after his death he was lost, he did not go to heaven nor hell. Him being lost and trapped means he has not found peace = revenge being suggested.

immediately indicate that the character speaking on stage is clearly dead. So, the audience now knows that they have been introduced to a ghost.

gali tikti bet kam, kai reikia rinktis iš daug ir/ar skirtingos rizikos pasirikimų

Analyse du Binôme de Direction en Milieu Scolaire : Vers un Modèle de Coresponsabilité

Résumé Exécutif

Ce document analyse les dynamiques complexes au sein du binôme de direction (chef d’établissement et adjoint) dans le système éducatif français.

Fondé sur les recherches de Rosenne Descré Rouillard, il met en lumière l'obsolescence du modèle traditionnel pyramidal qui conduit souvent à l'épuisement du dirigeant et à la frustration de l'adjoint.

L'analyse révèle que le binôme fonctionne comme un « couple forcé » où l'intime et le professionnel s'entremêlent, rendant la relation soit extrêmement puissante, soit pathogène.

Pour transformer cette tension en partenariat efficace, il est impératif de passer d'une répartition des tâches subie à une coresponsabilité basée sur la confiance, la transparence et la reconnaissance des compétences individuelles.

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1. La Déconstruction du Modèle Traditionnel

Le modèle classique de direction est marqué par une division du travail héritée et sociale, bien que non inscrite officiellement dans les textes.

Une division sociale et morale du travail

• La répartition hiérarchique : Traditionnellement, le chef d'établissement conserve le pilotage stratégique et pédagogique, tandis que l'adjoint est cantonné à l'organisationnel, au technique et à l'exécution.

• Le « sale boulot » : Les recherches décrivent l'adjoint comme un « artisan du quotidien » occupant une fonction intervalle.

Il récupère souvent les tâches les moins valorisées et les plus invisibles, ce que la sociologie qualifie de « sale boulot ».

• L’asymétrie de fonction : Bien qu'appartenant au même corps de métier (personnel de direction), l'adjoint doit rester en « seconde cordée » ou agir comme un « copilote », ce qui crée un décalage entre sa formation de chef et sa réalité opérationnelle.

Conséquences du modèle conventionnel

• Charge mentale explosive : Le chef d'établissement, seul responsable légal et comptable, subit une pression qui freine la délégation.

• Sous-utilisation des compétences : L'adjoint peut ressentir une frustration légitime lorsque ses compétences stratégiques sont ignorées au profit d'une gestion purement logistique.

• Atterrissage brutal : Pour beaucoup de nouveaux adjoints, le passage du concours à la réalité du terrain est vécu comme un choc, car ils sont formés pour diriger mais se retrouvent en position subalterne.

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2. L'Épreuve Bicéphale : Le Binôme comme « Couple »

La relation entre le chef et l'adjoint dépasse le simple cadre fonctionnel pour toucher à la sphère de l'intime.

Un « mariage forcé » professionnel

• L'absence de choix : Les membres du binôme ne se choisissent pas.

Cette union imposée par l'institution crée une « épreuve bicéphale » où partager le pouvoir et l'autorité devient un défi quotidien.

• L'isolement à deux : Contrairement aux enseignants ou aux CPE qui travaillent en communauté, le binôme de direction est souvent isolé.

Cette solitude partagée renforce la nécessité d'une entente parfaite.

• L'impact de la personnalité : Quand le binôme « matche », il devient une force extrême.

Quand il « clashe », cela peut mener à des maladies professionnelles tant l'implication personnelle est forte.

La métaphore du couple parental

Le binôme doit « parler d'une seule voix » devant la communauté éducative (enseignants, élèves, parents), à l'instar d'un couple de parents devant ses enfants.

Les désaccords doivent être réglés en privé pour éviter que les tiers ne s'engouffrent dans les failles de la direction.

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3. Piliers d'un Partenariat Puissant

Pour sortir des tensions, le binôme doit instaurer un modèle de coresponsabilité.

| Pilier | Description et Mise en Œuvre | | --- | --- | | Loyauté et Confiance | Socle indispensable qui doit être total et réciproque pour permettre au binôme de « faire front » face aux pressions institutionnelles. | | Transparence Absolue | Partage intégral des informations pour qu'aucun membre ne soit pris au dépourvu. | | Complémentarité | S'appuyer sur les appétences et les métiers d'origine (ex: un ancien CPE sur le leadership éducatif, un enseignant sur la pédagogie). | | Unité de Façade | Adopter une position commune indéfectible à l'extérieur, même si les tonalités de voix diffèrent. | | Égalité de Coopération | Considérer l'adjoint comme un véritable partenaire d'égal à égal plutôt que comme un « super secrétaire ». |

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4. Stratégies et Bonnes Pratiques Opérationnelles

La transition vers une direction partagée nécessite des actions concrètes et des rituels de communication.

Clarification et Autonomie

• Délégation complète : Le chef doit autoriser l'adjoint à gérer des dossiers de A à Z sans intervenir de manière intempestive, favorisant ainsi l'autonomie et la montée en compétences.

• Lettre de mission évolutive : Cet outil doit être coconstruit et révisé à chaque changement de binôme pour refléter les compétences réelles et non une répartition automatique.

• Interchangeabilité : Dans un binôme fluide, chaque membre doit être capable de prendre le relais sur les dossiers de l'autre en cas d'absence.

Rituels de Communication

• Échanges informels quotidiens : Maintenir une politique de « bureau porte ouverte » pour une interconnexion permanente.

• Le point hebdomadaire : Se réserver un temps dédié (par exemple le vendredi soir) pour « rembobiner le fil de la semaine », analyser les pratiques et évacuer les tensions.

Prendre soin de l'autre

• Protection mutuelle : Le chef a un rôle de protecteur ultime envers l'adjoint, mais l'adjoint doit aussi veiller sur le chef.

• Balises horaires : S'imposer des limites mutuelles sur le temps de travail et l'usage du numérique pour prévenir l'épuisement, particulièrement complexe dans le cadre des logements de fonction.

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5. Perspectives et Évolutions Institutionnelles

L'analyse conclut que l'institution doit évoluer pour soutenir ces nouvelles formes de gouvernance.

• Vers la coresponsabilité légale : Une évolution législative pourrait instaurer une véritable codirection, soulageant ainsi la responsabilité unique du chef.

• Amélioration des RH : Dépasser les règles d'ancienneté pour former des binômes basés sur la complémentarité des profils.

• Formation continue : Intégrer la gestion de la relation humaine et du binôme dès la préparation au concours pour éviter « l'atterrissage brutal ».

• Espaces de parole : Développer des temps d'analyse de pratique ou de coaching collectif, extérieurs à la hiérarchie, pour permettre aux personnels de direction de se « resocialiser professionnellement » à chaque changement de partenaire.

En résumé, le succès d'un binôme de direction repose sur sa capacité à transformer une hiérarchie rigide en un management horizontal partagé, où l'humain est placé au centre de la stratégie de pilotage.

A hexagon map editor for fantasy mapping as plugin for Obsidian. Vgl fantasy cartography at CaL 2019, https://www.zylstra.org/blog/2019/06/getting-frodo-to-mordor-with-geo-data-analysis/

Gestion des élèves perturbateurs : approches psychopédagogiques et cadres éthiques

Résumé analytique

Le comportement perturbateur d'un élève ne doit pas être perçu comme une simple transgression, mais comme le symptôme d'un mal-être profond, souvent enraciné dans un vécu personnel ou scolaire difficile.

La gestion efficace de ces situations repose sur la reconnaissance des besoins psychologiques fondamentaux de l'élève (sécurité, reconnaissance, justice, estime de soi) et sur la mise en place d'espaces de parole institutionnalisés.

L'analyse souligne que de nombreux élèves perturbateurs, y compris les harceleurs, sont eux-mêmes en situation de souffrance.

Pour répondre à ces défis, les personnels de direction et les équipes éducatives doivent naviguer entre quatre orientations éthiques :

• la déontologie (la règle),
• le conséquentialisme (l'impact de la sanction),
• la vertu (la confiance) et
• l'éthique du care (le soin).

L'équilibre entre ces dimensions permet de maintenir le lien de confiance entre l'élève et l'institution, évitant ainsi le décrochage ou l'exclusion définitive des profils les plus vulnérables.

La nature du comportement perturbateur : un symptôme de mal-être

Le comportement perturbateur est défini comme une manifestation de symptômes liés à une insatisfaction des besoins psychologiques fondamentaux.

Aider un élève nécessite d'être attentif à ces signes, qu'ils soient émotionnels ou plus subtils.

Les besoins psychologiques fondamentaux

Pour remédier aux comportements problématiques, l'institution doit prendre en considération :

• • Le besoin de sécurité (affective et physique).
• • Le besoin de reconnaissance et de justice.
• • Le besoin d'écoute et d'expression de soi.
• • Le besoin d'estime de soi.

Stratégies d'intervention et espaces de parole

L'intervention repose sur une distinction claire entre les problématiques collectives et individuelles, ainsi que sur la création de structures d'échange formelles.

La règle d'or de la communication

• Problème collectif : Doit faire l'objet d'une discussion collective.

• Problème individuel : Le comportement d'un élève spécifique doit être traité exclusivement avec lui, afin de préserver sa dignité et de favoriser un dialogue constructif.

Institutionnalisation de l'écoute

La mise en place de "cellules d'écoute" ou d'espaces de parole sécurisés est présentée comme une solution aux résultats rapides et significatifs.

• L'écoute active : Les adultes doivent être formés pour permettre à l'élève d'élaborer lui-même le sens de son vécu.

• Efficacité constatée : Des exemples, notamment dans l'académie de Grenoble, montrent qu'une participation à deux ou trois reprises à ces espaces peut transformer le comportement des jeunes.

• Sécurité affective : L'espace doit permettre à l'élève de dire ce qu'il ressent sans crainte immédiate de jugement ou de répression.

Le cadre disciplinaire et le conseil de discipline

Face à des actes graves (comme des injures envers un enseignant), la sanction demeure nécessaire.

Cependant, la procédure doit respecter des principes éthiques et réglementaires stricts.

• Le principe du contradictoire : Avant et pendant le conseil de discipline, toutes les parties doivent pouvoir s'exprimer et clarifier les faits.

• L'analyse de la souffrance : Il est impératif de considérer que l'élève auteur d'actes délictueux est souvent un élève qui souffre.

Le document note par exemple qu'un grand nombre de harceleurs sont eux-mêmes victimes de harcèlement.

• Dialogue avec la famille : La compréhension du contexte familial est cruciale pour identifier les racines du comportement de l'adolescent.

Les quatre orientations de l'éthique professionnelle

Le chef d'établissement et son équipe doivent composer avec quatre dimensions éthiques lors de la prise de décision disciplinaire :

| Orientation éthique | Définition et application | | --- | --- | | Déontologique | Respect strict du règlement intérieur et de la loi. C'est l'approche systématique : "à tel acte correspond telle sanction". Essentiel pour la responsabilité professionnelle du chef d'établissement. | | Conséquentialiste | Attention portée aux conséquences de la sanction sur l'avenir de l'élève. Par exemple, éviter d'informer des parents violents d'une faute mineure pour ne pas infliger une "double peine" à l'enfant. | | Exercice des vertus | Mise sur la patience, la prudence et la confiance. On donne du temps à l'élève pour s'améliorer en privilégiant un blâme ou un avertissement plutôt qu'une exclusion. | | Éthique du Care (Soin) | Posture indispensable vis-à-vis des élèves les plus vulnérables traversant des souffrances psychiques graves. Il s'agit de maintenir la "tête hors de l'eau" pour l'élève par un regard attentif et bienveillant. |

Conclusion : Le rôle de l'arbitrage institutionnel

Le chef d'établissement a la responsabilité première de garantir le respect de la règle et du droit (réflexe déontologique) pour éviter toute faute professionnelle. Toutefois, la réalité du terrain impose une composition entre ces différentes éthiques.

Une décision efficace est souvent hybride : elle rappelle la règle (déontologie), tout en tempérant la sanction au regard du contexte (conséquentialisme) et en demandant à l'équipe pédagogique une "bienveillance attentive" (care).

Cette approche intégrée est présentée comme le seul moyen de préserver la confiance des élèves les plus fragiles envers l'école et les adultes, prévenant ainsi leur exclusion définitive du système scolaire.

And who is fighting to go to the World Championships? Much like in mainstream sports, white (or asian), young, rich, males.

Campbell's or Goodhart's laws: The more any quantitative social indicator is used for social decision-making, the more subject it will be to corruption pressures and the more apt it will be to distort and corrupt the social processes it is intended to monitor.

In other words, positivist metricism; which is a form of snob credentialism.

eLife Assessment

In this valuable study, through carefully executed and rigorously controlled experiments, the authors challenged a previously reported role of the Death Receptor 6 (DR6/Tnfrsf21) in Wallerian degeneration (WD). Using two DR6 knockout mouse lines and multiple WD assays, both in vitro and in vivo, the authors provided convincing evidence that loss of DR6 in mice does not protect peripheral axons from WD after injury, at least in the specific contexts of the mice and analyses performed in this study. Due to the lack of certain specific parameters from previous studies (sex, age, mouse strains etc.), the exact reasons underlying the observed inconsistencies between current and previous reports on the protective effects of DR6 remains to be determined. Overall, this is a carefully executed study providing invaluable information toward understanding DR6's role (or lack thereof) in axon degeneration.

