éviter l'hospitalisation en renforçant la prise en charge en ville et en structurant des filières d'accès aux soins psychiatriques pour prévenir les hospitalisations non maîtrisées.

Le Dispositif "Mon Soutien Psy" : Bilan et Perspectives

Lancé après une expérimentation en 2018, le dispositif de remboursement des séances de psychologues est considéré comme un levier majeur et un succès par l'Assurance Maladie.

• Montée en charge rapide : Plus de 6 500 psychologues cliniciens (sur environ 20 000) ont rejoint le dispositif, couvrant l'ensemble des départements.

• Impact sur les patients : Plus de 900 000 assurés ont déjà bénéficié de séances remboursées.

• Appropriation par les médecins : Le dispositif a été très rapidement adopté par les médecins traitants, qui y ont vu une réponse concrète à un besoin non satisfait. Cette rapidité d'adoption est qualifiée d'"inédite".

• Évolutions : Les tarifs ont été augmentés et l'accès est désormais direct, sans obligation de passer par un médecin, bien que l'interface avec ce dernier reste encouragée.

Malgré les critiques de certains professionnels, la CNAM estime que le "pari de cette prise en charge est en train d'être réussi" et que le dispositif constitue un progrès majeur.

Thèmes Transversaux et Enjeux Stratégiques

La Prévention comme Investissement à Rendement Élevé

L'Assurance Maladie se dit "absolument convaincue" que l'investissement dans la prévention a un impact médico-économique positif massif.

Cet argument est au cœur de sa stratégie.

• Le principe des "coûts évités" est central : une action précoce permet d'éviter des prises en charge plus lourdes et plus coûteuses à long terme.

• Un chiffre illustre cette conviction : "vous investissez 1 € dans la prévention de maladie en terme de santé mentale, vous en récoltez quatre".

• Cette logique justifie le déploiement de programmes de détection précoce et l'objectif de ne pas aggraver les dépenses de santé malgré la tendance épidémiologique défavorable.

L'Enjeu du Remboursement des Professionnels Non Conventionnés

Un point de friction majeur est la prise en charge de professionnels comme les psychomotriciens ou les ergothérapeutes, dont l'apport est reconnu mais dont le remboursement n'est pas généralisé.

• Le frein réglementaire : Beaucoup de ces professions ne sont pas reconnues comme "professions de santé", ce qui empêche un conventionnement national classique.

• La solution : le conventionnement localisé par parcours : Le modèle développé dans les PCO pour les TND, où des professionnels sont financés dans le cadre d'un parcours spécifique, est vu comme une voie d'avenir.

Les futurs Parcours Coordonnés Renforcés (PCR) permettront de généraliser cette approche.

• Position de la CNAM : L'Assurance Maladie se déclare "prête" sur le plan opérationnel à intégrer et rembourser ces professionnels dès que le législateur ouvrira ces nouvelles possibilités de prise en charge, affirmant ne mettre "aucun frein sur cette dépense".

La Problématique des Pénuries de Médicaments : Au-delà des Difficultés d'Approvisionnement

La CNAM exprime une vive préoccupation concernant les pénuries de médicaments, en distinguant clairement deux phénomènes.

Si des difficultés d'approvisionnement existent, une partie des pénuries relèverait de stratégies commerciales délibérées.

• L'accusation : Certains laboratoires, après avoir atteint leur objectif de population cible dans le cadre de négociations sur les prix avec les autorités françaises, choisiraient de ne plus livrer le marché français.

• Une forme de chantage : Cette pratique est qualifiée de "chantage à la négociation de prix", où l'arrêt des livraisons est utilisé comme un levier pour obtenir des tarifs plus élevés. Les patients sont ainsi "pris en otage".

• La responsabilité des acteurs : La CNAM souligne que dans ces cas, la responsabilité incombe directement au laboratoire qui ne respecte pas sa part du contrat, et non aux autorités publiques qui négocient les prix pour préserver le système de santé.

Citations Clés

Sur l'ampleur de la santé mentale : "Nous sommes aujourd'hui à près de 28 milliards d'euros de dépenses qui sont consacrées à des pathologies en lien avec des thématiques de de santé mentale [...] ça montre quelque part aussi l'investissement d'assurance maladie."

Sur la hiérarchie des soins : "Le premier traitement d'un trouble psychique mineur, c'est la psychothérapie. [...] il n'y a pas d'indication médicamenteuse au départ. Donc les pratiques sont très très loin de ça." - Dr. Catherine Grenier

Sur l'adoption du dispositif "Mon Soutien Psy" : "Honnêtement, on a été [...] surpris [...] on a vu la vitesse à laquelle ce dispositif a été appréhendé par les médecins traitants. [...] Là en l'espèce, ça a été extrêmement rapide, inédit, et ça traduit ce besoin." - Thomas Fatôme, Directeur Général

Sur le rôle des industriels dans les pénuries : "Si un laboratoire dit 'bah en fait si vous payez pas le prix je vous livre pas', ça s'appelle aussi du chantage à la négociation de prix. [...] c'est un peu prendre les patients en otage d'une négociation de prix." - Marguerite Cazeneuve

Sur la logique de la Commission d'enquête : "Cette commission d'enquête, c'est presque une demande d'aide pour nous faire la démonstration qu'il y a une plus-value et que ça dépasse le seul horizon de l'annualité budgétaire." - Sébastien Saint-Pasteur, Rapporteur

Briefing : Prise en Charge de la Santé Mentale et du Handicap en France

Résumé

Ce document de synthèse analyse les enjeux majeurs de la prise en charge de la santé mentale en France, en se basant sur les échanges tenus à l'Assemblée nationale.

