This point exactly. Child pornograph will never be victimless

Completely agree, as mentioned perviously, normailzed behaviors and embolden to act on urges in real life. Feeds into the urges thus growing an appetite. Short-term solution for a long-term problem.

If the AI material creates a complex problems for law enforcement why make it anymore acceptable. Often material is created with existing photos of children the offender is targeting. In addition, from my understaning AI can be trained and coded against outputs. While I agree, easier said the then done, isn't it worth the effort?

3) Treatment for these biological urges should not make AI imagery more acceptable, therapies should be a first line for stopage. To me it seems to normalizes these urges and depited behaviors.

2) The comparison between pedophilia/consumption of child pornography and herione does not seem appropriate. Addiction can be just as complex and alter the brain.

1) While I see the point Bernstein is trying to make, however, it seem like an excuse. Therapies have been developed for these types of negative urges that victimize others.

This whole paragraph does not sit well with me in general for several points:

AI- generated CP is not a victimless crime. There are explicit images of childen that will follow them for the rest of their lives. While the abuse may not have occurred, it normalizes images and the actions and abuse depicted and could encourage viewer the act out in the real world.

Reviewer #3 (Public review):

This work by Du et al. addresses a critical problem in cryo-electron microscopy. To date, there are few ways of generating phase contrast during cryo-EM imaging while remaining in focus. Cryo-EM practitioners today must generate contrast by collecting out-of-focus exposures, a process that introduces aberrations in the resulting image data. Recent work has shown that standing wave lasers are capable of using the ponderomotive effect to shift the phase of electrons in transmission electron microscopy to generate in-focus phase contrast imaging for cryo-EM. A limitation of this 'laser phase plate' is the high laser power required, which can damage optical mirrors and necessitate high laser safety. Thus, alternative approaches are needed for phase contrast imaging in cryo-EM.

In this manuscript, Du et al. exploit their expertise in ultrafast electron microscopy to explore the ability to shift the phase of electrons using pulsed electrons and lasers. The motivation for exploring pulsed laser phase plates stems from the fact that femtosecond pulses from 9W lasers can generate extremely high power (as much as the standing-wave laser phase plate, > 1 gigawatt) at the back focal plane. If successful, this type of instrument will likely be much more affordable and easier to deploy worldwide.

The work outlined here shows a proof of principle, highlighting that an ultrafast scanning electron microscopy beam at 30 kV can have the electron packets phase shift by 430 radians (24637 degrees), which is much greater than the required 1.5 radians (90 degrees) needed for phase contrast imaging. The data presented do not use any biological samples; instead, they measure the spread of the electron beam on a test sample to assess the ability to target pulsed lasers onto electron packets and the amount of electron spread (which relates to the phase shift). They were also able to take their system a step further to measure how changes to the system in terms of laser power affect performance, and show that the system can be stable for 10+ hours.

The only weaknesses relate to the broad readability of the text. Improved textual clarity will help ensure a wider readership.

Overall, this work is an important step toward developing lower-cost alternatives to the standing-wave laser phase plate.

Reviewer #2 (Public review):

Summary:

In this manuscript, the authors present the development and characterization of a pulsed ponderomotive phase plate for transmission electron microscopy (TEM). The primary goal is to overcome the long-standing challenge of generating stable, tunable phase contrast for weakly scattering biological specimens - a capability that has remained elusive despite decades of development. While the commercially available Volta Phase Plate offers phase enhancement, it suffers from a lack of control and stability. More recent efforts have focused on continuous-wave (CW) laser phase plates; however, these systems face significant practical hurdles, including extreme optical power requirements, thermal instability of mirrors, and the necessity for high-finesse optical cavities that act as diffraction gratings for the electron beam. The authors aim to demonstrate that a pulsed, free-space laser interaction can circumvent these limitations, offering a more robust path toward practically usable phase plates

Strengths:

The most significant strength of this work is the elegant use of a free-space pulsed interaction, which fundamentally simplifies the hardware requirements compared to cavity-based designs. By utilizing a high-intensity pulsed laser focus rather than a standing wave inside a resonator, the authors eliminate the need for complex locking feedback loops and avoid the thermal mirror deformation that currently limits CW systems.

Furthermore, this approach provides a critical theoretical advantage regarding image quality. Current CW cavity-based designs must grapple with the Kapitza-Dirac effect, where the standing wave creates a diffraction grating that generates unwanted "ghost images," delocalizing the signal. Recent proposals have had to resort to complex crossed-beam geometries to mitigate these artifacts. In contrast, the traveling-wave nature of the pulsed interaction described here inherently avoids the creation of a standing wave grating, thereby eliminating ghost images entirely without requiring elaborate compensation strategies.

The authors successfully demonstrate a proof-of-concept implementation, reporting a pronounced peak phase shift of approximately 430 radians and a stable angular deflection of the electron beam. The stability data, covering a 10-hour period, suggests that this approach is robust enough for data collection sessions typical in structural biology.

Weaknesses:

However, the strength of the evidence is modestly tempered by limitations in data presentation and analysis. The agreement between the experimental data and the theoretical simulation in Figure 2b is imperfect; the simulation underestimates the depth of the central signal trough. While the authors acknowledge this "muted" prediction, the discrepancy suggests that the theoretical model or the estimation of experimental parameters (such as electron beam size or laser intensity) requires refinement to fully describe the interaction.

While the authors claim stability over many hours, the data in Figure 3c reveal a significant drift in the baseline reference signal. Although attributed to a weakening electron beam, this drift complicates the reader's ability to assess the true stability of the laser-induced phase shift. A drift-corrected analysis would have provided more compelling evidence of the "stable angular kick" described.

Despite these specific weaknesses in data presentation, the work represents a fundamental step forward. The authors have effectively demonstrated that the trade-off between beam current and spatiotemporal resolution (driven by space-charge effects) can be managed to achieve significant phase modulation. By moving the field away from the tight constraints of optical cavities and toward free-space pulsed interactions, this work establishes a potentially more viable route for integrating laser phase plates into routine biological imaging workflows. This study will be of high value to biophysicists and microscopists seeking to push the boundaries of contrast in cryo-EM

Reviewer #1 (Public review):

Summary:

Du, Daniel X. et al studied the interaction of the ultrashort electron and laser pulses inside a scanning electron microscopy (SEM), aiming to build a foundation for pulsed laser phase plate electron microscopy, in which the contrast of cryo samples can be significantly increased. The author modified a commercial SEM to accommodate optics to introduce a laser beam inside the instrument to overlap with the electron beam and performed multiple experiments aimed to characterize the electron-light interaction, particularly reaching an extremely high phase shift of >400 rad. Moreover, the authors built a theoretical model for this interaction and estimated the laser beam parameters needed to reach 90 degrees phase shift in transmission electron microscopy (TEM).