Reviewer #1 (Public review):

Summary:

The authors show that genetic deletion of the orphan tumor necrosis factor receptor DR6 in mice does not protect peripheral axons against degeneration after axotomy. Similarly, Schwann cells in DR6 mutant mice react to axotomy similarly to wild type controls. These negative results are important because previous work has indicated that loss or inhibition of DR6 is protective in disease models and also against Wallerian degeneration of axons following injury. This carefully executed counterexample is important for the field to consider.

Strengths:

A strength of the paper is the use of two independent mouse strains that knockout DR6 in slightly different ways. The authors confirm that DR6 mRNA is absent in these models (western blots for DR6 protein are less convincingly null, but given the absence of mRNA, this is likely an issue of antibody specificity). One of the DR6 knockout strains used is the same strain used in a previous paper examining the effects of DR6 on Wallerian degeneration.

The authors use a series of established assays to evaluate axon degeneration, including light and electron microscopy on nerve histological samples and cultured dorsal root ganglion neurons in which axons are mechanically severed and degeneration is scored in time lapse microscopy. These assays consistently show a lack of effect of loss of DR6 on Wallerian degeneration in both mouse strains examined.

Additional strengths are that the authors examine both the axonal response and the Schwann cell response to axotomy and use both in vivo and in vitro assays.

Therefore, these experiments, the author's data support their conclusion that loss of DR6 does not protect against Wallerian degeneration.

Weaknesses:

A weakness of this paper is that no effort is made to determine why the results presented here may differ from previous studies. A notable possibility is that the original mouse strain that showed 5 of 13 mice being protected from Wallerian degeneration was studies on a segregating C57BL/6.129S background.

Finally, it is important to note that previously reported effects of DR6 inhibition, such as protection of cultured cortical neurons from beta-amyloid toxicity, are not necessarily the same as Wallerian degeneration of axons distal to an injury studied here. The negative results presented here showing that loss of DR6 is not protective against Wallerian degeneration induced by injury are important given the interest in DR6 as a therapeutic target. However, care should be taken in attempting to extrapolate these results to other disease contexts such as ALS or Alzheimer's disease.

Reviewer #3 (Public review):

Summary:

The authors revisit the role of DR6 in axon degeneration following physical injury (Wallerian degeneration), examining both its effects on axons and its role in regulating the Schwann cell response to injury. Surprisingly, and in contrast to previous studies, they find that DR6 deletion does not delay the rate of axon degeneration after injury, suggesting that DR6 is not a mediator of this process.

Overall, this is a valuable study. As the authors note, the current literature on DR6 is inconsistent, and these results provide useful new data and clarification. This work will help other researchers interpret their own data and re-evaluate studies related to DR6 and axon degeneration.

Strengths:

(1) The use of two independent DR6 knockout mouse models strengthens the conclusions, particularly when reporting the absence of a phenotype.

(2) The focus on early time points after injury addresses a key limitation of previous studies. This approach reduces the risk of missing subtle protective phenotypes and avoids confounding results with regenerating axons at later time points after axotomy.

Comments on revisions:

I thank the authors for their thorough responses to my previous comments. The revisions have addressed the points raised and have improved the clarity and overall quality of the manuscript. I appreciate the effort taken to strengthen the presentation of the work.

Author response:

The following is the authors’ response to the original reviews.

Public Reviews:

Reviewer #1 (Public review):

Summary:

The authors show that genetic deletion of the orphan tumor necrosis factor receptor DR6 in mice does not protect peripheral axons against degeneration after axotomy. Similarly, Schwann cells in DR6 mutant mice react to axotomy similarly to wild-type controls. These negative results are important because previous work has indicated that loss or inhibition of DR6 is protective in disease models and also against Wallerian degeneration of axons following injury. This carefully executed counterexample is important for the field to consider.

Strengths:

A strength of the paper is the use of two independent mouse strains that knock out DR6 in slightly different ways. The authors confirm that DR6 mRNA is absent in these models (western blots for DR6 protein are less convincingly null, but given the absence of mRNA, this is likely an issue of antibody specificity). One of the DR6 knockout strains used is the same strain used in a previous paper examining the effects of DR6 on Wallerian degeneration.

The authors use a series of established assays to evaluate axon degeneration, including light and electron microscopy on nerve histological samples and cultured dorsal root ganglion neurons in which axons are mechanically severed and degeneration is scored in time-lapse microscopy. These assays consistently show a lack of effect of loss of DR6 on Wallerian degeneration in both mouse strains examined.

Therefore, in the specific context of these experiments, the author's data support their conclusion that loss of DR6 does not protect against Wallerian degeneration.

Weaknesses:

(1) The major weaknesses of this paper include the tone of correcting previously erroneous results and the lack of reporting on important details around animal experiments that would help determine whether the results here really are discordant with previous studies, and if so, why.

The authors do not report the genetic strain background of the mice used, the sex distributions of their experimental cohorts, or the age of the mice at the time the experiments were performed. All of these are important variables.

(Response 1) We thank the reviewer for emphasizing the importance of reporting the sex, age, and genetic background of the experimental animals used in our axon protection analyses. We have incorporated this information into the revised manuscript wherever available. The sole exception concerns the genetic background of the conditional DR6 mice generated by Genentech, which remains unknown. The original publication describing these mice (Tam et al., 2012, Dev Cell, PMID 22340501) did not report this information, and we were unable to obtain it directly from Genentech. Details regarding the genetic background of the Wld^S and aPhr1 mutant mice are provided in their respective original publications, which are cited in our manuscript. Because the Gamage et al. study from the Deppmann laboratory did not report the sex or age of the animals used, we were unable to assess whether these variables might contribute to the differences observed between the two studies. Moreover, we are not aware of published evidence identifying sex or age as modifiers of structural axon preservation in axotomized peripheral nerve stumps in mouse models of delayed Wallerian degeneration. Furthermore, in the original publications describing the phenotypes of transgenic Nmnat2 and Wld^S mice, as well as Sarm1 or Phr1 knockout mice, sex and age of the animals used in the Wallerian degeneration assays were not reported (PMIDs 23995269, 12106171, 22678360, 23665224). Although, to our knowledge, no large-scale systematic studies have been conducted, over the last 15 years we have never observed any sex-based differences in Wallerian degeneration phenotypes in these mutants exhibiting prominent axon protection. This topic was discussed informally at conferences, and we are also not aware of other investigators having observed such effects.

In response to the reviewer’s comment regarding “tone”, we made sure that our data and interpretations are presented in a professional, balanced, and objective manner, including a detailed discussion of potential alternative explanations for the discrepant findings.

(2) The DR6 knockout strain reported in Gamage et al. (2017) was on a C57BL/6.129S segregating background. Gamage et al. reported that loss of DR6 protected axons from Wallerian degeneration for up to 4 weeks, but importantly, only in 38.5% (5 out of 13) mice they examined. In the present paper, the authors speculate on possible causes for differences between the lack of effect seen here and the effects reported in Gamage et al., including possible spontaneous background mutations, epigenetic changes, genetic modifiers, neuroinflammation, and environmental differences. A likely explanation of the incomplete penetrance reported by Gamage et al. is the segregating genetic background and the presence of modifier loci between C57BL/6 and 129S. The authors do not report the genetic background of the mice used in this study, other than to note that the knockout strain was provided by the group in Gamage et al. However, if, for example, that mutation has been made congenic on C57BL/6 in the intervening years, this would be important to know. One could also argue that the results presented here are consistent with 8 out of 13 mice presented in Gamage et al.

(Response 2) As noted above, we now provide information on the genetic background of the mice in the revised manuscript, where available. We have not backcrossed the constitutive DR6 knockout mice obtained from the Deppmann laboratory (Gamage et al.) to a C57BL/6 background; our colony was maintained primarily through intercrosses of heterozygous animals. Similarly, the conditional DR6 mutant mice used in this study were also not backcrossed to C57BL/6 mice.

We respectfully hold a different view regarding the reviewer’s final point. We understand it is not appropriate to infer consistency between two datasets by disregarding the subset of results that do not align. By the same logic, it would be flawed to draw conclusions from the Gamage et al. study based solely on the single Wld^S mouse out of five that did not show axon preservation after nerve injury. Selectively omitting conflicting data does not provide a valid basis for establishing phenotype concordance across studies.

To further strengthen our study, we note that we performed additional analyses on three more nerve samples from constitutive DR6 null mice during the revision process and have incorporated the resulting data in Fig. 1.

(3) Age is also an important variable. The protective effects of the spontaneous WldS mutation decrease with age, for example. It is unclear whether the possible protective effects of DR6 also change with age; perhaps this could explain the variable response seen in Gamage et al. and the lack of response seen here.

(Response 3) As discussed above, we now provide the age information for the mice used for the Wallerian degeneration assessments in the respective figure legends. To our knowledge, there are no prior reports suggesting that age is a significant determinant of structural axon preservation in the indicated mutants. Electrophysiological function and neuromuscular junction preservation decrease with age in axotomized Wld^S mice (e.g., PMIDs 12231635, 19158292, 15654865), but these parameters are not subject of our study, and we have not studied them. Unfortunately, a direct comparison of ages between our DR6 mutant mice and those used in Gamage et al. (2017) is not possible, as the earlier study from the Deppmann laboratory did not report this information.

(4) It is unclear if sex is a factor, but this is part of why it should be reported.

(Response 4) We now report the requested sex information for our axon preservation analyses during nerve injury-induced Wallerian degeneration in the DR6 mouse models in Figs. 1 and 2.

(5) The authors also state that they do not see differences in the Schwann cell response to injury in the absence of DR6 that were reported in Gamage et al., but this is not an accurate comparison. In Gamage et al., they examined Schwann cells around axons that were protected from degeneration 2 and 4 weeks post-injury. Those axons had much thinner myelin, in contrast to axons protected by WldS or loss of Sarm1, where the myelin thickness remained relatively normal. Thus, Gamage et al. concluded that the protection of axons from degeneration and the preservation of Schwann cell myelin thickness are separate processes. Here, since no axon protection was seen, the same analysis cannot be done, and we can only say that when axons degenerate, the Schwann cells respond the same whether DR6 is expressed or not.

(Response 5) We appreciate the reviewer’s detailed comments. Our intention was not to directly compare our findings with those of Gamage et al. regarding the myelin behavior at these time points (because we never observed axon protection), but rather to note that we did not observe any DR6-dependent alterations in Schwann cell responses under conditions where axons undergo normal Wallerian degeneration. As the reviewer correctly points out, Gamage et al. analyzed Schwann cell myelin surrounding axons that were protected from degeneration for extended periods, a context fundamentally different from the complete lack of axon protection observed in our DR6-deficient models. Therefore, the specific dissociation between axon preservation and myelin maintenance claimed by Gamage et al. cannot be evaluated in our study. A statement to make this point clearer has been incorporated in the revised manuscript.

We fully agree with the reviewer’s concluding point: in our experiments, once axons degenerate, Schwann cell responses proceed similarly regardless of DR6 expression. This agreement reinforces one of the central conclusions of our work.

(6) The authors also take issue with Colombo et al. (2018), where it was reported that there is an increase in axon diameter and a change in the g-ratio (axon diameter to fiber diameter - the axon + myelin) in peripheral nerves in DR6 knockout mice. This change resulted in a small population of abnormally large axons that had thinner myelin than one would expect for their size. The change in g-ratio was specific to these axons and driven by the increased axon diameter, not decreased myelin thickness, although those two factors are normally loosely correlated. Here, the authors report no changes in axon size or g-ratio, but this could also be due to how the distribution of axon sizes was binned for analysis, and looking at individual data points in supplemental figure 3A, there are axons in the DR6 knockout mice that are larger than any axons in wild type. Thus, this discrepancy may be down to specifics and how statistics were performed or how histograms were binned, but it is unclear if the results presented here are dramatically at odds with the results in Colombo et al. (2018).

(Response 6) Several points raised by the reviewer appear to reflect differences in interpretation of the findings reported in Colombo et al. (2018). That study did not report altered myelination in DR6 null mice at stages when myelination is largely complete (P21). Instead, modest changes were observed at P1, which were reduced by P7, and P21 mutants were reported to be indistinguishable from controls. No analyses of peripheral nerves in older animals were presented, and the authors concluded in the discussion that myelination in young adult DR6 null mice appears normal. In contrast, our analysis of constitutive DR6 null mice at P1 does not reproduce the increase in the number of myelinated fibers per unit area reported by Colombo et al. We obtained similar results in the independent conditional DR6 knockout mouse line. Differences in nerve tissue processing, embedding, staining, or in the microscopic imaging and quantification of thinly myelinated axons in P1 sciatic nerve cross-sections may have contributed to the observed discrepancy. However, because the relevant methodological details were not described in Colombo et al., the underlying reasons for these differences cannot be determined and remain speculative.