Il en ressort un paradoxe central : malgré des efforts budgétaires significatifs et le déploiement de dispositifs structurants, le secteur de la psychiatrie est en proie à une crise profonde, principalement due à une pénurie critique de ressources humaines.

Les points à retenir sont les suivants :

1. Crise d'Attractivité Sévère : La psychiatrie souffre d'un déficit majeur d'attractivité, avec plus de 23 % de postes de praticiens hospitaliers vacants dans le secteur public et 30 % des postes d'internes non pourvus.

Cette pénurie, qualifiée de "cercle vicieux", entrave la capacité du système à répondre à la demande croissante.

2. Dissonance entre Investissements et Réalité de Terrain : Des financements conséquents ont été alloués via des programmes comme le Fonds d'Innovation Organisationnelle en Psychiatrie (FIOP) et des appels à projets pour la pédopsychiatrie.

Le dispositif "Mon Soutien Psy" a également permis de réaliser plus de 2,5 millions de séances.

Cependant, ces efforts se heurtent à une réalité marquée par des délais d'attente, des défauts de prise en charge et un manque de diagnostics.

3. Impératif du Repérage Précoce : Un consensus se dégage sur la nécessité de basculer d'une approche majoritairement curative vers une stratégie axée sur la prévention et le repérage précoce des troubles.

Les médecins généralistes, la santé scolaire et les maisons des adolescents sont identifiés comme des acteurs clés de cette stratégie, qui est perçue comme un levier de "coûts évités" majeur.

4. Angle Mort sur les Données et l'Évaluation :

Il existe un manque critique de données médico-économiques sur l'impact du non-dépistage précoce et des hospitalisations évitées.

Ce déficit de modélisation affaiblit les plaidoyers pour un investissement accru dans la prévention et le suivi post-hospitalisation.

5. Structuration des Parcours et Coordination Territoriale :

Les Projets Territoriaux de Santé Mentale (PTSM) sont considérés comme un outil essentiel pour améliorer la coordination des acteurs.

Leur renforcement et leur évaluation sont des priorités, tout comme le développement de pratiques innovantes pour fluidifier les parcours entre la ville et l'hôpital.

Analyse Détaillée des Thématiques

1. La Crise d'Attractivité des Métiers en Psychiatrie

Le principal frein à l'amélioration de l'offre de soins en santé mentale est la pénurie de personnel qualifié, en particulier de psychiatres.

• Constat d'une Pénurie Sévère :

• ◦ La ressource humaine en psychiatrie est qualifiée de "denrée rare".   
• ◦ Postes vacants : Plus de 23 % des postes de psychiatres dans les hôpitaux publics ne sont pas pourvus.  
• ◦ Déficit de formation : Chaque année, 30 % des postes d'internes en psychiatrie restent vacants.  
• ◦ Recours aux praticiens étrangers (Padu) : Même en doublant les postes offerts aux praticiens à diplôme hors Union européenne, le taux de vacance reste extrêmement élevé, atteignant 30 % à 50 % selon les régions.

• Un Cercle Vicieux : Cette crise d'attractivité crée un "cercle vicieux" : les étudiants en médecine réalisant leurs stages dans des services en sous-effectif sont peu enclins à choisir cette spécialité, ce qui perpétue la pénurie.

• Pistes de Solution Évoquées :

◦ Valoriser les stages : Mettre l'accent sur la qualité de l'encadrement des stagiaires pour améliorer l'image de la profession.  

◦ Flexibiliser l'exercice : Encourager et faciliter l'exercice mixte (ville-hôpital, public-privé) et le temps partagé, qui correspondent aux aspirations des jeunes médecins ne souhaitant plus un exercice unique et à temps plein.

Des verrous réglementaires ont été levés depuis 2020 pour faciliter l'exercice mixte ville-hôpital.  

◦ Formation des paramédicaux : La réforme du métier d'infirmier intègre une obligation de stage en psychiatrie d'une durée minimale.

Par ailleurs, plus de 540 infirmiers en pratique avancée (IPA) en santé mentale ont déjà été formés.

2. Dissonance entre Efforts Budgétaires et Réalité de Terrain

Des investissements financiers importants ont été réalisés, mais leurs effets sont encore insuffisants pour répondre à l'ampleur des besoins.