Strengths:

The conclusion on the interaction of the electron pulses and laser pulses is well described and supported by the experiment.

The presented instrument can serve as a great tool for studying fundamental interactions of electrons with extremely intense light pulses.

Weaknesses:

The authors motivate the project by using the pulsed electron beam with a phase shift for improving the contrast in cryo-EM, and while they indicate the low current in UEM, they do not discuss the limitations of the laser beam properties.

Such, even for 1 ps electron pulses with the repetition rate of 100 GHz (duty cycle of 10%), they will need to use 100 GHz laser pulses with pulse energies of at least ~1 uJ a second (the lowest pulse energy reported in the simulations in Figure 4), which would mean that ~10 kW of optical power needs to enter the electron microscope and be dumped somewhere after leaving the instrument. This significantly complicates the system and, in my view, makes it harder to use a pulsed laser phase plate in cryo-EM due to either low acquisition rate at lower repetition rates or extreme difficulties to operate multi kW ultrafast laser system.

I would also expect the unscattered electron beam diameter to be <1 micron, which would significantly change the plot in 4b for the 300 keV electron beam.

Adding experimental parameters for a typical cryo-EM experiment with the pulsed phase plate, including the repetition rate, electron pulse duration, number of electrons per pulse, electron beam size, and the parameters of the laser beam (wavelength, laser pulse duration, pulse energy), will help readers better understand technical requirements for the proposed cryo-EM experiments.

eLife Assessment

This important study introduces a pulsed laser phase plate that generates stable phase contrast in electron microscopy, offering a practical alternative to continuous-wave designs that suffer from optical instabilities and diffraction artifacts. The experimental results demonstrate a controllable and stable electron phase shift, and the evidence supporting the feasibility of this approach for phase-contrast electron microscopy is convincing. Clarifying the agreement between experiment and theory and further elaborating on possible applications would strengthen the manuscript.

yes

On devrait lire « Chine ».

This makes sense as adding a solute will increase density, making it harder for particles to escape. But this also seems wrong because adding salt to water lowers the boiling point, which in theory should increase vapor pressure and decrease the enthalpy of vaporization.

• https://polymarket.com/@Rundeep?via=tostitos&tab=activity
• NBC https://www.nbcnews.com/world/israel/israel-charges-reservist-classified-information-bet-polymarket-rcna258709
• reuters https://www.reuters.com/world/middle-east/israel-indicts-reservist-civilian-over-betting-military-operations-2026-02-12/

Encomium means a speech or writing that praises someone or something highly.

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eLife Assessment

This important study reports an endometrial organoid culture system mimicking the window of implantation. The evidence supporting the conclusion drawn is convincing. The data will be of interest to embryologists and investigators working on reproductive biology and medicine.

Reviewer #2 (Public review):

Zhang et al. have developed an advanced three-dimensional culture system of human endometrial cells, termed a receptive endometrial assembloid, that models the uterine lining during the crucial window of implantation (WOI). During this mid-secretory phase of the menstrual cycle, the endometrium becomes receptive to an embryo, undergoing distinctive changes. In this work, endometrial cells (epithelial glands, stromal cells, and immune cells from patient samples) were grown into spheroid assembloids and treated with a sequence of hormones to mimic the natural cycle. Notably, the authors added pregnancy-related factors (such as hCG and placental lactogen) on top of estrogen and progesterone, pushing the tissue construct into a highly differentiated, receptive state. The resulting WOI assembloid closely resembles a natural receptive endometrium in both structure and function. The cultures form characteristic surface structures like pinopodes and exhibit abundant motile cilia on the epithelial cells, both known hallmarks of the mid-secretory phase. The assembloids also show signs of stromal cell decidualization and an epithelial mesenchymal transition, like process at the implantation interface, reflecting how real endometrial cells prepare for possible embryo invasion.

Although the WOI assembloid represents an important step forward, it still has limitations: the supportive stromal and immune cell populations decrease over time in culture, so only early-passage assembloids retain full complexity. Additionally, the differences between the WOI assembloid and a conventional secretory-phase organoid are more quantitative than absolute; both respond to hormones and develop secretory features, but the WOI assembloid achieves a higher degree of differentiation due to the addition of "pregnancy" signals. Overall, while it's a reinforced model (not an exact replica of the natural endometrium), it provides a valuable in vitro system for implantation studies and testing potential interventions, with opportunities to improve its long-term stability and biological fidelity in the future.

[Editors' note: the authors have responded to the previous round of recommendations.]

Author response:

The following is the authors’ response to the previous reviews

Public Reviews:

Reviewer #1 (Public review):

Summary:

This study generated 3D cell constructs from endometrial cell mixtures that were seeded in the Matrigel scaffold. The cell assemblies were treated with hormones to induce a "window of implantation" (WOI) state. Although many bioinformatic analyses point in this direction, there are major concerns that must be addressed.

Strengths:

The addition of 3 hormones to enhance the WOI state (although not clearly supported in comparison to the secretory state).

Comments on revisions:

The authors did their best to revise their study according to the Reviewers' comments. However, the study remains unconvincing, incomplete and at the same time still too dense and not focused enough.

Reviewer #2 (Public review):

Zhang et al. have developed an advanced three-dimensional culture system of human endometrial cells, termed a receptive endometrial assembloid, that models the uterine lining during the crucial window of implantation (WOI). During this mid-secretory phase of the menstrual cycle, the endometrium becomes receptive to an embryo, undergoing distinctive changes. In this work, endometrial cells (epithelial glands, stromal cells, and immune cells from patient samples) were grown into spheroid assembloids and treated with a sequence of hormones to mimic the natural cycle. Notably, the authors added pregnancy-related factors (such as hCG and placental lactogen) on top of estrogen and progesterone, pushing the tissue construct into a highly differentiated, receptive state. The resulting WOI assembloid closely resembles a natural receptive endometrium in both structure and function. The cultures form characteristic surface structures like pinopodes and exhibit abundant motile cilia on the epithelial cells, both known hallmarks of the mid-secretory phase. The assembloids also show signs of stromal cell decidualization and an epithelial mesenchymal transition, like process at the implantation interface, reflecting how real endometrial cells prepare for possible embryo invasion.