(7) Finally, it is important to note that previously reported effects of DR6 inhibition, such as protection of cultured cortical neurons from beta-amyloid toxicity, are not necessarily the same as Wallerian degeneration of axons distal to an injury studied here. The negative results presented here, showing that loss of DR6 is not protective against Wallerian degeneration induced by injury, are important given the interest in DR6 as a therapeutic target, but they are specific to these mice and this mechanism of induced axon degeneration. The extent to which these findings contradict previous work is difficult to assess due to the lack of detail in describing the mouse experiments, and care should be taken in attempting to extrapolate these results to other disease contexts, such as ALS or Alzheimer's disease.

(Response 7) We agree with the reviewer’s point and emphasize that our manuscript carefully differentiates our data regarding the function of DR6 in Wallerian degeneration from the potential involvement of DR6 in other forms of axon degeneration. Our findings do not conflict with previous work on DR6 in the context of in vitro beta-amyloid and prion toxicity as well as in vitro models of ALS and multiple sclerosis. We believe these distinctions are explicitly and appropriately articulated throughout the entire manuscript and in more detail in the discussion section.

Reviewer #1 (Recommendations for the authors):

(1) The authors should include additional information about the mice used, including strain background for both the DR6 mice and the Cre transgenes crossed into the DR6 conditional knockout, the age of the mice when the nerve crush experiments were performed, and the sex distributions of the experimental cohorts. This information is critical for reproducibility in animal experiments, and that point is compounded here, where the major focus of this paper is taking issue with the reproducibility of previous work.

(Response 8) This information has been included in the revision. See above responses.

(2) In the abstract, reference 5 is cited as a study on the response to Schwann cells to injury in a DR6 background, but this probably should be reference 10.

(Response 9) This typo has been corrected.

(3) "Site-by-site comparison" in line 201 should be side-by-side?

(Response 10) This typo has been corrected.

(4) The paper contains a lot of self-evaluative wording, "surprising contrast," "compelling evidence," "robust results." Whether those adjectives apply should be for the reader to decide, and a drier, more objective tone in the presentation would improve the paper.

(Response 11) We agree that excessive self-evaluative wording can weaken objectivity. In the manuscript, such phrasing is used sparingly and intentionally to highlight differences from previously published studies, guide the reader, and convey scholarly judgment. We do not consider this limited use to be counterproductive. The adjectives “surprising,” “compelling,” and “robust” each appear only one to three times across the entire manuscript, and the specific phrase “robust results” does not appear at all.

(5) In Figure 2A, DR6-/-, there is no significant difference, but there is also a lot of variability, and one could argue the authors are seeing axon protection comparable to WldS in 40% of their samples (2/5), which is very similar to Gamage et al.

(Response 12) We respectfully disagree with this reasoning as it relies on selectively emphasizing only a subset of the data. Please also see our response #2 for more detailed discussion.

(6) Overall, the data presented here are convincing and support the conclusions drawn, but the paper needs to focus more on the negative results at hand and less on bashing previous studies, particularly when the results presented here do definitively show that the previous studies were incorrect and plausible explanations for differences in outcome exist.

(Response 13) We have carefully revisited the wording of the manuscript and are confident that our emphasis remains on the central negative finding that DR6 does not regulate axon degeneration and Schwann cell injury responses during Wallerian degeneration. We do not believe the manuscript “bashes” previous studies; nonetheless, we thoroughly re-examined all relevant sections to ensure that our language is neutral, accurate, and non-inflammatory. We believe the current phrasing presents our interpretations in an appropriately balanced, objective, and professional manner.

Reviewer #2 (Public review):

Summary:

This manuscript by Beirowski, Huang, and Babetto revisits the proposed role of Death Receptor 6 (DR6/Tnfrsf21) in Wallerian degeneration (WD). A prior study (Gamage et al., 2017) suggested that DR6 deletion delays axon degeneration and alters Schwann cell responses following peripheral nerve injury. Here, the authors comprehensively test this claim using two DR6 knockout mouse models (the line used in the earlier report plus a CMV-Cre derived floxed ko line) and multiple WD assays in vivo and in vitro, aligned with three positive controls, Sarm1 WldS and Phr1/Mycbp2 mutants. Contrary to the prior findings, they find no evidence that DR6 deletion affects axon degeneration kinetics or Schwann cell dynamics (assessed by cJun expression or [intact+degenerating] myelin abundance after injury) during WD. Importantly, in DRG explant assays, neurites from DR6-deficient mice degenerated at rates indistinguishable from controls. The authors conclude that DR6 is dispensable for WD, and that previously reported protective effects may have been due to confounding factors such as genetic background or spontaneous mutations.

Strengths:

The authors employ two independently generated DR6 knockout models, one overlapping with the previously published study, and confirm loss of DR6 expression by qPCR and Western blotting. Multiple complementary readouts of WD are applied (structural, ultrastructural, molecular, and functional), providing a robust test of the hypothesis.

Comparisons are drawn with established positive controls (WldS, SARM1, Phr1/Mycbp2 mutants), reinforcing the validity of the assays.

By directly addressing an influential but inconsistent prior report, the manuscript clarifies the role of DR6 and prevents potential misdirection of therapeutic strategies aimed at modulating WD in the PNS. The discussion thoughtfully considers possible explanations for the earlier results, including colony-specific second-site mutations that could explain the incomplete penetrance of the earlier reported phenotype of only 36%.

Weaknesses:

(1) The study focuses on peripheral nerves. The manuscript frequently refers to CNS studies to argue for consistency with their findings. It would be more accurate to frame PNS/CNS similarities as reminiscences rather than as consistencies (e.g., line 205ff in the Discussion).

(Response 14) Axon protection in all key genetic models of delayed axon degeneration, including Wld^S, SARM1, Phr1/Mycbp2 mutants, has been demonstrated in both the peripheral and central nervous systems. This observation supports the view that core molecular mechanisms regulating axon degeneration are conserved across neuronal populations throughout the entire nervous system. We have scrutinized the wording in our manuscript and are not aware that we frequently refer to CNS studies in regards to axon degeneration. Nevertheless, we have replaced the term “consistent” to avoid potential ambiguity when we discuss the earlier study showing normal Wallerian degeneration in the optic nerves from DR6 knockout mice.

(2) The DRG explant assays are convincing, though the slight acceleration of degeneration in the DR6 floxed/Cre condition is intriguing (Figure 4E). Could the authors clarify whether this is statistically robust or biologically meaningful?

(Response 15) We thank the reviewer for noting this aspect of our in vitro data in Fig. 4. The difference observed in the DR6 floxed/Cre condition is statistically significant at the 6h time point following disconnection, as indicated by the p value shown in Fig. 4E. However, a similarly statistically significant acceleration of axon degeneration was not observed in DRG axotomy experiments using constitutive DR6 knockout preparations, although a trend toward more rapid axon breakdown is apparent at 6 h post-axotomy (Fig. 4B). These observations may suggest reduced stability of DR6-deficient axons in this specific neuron-only in vitro context. Further investigation would be required to determine the biological significance of this effect. In contrast, our in vitro quantitative analyses of the initiation and early phases of Wallerian degeneration (Fig. 2) revealed no evidence of accelerated axon disintegration in the DR6 mutant mouse models, highlighting potential differences between in vitro and in vitro systems.

(3) In the summary (line 43), the authors refer to Hu et al. (2013) (reference 5) as the study that previously reported AxD delay and SC response alteration after injury. However, this study did not investigate the PNS, and I believe the authors intended to reference Gamage et al. (2017) (reference 10) at this point.

(Response 16) Thanks for pointing this out. We have corrected this typo in the revised manuscript.

(4) In line 74ff of the results section, the authors claim that developmental myelination is not altered in DR6 mutants at postnatal day 1. However, the variability in Figure S2 appears substantial, and the group size seems underpowered to support this claim. Colombo et al. (2018) (reference 11) reported accelerated myelination at P1, but this study likewise appears underpowered. Possible reasons for these discrepancies and the large variability could be that only a defined cross-sectional area was quantified, rather than the entire nerve cross-section.

(Response 17) We confirm that the quantification of thinly myelinated axons was performed on entire sciatic nerves from P1 mouse pups, as described in the methods section in our original manuscript. The data shown in Fig. S2 were obtained from 5-9 pups per experimental group. Sample sizes were determined based on a priori power analyses using pilot data, which indicated that a minimum of five biological replicates was sufficient to detect statistically significant differences with acceptable confidence. Comparable sample sizes have been used in our previous studies and by other groups to assess early postnatal myelination (e.g., PMIDs 21949390, 28484008). Several published studies have reported analyses using 3-4 animals per group (e.g., PMIDs 28484008, 25310982, 29367382). For comparison, the study by Colombo et al. used 3-8 pups for the analysis presented in their Fig. 3. We note that the apparent variability in Fig. S2 may be accentuated by the scaling of the y-axis, which was chosen to ensure that individual data points are clearly resolved and visible.

(5) The authors stress the data of Gamage et al. (2017) on altered SC responses in DR6 mutants after injury. They employed cJun quantification to show that SC reprogramming after injury is not altered in DR6 mutants. This approach is valid and the conclusion trustworthy. Here, the addition of data showing the combined abundance of intact and degenerated myelin does not add much insight. However, Gamage et al. (2017) reported altered myelin thickness in a subset of axons at 14 days after injury, which is considerably later than the time points analyzed in the present study. While, in the Reviewer's view, the thin myelin observed by Gamage et al. in fact resembles remyelination, the authors may wish to highlight the difference in the time points analyzed.

(Response 18) We consider the additional quantification of the area occupied by intact myelin and myelin debris to provide complementary information that supports the c-Jun-based conclusion that Schwann cell injury responses are normal in DR6-deficient nerves following lesion. We agree with this reviewer that the thin myelin observed by Gamage et al. resembles remyelination, raising the possibility that axon regeneration occurred into the distal nerve stump at the studied 14d post-injury time point (see their Fig. 3). This may have been interpreted as axon protection in this study. In our study, it was impossible to examine such myelin effects since axon protection was never observed in any of the DR6 mutant models at any of the time point we investigated. We have incorporated appropriate additional text to highlight this difference. See also response #5 above.

Reviewer #3 (Public review):

Summary:

The authors revisit the role of DR6 in axon degeneration following physical injury (Wallerian degeneration), examining both its effects on axons and its role in regulating the Schwann cell response to injury. Surprisingly, and in contrast to previous studies, they find that DR6 deletion does not delay the rate of axon degeneration after injury, suggesting that DR6 is not a mediator of this process.

Overall, this is a valuable study. As the authors note, the current literature on DR6 is inconsistent, and these results provide useful new data and clarification. This work will help other researchers interpret their own data and re-evaluate studies related to DR6 and axon degeneration.

Strengths:

(1) The use of two independent DR6 knockout mouse models strengthens the conclusions, particularly when reporting the absence of a phenotype.

(2) The focus on early time points after injury addresses a key limitation of previous studies. This approach reduces the risk of missing subtle protective phenotypes and avoids confounding results with regenerating axons at later time points after axotomy.

Weaknesses:

(1) The study would benefit from including an additional experimental paradigm in which DR6 deficiency is expected to have a protective effect, to increase confidence in the experimental models, and to better contextualize the findings within different pathways of axon degeneration. For example, DR6 deletion has been shown in more than one study to be partially axon protective in the NGF deprivation model in DRGs in vitro. Incorporating such an experiment could be straightforward and would strengthen the paper, especially if some of the neuroprotective effects previously reported are confirmed.

(Response 19) We thank the reviewer for these suggestions. We would like to highlight that our study addresses the role of DR6 in Wallerian degeneration, whereas in vitro NGF deprivation has been used to model developmental axon pruning. Previous work indicates fundamental biological differences between these regressive pathways regulating the stereotyped removal of axon segments. We feel that studying this alternative form of axon degeneration is beyond the scope of the current work and could be addressed in a separate manuscript. Although additional tests will be needed, we note that our preliminary data using samples from both DR6 knockout mouse models suggest no axon protection after NGF-deprivation in DRG neuron preparations in our hands (deprivation of the growth factor and administration of anti-NGF antibody).

(2) The quality of some figures could be improved, particularly the EM images in Figure 2. As presented, they make it difficult to discern subtle differences.

(Response 20) We have pseudocolored intact (turquoise) and degenerated (magenta) myelinated fibers on the high-resolution semithin micrographs (not electron micrographs) in the new Fig. 2 to make the distinction between the two fiber categories clearer.

Reviewer #3 (Recommendations for the authors):

(1) Line 121: The authors mention toluidine blue staining, but it does not appear to be shown in Figure S5.

(Response 21) This appears to be a misunderstanding. Fig. S5A shows the ultrastructure of dedifferentiated Schwann cells in transmission electron micrographs, while Figs. S5B and C show quantification of the area occupied by myelin sheaths and myelin debris profiles on osmium tetroxide and toluidine blue stained nerve sections from the two DR6 mutant models, based on semithin light microscopy. These are two different aspects of the analysis. The text has been modified in the revised manuscript to make the distinction clearer.

(2) Line 175: The authors should add NMNAT2 to the list of enzymes implicated in the regulation of Wallerian degeneration in mammals.

(Response 22) Nmnat2 and a literature reference (Milde et al., 2013) has been incorporated in the discussion of the revised manuscript to address this point.

(3) Line 201: Please correct the typo "site-by-site" to "side-by-side."