• Investissements Financiers Conséquents :

• ◦ Fonds d'Innovation Organisationnelle en Psychiatrie (FIOP) : Depuis 2019, 288 millions d'euros ont été mobilisés pour accompagner 268 projets innovants. Le fonds a été reconduit en 2025.  
• ◦ Pédopsychiatrie et Psychiatrie Périnatale : Un appel à projets a permis de financer 435 projets, avec des crédits annuels compris entre 20 et 35 millions d'euros. 
• ◦ Dispositif "Mon Soutien Psy" : Fin 2024, le dispositif comptait plus de 4 100 psychologues conventionnés et avait bénéficié à près de 480 000 patients (dont 26 % de mineurs), pour un total de 2,5 millions de séances réalisées.

• Difficultés Persistantes sur le Terrain :

◦ Malgré ces chiffres, une "dissonance" est constatée entre les efforts budgétaires et la réalité vécue par les usagers et les professionnels : délais d'attente prolongés, défauts de prise en charge et manque de diagnostics.  

◦ Il est souligné que le système reste trop focalisé sur le "curatif" au détriment du "préventif".

3. L'Impératif de la Prévention et du Repérage Précoce

Le repérage précoce est identifié comme un axe stratégique majeur pour éviter l'aggravation des troubles et les conséquences sociales et familiales associées.

• Un Axe Prioritaire : Le dépistage est considéré comme "un des axes forts qu'il nous faut développer". Une mission a été confiée à trois personnalités qualifiées pour formuler des recommandations sur ce sujet.

• Les Acteurs Clés du Repérage :

◦ Médecins généralistes : Ils sont en première ligne, assurant 76 % des premières consultations pour troubles psychiatriques et traitant 73 % des dépressions.

L'enjeu est de mieux les "outiller" et de renforcer le lien avec les spécialistes.  

◦ Santé scolaire : Une circulaire conjointe (Santé/Éducation Nationale) est en cours de rédaction pour formaliser des "circuits courts" entre les établissements scolaires et les Centres Médico-Psychologiques (CMP).  

◦ Maisons des Adolescents : Leur cahier des charges est en cours de rénovation pour y intégrer pleinement la dimension de repérage. Leurs moyens financiers seront renforcés de façon "considérable".

• L'Enjeu des "Coûts Évités" : L'investissement dans la prévention et le diagnostic précoce est présenté non seulement comme une plus-value pour les personnes concernées, mais aussi comme une source d'économies "majeures" pour la collectivité en évitant des prises en charge plus lourdes à long terme.

4. Structuration de l'Offre et Coordination des Parcours

L'organisation des soins sur les territoires et la fluidité des parcours patients sont des défis centraux.

• Projets Territoriaux de Santé Mentale (PTSM) :

◦ Considérés comme un "outil intéressant", ils mobilisent les acteurs du sanitaire, du social et du médico-social.  

◦ Chaque PTSM bénéficie d'un poste de coordinateur financé.  

◦ Une "deuxième génération" de PTSM est en préparation pour aller plus loin dans la structuration des parcours.  

◦ Une carte interactive des PTSM sera mise en ligne sur le site du ministère pour améliorer la lisibilité et le partage de bonnes pratiques.

• Défis de la Coordination :

◦ Post-hospitalisation : L'organisation des sorties d'hospitalisation psychiatrique présente des "vraies difficultés", entraînant des réhospitalisations au coût "relativement conséquent", un point déjà soulevé par la Cour des comptes en 2021. 

◦ Innovation organisationnelle : Le FIOP vise précisément à soutenir des projets qui testent de nouvelles organisations pour améliorer la coordination ville-hôpital et la graduation des soins.

5. Manque de Données et Nécessité d'Évaluation

Un "angle mort" important subsiste concernant les données chiffrées, ce qui freine l'optimisation de l'allocation des ressources.

• Absence de Modélisation Médico-Économique :

◦ Il y a un manque de données sur le "coût médico-économique du non-dépistage précoce" et sur les hospitalisations potentiellement évitées.  

◦ L'approche culturelle française est perçue comme moins avancée que dans les pays anglo-saxons sur l'utilisation d'outils comme les QALY/DALY pour prioriser les investissements.

• Évaluation des Politiques Publiques :

◦ Le FIOP comme modèle : Ce fonds est cité en exemple pour son processus d'évaluation "extrêmement rigoureuse", menée par des experts indépendants après trois ans de financement, pouvant mener à la pérennisation, la généralisation ou l'arrêt du projet.  

◦ L'évaluation des PTSM : Si une évaluation qualitative a été menée (le "Tour de France" de Franck Bélivier), un besoin d'évaluation plus systématique et comparative des performances est exprimé pour mieux identifier et diffuser les bonnes pratiques.

6. Enjeux Spécifiques à Certaines Populations

• Pédopsychiatrie :

◦ Le secteur est "assez dépourvu" en lits, ce qui conduit à des hospitalisations d'enfants dans des services pour adultes.  