Although the WOI assembloid represents an important step forward, it still has limitations: the supportive stromal and immune cell populations decrease over time in culture, so only earlypassage assembloids retain full complexity. Additionally, the differences between the WOI assembloid and a conventional secretory-phase organoid are more quantitative than absolute; both respond to hormones and develop secretory features, but the WOI assembloid achieves a higher degree of differentiation due to the addition of "pregnancy" signals. Overall, while it's a reinforced model (not an exact replica of the natural endometrium), it provides a valuable in vitro system for implantation studies and testing potential interventions, with opportunities to improve its long-term stability and biological fidelity in the future.

Recommendations for the authors:

Reviewer #1 (Recommendations for the authors):

This study generated 3D cell constructs (i.e., assembloids) that were treated with hormones to induce a 'window of implantation' (WOI) state. While the authors have made large efforts to address the reviewers' feedback, the study's findings remain unconvincing and incomplete.

(1) The authors have appropriately revised the terminology from 'organoids' to 'assembloids' in several parts of the manuscript. However, this revision remains incomplete, as the main title, figure legends, and figure titles still contain the incorrect term. A thorough review of the entire manuscript is recommended to ensure consistent and accurate use of terminology.

Thank you for your meticulous review. We have now conducted a full check and confirmed that terminology is used consistently and accurately throughout the text.

(1) Previous comments raised concerns about the feasibility of robustly passaging assembloid structures - comprising epithelial, stromal and immune cells - under epithelial growth conditions. The authors responded by stating that they optimized the expansion medium with a stromal cell-promoting factor. Additionally, rather than conducting scRNA-seq on both early and late passages (P6-P10) as suggested, they performed immunofluorescence staining, which confirmed the persistence of stromal cells at passage 6. However, the presence of immune cells was not addressed. Confirmation of their presence is essential for all further claims. Moreover, a more zoomed-out view of the immunostaining would help clarify the overall cellular composition across the entire well and facilitate comparison with corresponding brightfield images.

Whole-mount immunofluorescence of the 6th - generation assembloids revealed that CD45⁺ immune cells surrounded FOXA2⁺ glands, with a more zoomed-out view provided.

Author response image 1.

Whole-mount immunofluorescence showed that CD45⁺ cells (immune cells) were arranged around the glandular spheres that were FOXA2⁺. Scale bar =50 μm (left) and 30 μm (right).

In their response, the authors mention using the first three passages to ensure optimal cell diversity and viability. However, the manuscript states that 'assembloids derived from the first generation are used for experiments' (line 106). This discrepancy must be clarified.

Thank you for your suggestion. We have revised the relevant content to “The assembloids derived from the first three generation are used for experiments” (Line 90-91).

(2) The authors have made a commendable effort to bring more focus to the manuscript, which has improved readability.

We thank you for your insightful suggestions, which have greatly improved the quality of our manuscript.

(3) The "embryo implantation" part remains very unconvincing. How did authors define "the blastoids could grow within the endometrial assembloids and interact with them"? What did they mean with "grow"? Did blastoids further differentiate? Normally, blastoids cannot further "grow". "Survival rates of blastoids" is not equal to "growth". It is not clear how the survival rate was quantified. Besides, regarding the "interaction rates", how did authors define and quantify it? Actually, blastoids are able to attach to Matrigel efficiently (even without any endometrial cells), so authors cannot simply define the "interaction" as the co-localization of blastoids and assembloids via brightfield images. In addition, for the assembloids as the 3D structures grow in the Matrigel, the epithelial parts are normally apical-in, while the blastoids attach to the apical (lumen) side of the epithelial cells, so physiologically, blastoids should interact with the apical part of the epithelial cells instead of the outside of the assembloids.

(1) What did they mean with "grow"? Did blastoids further differentiate?

On the one hand, volume and morphology undergo continuous dynamic changes; on the other hand, only the inner cell mass and trophectoderm exist at the blastocyst stage, with the ICM further differentiating into OCT4⁺ epiblast and GATA6⁺ hypoblast.

(2) Survival rates of blastoids" is not equal to "growth". It is not clear how the survival rate was quantified.

The definition of "survival rate" is as follows: morphologically, the blastocoel remains noncollapsed and the cell boundaries are distinct (with no obvious cell detachment); molecularly, the markers of epiblast, hypoblast and trophectoderm are expressed. The survival rate is calculated as the ratio of viable embryoids to the total number of embryoids.

(3) Besides, regarding the "interaction rates", how did authors define and quantify it? Actually, blastoids are able to attach to Matrigel efficiently (even without any endometrial cells), so authors cannot simply define the "interaction" as the co-localization of blastoids and assembloids via brightfield images.

The criteria for determining interaction include not only attachment between the blastoids and assembloids observed via brightfield images, but also their sustained tight adhesion against external mechanical perturbations (e.g., medium replacement, immunostaining procedures).

(4) In addition, for the assembloids as the 3D structures grow in the Matrigel, the epithelial parts are normally apical-in, while the blastoids attach to the apical (lumen) side of the epithelial cells, so physiologically, blastoids should interact with the apical part of the epithelial cells instead of the outside of the assembloids.

You are absolutely correct. In vivo, the embryo indeed makes initial contact with the apical side of the epithelial cells. The introduction of the blastoid co-culture model herein is intended to demonstrate that this receptive endometrial assembloids can better support blastoid growth and development.

(4) Previous comments highlighted the absence of distinct shifts in gene expression profiles between SEC assembloids and WOI assembloids, which contrasts with findings from primary endometrial tissue reported by Wang et al. (2020). While the authors have expanded their analysis using the Mfuzz algorithm and identified changes in mitochondria- and cilia-associated genes, the manuscript still lacks evidence of significant transcriptional changes in key WOI marker genes, as described in Wang et al. This discrepancy must be addressed and discussed in greater depth to clarify the biological relevance of their model.

The endometrium in vivo involves complex crosstalk among multiple cell types and is tightly regulated by the hypothalamic-pituitary-ovarian (HPO) axis, thus exhibiting distinct shifts in gene expression during the peri-implantation period.

In our in vitro model, alterations in mitochondria- and cilia-related genes were observed, which to a certain extent demonstrates that these window of implantation (WOI) assembloids possess receptive-phase characteristics and can be employed to investigate WOI-associated scientific questions or conduct in vitro drug screening.