(Response 23) This typo has been corrected.

eLife Assessment

This fundamental work significantly advances our understanding of how contact-dependent antagonism enables keystone bacteria to establish and maintain their niche over time. The evidence obtained is convincing, supporting most of the conclusions drawn. This work will be of significant interest to the microbiome research community.

Reviewer #1 (Public review):

Summary:

In this study, the authors investigate the physiological role of the Type VI secretion system (T6SS) in a naturally evolved gut microbiome derived from wild mice (the WildR microbiome). Focusing on Bacteroides acidifaciens, the authors use newly developed genetic tools and strain-replacement strategies to test how T6SS-mediated antagonism influences colonization, persistence, and fitness within a complex gut community. They further show that the T6SS resides on an integrative and conjugative element (ICE), is distributed among select community members, and can be horizontally transferred, with context-dependent effects on colonization and persistence. The authors conclude that the T6SS stabilizes strain presence in the gut microbiome while imposing ecological and physiological constraints that shape its value across contexts.

This study is likely to have a significant impact on the microbiome field by moving experimental tests of T6SS function out of simplified systems and into a naturally co-evolved gut community. The WildR system, together with the strain replacement strategy, ICE-seq approach, and genetic toolkit, represents a powerful and reusable platform for future mechanistic studies of microbial antagonism and mobile genetic elements in vivo.

The datasets, including isolate genomes, metagenomes, and ICE distribution maps, will be a valuable community resource, particularly for researchers interested in strain-resolved dynamics, horizontal gene transfer, and ecological context dependence. Even where mechanistic resolution is incomplete, the work provides a strong experimental foundation upon which such questions can be directly addressed.

Overall, this study occupies a space between system building and mechanistic dissection. The authors demonstrate that the T6SS influences persistence and community structure in vivo, but the physiological basis of these effects remains unresolved. Interpreting the results as evidence of fitness costs or selective advantage, therefore, requires caution, as multiple ecological and host-mediated processes could produce similar abundance trajectories.

Placing the findings within the broader literature on microbial antagonism, particularly work emphasizing measurable costs, benefits, and tradeoffs, would help readers better contextualize what is directly demonstrated here versus what remains an open question. Viewed in this light, the principal contribution of the study is to show that such questions can now be addressed experimentally in a realistic gut ecosystem.

Strengths:

A major strength of this study is that it directly interrogates the physiological role of the T6SS in a naturally evolved gut microbiome, rather than relying on simplified pairwise or in vitro systems. By working within the WildR community, the authors advance beyond descriptive surveys of T6SS prevalence and address function in an ecologically relevant context.

The authors provide clear genetic evidence that Bacteroides acidifaciens uses a T6SS to antagonize co-resident Bacteroidales, and that loss of T6SS function specifically compromises long-term persistence without affecting initial colonization. This temporal separation is well designed and supports the conclusion that the T6SS contributes to maintenance rather than establishment within the community.

Another strength is the identification of the T6SS on an integrative and conjugative element (ICE) and the demonstration that this element is distributed among, and exchanged between, community members. The use of ICE-seq to track distribution and transfer provides strong support for horizontal mobility and adds mechanistic depth to the study.

Finally, the transfer of the T6SS-ICE into Phocaeicola vulgatus and the observation of context-dependent colonization benefits followed by decline is a compelling result that moves the study beyond simple "T6SS is beneficial" narratives and highlights ecological contingency.

Weaknesses:

Despite these strengths, there is a mismatch between the precision of the claims and the precision of the measurements, particularly regarding fitness costs, physiological burden, and the mechanistic role of the T6SS.

First, while the authors conclude that the T6SS "stabilizes strain presence" and that its value is constrained by fitness costs, these costs are not directly measured. Persistence, abundance trajectories, and eventual loss are informative outcomes, but they do not uniquely identify fitness tradeoffs. Decline could arise from multiple non-exclusive mechanisms, including community restructuring, host-mediated effects, incompatibilities of the ICE in new hosts, or ecological retaliation, none of which are disentangled here.

Second, the manuscript frames the T6SS as having a defined physiological role, yet the data do not resolve which physiological processes are under selection. The experiments demonstrate that T6SS activity affects persistence, but they do not distinguish whether this occurs via direct killing, resource release, niche modification, or higher-order community effects. As a result, "physiological role" remains underspecified and risks being conflated with ecological outcome.

Third, although the authors emphasize context dependence, the study offers limited quantitative insight into what aspects of context matter. Differences between native and recipient hosts, or between early and late colonization phases, are described but not mechanistically interrogated, making it difficult to generalize beyond the specific cases examined.

Fourth is the lack of engagement with recent experimental literature demonstrating functional roles of the T6SS beyond simple interference competition. While the authors focus on persistence and competitive outcomes, they do not adequately situate their findings within recent work demonstrating that T6SS-mediated antagonism can serve additional physiological functions, including resource acquisition and DNA uptake, thereby linking killing to measurable benefits and tradeoffs. The absence of this literature makes it difficult to place the authors' conclusions about physiological role and fitness cost within the current conceptual framework of the field. Without this context, the physiological interpretation of the results remains incomplete, and alternative functional explanations for the observed dynamics are underexplored.

A further limitation concerns the taxonomic scope of the functional analysis. The authors state that the role of the T6SS in the murine environment is functionally investigated using genetically tractable Bacteroides species, citing the lack of genetic tools for Mucispirillum schaedleri. While this is a reasonable, practical choice, it means that a substantial fraction of T6SS-encoding species in the WildR community are not experimentally interrogated. Consequently, conclusions about the role of the T6SS in the murine gut necessarily reflect the subset of taxa that are genetically accessible and may not fully capture community-level or niche-specific functions of T6SS activity. Given that M. schaedleri is represented as a metagenome-assembled genome, its isolation and genetic manipulation would be technically challenging. Nonetheless, explicitly acknowledging this limitation and slightly tempering claims of generality would strengthen the manuscript.

Finally, several interpretations would benefit from more cautious language. In particular, claims invoking fitness costs, selective advantage, or physiological burden should be explicitly framed as inferences from persistence dynamics, rather than as direct measurements, unless supported by additional quantitative fitness or growth assays.

Reviewer #2 (Public review):

Summary:

In this study, the authors set out to determine how a contact-dependent bacterial antagonistic system contributes to the ability of specific bacterial strains to persist within a complex, native gut community derived from wild animals. Rather than focusing on simplified or artificial models, the authors aimed to examine this system in a biologically realistic setting that captures the ecological complexity of the gut environment. To achieve this, they combined controlled laboratory experiments with animal colonization studies and sequencing-based tracking approaches that allow individual strains and mobile genetic elements to be followed over time.

Strengths:

A major strength of the work is the integration of multiple complementary approaches to address the same biological question. The use of defined but complex communities, together with in vivo experiments, provides a strong ecological context for interpreting the results. The data consistently show that the antagonistic system is not required for initial establishment but plays a critical role in long-term strain persistence. This insight that moves beyond traditional invasion-based views of microbial competition. The observation that transferable genetic elements can confer only temporary advantages, and may impose longer-term costs depending on community context, adds important nuance to current understanding of microbial fitness.

Weaknesses:

Overall, there is not a lack of evidence, but a deliberate trade-off between ecological realism and mechanistic resolution, which leaves some causal pathways open to interpretation.

Reviewer #3 (Public review):

Summary:

Shen et al. investigate the contribution of the type VI secretion system of Bacteroidales in the gut microbiome assembly and targeting of closely related species. They demonstrate that B. acidifaciens relies on T6SS-mediated antagonism to prevent displacement by co-resident Bacteroidales and other members of the microbiome, allowing B. acidifaciens to persist in the gut.

Strengths:

Using a gnotobiotic model colonized with a wild-mouse microbiome is a significant strength of this study. This approach allows tracking of microbiome changes over time and directly examining targeting by Bacteroidales carrying T6SS in a more natural setting. The development of ICE-seq for mapping the distribution of the T6SS in the microbiome is remarkable, enabling the study of how this bacterial weapon is transferred between microbiome members without requiring long-read metagenomics methods.

Weaknesses:

Some conclusions are based on only four mice per condition. The author should consider increasing the sample size.

Overall, the authors successfully achieved their objectives, and their experimental design and results support their findings. As mentioned in the discussion, it would be important to investigate the role of the T6SS in resilience to disturbances in the microbiome, such as antibiotics, diet, or pathogen invasion. This work represents a step forward in understanding how contact-dependent competition influences the gut microbiome in relevant ecological contexts.

Author response:

We appreciate that the reviewers provided an overall positive assessment of our manuscript and offered constructive suggestions for improvement. All three reviewers noted that a key strength of our study is the implementation of a gut microbiome model for the characterization of interbacterial antagonism pathways such as the type VI secretion system (T6SS) that approaches natural complexity. They note our work represents a significant advance in microbiome research, and generates resources that will be of use to many researchers in the field. Two of the reviewers point out that the complexity of our model limits the nature of measurements we can make, and suggest we temper the strength of the some of the conclusions we draw. As noted in more detail below, in our revised manuscript, we will be more precise in the wording we use to characterize our findings, and we will be more explicit about what the measurements we are able to make allow us to conclude about the physiological role of the T6SS in the gut microbiome.

Reviewer #1 (Public review):

Summary:

In this study, the authors investigate the physiological role of the Type VI secretion system (T6SS) in a naturally evolved gut microbiome derived from wild mice (the WildR microbiome). Focusing on Bacteroides acidifaciens, the authors use newly developed genetic tools and strain-replacement strategies to test how T6SS-mediated antagonism influences colonization, persistence, and fitness within a complex gut community. They further show that the T6SS resides on an integrative and conjugative element (ICE), is distributed among select community members, and can be horizontally transferred, with context-dependent effects on colonization and persistence. The authors conclude that the T6SS stabilizes strain presence in the gut microbiome while imposing ecological and physiological constraints that shape its value across contexts.

This study is likely to have a significant impact on the microbiome field by moving experimental tests of T6SS function out of simplified systems and into a naturally co-evolved gut community. The WildR system, together with the strain replacement strategy, ICE-seq approach, and genetic toolkit, represents a powerful and reusable platform for future mechanistic studies of microbial antagonism and mobile genetic elements in vivo.

The datasets, including isolate genomes, metagenomes, and ICE distribution maps, will be a valuable community resource, particularly for researchers interested in strain-resolved dynamics, horizontal gene transfer, and ecological context dependence. Even where mechanistic resolution is incomplete, the work provides a strong experimental foundation upon which such questions can be directly addressed.

Overall, this study occupies a space between system building and mechanistic dissection. The authors demonstrate that the T6SS influences persistence and community structure in vivo, but the physiological basis of these effects remains unresolved. Interpreting the results as evidence of fitness costs or selective advantage, therefore, requires caution, as multiple ecological and host-mediated processes could produce similar abundance trajectories.

Placing the findings within the broader literature on microbial antagonism, particularly work emphasizing measurable costs, benefits, and tradeoffs, would help readers better contextualize what is directly demonstrated here versus what remains an open question. Viewed in this light, the principal contribution of the study is to show that such questions can now be addressed experimentally in a realistic gut ecosystem.

We thank the reviewer for this thoughtful summary of our study. We were glad to read they conclude our work will have a significant impact on the microbiome field and that the resources we have developed will be of value to the community.

Strengths:

A major strength of this study is that it directly interrogates the physiological role of the T6SS in a naturally evolved gut microbiome, rather than relying on simplified pairwise or in vitro systems. By working within the WildR community, the authors advance beyond descriptive surveys of T6SS prevalence and address function in an ecologically relevant context.

The authors provide clear genetic evidence that Bacteroides acidifaciens uses a T6SS to antagonize co-resident Bacteroidales, and that loss of T6SS function specifically compromises long-term persistence without affecting initial colonization. This temporal separation is well designed and supports the conclusion that the T6SS contributes to maintenance rather than establishment within the community.

Another strength is the identification of the T6SS on an integrative and conjugative element (ICE) and the demonstration that this element is distributed among, and exchanged between, community members. The use of ICE-seq to track distribution and transfer provides strong support for horizontal mobility and adds mechanistic depth to the study.

Finally, the transfer of the T6SS-ICE into Phocaeicola vulgatus and the observation of context-dependent colonization benefits followed by decline is a compelling result that moves the study beyond simple "T6SS is beneficial" narratives and highlights ecological contingency.

We appreciate this detailed and nuanced characterization of the strengths of our study.

Weaknesses:

Despite these strengths, there is a mismatch between the precision of the claims and the precision of the measurements, particularly regarding fitness costs, physiological burden, and the mechanistic role of the T6SS.

We acknowledge that in some places, our manuscript could benefit from greater precision in the language we use when linking the outcomes we observe in our study to their potential underlying causes. Specific revisions we propose to address this concern are described below.

First, while the authors conclude that the T6SS "stabilizes strain presence" and that its value is constrained by fitness costs, these costs are not directly measured. Persistence, abundance trajectories, and eventual loss are informative outcomes, but they do not uniquely identify fitness tradeoffs. Decline could arise from multiple non-exclusive mechanisms, including community restructuring, host-mediated effects, incompatibilities of the ICE in new hosts, or ecological retaliation, none of which are disentangled here.