◦ Une inquiétude est soulevée quant au risque de "surdiagnostic", en référence à un rapport de la Cour des comptes, appelant à une vision plus globale de l'accompagnement.

• Santé Mentale en Milieu Carcéral :

◦ Prévalence élevée : Environ 30 % des détenus présentent des troubles psychiatriques.

Pour beaucoup, l'incarcération représente le "premier contact avec le soin". 

◦ Crise d'attractivité aggravée : Les difficultés de recrutement sont "probablement pires" dans ce milieu. L'exemple du centre pénitentiaire de Fresnes, passé de 19 à 6 psychiatres, est emblématique. 

◦ Solutions : Le développement de postes à temps partagé est crucial pour attirer des praticiens. Une "feuille de route santé des personnes placées sous main de justice" co-pilotée par les ministères de la Santé et de la Justice vise à travailler sur cet enjeu.

Note de Synthèse : La Politique de Santé Mentale en France selon la Direction Générale de la Santé

Synthèse

Cette note synthétise les perspectives et les actions de la Direction Générale de la Santé (DGS) concernant la santé mentale en France, telles que présentées lors d'une audition parlementaire.

Le constat principal est une dégradation "nette et durable" de la santé mentale de la population depuis la crise du Covid-19, se manifestant par une hausse significative des troubles anxieux, dépressifs et des idées suicidaires, particulièrement chez les jeunes.

En 2023, 23 % des adultes déclaraient un niveau d'anxiété élevé et 16 % se disaient déprimés, des chiffres en nette augmentation depuis 2019.

Le rôle de la DGS se concentre sur la prévention et la promotion de la santé mentale, en amont de la prise en charge psychiatrique. Son action repose sur quatre leviers stratégiques :

1. Améliorer les connaissances et lutter contre la stigmatisation via des campagnes de communication et des actions locales.

2. Promouvoir les comportements bénéfiques, notamment par le développement des compétences psychosociales, l'amélioration du sommeil et la prévention de l'usage problématique des écrans.

3. Renforcer le repérage précoce à travers des programmes comme les "Premiers secours en santé mentale".

4. Déployer une stratégie nationale de prévention du suicide, s'appuyant sur des dispositifs éprouvés comme le numéro national 3114 et le programme de recontact Vigilance, qui réduit de 38 % le risque de récidive.

Malgré ces efforts, des défis majeurs persistent.

La commission parlementaire souligne le décalage entre un diagnostic largement partagé et la mise en œuvre concrète sur le terrain, due notamment à un manque de professionnels (médecins scolaires, psychologues).

Un débat central porte sur la faible culture de la prévention en France, qui privilégie historiquement le curatif, et sur la difficulté à sécuriser des financements pluriannuels pour des actions dont les bénéfices ne sont visibles qu'à long terme.

La "Grande Cause Nationale 2025" est perçue comme une opportunité importante mais dont le démarrage a été freiné par le contexte politique.

1. Rôle de la DGS et Contexte

La Direction Générale de la Santé (DGS) positionne la santé mentale au cœur de ses priorités, avec un bureau dédié.

Son action se distingue de celle de la Direction Générale de l'Offre de Soins (DGOS), qui gère la prise en charge psychiatrique.

La DGS se concentre exclusivement sur les politiques de prévention et de promotion de la santé mentale.

L'approche de la DGS est double :

• Intersectorielle : La santé mentale étant multifactorielle, elle est prise en compte dans tous les milieux de vie (école, travail, loisirs) en lien avec les ministères concernés.

• Populationnelle : Une attention particulière est portée aux publics les plus vulnérables, incluant les jeunes, les personnes âgées, les personnes en situation de handicap, en situation de précarité ou détenues.

Il est précisé que la prise en charge globale du handicap relève de la Direction Générale de la Cohésion Sociale (DGCS).

2. Diagnostic de la Santé Mentale en France : Un Constat Préoccupant

L'Impact "Net et Durable" de la Crise Sanitaire

La crise du Covid-19 a marqué un "véritable tournant", provoquant une dégradation significative et persistante de la santé mentale de la population française.

• Chez les adultes : Selon l'enquête CoviPrev de Santé publique France, en 2023 :

◦ 23 % des personnes interrogées déclaraient un niveau d'anxiété élevé (+6 points par rapport à 2019).    ◦ 16 % se disaient déprimées (+5 points par rapport à 2019).

• Populations vulnérables : Les femmes, les jeunes adultes, les personnes précaires et celles ayant des antécédents de troubles psychiques présentent des indicateurs de santé mentale durablement dégradés.

Le Suicide : Une Préoccupation Majeure

Le suicide demeure un indicateur alarmant en France.

• En 2022, le taux de suicide était de 13,3 pour 100 000 habitants, l'un des plus élevés d'Europe.

• Ce taux est trois fois plus élevé chez les hommes que chez les femmes.

• Après une baisse depuis les années 80, le taux a atteint un plateau sur lequel il est devenu difficile d'agir.