However, substantial efforts are still required to optimize the current model for fully recapitulating the dynamic changes in endometrial gene expression across different phases in vivo, and this aspect is further addressed in the Limitations section of our discussion (Line 342-353).

“However, our WOI endometrial assembloids also exhibit some limitations. It is undeniable that the assembloids cannot perfectly replicate the in vivo endometrium, which comprises functional and basal layers with a greater abundance of cell subtypes, under superior regulation by hypothalamic-pituitary-ovarian (HPO) axis. Specifically, stromal and immune cells are challenging to stably passage, and their proportion is lower than in the in vivo endometrium. While the in vivo peri-implantation period exhibits intricate gene expression dynamics driven by systemic regulation, our models only partially recapitulate these changes, primarily in mitochondria- and cilia-associated genes. Nevertheless, to some extent, these WOI assembloids possess receptivity characteristics and can be utilized for investigating receptivity-related scientific questions or conducting in vitro drug screening. Further refinements are required to fully simulate the dynamic endometrial gene expression patterns across all menstrual cycle stages. We are looking forward to integrating stem cell induction, 3D printing, and microfluidic systems to modify the culture environment.”

(5) In the authors' response document, they present data integrating their results with those of Garcia Alonso et al. (2021). However, these integrated analyses are not included in the revised manuscript (which should be, if answering a major concern).

Thanks for your valuable suggestions. We have now integrated the findings of Garcia Alonso et al. (2021) into the revised manuscript (Line 132) and Figure S2E–F.

(8) Fig 2D: The authors have clarified that CD45+ staining is used. However, they have not yet adapted the typo in the figure legend of the right picture.

Thanks for your thorough review. The left panel of Figure 2D is stained with CD45 to label immune cells, while the right panel is stained with CD44. These details have been clearly indicated in both the manuscript and the figure legend.  

(9) All quantification analyses (as described in the authors' response document) should be clearly described in the Materials & Methods section.  

Thanks for your valuable suggestions. All quantification analyses have now been added to the Supporting Materials and Methods section (Line 94-104, Line 110-111, Line 241244).

(10) The authors have provided clarification regarding their method for quantifying immunofluorescence staining (e.g., OLFM4 expression in Fig. 3C) in their response document. However, these methodological details are not included in the revised manuscript. It is important that such information is incorporated into the manuscript itself to ensure transparency and reproducibility for others.

Thanks for your valuable suggestions. All quantification analyses have now been added to the Supporting Materials and Methods section (Line 94-104).

(13) It is needed to include the author's response to the comment about literature showing the opposite of increased number of cilia during the WOI into the discussion part of the paper.

We appreciate your suggestions. The relevant content has now been added to the Discussion section (Lines 319–323).

(14) In the authors' response, they explain the difference between pinopodes and microvilli. They should include this explanation briefly in the manuscript. Moreover, Fig. 3F lacks a picture of cilia structure in CTRL condition. In addition, the structures that are indicated as cilia with an orange arrow seem to not be attached to the endometrial cells (anymore). It would be useful to show another more representative picture for the cilia.

(1) Thank you for your valuable suggestions. The distinction between pinopodes and microvilli has now been added to the Supporting Materials and Methods section (Line 230-236).

(2) You are probably referring to Figure 2F—we did not observe ciliary structures in the CTRL group.

(3) The cilia structure was visualized via transmission electron microscopy (TEM), which requires ultrathin sectioning. Thus, the cilia shown in the image correspond to a single cross-section of the captured assembloids. Owing to technical limitations, three-dimensional visualization of cilia on the cells cannot be achieved.

(17) The results on co-culturing blastoids with the WOI assembloids is not convincing. The blastoids are exposed to the basolateral side of the endometrial epithelial cells, while in vivo, blastocysts interact with the apical side of the endometrial epithelial cells first (apposition and attachment), followed by invasion into the endometrium. This means that the interaction shown here is not physiological. Therefore, it is not justified to say that this platform holds promise to investigate maternal-fetal interactions.

We agree with your perspective that discrepancies exist between this model and the physiological processes in vivo. However, such differences do not negate the scientific value of the model.

The core merit of this study lies in the successful establishment of co-culture systems for blastoids and WOI assembloids. Notably, genuine cross-talk occurs between the two components, thereby providing a practical and operational tool for subsequent research.

Although the current contact orientation differs from that observed in vivo, future optimization of the cell culture protocol (via modulation of cell polarity) will enable the model to better recapitulate physiological conditions. Therefore, the innovation and operability of this model within specific research contexts still render it a robust platform for investigating maternal-fetal interactions.

Overall, it is highly recommended that the authors carefully review the manuscript for grammatical errors, inconsistencies and issues with scientific phrasing. The language throughout the text requires substantial editing to improve clarity, readability and precision. 

We appreciate your suggestions. A full manuscript check was performed to rectify grammatical errors, inconsistencies, and inappropriate scientific phrasing, with further language refinement by a native English-speaking specialist.

Fig 1A: This overview is unclear. How many days do the assembloids grow before being stimulated with hormones? Are CTRL assembloids only kept in culture until day 2 and SEC and WOI assembloids until day 8? This is also not clear form the Materials and Methods section. Should be clarified.

Thanks for your valuable suggestions. We have now updated the overview (Figure 1A) and Materials and Methods section (Line 370-371, Line 379-381).

“Hormonal treatment was initiated following the assembly of the endometrial assembloids (about 7-day growth period).”

“The CTRL group was cultured in ExM without hormone supplementation and subjected to parallel culture for 8 days along with the two aforementioned groups.”

Fig 1B: From these brightfield images, it appears that the size of the assembloids remains relatively consistent from Day 0 to Day 3 and up to Day 11 (especially in CTRL). However, in Fig S1A, the assembloids on Day 11 appear significantly larger compared to those on Day 2 (or Day 4). Authors should clarify this discrepancy (since both of the figures are shown as "brightfield of endometrial assembloids").

You are probably referring to the observation that the assembloids at Day 11 in Fig. S1A are smaller in size than those at Day 2 (or Day 4) in Fig. 1B. This discrepancy arises because the time points in Fig. 1B are calculated starting from the initiation of hormone treatment for the SEC and WOI groups, rather than from the beginning of the overall culture as in Fig. S1A. In addition, assembloids exhibit size variability during the same culture period due to individual heterogeneity.