We agree that multiple mechanisms could explain why P. vulgatus carrying a T6SS-encoding ICE declines over time. Our use of the term “fitness cost” to describe this trend was not meant to imply any particular underlying mechanism, but was rather our attempt to characterize the phenotypic outcome we observed in simplified terms. We note that ecological context is an important determinant of the fitness cost or benefit of any given trait, and our study sheds light on the importance of the presence of the WildR community and the mouse intestinal environment to the fitness contribution of the ICE to P. vulgatus. Nonetheless, to avoid implying an overly simplistic interpretation of our results, we propose to modify the language used in the manuscript when describing the contribution of the T6SS to species persistence in WildR-colonized mice.

Second, the manuscript frames the T6SS as having a defined physiological role, yet the data do not resolve which physiological processes are under selection. The experiments demonstrate that T6SS activity affects persistence, but they do not distinguish whether this occurs via direct killing, resource release, niche modification, or higher-order community effects. As a result, "physiological role" remains underspecified and risks being conflated with ecological outcome.

We acknowledge that our study does not fully resolve the physiological processes under selection that mediate role of the T6SS in maintaining B. acidifaciens populations in WildR-colonized mice. Indeed, several of the outcomes of T6SS activity the reviewer lists, such as target cell killing and nutrient release, are inextricably linked and thus inherently difficult to disentangle. We note that we did attempt to measure higher-order community effects of T6SS activity with metagenomic sequencing, but acknowledge that this approach may not have been sufficiently sensitive to detect small community shifts mediated by a relatively low-abundance species. To address the concern that our current framing implies more of a mechanistic understanding that our study achieves, we propose to substitute “ecological” for “physiological” where appropriate when summarizing our key findings.

Third, although the authors emphasize context dependence, the study offers limited quantitative insight into what aspects of context matter. Differences between native and recipient hosts, or between early and late colonization phases, are described but not mechanistically interrogated, making it difficult to generalize beyond the specific cases examined.

We are not entirely clear what the reviewer means by “differences between native and recipient hosts”, but we agree that additional quantitative studies will be needed to address the generalizability of our findings. Future studies are also needed to address the mechanistic basis for the difference in the benefit conferred by the T6SS that we observed between P. vulgatus and B. acidifaciens.

Fourth is the lack of engagement with recent experimental literature demonstrating functional roles of the T6SS beyond simple interference competition. While the authors focus on persistence and competitive outcomes, they do not adequately situate their findings within recent work demonstrating that T6SS-mediated antagonism can serve additional physiological functions, including resource acquisition and DNA uptake, thereby linking killing to measurable benefits and tradeoffs. The absence of this literature makes it difficult to place the authors' conclusions about physiological role and fitness cost within the current conceptual framework of the field. Without this context, the physiological interpretation of the results remains incomplete, and alternative functional explanations for the observed dynamics are underexplored.

We thank the reviewer for specifically highlighting the potential pertinence of this literature to our study. Indeed, we did not cite studies indicating a link between T6SS activity and the uptake of DNA and other resources released by targeted cells. As we note above, the release of intracellular contents from target cells is an inevitable consequence of the delivery of lytic effectors. Thus, distinguishing between fitness benefits conferred from the elimination of competitor species and those arising from scavenging the nutrients released during this process is not straightforward. Measuring the benefits deriving from the uptake of certain released molecules, such as DNA, was not immediately feasible in the system employed in this study and instead we focused on the direct lytic consequences of the effectors delivered via the T6SS. We will revise our Discussion to include reference to how downstream consequences of T6SS activity on target cells could impact the community, and thus the adaptive role of the T6SS in the microbiome.

A further limitation concerns the taxonomic scope of the functional analysis. The authors state that the role of the T6SS in the murine environment is functionally investigated using genetically tractable Bacteroides species, citing the lack of genetic tools for Mucispirillum schaedleri. While this is a reasonable, practical choice, it means that a substantial fraction of T6SS-encoding species in the WildR community are not experimentally interrogated. Consequently, conclusions about the role of the T6SS in the murine gut necessarily reflect the subset of taxa that are genetically accessible and may not fully capture community-level or niche-specific functions of T6SS activity. Given that M. schaedleri is represented as a metagenome-assembled genome, its isolation and genetic manipulation would be technically challenging. Nonetheless, explicitly acknowledging this limitation and slightly tempering claims of generality would strengthen the manuscript.

The reviewer points out that studying the T6SS activity in M. schadleri would potentially expand the generality of our claims. We agree that having an isolate of this species along with genetic tools for its manipulation would allow us to probe the importance of the T6SS in the gut microbiome more broadly. At the suggestion of the reviewer, we will add explicit mention for the need to develop such tools, an endeavor that lies outside of the scope of the current study.

Finally, several interpretations would benefit from more cautious language. In particular, claims invoking fitness costs, selective advantage, or physiological burden should be explicitly framed as inferences from persistence dynamics, rather than as direct measurements, unless supported by additional quantitative fitness or growth assays.

We agree with the reviewer that invoking fitness costs, selective advantages or physiological burdens should be done cautiously, and in our revised manuscript we will carefully re-evalute our usage of those terms. However, we would also argue invoking fitness costs and benefits when describe strain persistence dynamics in mice has substantial precedent in the literature ((Feng et al. 2020, Brown et al. 2021, Park et al. 2022, Segura Munoz et al. 2022), to list a handful of representative examples published by different groups). It is unclear to us what additional in vivo growth measurements could be taken to substantiate our claim that the T6SS provides a fitness benefit to B. acidifaciens during prolonged gut colonization, or that carrying the ICE imposes a fitness cost on P. vulgatus during long-term colonization. Our in vitro experiments evaluating the competitiveness conferred by T6SS activity provide a measure of insight into its fitness benefits, but as our in vivo strain persistence data and the work of many others show, in vitro measurements do not necessarily capture in vivo parameters.

Reviewer #2 (Public review):

Summary:

In this study, the authors set out to determine how a contact-dependent bacterial antagonistic system contributes to the ability of specific bacterial strains to persist within a complex, native gut community derived from wild animals. Rather than focusing on simplified or artificial models, the authors aimed to examine this system in a biologically realistic setting that captures the ecological complexity of the gut environment. To achieve this, they combined controlled laboratory experiments with animal colonization studies and sequencing-based tracking approaches that allow individual strains and mobile genetic elements to be followed over time.

Strengths:

A major strength of the work is the integration of multiple complementary approaches to address the same biological question. The use of defined but complex communities, together with in vivo experiments, provides a strong ecological context for interpreting the results. The data consistently show that the antagonistic system is not required for initial establishment but plays a critical role in long-term strain persistence. This insight that moves beyond traditional invasion-based views of microbial competition. The observation that transferable genetic elements can confer only temporary advantages, and may impose longer-term costs depending on community context, adds important nuance to current understanding of microbial fitness.

We thank the reviewer for the positive feedback and are glad they agree our study provides new insight into the role of interbacterial antagonism in natural communities.

Weaknesses:

Overall, there is not a lack of evidence, but a deliberate trade-off between ecological realism and mechanistic resolution, which leaves some causal pathways open to interpretation.

The reviewer makes a good point that the complexity of the experimental system we employ precludes some lines of experimentation that would yield more mechanistic information. As the reviewer notes, we were aware of the tradeoff between mechanistic resolution and ecological realism when selecting our experimental system. Our deliberate choice to favor biological complexity over mechanistic clarity in this study stemmed from our perception that a major gap in understanding of the T6SS and other antagonism pathways lies in defining their ecological function in complex microbial communities.

Reviewer #3 (Public review):

Summary:

Shen et al. investigate the contribution of the type VI secretion system of Bacteroidales in the gut microbiome assembly and targeting of closely related species. They demonstrate that B. acidifaciens relies on T6SS-mediated antagonism to prevent displacement by co-resident Bacteroidales and other members of the microbiome, allowing B. acidifaciens to persist in the gut.

Strengths:

Using a gnotobiotic model colonized with a wild-mouse microbiome is a significant strength of this study. This approach allows tracking of microbiome changes over time and directly examining targeting by Bacteroidales carrying T6SS in a more natural setting. The development of ICE-seq for mapping the distribution of the T6SS in the microbiome is remarkable, enabling the study of how this bacterial weapon is transferred between microbiome members without requiring long-read metagenomics methods.

We thank the reviewer for their enthusiasm toward our study.

Weaknesses:

Some conclusions are based on only four mice per condition. The author should consider increasing the sample size.

We agree that in some experiments it would be beneficial to increase the sample size from four mice. However, the experiments we performed for this study are time and resource intensive. Additionally, the experiments on which we base our primary conclusions were all independently replicated with similar results. Given these factors, we determined that the extra confidence that might be afforded by increasing our sample size did not merit the delay in publication and investment in resources that would be required.

Overall, the authors successfully achieved their objectives, and their experimental design and results support their findings. As mentioned in the discussion, it would be important to investigate the role of the T6SS in resilience to disturbances in the microbiome, such as antibiotics, diet, or pathogen invasion. This work represents a step forward in understanding how contact-dependent competition influences the gut microbiome in relevant ecological contexts.

We agree that investigating the role of the T6SS during perturbations of the microbiome is a key next step for this work and thank the reviewer for highlighting this important future direction.

References

Brown, E. M., H. Arellano-Santoyo, E. R. Temple, Z. A. Costliow, M. Pichaud, A. B. Hall, K. Liu, M. A. Durney, X. Gu, D. R. Plichta, C. A. Clish, J. A. Porter, H. Vlamakis and R. J. Xavier (2021). "Gut microbiome ADP-ribosyltransferases are widespread phage-encoded fitness factors." Cell Host Microbe 29(9): 1351-1365 e1311.

Feng, L., A. S. Raman, M. C. Hibberd, J. Cheng, N. W. Griffin, Y. Peng, S. A. Leyn, D. A. Rodionov, A. L. Osterman and J. I. Gordon (2020). "Identifying determinants of bacterial fitness in a model of human gut microbial succession." Proc Natl Acad Sci U S A 117(5): 2622-2633.

Park, S. Y., C. Rao, K. Z. Coyte, G. A. Kuziel, Y. Zhang, W. Huang, E. A. Franzosa, J. K. Weng, C. Huttenhower and S. Rakoff-Nahoum (2022). "Strain-level fitness in the gut microbiome is an emergent property of glycans and a single metabolite." Cell 185(3): 513-529 e521.

Segura Munoz, R. R., S. Mantz, I. Martinez, F. Li, R. J. Schmaltz, N. A. Pudlo, K. Urs, E. C. Martens, J. Walter and A. E. Ramer-Tait (2022). "Experimental evaluation of ecological principles to understand and modulate the outcome of bacterial strain competition in gut microbiomes." ISME J 16(6): 1594-1604.

Guide de Scolarisation des Élèves Présentant des Troubles à Expression Comportementale

Résumé Exécutif

Ce document synthétise les stratégies et outils destinés aux enseignants pour scolariser efficacement les élèves manifestant des troubles du comportement.

La distinction fondamentale repose sur la différence entre une opposition ponctuelle (réactionnelle et passagère) et des troubles du comportement avérés (crises intenses, incapacité de régulation, dangerosité).

La prise en charge repose sur trois piliers :

1. La Prévention : Création d’un environnement sécurisant par une organisation spatiale et temporelle stable et une posture d'enseignant prévisible.

2. L’Adaptation : Utilisation d’outils de structuration (contrats de comportement, thermomètres émotionnels, espaces de répit) pour répondre aux besoins spécifiques de l'élève.

3. La Gestion de Crise : Application de protocoles de désescalade et mise en sécurité, suivies d'une phase d'analyse rigoureuse pour ajuster les interventions futures.

L'objectif central est de passer d'une gestion réactive à une approche proactive, visant l'apaisement de l'élève et la préservation du climat d'apprentissage pour l'ensemble de la classe.

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I. Définitions et Cadre d'Analyse

Il est crucial pour l'enseignant de diagnostiquer la nature de la perturbation afin d'y apporter la réponse appropriée.

1. Opposition Ponctuelle vs Troubles Avérés

Le tableau suivant distingue les deux types de manifestations comportementales :

| Caractéristiques | Opposition Ponctuelle | Troubles du Comportement Avérés | | --- | --- | --- | | Manifestations | Refus temporaire, frustration verbale, énervement bref. | Crises fréquentes, violences physiques (soi, autres, matériel), agressivité constante. | | Capacité de régulation | Retrouve son calme après un rappel ou une redirection. | Incapacité à se réguler seul, même avec soutien. | | Origine | Fatigue, difficulté de compréhension, test des limites. | Épuisement émotionnel ou sensoriel, déconnecté de la situation immédiate. | | Impact | Ne perturbe pas durablement la classe. | Perturbation majeure du climat de classe et des apprentissages. |

2. La Crise Majeure

Une crise majeure se définit par une perte totale de contrôle. Elle est caractérisée par une intensité forte (hurlements, violences), une durée significative (minutes à heures), et un danger potentiel. Dans cet état, l'élève n'est plus dans une logique de calcul ou d'opposition délibérée.

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II. Stratégies de Prévention : L'Environnement Sécurisant

La prévention consiste à être proactif pour minimiser les déclencheurs comportementaux.

1. Organisation Spatiale et Temporelle

• Stabilité Spatiale : Les places doivent être fixées. L'enseignant doit voir et être vu de tous. Les déplacements doivent être aisés et les procédures de rangement enseignées.