La Vulnérabilité Particulière des Jeunes et des Personnes en Situation de Handicap

• Les jeunes : Les indicateurs sont "particulièrement préoccupants".

Le nombre de passages aux urgences pour gestes suicidaires chez les 11-17 ans est en hausse.

En 2023, 86 femmes de 15 à 19 ans sur 100 000 ont été hospitalisées pour gestes auto-infligés, une hausse de 46 % par rapport à 2017.

• Personnes en situation de handicap : Elles présentent un risque suicidaire majoré.

Des études montrent un risque 7 à 10 fois plus important pour les personnes présentant des troubles du spectre autistique.

Des Causes Multifactorielles

Ces évolutions sont attribuées à une combinaison de facteurs :

• Environnementaux : L'éco-anxiété est une réalité, notamment chez les jeunes.

• Géopolitiques et économiques : Les conflits, les attentats et l'instabilité économique.

• Sociétaux : La pression scolaire, les usages numériques et l'exposition aux réseaux sociaux sont corrélés à une dégradation de la santé mentale des plus jeunes.

3. Les Levier d'Action de la Direction Générale de la Santé

Face à ces constats, la DGS déploie une stratégie de prévention et de promotion articulée autour de quatre axes principaux.

Axe 1 : Amélioration des Connaissances et Lutte contre la Stigmatisation

L'objectif est de lever les freins à l'accès aux soins, notamment l'auto-stigmatisation.

• Campagnes de communication : Santé publique France déploie des campagnes grand public et ciblées, avec un site internet dédié.

• Actions territorialisées : Les "Semaines d'information en santé mentale" (SISM) et les "Conseils locaux de santé mentale" (CLSM) sont déployés pour réunir localement élus, citoyens, associations et professionnels.

Axe 2 : Promotion des Comportements Bénéfiques à la Santé Mentale

• Développement des compétences psychosociales (CPS) : Une stratégie interministérielle (portée par 7 ministères) vise à développer dès le plus jeune âge des compétences comme l'estime de soi, la relation à l'autre et l'esprit critique pour renforcer la résilience.

• Qualité du sommeil : Une feuille de route interministérielle a été lancée, rappelant qu'un sommeil altéré double le risque de développer une dépression.

• Prévention de l'usage excessif des écrans : Des actions sont menées pour contrer la corrélation observée entre le temps d'écran, l'exposition à des contenus inadaptés et les troubles dépressifs chez les jeunes.

Axe 3 : Repérage Précoce des Troubles

• Premiers secours en santé mentale : Inspiré d'un programme australien, ce dispositif vise à former plus de 200 000 secouristes capables de repérer les situations de détresse dans leur entourage. Le ministre a annoncé un objectif porté à 300 000 formés d'ici 2027.

• Mon bilan prévention : Mis en place en 2023, ce dispositif invite les citoyens à des âges clés de la vie à faire un bilan global de leurs comportements en santé, incluant la santé mentale.

Axe 4 : Stratégie Nationale de Prévention du Suicide

Cette stratégie, pilotée par la DGS, a permis de mettre en place des dispositifs clés qui ont démontré leur efficacité.

Dispositif

Description

Données Clés et Résultats

3114

Numéro national d'appel pour la prévention du suicide, accessible 24/7.

Plus de 1000 appels par jour. Un budget de 23 millions d'euros.

Vigilance

Dispositif de recontact des personnes passées aux urgences pour une tentative de suicide.

Réduit de 38 % le risque de réitération suicidaire. Retour sur investissement de 2 € pour 1 € investi. Aujourd'hui généralisé à 17 régions.

Prévention de la contagion suicidaire

Plans d'action locaux menés avec les Agences Régionales de Santé (ARS) et les élus pour prévenir les phénomènes de contagion après un suicide.

Efficacité démontrée par des retours d'expérience qualitatifs.

4. Enjeux, Débats et Perspectives

La "Grande Cause Nationale 2025" : Une Opportunité Mitigée

Reconnue comme une opportunité indéniable, la mise en œuvre de la "Grande Cause" a subi un "retard à l'embrayage" en raison du contexte politique (changement de gouvernement). Cependant, elle a permis de :

• Relancer la mobilisation interministérielle sur des thématiques transversales.

• Prioriser et concrétiser des projets, comme la campagne grand public de Santé publique France.

• Labelliser plus de 750 projets locaux, démontrant une appropriation territoriale.

Le Défi des Moyens Humains et de la Mise en Œuvre Locale

Un consensus émerge sur le fait que le diagnostic est connu, mais que l'action sur le terrain manque cruellement de moyens.

• La prévention et le repérage précoce se heurtent à une pénurie de professionnels (infirmières scolaires, médecins scolaires, psychologues).

• Les dispositifs comme les Conseils Locaux de Santé Mentale (CLSM) et les Projets Territoriaux de Santé Mentale (PTSM) visent à améliorer la coordination locale, mais la marche reste haute.

Le Modèle Économique de la Prévention

Le débat met en lumière une tension structurelle dans le système de santé français.