To eliminate ambiguity, we have now labeled “Hormone Day 0, Day 2, Day 8” in Fig. 1B and revised the corresponding figure legend to read: “Endometrial assembloids from the CTRL, SEC, and WOI groups, which were subjected to hormone treatment on Days 0, 2, and 8, exhibited comparable growth patterns throughout the culture period.”

Fig 2G: authors still used the description "organoids" here instead of "assembloids".

We appreciate your careful review. Corrections have been made accordingly.

Fig. 3C: For the OLFM4 staining quantification, in the Y-axis authors wrote "proportion of OLFM4 (+) cells (OLFM4 (+)/total", but in the rebuttal letter they mention "its fluorescence intensity (quantified as mean grey value) was significantly stronger in both the SEC and WOI groups compared to the CTRL group". This is confounding and should be clarified.

We apologize for incorrectly writing "fluorescence intensity" in the rebuttal letter; the correct term should be the "proportion of OLFM4 (+) cells (OLFM4 (+)/total)" as shown in Fig. 3C.

Fig 5D: Acetyl-α-tubulin is the marker of ciliated cells and should be expressed in the cilia instead of the whole cells. It is very strange to quantify as "mean fluorescence intensity (acetyl-αtubulin/DAPI)" to assess the cilia. Please clarify.

Thank you for your insightful comment. To clarify, the ratio "mean fluorescence intensity (acetyl-α-tubulin/DAPI)" was calculated within individual acetyl-α-tubulin⁺ ciliated cells. Acetyl-αtubulin fluorescence was normalized to the DAPI signal of the same cell nucleus, not the wholecell population. This corrected for variations in cell number and staining efficiency to ensure data accuracy.

Fig 5F: it is very bizarre that unciliated epithelium was transformed from ciliated epithelium, and CTRL was transformed from SEC and WOI. Should be clarified and discussed.

Pseudotime analysis sorts discrete cells along a "pseudotime axis" based on similarities and differences in cellular gene expression, thereby simulating cell state transitions.

Ciliated epithelium → unciliated epithelium: During the menstrual cycle, ciliated and unciliated epithelia undergo mutual transformation from the secretory phase (or mid-secretory phase) to the menstrual phase, and then to the proliferative phase. Here, we demonstrate the transition of ciliated cells to unciliated cells from the SEC and WOI stages to the CTRL stage.

Notably, the two cell types coexist, and what is presented here merely reflects a transformation trend. Relative content has been incorporated into the Discussion section (Line 319-321).

“Throughout the menstrual cycle, ciliated and unciliated epithelia undergo mutual transformation from the secretory phase (or mid-secretory phase) to the menstrual phase, and then to the proliferative phase.”

Fig 5H: To show "enhanced invasion ability", authors must provide some quantification and statistic analysis. It is very hard to see the difference between the CTRL and SEC regarding ROR2Wnt5A.

We appreciate your suggestion. Quantification and statistic analysis have been added to Figure 5H.

Fig 6A: please elaborate the "mIVC1" and "mIVC2" in the figure legends.

Additions have been made to the figure legends accordingly, as follows: "mIVC1: modified In Vitro Culture Medium 1; mIVC2: modified In Vitro Culture Medium 2."

Fig S1D: Is the PAS staining also done in CTRL assembloids? In addition, it is stated that the assembloids secrete glycogen because of a positive PAS staining, while it could also be neutral mucins, glycoproteins, etc, which are all detected by PAS staining. So, the authors should be more careful in stating that it is glycogen, or a PAS staining with diastase digestion should be done.

The PAS staining results for the CTRL group are presented in Fig. S1I. In addition, results of PAS staining with diastase digestion are included in Figure S1.

Line 120: references?

The reference has been added accordingly.

Line 178: The term 'Endometrial Receptivity Test (ERT)' is used. Do the authors mean Endometrial Receptivity Analysis (ERA) test? ERA is the commonly used abbreviation for this test. Moreover, the authors describe ERA as 'a kind of gene analysis-based test.' This should be rephrased more scientifically correct.

Thank you for your valuable suggestion. We have revised the term to ERA, and modified the phrase "a kind of gene analysis-based test" to "gene expression profiling-based diagnostic assay" (Lines 160–163).

“We performed Endometrial Receptivity Analysis (ERA), a gene expression profiling-based diagnostic assay that integrates high-throughput sequencing and machine learning to quantify the expression of endometrial receptivity-associated genes.”

Line 83: assemblies à assembloids

We appreciate your suggestion. The text has been updated to “the endometrial assembloids progressed from epithelial organoids, to assemblies of epithelial and stromal cells and then to stem cell-laden 3D artificial endometrium”.

The Materials and Methods section currently lacks the needed details. Authors should substantially expand this section to clearly describe all experimental and analytical procedures, including, aùmong others, immunofluorescence staining, quantification methods, bioinformatics analyses and statistical approaches. Providing comprehensive methodological information is essential.

A detailed description of these methods is provided in the Supporting Materials and Methods section.

Reviewer #2 (Recommendations for the authors): 

The revised manuscript is much improved in clarity, focus, and experimental support. The authors have thoughtfully addressed the major concerns from the previous review. In particular, the logic and flow of the paper are clearer, it now guides the reader through the rationale (constructing a WOI model), the comparative analysis against in vivo tissue and simpler organoids, and the key features that distinguish the WOI assembloid. The added functional validation (especially the blastoid co-culture experiment) significantly strengthens the work by showing a tangible outcome of "receptivity" beyond molecular profiling. The distinction between the standard secretory-phase organoid and the WOI assembloid is now more convincing, as the authors highlight several specific differences in morphology (more cilia, pinopodes), metabolism, and implantation success that favor the WOI model. The manuscript also reads cleaner with the bioinformatic sections condensed to the most important findings (excess detail was trimmed or moved to supplements) and the rationale for gene/pathway selection explicitly stated.

The manuscript has been significantly strengthened through the addition of functional assays (like the blastoid co-culture), clearer transcriptomic and proteomic data, and detailed analyses of hormone treatments, cilia biology, and stromal and immune cell behavior in early passages. These updates confirm that the WOI assembloid supports embryo attachment and outperforms standard secretory organoids, while integrating external references and clarifications on terminology. Minor suggestions remain, such as clarifying statistical significance and adding functional interpretations for certain observations, but overall, the manuscript is now more robust and biologically convincing.

Remaining points for clarification: There are a few minor points that still merit attention:

- Use of the Endometrial Receptivity Test (ERT): As previously mentioned, if the authors have ERT data for the SEC organoid group, including that information would further support the claim that the WOI assembloid is uniquely receptive. If not, it would be helpful to add a statement clarifying that the ERT was employed specifically as a confirmatory test for the WOI assembloids, rather than as a comparative measure across all groups.