• Stabilité Temporelle : Utilisation d'un emploi du temps hebdomadaire stable, affichage de l'emploi du temps quotidien et mise en place de rituels et routines systématiques.

2. La Prévisibilité de l'Adulte

L'enseignant doit incarner un modèle de stabilité :

• Élaborer le règlement de classe avec les élèves et l'afficher.

• Formuler les règles de manière affirmative (expliciter le comportement attendu plutôt que l'interdit).

• Avoir des réactions prévisibles et mesurées.

• Agir avec crédibilité : "Dire ce que je fais et faire ce que je dis."

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III. Réponses aux Besoins Spécifiques et Aménagements

Chaque besoin identifié doit correspondre à un aménagement technique ou pédagogique précis.

1. Outils de Structuration

• Espace : Prévoir un espace de travail individualisé et un espace d'apaisement (coin détente avec livres, casque de musique) dont le temps d'accès est limité par un timer.

• Temps : Utiliser des supports visuels (horloges, sabliers, timers) et des emplois du temps individualisés pour rendre les durées concrètes.

• Émotions : Utiliser le "thermomètre des émotions" ou "l'humeur du jour" pour aider l'élève à identifier son état interne.

• Relation aux autres : Mettre en place des signaux discrets, comme le Tétra-aide, pour que l'élève puisse appeler à l'aide sans perturber le groupe.

2. Le Contrat de Comportement

Cet outil d'engagement mutuel vise à valoriser les comportements adaptés :

• Fixation d'objectifs simples.

• Auto-évaluation quotidienne par l'élève.

• Valorisation systématique des réussites (parole positive ou accès à une activité appréciée).

• Implication de la famille dans le suivi des progrès.

3. Adaptations Pédagogiques et Numériques

Il est nécessaire d'adapter les exigences aux capacités de l'élève (via PAP ou PPRE) :

• Détailler spécifiquement le comportement attendu pour chaque tâche.

• Privilégier les appels positifs ("Tu rejoins la table") plutôt que les questions ouvertes.

• Ressources numériques : Utiliser des sites comme Cap Ecole Inclusive ou Araasac (pictogrammes), et des logiciels comme Lire Couleur (aide à la lecture) ou Dicom (prédiction de mots).

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IV. La Gestion de Crise : Du Passage à l'Acte à l'Analyse

La gestion d'une crise suit un cycle spécifique nécessitant des interventions ciblées à chaque phase.

1. Les Phases du Passage à l'Acte

L'objectif est d'intervenir idéalement dès la phase d'activation pour éviter l'escalade :

1. Calme

2. Activation : Signes subtils (anxiété, erreurs de jugement, maux de tête/ventre).

3. Agitation / Accélération : Difficulté à réguler la parole, besoin d'attention, agitation psychomotrice.

4. Point culminant (Crise) : Perte de contrôle.

5. Décélération / Récupération

2. Posture et Protocole d'Intervention

• Fermeté : Sur les actes inacceptables (violence, jet de matériel) entraînant un écart immédiat du groupe.

• Apaisement : Utiliser une voix basse et des paroles contenantes ("Tout va bien", "Je vais t'aider", "Ton bien-être compte pour moi").

• Protocole : Un protocole écrit doit définir qui prend en charge l'élève, qui gère le reste de la classe, et qui prévient la famille ou les secours (le 15 en cas de gravité extrême).

3. Phase d'Analyse (Post-Crise)

Une fois le calme revenu, un travail d'analyse est indispensable :

• Constater : Consigner les faits (avant, pendant, après).

• Analyser : Échanger avec l'élève et la famille pour identifier les déclencheurs ou les éléments renforçateurs.

• Réajuster : Proposer de nouvelles adaptations ou modifier le protocole de crise si nécessaire.

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V. Citations et Principes Clés

"Dans une crise majeure, l’élève n’est pas dans une logique d’opposition ou de calcul, mais dans un état d’épuisement émotionnel ou sensoriel."

"Dire ce que je fais et faire ce que je dis. (paroles suivies des actions)"

"L’objectif de ce protocole est de viser l’extinction des crises en gardant les exigences pour l’élève."

hello friends

arcive.dweb:do.search.google?q=visualize+IPFS+File+System

Poultney

Recall

La Bienveillance en Milieu Scolaire : Enjeux, Défis et Pratiques Professionnelles

Résumé Exécutif

Ce document synthétise les échanges issus d'une table ronde portant sur le concept de bienveillance à l'école.

Loin d'être synonyme de laxisme ou de complaisance, la bienveillance est définie comme une condition essentielle de l'équité et de l'efficacité du système éducatif, particulièrement pour les élèves les plus vulnérables.

Elle repose sur une tension constructive entre exigence et soutien, visant le développement à long terme de l'élève.

Sa mise en œuvre nécessite une clarification conceptuelle pour lever les résistances professionnelles, l'adoption de gestes professionnels spécifiques (feedback positif, écoute active) et une réinvention des espaces et des modalités d'évaluation.

En somme, la bienveillance est un levier de réussite qui engage tant la posture individuelle de l'enseignant que la stratégie collective de l'établissement.

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1. Définition et Clarification Conceptuelle

La bienveillance en éducation souffre souvent de représentations simplistes ou erronées. Il est nécessaire d'en préciser les contours épistémologiques :

• Étymologie et intention : Littéralement, la bienveillance consiste à « vouloir du bien à autrui ».

C'est une disposition favorable qui vise la réussite et la réalisation personnelle de l'autre.

• Temporalité (Court terme vs Long terme) : La bienveillance peut impliquer de sacrifier le confort immédiat pour le bien de l'élève à long terme.

Ainsi, la fermeté, l'exigence ou même une sanction peuvent être des actes bienveillants s'ils sont explicités et pratiqués dans le respect de l'élève.

• Distinction fondamentale : Elle ne doit pas être confondue avec :

• ◦ Le laxisme.  
• ◦ La complaisance.   
• ◦ La mansuétude.

• Cadre institutionnel : La notion est devenue une valeur centrale de l'Éducation nationale depuis la circulaire de 2014, bien qu'elle fût déjà présente dans le secteur privé et les services publics.

La DGESCO (2013) l'associe à un ensemble d'attitudes physiques, morales et psycho-affectives positives et constantes (respect, confiance, encouragement).

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2. Analyse des Résistances Professionnelles

Malgré un consensus apparent, le terme suscite des tensions sur le terrain :

| Type de résistance | Argumentation observée | | --- | --- | | Sentiment de jugement | Certains enseignants perçoivent l'injonction à la bienveillance comme une critique de leurs pratiques passées, sous-entendant qu'ils ne l'auraient pas été auparavant. | | Opposition à l'exigence | Une crainte que l'attention portée au bien-être des élèves ne se fasse au détriment de l'effort nécessaire à la réussite académique. | | Crise de l'autorité | La bienveillance est parfois vue comme une entrave à l'autorité face à des manquements disciplinaires chroniques. | | Complexité systémique | La multiplication des élèves à besoins éducatifs particuliers (EBEP) met les équipes sous pression, rendant la posture bienveillante difficile à maintenir sans formation adéquate. |

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3. Les Gestes Professionnels de la Bienveillance

La bienveillance se traduit par des actes concrets et une posture éthique dans la relation pédagogique :

La puissance du Feedback

Le levier le plus efficace pour la réussite des élèves est le feedback positif. Il doit être :

• Centré sur l'activité et la méthodologie de l'élève.

• Formulé chaleureusement.

• Porteur de confiance et d'espoir dans les capacités de l'élève.

L'attention aux signaux de vulnérabilité

Le professionnel bienveillant doit être attentif aux signes de fragilité qui peuvent mener au décrochage :

• Signes de découragement ou discours négatif sur l'école.

• Absentéisme et arythmies.

• Sentiments d'insécurité (peur de prendre la parole, honte).

• Mutisme, isolement ou passages fréquents à l'infirmerie/vie scolaire.

Une communication renouvelée

L'horizontalité et l'authenticité sont cruciales pour les nouvelles générations :

• Passer d'un rôle purement académique à une relation de personne à personne.

• Pratiquer l'écoute active (savoir se taire pour laisser l'élève s'exprimer).

• Faire preuve de transparence et de prévisibilité.

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4. Domaines d'Application et Leviers d'Action

L'Évaluation comme espace de sécurisation

L'évaluation est une source majeure de stress (environ 60 % des élèves se disent angoissés par les évaluations). Une évaluation bienveillante implique :

• La suppression de l'implicite.

• Le droit à l'erreur et à la remédiation (possibilité de recommencer).

• Un cadre rassurant qui ne sacrifie pas l'exigence intellectuelle.

La lutte contre le harcèlement (Programme PHARE)

La bienveillance s'incarne dans la création d'une « communauté protectrice » :

• Utilisation de la méthode de la « préoccupation partagée ».

• Recherche d'alternatives à la sanction punitive immédiate pour l'intimidateur, en visant le développement de compétences psychosociales.

La transformation des espaces

La bienveillance passe par une réflexion sur le cadre de vie :

• Création de « jardins zen » ou de salles de calme.

• Réinvention des salles d'étude (espaces de coworking, possibilité de travailler debout ou dans des fauteuils).

• Mise en place de dispositifs permettant le mouvement (ballons, vélos-bureaux) pour favoriser la concentration, notamment des élèves hyperactifs.

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5. Éthique et Pilotage : La Bienveillance Collective

La bienveillance ne doit pas être une initiative isolée mais une stratégie d'établissement.

• Le rôle du diagnostic : Utiliser l'auto-évaluation (domaine du climat scolaire et du bien-être) pour identifier les besoins réels des élèves et des familles, en évitant les solutions préconçues.

• La Qualité de Vie au Travail (QVT) : Il existe un lien direct entre le bien-être des personnels et celui des élèves. Un encadrement bienveillant (feedback positif du chef d'établissement, convivialité, confiance déléguée) favorise l'engagement des équipes.

• L'éthique de la rencontre : S'intéresser à la singularité de ce que vit l'élève, au-delà de ses difficultés scolaires. Comme le souligne la sociologie, l'éducation par la rencontre est un levier de raccrochage puissant.

• Le partage et la convivialité : Des actions simples, comme le partage de nourriture (fruits en libre-service, repas de Noël partagé entre agents, élèves et chefs étoilés), peuvent transformer radicalement la relation sociale au sein d'un établissement.

Conclusion sur l'autorité bienveillante

L'autorité et la bienveillance sont compatibles. L'autorité s'exerce de manière éthique lorsqu'elle respecte l'intégrité morale de l'élève.

La sincérité de l'adulte, y compris dans l'expression de ses propres limites ou l'admission d'une erreur, renforce paradoxalement sa légitimité auprès des jeunes.

self-hosting

>>> en.wikipedia.org/wiki/Self-hosting_(compilers)

archive.dweb~M-expression

eLife Assessment

This study reports an important and novel finding that TENT5A, an enzyme involved in fine-tuning poly(A) tail length on selected mRNAs, is required for proper enamel mineralization in mice. The evidence supporting the authors' conclusion that reduced expression of enamel matrix proteins (EMPs) in TENT5A-deficient mice results from shortened poly(A) tails remains incomplete, as TENT5A may possess additional functions independent of post-transcriptional regulation that are not addressed in the current study.

Reviewer #1 (Public review):

Summary:

The authors aim to determine whether TENT5A, a post-transcriptional regulator previously implicated in bone formation, also plays a role in enamel development. Using a mouse model lacking TENT5A, they report hypomineralized enamel with structural defects, accompanied by reduced expression, altered poly(A) tail length, and impaired secretion of enamel matrix proteins, particularly amelogenin. By combining ultrastructural imaging, transcriptomics, direct RNA sequencing, and protein localization analyses, the study proposes that TENT5A promotes cytoplasmic polyadenylation and translation of a subset of extracellular matrix transcripts required for enamel biomineralization.

Strengths:

A major strength of this work is its conceptual novelty. To my knowledge, this is the first study to demonstrate that a non-canonical poly(A) polymerase plays a direct role in enamel development, extending post-transcriptional regulation by cytoplasmic polyadenylation from bone to enamel, a biologically distinct and non-regenerative mineralized tissue. The identification of amelogenin as a dominant, tissue-specific target provides a new perspective on how enamel matrix production is regulated beyond transcriptional control.

In addition, the study is supported by a comprehensive and complementary set of approaches linking molecular changes to tissue-level phenotypes. The use of direct RNA sequencing provides strong evidence for selective regulation of poly(A) tail length in specific transcripts rather than global effects on mRNA metabolism, and the phenotypic analyses convincingly connect altered post-transcriptional regulation to defects in enamel structure and mineralization.

Weaknesses:

Although the data support a role for TENT5A in stabilizing and promoting translation of amelogenin and related transcripts, the mechanism underlying substrate specificity remains unresolved. Poly(A) tail length alone does not explain why certain transcripts are regulated while others are not, and the proposed involvement of protein partners or RNA processing steps remains speculative. This limitation should be more clearly framed as an open question rather than an emerging mechanism.

A further limitation is the lack of direct human genetic or clinical evidence linking TENT5A to enamel defects. In humans, loss-of-function variants in TENT5A are known to cause a recessive form of osteogenesis imperfecta, but TENT5A has not been associated with amelogenesis imperfecta or other enamel phenotypes. This limits immediate translational interpretation of the mouse enamel phenotype and highlights the need for future human genetic or clinical studies.