• Faiblesse de l'investissement : Les dépenses de prévention en France représentent 2 à 3 % des dépenses de santé, un niveau bas comparé aux standards de l'OCDE. La France a historiquement privilégié une culture du soin curatif.

• Logique de court terme : Les décideurs politiques sont contraints par des arbitrages budgétaires annuels, alors que les retours sur investissement de la prévention s'étalent sur plusieurs années. Le coût sociétal total des suicides et tentatives de suicide a été estimé à 24 milliards d'euros en 2019.

• Débat sur la pluriannualité : La proposition d'une loi de programmation pluriannuelle pour la santé mentale est avancée pour garantir des investissements à long terme. La DGS exprime une réserve, soulignant que la multiplication de telles lois rigidifie la dépense publique.

Le Dispositif "Mon Soutien Psi"

Ce dispositif, qui permet une prise en charge de séances de psychologue, est reconnu comme un progrès pour lever les freins financiers.

Il est cependant noté qu'il a pu contribuer à une "fuite" des psychologues du secteur public (hôpitaux, Centres Médico-Psychologiques) vers le secteur libéral, affaiblissant la prise en charge des troubles plus lourds qui nécessitent une approche pluridisciplinaire.

5. Focus sur des Populations Spécifiques

• Personnes âgées : Le taux de suicide chez les 85-94 ans est de 35 pour 100 000, soit près du triple du taux de la population générale, un chiffre largement attribué à l'isolement.

• Jeunes : Le harcèlement scolaire est identifié comme un facteur de risque majeur. La DGS collabore étroitement avec l'Éducation Nationale pour déployer les programmes de compétences psychosociales afin de mieux armer les élèves.

• Agriculteurs : Cette population connaît des taux de suicide extrêmement élevés. Des dispositifs spécifiques comme les "sentinelles" sont déployés par la MSA dans le cadre du suivi du mal-être agricole.

Même si les réseaux ont toutes ces caractéristiques, ils ne sont pas idéales à la société et ils ont des inconvénients à la santé mentale physique, dans la relation entre les être humains, et politiquement, et peut être dans le futur se sera plus pire et on va découvrir des nouveaux enjeux qu’on ne peut pas les contrôler

Synthèse de l'Audition de la Défenseure des droits sur la Santé Mentale et le Handicap

Résumé

L'audition de la Défenseure des droits devant la commission d'enquête de l'Assemblée nationale dresse un tableau alarmant des défaillances systémiques dans la prise en charge de la santé mentale et du handicap en France.

Le handicap constitue le premier motif de saisine pour discrimination (22 % des réclamations en 2024), soulignant un écart persistant entre les droits annoncés et leur effectivité.

Les politiques de santé mentale sont jugées gravement insuffisantes, tant pour les majeurs que pour les mineurs.

La situation est particulièrement critique en milieu carcéral, où la surreprésentation des troubles mentaux, conjuguée à la surpopulation et au manque de soins, conduit à des traitements qualifiés d'inhumains.

Pour les jeunes, les données sont alarmantes (25 % souffrent de dépression), mais les services de pédopsychiatrie sont saturés, avec des délais d'attente dépassant un an, et un manque criant de données fiables pour piloter les politiques publiques.

Le recours abusif à l'isolement et à la contention, notamment sur des mineurs hospitalisés en services pour adultes sans contrôle judiciaire, constitue une atteinte grave aux droits fondamentaux.

Concernant le handicap, la loi de 2005, bien qu'ayant permis des avancées, est loin d'être intégralement appliquée.

L'éducation inclusive reste un défi majeur, marqué par un manque d'AESH, des difficultés d'aménagement des examens et une absence de données précises sur le temps de scolarisation réel.

L'emploi demeure le premier domaine de discrimination, et l'accessibilité (transports, logement, numérique) accuse un retard considérable. Les aides à l'autonomie sont insuffisantes et inégalitaires, notamment en raison du maintien d'une barrière d'âge à 60 ans.

La Défenseure des droits insiste sur le fait que le non-respect des droits fondamentaux représente un coût social et économique élevé à terme, bien supérieur à celui d'un investissement dans la prévention et une prise en charge effective.

L'urgence est de commencer par appliquer les textes existants et de prendre conscience de la détresse de la jeunesse.

Introduction : Rôle et Observations du Défenseur des droits

L'institution du Défenseur des droits est un observateur privilégié des carences des politiques publiques, car la question des droits des personnes handicapées traverse l'intégralité de ses cinq missions :

• 1. Droits des usagers des services publics

• 2. Lutte contre les discriminations

• 3. Protection des droits des enfants

• 4. Déontologie des forces de sécurité

• 5. Protection des lanceurs d'alerte

L'institution est également chargée du suivi de l'application de la Convention internationale relative aux droits des personnes handicapées (CIDPH), ratifiée par la France en 2019.