Thank you for your valuable suggestion. We have now supplemented the description in the Supporting Materials and Methods section (Lines 160–162) as follows: “ERA was employed specifically as a confirmatory test for the WOI assembloids, rather than as a comparative measure across all groups.”

- Because the assembloids are created from primary tissue samples, it would be helpful to briefly comment on how consistent the findings were across different patient-derived samples. For example, did all biological replicates show similar expression of receptivity markers and comparable capacity to support blastoid attachment? Although this seems implied, including a sentence in the Methods or Results sections that specifies the number of donor lines tested would help readers assess the model's variability and reproducibility.

We appreciated your advice. The relevant statement has been added to the Supporting Materials and Methods section. (Line 312-313).

“All biological replicates (fourteen individuals) of endometrial assembloids show similar expression of receptivity markers and comparable capacity to support blastoid attachment.”

- The authors mention promising future directions, such as integrating 3D printing and microfluidics to further enhance the model, which is an excellent forward-looking statement. It would also be valuable to suggest the inclusion of additional cell types, like more robust immune cell populations or endothelial components, as future improvements to create an even more comprehensive model of the endometrial lining.

Thank you for your valuable suggestion. 3D printing and microfluidics serve as approaches for introducing multiple cell types. We have supplemented the following statement in the manuscript: “We are looking forward to integrating stem cell induction, 3D printing, and microfluidic systems to modify the culture environment.” (Line 352-353).

We are grateful for your valuable feedback and constructive criticism, which have helped us improve the quality of our work in terms of content and presentation. We have diligently revised the manuscript and made necessary changes. Here, we have attached the revised manuscript, figures, and all supplementary materials for your re-evaluation. Thank you again for your continued support and look forward to your favorable decision.

We should be more efficient, faster, more productive, more happy, beautiful, live more, have more objects: PROGRESS, EVOLUTION. These ideas are engraved into innate blank slate free will mythologies that juxtapose the ordered Western Philosopher Republic or the Magnanimous Eastern King to the absurd mutual aid Anarchocommunism that would degenerate in a battle royale. It's only natural, yet our current hedonistic tech accelerationist post-modern innovation dogma, has mostly outstripped the traditionalistic stability homogeneity lifestyle. Because it enabled a deeper sterelisation, it allowed the perpetuation of rich people through a facade of satisfaction, BUSY satisfaction, self-convinced WORK beyond your small rural family.

Of course, Meritocracy is the scientifically proven, objective, real, true, valid way of assessing things! Singularly, this completely buys into Plato's world of idea-ls... that we must strive for PERFECTION, that there is AN ULTIMATE JUDGE, that we should RANK stuff.

Son of a bitch is also a common one. Faggot too, specially thrown against individuals who show care, stripping them of their privilege.

Matthew effect. Survivors survive, rich get richer. Of course, spotlight bias would have us imagine otherwise it's possible, and actually rich people make sure to create that image by buying news outlets, marketing, philantropies or even social media sites, to shout how many people went from zero to hero. Actually, just check the 1%, and see how monopolistic aristocrats relate and feed on to monopolistic aristocrats.

Trump, Elon, Bezos, Gates, Zuckerberg, are white, straight, cis, men BORN IN RICH FAMILIES.

Of course, because becoming powerful is luring, sexy, it reificates a type of lifestyle, of desire, of righteousness, of imperialistic white saviourism. It's the marketing American cold war (once purportedly anti-slavery) Dream old fairy tale of economic mobility. It's a post-hoc rationalisation of Plato's or Confuncius' stupid concepts of virtue. It's "justice served", "eye-for-an-eye".

I find more scary games and shows like "When Life Gives You Tangerines" that promote self-exploitation, because it's those people that end up invisiblising vulnerable people.

eLife Assessment

The authors developed a fundamental computational method, which is intended to automatically process bioluminescence imaging-derived tumour images across anatomical regions and over time. This allows quantitative analysis of such data, and the authors applied it to describe the spatiotemporal distribution of tumour cells in response to CD19-targeted CAR-T cells that contained either CD28 or 4-1BB costimulatory domains. Some operational limitations were identified, which relate to the pipeline's reliance on predefined regions of interest instead of aligning signal sites with anatomical information, scaling, and limitations in taking animal pose into account. Overall, the authors provide compelling evidence for the functionality of their computational approach towards automated analysis of bioluminescence imaging data, while applying it to a current topic of wide interest in cell therapy research.

Reviewer #1 (Public review):

Summary:

This paper presents maRQup a Python pipeline for automating the quantitative analysis of preclinical cancer immunotherapy experiments using bioluminescent imaging in mice. maRQup processes images to quantify tumor burden over time and across anatomical regions, enabling large-scale analysis of over 1,000 mice. The study uses this tool to compare different CAR-T cell constructs and doses, identifying differences in initial tumor control and relapse rates, particularly noting that CD19.CD28 CAR-T cells show faster initial killing but higher relapse compared to CD19.4-1BB CAR-T cells. Furthermore, maRQup facilitates the spatiotemporal analysis of tumor dynamics, revealing differences in growth patterns based on anatomical location, such as the snout exhibiting more resistance to treatment than bone marrow.

Strengths:

(1) The maRQup pipeline enables the automatic processing of a large dataset of over 1,000 mice, providing investigators with a rapid and efficient method for analyzing extensive bioluminescent tumor image data.

(2) Through image processing steps like tail removal and vertical scaling, maRQup normalizes mouse dimensions to facilitate the alignment of anatomical regions across images. This process enables the reliable demarcation of nine distinct anatomical regions within each mouse image, serving as a basis for spatiotemporal analysis of tumor burden within these consistent regions by quantifying average radiance per pixel.

Weaknesses:

(1) While the pipeline aims to standardize images for regional assessment, the reliance on scaling primarily along the vertical axis after tail removal may introduce limitations to the quantitative robustness of the anatomically defined regions. This approach does not account for potential non-linear growth across dimensions in animals of different ages or sizes, which could result in relative stretching or shrinking of subjects compared to an average reference.