Finally, the manuscript does not address whether other members of the TENT5 family are expressed in ameloblasts or could compensate for the loss of TENT5A, leaving open questions about redundancy and specificity within this family.

Reviewer #2 (Public review):

Summary:

The manuscript by Aranaz-Novaliches describes a study of Tent5a knockout (KO) mice. The authors demonstrate a severe enamel phenotype in these mice, characterized by hypoplastic enamel with markedly disturbed organization of enamel rods. Additionally, they report that Amelx expression is reduced in the mutant compared to wild type (WT) at both mRNA and protein levels. The authors also examine the distribution and co-localization of Amelx and Ambn in ameloblasts and the enamel matrix. These findings are novel and provide important insights into the role of polyadenylation in regulating enamel matrix protein translation and its downstream effects on protein trafficking, secretion, and enamel formation. However, I have multiple concerns regarding the data and its analysis that need to be addressed.

Specific comments:

(1) Introduction

The structure of the introduction is unconventional. The first sentence of the third paragraph states that the goal of this study is to investigate the role of TENT5A in enamel formation, but the rest of the paragraph focuses on enamel in general. The following paragraph claims that the authors discovered the effects of Tent5a deficiency on enamel formation for the first time, yet most of the paragraph discusses enamel proteins and amelogenesis. The choice of references is problematic. The authors cite Sire et al. (2007), which focuses on the origin and evolution of enamel mineralisation genes, a poor fit for this context. A more appropriate source would be a recent review, e.g., Lacruz R et al., Physiol Rev. 2017;97(3):939-993. Ambn constitutes ~5% of the enamel matrix, not 10%. Reference 16 (Martin) is not ideal for murine enamel; more detailed studies exist, e.g., Smith CE et al., J Anat. 2019;234(2):274-290. References on protein-protein interactions (17-19) are also off: Wald et al. studied Ambn-Ambn and Amelx-Amelx interactions separately; Fang et al. focused on Amelx self-assembly only; Kawasaki and Weiss addressed gene evolution. The authors should cite work from Moradian-Oldak's lab, which clearly demonstrates Amelx-Ambn interactions. The last paragraph contains confusing statements, e.g., "TENT5a localized in rER promotes the expression of AmelX and other secreted protein transcripts." Also, the manuscript does not convincingly show disruption of self-assembly beyond overall enamel disorganization.

(2) Results

(a) microCT

Quantitative microCT analyses of WT and KO enamel are needed. At a minimum, enamel thickness and density should be measured from at least three biological replicates per genotype. Severe malocclusion in KO mice is not discussed. The mandibular incisor appears abraded, while the maxillary incisor is overgrown. Is maxillary enamel as affected as mandibular? The age of the mice is not specified. High-resolution scans of isolated mandibular incisors described in Materials and Methods should be included.

(b) SEM

The term "disorganized crystal structure" is incorrect - SEM cannot reveal crystal structure. This requires electron/X-ray diffraction or vibrational spectroscopy. Likely, the authors meant disorganized rods and interrod enamel. The phrase "weak HAP composition" is unclear. Can the increase in interprismatic matrix volume and reduction in rod diameter be quantified? Since rods are secreted by distal Tomes' processes and interrod by proximal Tomes' processes, an imbalance may indicate alterations in the ameloblast secretory apparatus. TEM studies of demineralized incisors are recommended to assess ameloblast ultrastructure.

(c) EMP expression

There is a discrepancy between WB images and data in Figure S2a. In Figure 2b, Amelx band is stronger than Ambn (expected, as Amelx is ~20× more abundant), but in Figure S2a, Ambn appears higher. How was protein intensity in Fig. S2a calculated? Optical density? Was normalization applied? Co-localization in Figure 2d was performed on LS8 cells, which lack a true ameloblast phenotype. Amelx expression in LS8 cells is ~2% of actin (Sarkar et al., 2014), whereas in murine incisors, it is ~600× higher than actin (Bui et al., 2023). Ambn signal is weaker than Amelx, which may affect co-localization results.

(d) Splicing products in Figure 2e

All isoforms except one contain exon 4. The major functional splice product of Amelx lacks exon 4 (Haruyama et al. J Oral Biosci. 2011;53(3):257-266), and there are some indications that the presence of exon 4 can lead to enamel defects. Can it be that the observed phenotype is due to the presence of exon 4?

(e) Co-localization studies

The presented co-localization studies do not demonstrate self-assembly defects; they reflect enamel microstructural defects observed by SEM. Self-assembly occurs at the nanoscale and cannot be assessed by light microscopy except with advanced optical methods. Conclusions based on single images are weak. The authors should perform experiments at least on three biological replicates per genotype, quantify results (e.g., total gray values per ROI of equal pixel size), and use co-localization metrics such as Mander's coefficient. Claims about alternative secretory pathways require much stronger evidence.

The authors should avoid implying that mRNA is inside the ER lumen. It is likely associated with the outer rER surface, which is expected. The resolution of the methods used is insufficient to confirm ER lumen localization.

Reviewer #3 (Public review):

Summary:

It is well established that poly(A) tails at the 3' end of mRNA are critical for mRNA stability, providing another layer of gene regulation. TENT5A is one of the non-canonical poly(A) polymerases that add an extra poly(A) tail. This manuscript demonstrates that the Tent5A mutation leads to mineralization abnormalities in the tooth, shorter poly(A) tails in amelogenin mRNA and some other selected mRNAs, and provides a list of TENT5A interacting proteins.

Strengths:

(1) The authors show in vivo genetic evidence that Tent5a is critical for normal tooth mineralization.

(2) The authors show that the length of the poly(A) tail in amelogenin (AmelX) is 13 bases shorter in Tent5a mutants but not in other mRNAs, such as ameloblastin (Ambn).

(3) Differentially expressed genes (DEGs) in Tent5A mutant tissues (cervical loop) are identified, and some of them show different lengths of poly(A) tails.

(4) TENT5A interacting proteins are identified. Together with the DEGs, these datasets will provide valuable research tools to the community.

Weaknesses:

(1) There is no direct evidence to support the main conclusion; the length of the poly(A) tail is critical for normal tooth mineralization.

(2) The RNAseq data to identify TENT5A substrate is based on the assumption that shorter poly(A) tailed RNA is less stable. However, there are multiple reasons for the differential expression of RNA in Tent5A mutant tissues.

(3) Several TENT5A-interacting proteins have been identified, but, beyond their colocalization with a target mRNA, no mechanistic studies have been conducted.

Author response:

We thank the editors and reviewers for their careful and constructive evaluation of our manuscript. We appreciate the recognition of the conceptual novelty and in vivo relevance of our findings. We have carefully considered all comments and outline below the major revisions and additional analyses we will undertake. For clarity, we address the reviewers’ comments in thematic sections.

Cell-autonomous contribution of Tent5a to phenotype

We agree that the use of a complete knockout model raises the possibility of indirect or non-cell-autonomous effects on tooth development, particularly given the observed dentin alterations. To address this point directly, we are generating and analyzing an ameloblast-specific conditional model we have already on shelf (Ambn-Cre; Tent5a^flox/flox) to determine whether the enamel phenotype arises from cell-autonomous loss of TENT5A in the secretory epithelium. This approach will allow us to distinguish epithelial-intrinsic effects from potential secondary contributions of odontoblasts or mesenchymal tissues. Results from this model will be incorporated into the revised manuscript.

Mechanistic basis and substrate specificity

We agree that the mechanism underlying substrate selectivity of TENT5A requires further clarification. We have performed multiple classical RNA–protein interaction assays, including CLIP-based approaches, without identifying a clear sequence-specific recognition motif. In the revised manuscript, we will present substrate specificity as an open mechanistic question rather than implying a defined recognition mechanism.

To strengthen this aspect, we will extend our analysis to include combined immunoprecipitation strategies and investigation of potential ribosome-associated or co-translational interactions of TENT5A.

In addition, we will further validate selected high-confidence TENT5A interactors identified in our dataset in context of putative changes in AmelX-polyA tail length.

Poly(A) tail length and functional causality

We acknowledge that shortening of the poly(A) tail alone does not formally establish causality. However, our data consistently show that TENT5A-dependent shortening of poly(A) tails correlates with reduced mRNA and protein levels of key enamel matrix components. In the revised manuscript, we will clarify this mechanistic framework more explicitly, integrating poly(A) length, transcript abundance, and protein-level data in a structured manner, while clearly distinguishing correlation from formal proof of causality.

We will also perform additional functional assays, including mRNA stability measurements in vitro in cells with genetic ablation of Tent5a, to further test the link between poly(A) shortening and reduced AmelX protein levels.

Quantitative microCT and enamel morphology

We will include quantitative microCT analyses of enamel thickness and mineral density from multiple biological replicates per genotype (n ≥ 3). Sample numbers will be explicitly stated throughout. Additional high-resolution scans of isolated incisors will be provided. We will also quantify occlusal angle and include whole-skull reconstructions to document malocclusion. Maxillary enamel will be analyzed and quantified alongside mandibular enamel.

SEM terminology will be corrected (e.g., replacing “crystal structure” with “rod/interrod organization”), and structural parameters such as rod diameter and interprismatic matrix proportion will be quantitatively assessed.

We agree that ultrastructural analysis of ameloblast secretory morphology is important. We have experience with TEM analysis of demineralized incisors and will perform additional ultrastructural examination to assess the integrity of Tomes’ processes and the secretory apparatus in Tent5a-deficient ameloblasts. These data will allow us to distinguish between primary alterations in secretory morphology and downstream effects on matrix organization.

Amelx splice variants

We will re-analyze our RNA-seq data with specific attention to exon 4-containing isoforms and clarify the distribution of splice variants in WT and KO samples. These findings will be explicitly discussed in the context of prior literature.

Co-localization and self-assembly claims

We agree that conventional light microscopy cannot directly resolve nanoscale self-assembly events. In Figure 3, our intention was to demonstrate differential subcellular distribution and partial segregation of AMELX and AMBN within secretory compartments, rather than to claim direct visualization of molecular self-assembly. In the revised manuscript, we will clarify this distinction, moderate the terminology accordingly, and provide explicit quantitative co-localization analyses across multiple biological replicates.

TENT5 family paralogs

To address potential redundancy within the TENT5 family, we will analyze published single-cell RNA-seq datasets (Sharir et al., 2019; Krivanek et al., 2020) to assess expression of TENT5 paralogs in ameloblasts. These findings will be validated using targeted transcriptional analyses.

Human clinical relevance

We appreciate the suggestion to examine potential human enamel phenotypes. We will pursue retrospective analysis of clinical and imaging data from patients carrying TENT5A variants through our collaborations with rare disease networks and specialized centers in Europe and the United States. Any relevant findings will be incorporated into the revised manuscript.

Tissue sampling clarification

We apologize for imprecise terminology regarding transcriptomic sampling. The analyzed tissue corresponds to the proximal incisor region up to the mineralization stage. We will include a schematic and clarify nomenclature throughout the manuscript.

Language and data clarity

The manuscript will be thoroughly revised for clarity, consistency of terminology, figure referencing, and accuracy of citations. We will explicitly clarify the methodology used for protein quantification, including normalization strategy and densitometric analysis, to address inconsistencies noted in the supplementary data. We will also expand the discussion to address the biological relevance of moderate poly(A) shortening, referencing established literature demonstrating that even subtle changes in tail length can significantly influence translational efficiency.

Although AMELX is the most abundant enamel matrix protein and exhibits a consistent TENT5A-dependent poly(A) shortening phenotype, our data demonstrate that multiple secreted proteins are similarly affected. We will revise the text to clearly articulate that the enamel phenotype likely reflects the combined contribution of multiple TENT5A-regulated secretory factors rather than a single-gene effect.

We believe these revisions will substantially strengthen the mechanistic, quantitative, and conceptual framework of the study and provide a clearer foundation for interpreting TENT5A-dependent regulation of enamel biomineralization.

Note de Synthèse : Les Enjeux de la Professionnalité Enseignante et de l'Éthique Relationnelle

Résumé Analytique

Ce document synthétise les interventions du webinaire du 12 avril 2023, animé par Christophe Marsollier, Inspecteur général de l'éducation, du sport et de la recherche.

L'analyse explore la mutation profonde du métier d'enseignant face à la complexité croissante du milieu scolaire. Les points de bascule majeurs identifiés incluent l'intégration systémique des compétences psychosociales (CPS), l'adoption de pédagogies institutionnelles et coopératives, et le passage d'une posture de « sachant » à celle d'« écoutant ».

La réussite de l'élève est ici pensée non seulement par la transmission académique, mais par une « éthique relationnelle » fondée sur la confiance, la reconnaissance de la vulnérabilité et le bien-être eudémonique.

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I. Les Compétences Psychosociales (CPS) : Socle de la Réussite et de l'Équilibre

Le développement des CPS n'est plus considéré comme une activité périphérique, mais comme la « trame de fond » de la réussite scolaire et de la santé mentale.

1. Définition et Objectifs

Les CPS englobent les capacités permettant à l’élève de :

• Gérer ses émotions : Appréhender son ressenti et celui d'autrui.