Le Handicap : Premier Motif de Discrimination

Depuis plusieurs années, le handicap est le premier motif de saisine en matière de discrimination. Cette constance révèle une problématique structurelle profonde.

Année

Nombre total de saisines (Discrimination)

Part relative au handicap

Nombre de réclamations (Handicap)

2024

5 679

22%

1 249

Ces discriminations s'exercent dans de multiples domaines, incluant l'emploi, la scolarisation, la santé, la justice, les loisirs, le sport et la culture. L'institution se positionne comme un "très bon observatoire de ce qui ne va pas", mettant en lumière l'écart entre le droit annoncé et son effectivité sur le terrain.

L'Argument Central : Le Coût du Non-Respect des Droits

La Défenseure des droits conteste fermement l'idée que l'application des droits fondamentaux représenterait un coût financier trop important.

Elle soutient au contraire que "c'est le non-respect des droits fondamentaux qui entraînera à terme un coût élevé pour la société", un argument particulièrement pertinent en période d'incertitude budgétaire.

Les Défaillances dans la Prise en Charge de la Santé Mentale

La Situation des Personnes Majeures

La réponse des pouvoirs publics à la crise de la santé mentale, aggravée par la pandémie de Covid-19, reste insuffisante. Un Français sur trois sera confronté à un trouble psychiatrique au cours de sa vie. Les défaillances sont multiples :

• Quantitatives : Offres de soins trop faibles, capacités d'hospitalisation limitées, déserts médicaux.

• Organisationnelles : Système mal organisé et cloisonné entre le sanitaire et le médico-social.

• Humaines : Le secteur de la psychiatrie peine à recruter alors que les besoins augmentent.

Ces carences entraînent des atteintes graves et répétées aux droits fondamentaux, notamment le droit à la santé, avec des délais d'attente excessifs, des ruptures de soins et des inégalités territoriales criantes qui pénalisent les plus précaires.

Cas Spécifique : La Santé Mentale des Personnes Détenues

La santé mentale des personnes détenues se dégrade faute d'un accompagnement adapté.

• Statistiques : Entre juillet 2024 et juillet 2025, la plateforme d'appel pour les détenus (3141) a reçu 1 065 appels (7,6%) pour des difficultés d'accès aux soins et 106 appels spécifiques pour un risque suicidaire.

• Causes de la surreprésentation des troubles mentaux :

• 1. Une politique de désinstitutionnalisation qui a réduit les lits en psychiatrie sans développer de services de proximité en relais.  
• 2. Une diminution du nombre de personnes déclarées pénalement irresponsables, qui se retrouvent de ce fait en prison.

• Conséquence juridique : Maintenir en détention une personne nécessitant une prise en charge médicale revient à lui infliger des "traitements inhumains", comme l'a souligné la Cour européenne des droits de l'homme (arrêt GC c. France, 2012).

• Facteurs aggravants : La surpopulation carcérale et l'absence de continuité des soins à la sortie, qui augmente le risque de récidive.

La Situation des Mineurs

Les résultats d'une étude de 2025 (Institut Montaigne, Mutualité française, Institut Teram) sont jugés alarmants :

• 25% des jeunes (15-29 ans) souffrent de dépression.

• Ce chiffre atteint 39% dans les outre-mer, avec des pics à plus de 50% en Guyane, 44% en Martinique et 43% à Mayotte.

Problèmes Structurels Identifiés

1. Manque de données fiables : L'absence de données agrégées au niveau national sur le nombre d'enfants en attente de prise en charge fragilise le pilotage des politiques publiques.

Le rapport de la Cour des comptes de 2023 sur la pédopsychiatrie estime que sur 1,6 million d'enfants avec un trouble psychique, seuls 50 à 53% bénéficient de soins.

2. Inégalités territoriales et pénurie de médecins : La politique du "virage ambulatoire" a renforcé le rôle des Centres Médico-Psychologiques (CMP), mais leur répartition est inégale (10 par département en moyenne, avec de fortes disparités).

Les délais pour obtenir un premier rendez-vous dépassent souvent un an, ce qui est incompatible avec la nécessité d'une intervention rapide.

3. Prise en charge inadaptée : Une source d'inquiétude majeure est l'hospitalisation d'enfants et d'adolescents au sein de services psychiatriques pour adultes, souvent par défaut de solutions dans le secteur médico-social ou en protection de l'enfance.

Mesures d'Isolement et de Contention : Des Pratiques Abusives

Le manque d'effectifs conduit trop souvent à des restrictions injustifiées des libertés, telles que des mesures d'isolement et de contention.

• Pour les majeurs : Le contrôle systématique par un juge des libertés et de la détention (JLD) pour les hospitalisations sans consentement est jugé peu efficace.

Il repose principalement sur l'avis médical, et seules 10% des décisions aboutissent à une levée de la mesure. De plus, aucun contrôle judiciaire n'est prévu pour les soins ambulatoires sans consentement.

• Pour les mineurs : La situation est encore plus préoccupante. Un mineur hospitalisé à la demande de ses parents est placé sous le régime de "soins libres" et ne bénéficie d'aucun contrôle du JLD, même en cas d'isolement ou de contention.