(2) Furthermore, despite excluding severely slanted images, the pipeline does not fully normalize for variations in animal pose during image acquisition (e.g., tucked body, leaning). This pose variability not only impacts the precise relative positioning of internal anatomical regions, potentially making their definition based on relative image coordinates more qualitative than truly quantitative for precise regional analysis, but it also means that the bioluminescent light signal from the tumor will not propagate equally to the camera as photons will travel differentially through the tissue. This differing light path through tissues due to variable positioning can introduce large variability in the measured radiance that was not accounted for in the analysis algorithm. Achieving more robust anatomical and quantitative normalization might require methods that control animal posture using a rigid structure during imaging.

Comments on revisions:

(1) Clarification of 2D Analysis. We strongly recommend that the authors explicitly define maRQup as a 2D spatiotemporal analysis technique. Since optical imaging quantification is inherently dependent on tissue type and signal depth, characterizing this as a 3D or volumetric method without tomographic correction is inaccurate. Please precede "spatiotemporal" with "2D" throughout the text to ensure precision regarding the method's capabilities.

(2) Data Validation and Scaling in Supplemental Figure g currently lacks the units necessary to support the assertion.

Non-Uniform Growth: The authors' method implies that mouse growth is linear and uniform in all directions (isotropic). However, murine growth is not akin to the inflation of a balloon; animals elongate and widen at different rates. The current scaling does not account for these physiological non-linearities.

Pose Variability: The scaling approach appears to neglect significant variability in animal positioning. Even under anesthesia, animal pose is rarely identical across subjects or time points.

Requirement for Evidence: Without quantitative data, there appears to be significant differences between the individual images and the merged image. If the authors assert that this is a "classical setting" where mouse positioning is 100% consistent and growth curves are identical in multiple dimensions, please provide specific references that validate these assumptions. Otherwise, the scaling must be corrected to account for anisotropic growth and pose differences or stated that scaling was only based on one dimension.

(3) Methodology of Spatial Regions The manuscript does not currently indicate how the nine distinct spatial regions were determined. Please expand the methods section to include the specific segmentation algorithms or anatomical criteria used to define these regions, as this is critical for reproducibility.

Reviewer #3 (Public review):

Summary:

The paper "The 1000+ mouse project: large-scale spatiotemporal parametrization and modeling of preclinical cancer immunotherapies" is focused on developing a novel methodology for automatic processing of bioluminescence imaging data. It provides quantitative and statistically robust insights on preclinical experiments that will contribute to optimizing cell-based therapies. There is an enormous demand for such methods and approaches that enable the spatiotemporal evaluation of cell monitoring in large cohorts of experimental animals.

Strengths:

The manuscript is generally well written, and the experiments are scientifically sound. The conclusions reflect the soundness of experimental data. This approach seems to be quite innovative and promising to improve the statistical accuracy of BLI data quantification.<br /> This methodology can be used as a universal quantification tool for BLI data for in vivo assessment of adoptively transferred cells due to the versatility of the technology.

Comments on revisions:

The critiques have been taken care of appropriately.

Author response:

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

Public Reviews:

Reviewer #1 (Public review):

Summary:

This paper presents maRQup, a Python pipeline for automating the quantitative analysis of preclinical cancer immunotherapy experiments using bioluminescent imaging in mice. maRQup processes images to quantify tumor burden over time and across anatomical regions, enabling large-scale analysis of over 1,000 mice. The study uses this tool to compare different CAR-T cell constructs and doses, identifying differences in initial tumor control and relapse rates, particularly noting that CD19.CD28 CAR-T cells show faster initial killing but higher relapse compared to CD19.4-1BB CAR-T cells. Furthermore, maRQup facilitates the spatiotemporal analysis of tumor dynamics, revealing differences in growth patterns based on anatomical location, such as the snout exhibiting more resistance to treatment than bone marrow.

Strengths:

(1) The maRQup pipeline enables the automatic processing of a large dataset of over 1,000 mice, providing investigators with a rapid and efficient method for analyzing extensive bioluminescent tumor image data.

(2) Through image processing steps like tail removal and vertical scaling, maRQup normalizes mouse dimensions to facilitate the alignment of anatomical regions across images. This process enables the reliable demarcation of nine distinct anatomical regions within each mouse image, serving as a basis for spatiotemporal analysis of tumor burden within these consistent regions by quantifying average radiance per pixel.

Weaknesses:

(1) While the pipeline aims to standardize images for regional assessment, the reliance on scaling primarily along the vertical axis after tail removal may introduce limitations to the quantitative robustness of the anatomically defined regions. This approach does not account for potential non-linear growth across dimensions in animals of different ages or sizes, which could result in relative stretching or shrinking of subjects compared to an average reference.

Our answer to this comment is included in the Supplemental Methods. The standard deviation of the mouse pixels was calculated to ensure that the image processing steps did not alter the shape or size of the mice. Such consistency is particularly striking because our dataset was accrued by nine lab members over the last five years, before we conceived and carried out our analysis (c.f., answer to point #2). In fact, it is the very consistency of this IVIS measurement that led us to conceive our pipeline. As seen from Supplemental Figure 4G, there is minimal difference in the shape or size of the mice across 7,534 images. A total of 99 images were removed either due to being too slanted (91/7663, 1.2%) or due to processing errors (8/7633, 0.1%). Also, the vertical scaling was conducted while keeping the aspect ratio unchanged to prevent any non-anatomical scaling. Hence, we did not record any nonlinear growth of the mice that would warrant more convoluted alignment and/or batch correction for our images.

(2) Furthermore, despite excluding severely slanted images, the pipeline does not fully normalize for variations in animal pose during image acquisition (e.g., tucked body, leaning). This pose variability not only impacts the precise relative positioning of internal anatomical regions, potentially making their definition based on relative image coordinates more qualitative than truly quantitative for precise regional analysis, but it also means that the bioluminescent light signal from the tumor will not propagate equally to the camera, as photons will travel differentially through the tissue. This differing light path through tissues due to variable positioning can introduce large variability in the measured radiance that was not accounted for in the analysis algorithm. Achieving more robust anatomical and quantitative normalization might require methods that control animal posture using a rigid structure during imaging.

Reviewer #1 is correct that different mouse postures would be an issue when aligning the images and normalizing for size. However, all experiments are conducted for luminescence measurements in the IVIS system (i.e., this requires anesthesia and long integration time for imaging). In our experience and in our 1000+ mouse dataset, we noticed that all experiments (n=37) did place the anesthetized mice in a stretched/elongated position. Of note, these experiments were conducted by nine different researchers who were not instructed on how to place the mice on the machine for ideal image processing, thus showing that the standard protocol of imaging mice on IVIS does not introduce large variations in animal pose during image acquisition. We think the issue raised by Reviewer #1 is moot in the context of classical settings for mouse luminescence imaging.