• S'auto-réguler : Gérer les conflits en autonomie et appartenir au groupe.

• Développer sa citoyenneté : Favoriser le dialogue, l’échange et la collaboration.

2. Impact sur la Pratique de Classe

Les témoignages d'enseignants (notamment du réseau Jean Lolive à Pantin) soulignent une transformation concrète :

• Apaisement du climat : Moins de besoin de « faire le gendarme » ; les élèves règlent les conflits en amont.

• Disponibilité cognitive : Des élèves sereins et empathiques sont plus aptes à entrer dans les apprentissages pédagogiques.

• Transformation de l'enseignant : Le passage d'un scepticisme initial à une confiance réelle en la capacité d'agir des élèves.

3. Institutionnalisation et Formation

Une instruction interministérielle, rédigée par Santé Publique France, fixe un horizon à 2037 pour la formation généralisée de la population aux CPS.

• Cadre de référence : Publication d'un référentiel en février 2022 pour uniformiser les pratiques.

• Pédagogies préconisées : Utilisation de méthodes expérientielles comme le « théâtre forum » ou le « jeu des trois figures » pour favoriser le changement de rôle et l'empathie.

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II. Pédagogie Institutionnelle et Autonomie de l'Élève

L'analyse met en lumière la pédagogie institutionnelle (PI) comme levier de transformation, particulièrement en éducation prioritaire (REP+).

1. Le Système des « Ceintures d'Apprentissage »

Inspiré du mouvement Freinet, ce dispositif permet d'articuler éducation (épanouissement) et transmission (connaissances).

| Caractéristique | Fonctionnement et Bénéfices | | --- | --- | | Différenciation | L'élève choisit son niveau de ceinture par compétence (ex: se repérer dans le temps). | | Auto-évaluation | Utilisation de fichiers autocorrectifs ; l'élève identifie ses stratégies d'apprentissage. | | Évaluation Positive | La ceinture sanctionne la réussite (100% requis) et non le manque. L'échec est une étape formative. | | Coopération | Les élèves ayant validé des ceintures deviennent des « aides » pour leurs pairs. |

2. Les Institutions de la Classe

La classe est pensée comme une « petite société » régulée par :

• Le Conseil : Lieu de décision collective où l'on critique l'organisation et propose des améliorations.

• Les Responsabilités : Métiers spécifiques (responsable du temps, du matériel, des affichages) qui donnent une place à chacun.

• L'Espace de parole : Le « Quoi de neuf » et les temps de météo intérieure pour intégrer les affects.

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III. La Métaphore du Tisseur : Penser la Complexité

Le métier d'enseignant est comparé à celui d'un tisseur, créateur de liens et de sens dans un monde « déchiré ».

1. La Triple Reliance

S'appuyant sur les travaux d'Edgar Morin et d'Adrien Rivard, Christophe Marsollier évoque la nécessité de cultiver :

• 1. La reliance à soi : Apprendre à se connaître et à être présent à ses propres émotions.
• 2. La reliance aux autres : Développer des relations saines et authentiques.
• 3. La reliance à la nature : Répondre à l'anxiété climatique des jeunes générations par un retour à l'essentiel.

2. Les Quatre Réciprocités Fondamentales

Pour maintenir le « tissu » de la relation pédagogique, quatre piliers sont identifiés :

• La Confiance : Elle doit être mutuelle et engagée.

• Le Respect : L'élève doit être considéré comme une personne à part entière, avec sa dignité propre.

• L'Écoute : Sortir de l'écoute passive pour une écoute active des difficultés et erreurs.

• Le Droit à l'erreur : Admis pour l'élève, mais aussi pour l'enseignant qui doit pouvoir s'excuser.

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IV. Vulnérabilité et Éthique de l'Accompagnement

L'enseignement, particulièrement en milieu défavorisé, exige une attention particulière à la vulnérabilité des élèves.

• La Blessure Psychologique : Les élèves en grande vulnérabilité sont souvent touchés dans leurs besoins fondamentaux (sécurité, reconnaissance, justice).

• L'Intérêt pour la Singularité : Les recherches (Virginie Muniglia) montrent que le besoin premier des jeunes vulnérables est que l'adulte s'intéresse à leur singularité, et non qu'il les traite de manière standardisée.

• Le Tact Pédagogique : Capacité (théorisée par Éric Prairat) à trouver le bon geste et le bon mot au bon moment, en s'adaptant à l'imprévu.

--------------------------------------------------------------------------------

V. Vers une Redéfinition du Bien-être à l'École

Le document clarifie la notion de bien-être, souvent mal comprise dans le cadre scolaire.

1. Bien-être Hédonique vs Eudémonique

• Bien-être Hédonique : Recherche du plaisir immédiat (souvent critiqué à l'école).

• Bien-être Eudémonique : Sentiment de satisfaction ressenti lorsqu'on est captivé par une activité, qu'on dépasse une difficulté ou que l'on progresse.

C'est le « bien-être optimal » ou l'expérience autotélique.

2. Le Bien-être comme Condition, non comme Finalité

Le bien-être n'est pas le but ultime de l'école, mais la condition indispensable pour favoriser la réussite, notamment pour les élèves les plus fragiles.

Il permet de transformer la « souffrance relationnelle » en un climat d'exigence bienveillante.

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VI. Perspectives pour la Professionnalité Enseignante

En conclusion, le métier d'enseignant est décrit comme une profession de la relation, nécessitant :

• Le Travail Collectif : Créer des communautés d'apprentissage professionnel pour rompre l'isolement et penser la pratique (monographies, analyses de pratiques).

• La Foi en l'Éducabilité : Posture philosophique (Philippe Meirieu) consistant à croire inconditionnellement en la capacité de chaque élève à progresser.

• La Joie comme Boussole : Pour les jeunes enseignants, le critère de la joie et de l'alignement personnel est présenté comme le meilleur garant de la créativité et de l'efficacité pédagogique.

« La question n'est pas quel monde laisserons-nous à nos enfants, mais quels enfants laisserons-nous au monde. » — Philippe Meirieu (cité en conclusion).

<<< en.wikipedia.org/wiki/M-expression

DOI: 10.1158/0008-5472.CAN-25-2086

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DOI: 10.1016/j.celrep.2026.116971

Resource: (RRID:CVCL_B5P3)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_B5P3

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0A07

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: (ZFIN Cat# ZDB-ALT-050916-14,RRID:ZFIN_ZDB-ALT-050916-14)

Curator: @areedewitt04

SciCrunch record: RRID:ZFIN_ZDB-ALT-050916-14

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: (RRID:CVCL_0A05)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0A05

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: (ZFIN Cat# ZDB-ALT-060821-4,RRID:ZFIN_ZDB-ALT-060821-4)

Curator: @areedewitt04

SciCrunch record: RRID:ZFIN_ZDB-ALT-060821-4

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: (ZFIN Cat# ZDB-ALT-120723-3,RRID:ZFIN_ZDB-ALT-120723-3)

Curator: @areedewitt04

SciCrunch record: RRID:ZFIN_ZDB-ALT-120723-3

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:ZFIN_ZDB-ALT-110411-1

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:ZFIN_ZDB-ALT-040601-2

What is this?

DOI: 10.1016/j.celrep.2026.116971

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:ZFIN_ZDB-ALT-120828-2

What is this?

DOI: 10.1016/j.celrep.2026.116968

Resource: (RRID:CVCL_1056)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_1056

What is this?

DOI: 10.1016/j.cell.2026.01.009

Resource: (BCRJ Cat# 0278, RRID:CVCL_0132)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0132

What is this?

DOI: 10.1016/j.cell.2026.01.009

Resource: (RRID:CVCL_0063)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1016/j.cell.2026.01.009

Resource: (NCI-DTP Cat# NCI-H1299, RRID:CVCL_0060)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0060

What is this?

DOI: 10.1016/j.cell.2026.01.009

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:Addgene_55294

What is this?

DOI: 10.1016/j.cell.2026.01.009

Resource: (IMSR Cat# CRL_088,RRID:IMSR_CRL:088)

Curator: @areedewitt04

SciCrunch record: RRID:IMSR_CRL:088

What is this?

DOI: 10.1016/j.cell.2026.01.009

Resource: (RRID:CVCL_0042)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0042

What is this?

DOI: 10.1016/j.cell.2026.01.009

Resource: (CCLV Cat# CCLV-RIE 1035, RRID:CVCL_0023)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0023

What is this?

DOI: 10.1016/j.celrep.2026.116990

Resource: (RRID:CVCL_0063)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1016/j.cej.2026.174157

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_E2RM

What is this?

DOI: 10.1016/j.cej.2026.174137

Resource: (ATCC Cat# TIB-71, RRID:CVCL_0493)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0493

What is this?

DOI: 10.1016/j.canlet.2026.218328

Resource: (RRID:CVCL_0063)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1016/j.canlet.2026.218328

Resource: (NCI-DTP Cat# BT-549, RRID:CVCL_1092)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_1092

What is this?

DOI: 10.1016/j.canlet.2026.218328

Resource: (RRID:CVCL_0062)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0062

What is this?

DOI: 10.1016/j.canlet.2026.218328

Resource: (RRID:CVCL_0553)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0553

What is this?

DOI: 10.1007/s00109-026-02650-4

Resource: (BCRJ Cat# 0240, RRID:CVCL_0566)

Curator: @evieth

SciCrunch record: RRID:CVCL_0566

What is this?

DOI: 10.1007/s00109-026-02650-4

Resource: (DSMZ Cat# ACC-541, RRID:CVCL_2078)

Curator: @evieth

SciCrunch record: RRID:CVCL_2078

What is this?

DOI: 10.1007/s00109-026-02650-4

Resource: (RRID:CVCL_E332)

Curator: @evieth

SciCrunch record: RRID:CVCL_E332

What is this?

DOI: 10.1007/s00109-026-02650-4

Resource: (JCRB Cat# JCRB1179, RRID:CVCL_2989)

Curator: @evieth

SciCrunch record: RRID:CVCL_2989

What is this?

DOI: 10.1007/s00109-026-02650-4

Resource: (RRID:CVCL_J431)

Curator: @evieth

SciCrunch record: RRID:CVCL_J431

What is this?

DOI: 10.1007/s00109-026-02650-4

Resource: (DSMZ Cat# ACC-49, RRID:CVCL_1357)

Curator: @evieth

SciCrunch record: RRID:CVCL_1357

What is this?

DOI: 10.1002/advs.202513670

Resource: (MMRRC Cat# 032108-UCD,RRID:MMRRC_032108-UCD)

Curator: @AleksanderDrozdz

SciCrunch record: RRID:MMRRC_032108-UCD

What is this?

DOI: 10.7554/eLife.108259

Resource: Adobe Illustrator (RRID:SCR_010279)

Curator: @scibot

SciCrunch record: RRID:SCR_010279

What is this?

DOI: 10.7554/eLife.108259

Resource: Fiji (RRID:SCR_002285)

Curator: @scibot

SciCrunch record: RRID:SCR_002285

What is this?

DOI: 10.7554/eLife.108259

Resource: Imaris (RRID:SCR_007370)

Curator: @scibot

SciCrunch record: RRID:SCR_007370

What is this?

DOI: 10.7554/eLife.108259

Resource: RRID:BDSC_26669

Curator: @scibot

SciCrunch record: RRID:BDSC_26669

What is this?

DOI: 10.7554/eLife.108259

Resource: GraphPad Prism (RRID:SCR_002798)

Curator: @scibot

SciCrunch record: RRID:SCR_002798

What is this?

DOI: 10.7554/eLife.108259

Resource: (Thermo Fisher Scientific Cat# ICN55976, RRID:AB_2335286)

Curator: @scibot

SciCrunch record: RRID:AB_2335286

What is this?

DOI: 10.7554/eLife.108259

Resource: RRID:BDSC_35785

Curator: @scibot

SciCrunch record: RRID:BDSC_35785

What is this?

DOI: 10.7554/eLife.108259

Resource: RRID:BDSC_32194

Curator: @scibot

SciCrunch record: RRID:BDSC_32194

What is this?

DOI: 10.7554/eLife.108259

Resource: (Aves Labs Cat# GFP-1010, RRID:AB_2307313)

Curator: @scibot

SciCrunch record: RRID:AB_2307313

What is this?

DOI: 10.7554/eLife.108259

Resource: RRID:BDSC_36117

Curator: @scibot

SciCrunch record: RRID:BDSC_36117

What is this?

DOI: 10.7554/eLife.108259

Resource: (Abcam Cat# ab195173, RRID:AB_2687586)

Curator: @scibot

SciCrunch record: RRID:AB_2687586

What is this?

DOI: 10.7554/eLife.108259

Resource: RRID:BDSC_43963

Curator: @scibot

SciCrunch record: RRID:BDSC_43963

What is this?

DOI: 10.7554/eLife.108259

Resource: RRID:BDSC_5137

Curator: @scibot

SciCrunch record: RRID:BDSC_5137

What is this?

DOI: 10.7554/eLife.108048

Resource: RRID:Addgene_10878

Curator: @scibot

SciCrunch record: RRID:Addgene_10878

What is this?

DOI: 10.7554/eLife.108048

Resource: None

Curator: @scibot

SciCrunch record: RRID:CVCL_CW64

What is this?