Ce vide juridique constitue une atteinte grave à leurs droits fondamentaux.

Cas emblématique

Une adolescente de 15 ans, atteinte d'autisme sévère, a été hospitalisée pendant plus de deux ans dans un service psychiatrique pour adultes, faute de place en structure médico-sociale. Durant cette période, elle a été :

• Confinée dans une chambre d'isolement verrouillée plus de 20 heures par jour.

• Déscolarisée.

• Privée de soins somatiques essentiels (ex: soins dentaires). Cette situation, loin d'être un cas isolé, illustre les conséquences dramatiques du manque de solutions adaptées.

Les Lacunes des Politiques Publiques Relatives au Handicap

Éducation : Un Droit Garanti mais un Accès Difficile

La loi de 2005 a permis une impulsion mais n'est toujours pas intégralement appliquée.

• Statistiques : 30% des saisines relatives aux droits de l'enfant concernent la scolarisation d'enfants en situation de handicap.

• Obstacles persistants : Inadaptation des locaux et du matériel, rigidité des programmes, formation insuffisante des professionnels.

• Accompagnement (AESH) : Malgré la création de postes, le manque persiste. La loi du 27 mai 2024 prévoyant la prise en charge de l'accompagnement sur le temps méridien par l'État est "très loin d'être effective" en raison de blocages entre les collectivités et les académies.

• Aménagements des examens : Une augmentation inquiétante des réclamations a été constatée en 2024 concernant des refus d'aménagement pour des élèves ou étudiants, parfois au prétexte paradoxal que leurs résultats scolaires étaient bons.

Emploi : Premier Domaine de Discrimination

L'emploi est le domaine où s'exercent le plus de discriminations liées au handicap. Sur les 1 249 réclamations de 2024, 21% concernent l'emploi privé et 24% l'emploi public. L'obligation d'emploi de 6% ne suffit pas à garantir l'égalité de traitement.

• Difficultés récurrentes :

◦ Aménagement tardif du poste de travail.    ◦ Non-respect par l'employeur des préconisations du médecin du travail.    ◦ Difficultés de maintien dans l'emploi, menant à des licenciements ou des démissions forcées.

Accessibilité : Un Retard Important et Persistant

L'accessibilité est une condition essentielle à la participation sociale et à la jouissance des droits.

• Transports : La loi a été modifiée pour ne concerner que les "points d'arrêt prioritaires", ce qui est jugé insuffisant.

• Logement : L'assouplissement des règles via la loi ELAN est une source d'inquiétude.

• Accessibilité numérique : La dématérialisation a des effets ambivalents. Selon l'ARCOM, peu de sites publics atteignent 50% d'accessibilité et seulement 5% sont totalement conformes. L'ordonnance de septembre 2023 renforçant les sanctions est saluée, mais elle doit s'accompagner du maintien d'accueils physiques accessibles.

Aides à l'Autonomie : Insuffisantes et Inégales

Vingt ans après la loi de 2005, le droit à la compensation du handicap présente des limites flagrantes.

• Barrière de l'âge : Une différence de traitement persiste selon que le handicap survient avant ou après 60 ans. La fusion des régimes, prévue pour 2010, n'a pas eu lieu.

• Prestation de Compensation du Handicap (PCH) :

◦ L'aide humaine est limitée aux besoins essentiels, excluant la vie sociale.    ◦ Les aides techniques sont sous-financées.    ◦ La PCH parentalité (2021) est critiquée pour ses critères restrictifs et son forfait inadapté.

Conclusion et Recommandations Principales

La Défenseure des droits conclut en réaffirmant l'engagement de son institution et formule plusieurs pistes d'action prioritaires :

1. Application des textes existants : La première urgence, notamment pour le handicap, est "l'application pure et simple des textes votés par le parlement" et la publication des décrets d'application en attente.

2. Priorité à la jeunesse : La santé mentale, grande cause nationale en 2025, doit se traduire par une "véritable prise de conscience collective", en particulier pour les jeunes qui ne peuvent être laissés sans réponse. L'investissement dans les CMP et le dépistage précoce est essentiel.

3. Nécessité de données fiables : Il est impératif de collecter et d'agréger des données précises (ex: nombre d'heures de scolarisation effectives, nombre d'enfants en attente de place en IME) pour permettre un pilotage éclairé des politiques publiques.

4. Formation des acteurs : Une meilleure formation des employeurs sur "l'aménagement raisonnable", des enseignants et des professionnels de santé est indispensable pour faire évoluer les pratiques.

5. Abaisser la barrière d'âge de 60 ans : Il est nécessaire de mettre fin à cette distinction qui crée des inégalités de traitement injustifiées.

6. Décloisonner les systèmes : Améliorer l'articulation entre les secteurs sanitaire, médico-social et éducatif est crucial pour assurer une fluidité des parcours et éviter les ruptures de prise en charge.