Reviewer #2 (Public review):

Summary:

The authors developed a method that automatically processes bioluminescent tumor images for quantitative analysis and used it to describe the spatiotemporal distribution of tumor cells in response to CD19-targeting CAR-T cells, comprising CD28 or 4-1BB costimulatory domains. The conclusion highlights the dependence of tumor decay and relapse on the number of injected cells, the type of cells, and the initial growth rate of tumors (where initial is intended from the first day of therapy). The authors also determined the spatiotemporal analysis of tumor response to CAR T therapy in different regions of the mouse body in a model of acute lymphoblastic leukemia (ALL).

Strengths:

The analysis is based on a large number of images and accounts for many variables. The results of the analysis largely support their claims that the kinetics of tumor decay and relapse are dependent on the CAR T co-stimulatory domain and number of cells injected and tumor growth rates. 

Weaknesses:

The study does not specify how a) differences in mouse positioning (and whether they excluded not-aligned mice) and b) tumor spread at the start of therapy influenced their data. The study does not take into account the potential heterogeneity of CAR T cells in terms of CAR T expression or T cell immunophenotype (differentiation, exhaustion, fitness...).

See answer #2 to Reviewer #1.

Author response image 1.

Author response image 1 shows the average tumor radiance on day zero (when CAR-T cell therapy was administered) for all mice. While there is some spread, most mice had tumor localized to the liver or bone marrow.

Reviewer #3 (Public review):

Summary:

The paper "The 1000+ mouse project: large-scale spatiotemporal parametrization and modeling of preclinical cancer immunotherapies" is focused on developing a novel methodology for automatic processing of bioluminescence imaging data. It provides quantitative and statistically robust insights into preclinical experiments that will contribute to optimizing cell-based therapies. There is an enormous demand for such methods and approaches that enable the spatiotemporal evaluation of cell monitoring in large cohorts of experimental animals.

Strengths:

The manuscript is generally well written, and the experiments are scientifically sound. The conclusions reflect the soundness of experimental data. This approach seems to be quite innovative and promising to improve the statistical accuracy of BLI data quantification. 

This methodology can be used as a universal quantification tool for BLI data for in vivo assessment of adoptively transferred cells due to the versatility of the technology.

Weaknesses: 

No weaknesses were identified by this Reviewer. 

Recommendations for the authors:

Reviewer #1 (Recommendations for the authors):

In this paper, the authors propose a significant advancement in optical image data analysis by employing automation. They effectively demonstrate the valuable insights that can be gained from analyzing extensive datasets with a more unbiased methodology. At present, I do not have any specific suggestions for improvement.

However, it is important to note that this work is limited in its operational scope. Specifically, it relies on predefined ROIs rather than aligning the signal site with anatomical systems. The scaling model and image cropping are simplistic, animal pose is not taken into account, and the data output needs to be called semi-quantitative or qualitative, and would have been stronger utilizing an AI agent. Nevertheless, this work underscores the potential of automated systems in preclinical image analysis, which is a crucial step towards developing more sophisticated approaches to optical image data analysis.

While our analysis used predefined ROIs, the maRQup pipeline allows users to manually draw ROIs on the mouse image.

Reviewer #2 (Recommendations for the authors):

The writing and presentation of data are clear and accurate, but some additional information should be added regarding the imaging protocol used to acquire the original data. 

The authors mention fluorescence in Figure 1. I expected all the data to be generated from bioluminescent NALM-6 tumors, since bioluminescence is indeed measured in average radiance and can be per pixel (p/sec/cm2/sr/pixel). Fluorescence should be measured using radiance efficiency (p/sec/cm2/sr)/(µW/cm2), a unit that compensates for non-uniform excitation light pattern in the instrument. Would the author find different results if fluorescence data were analyzed separately?

Reviewer #2 is correct that the unit for fluorescence would be radiance efficiency. The word “fluorescent” was included in the label of Figure 1a  to highlight that our workflow could be applied to other types of light-generating methods (i.e., fluorescence vs. bioluminescence). However, in this study, measurements of bioluminescent tumors only were analyzed. If fluorescence measurements are to be analyzed, our methods of image acquisition and processing would be directly applicable.

Did the author ever check the signal of the snout in mice with no tumor?

In mice with no tumor, there is no detectable signal in the snout (or anywhere else, for that matter).

The urine of mice contains phosphor, and might give a background signal, especially if longer exposure is used at the end of the study.

For the mice with no tumor injection, the luminescence signal was below background (<10² p/sec/cm²/sr/pixel). In particular, we do not detect any signal in the bladder/urine. Additionally, as described in the Supplemental Methods and Figure 1b, only pixels that were on the mouse as determined from the brightfield image were used to calculate the tumor burden from the radiance of the luminescent image. This method ensures that any background signal (e.g., from phosphor in mouse urine) would be excluded in the radiance quantification and not bias the results.

Additionally, as described in the Methods, the exposure time was held constant at 30 seconds for each IVIS measurement across all 37 experiments.

The data using more than 2 million cells comes from only 10 mice, and maybe the biological relevance of this group is limited since it will not be achievable and translatable in humans (PMID: 33653113).

We appreciate Reviewer #2’s attention to this issue. The effect observed in our study is large enough to reach statistical significance despite the small number of mice. Note that the dosing regimen used was optimized for the murine NSG model and would require appropriate scaling before clinical application. Nonetheless, NSG mice remain the gold standard for pre‑clinical in vivo evaluation and their use is generally required by regulatory agencies, such as the FDA, for assessing novel CAR‑T cell therapies; thus these findings are relevant for advancing such treatments.

Briefing : Préparation de la 10ème Semaine de l'ESS à l'école (SESSE 2026)

Résumé Exécutif

Ce document synthétise les points clés du webinaire organisé par l'association L'ESPER en préparation de la 10ème édition de la Semaine de l'Économie Sociale et Solidaire (ESS) à l'école, qui se déroulera du 23 au 28 mars 2026.

Copiloté avec l'OCCE, cet événement vise à sensibiliser les élèves, du primaire au supérieur, aux modèles économiques alternatifs basés sur la démocratie, la justice sociale et l'intérêt général.

Le webinaire souligne une double ambition : éduquer à l'ESS (compréhension des modèles) et par l'ESS (expérimentation de projets collectifs).

Les interventions mettent en avant des dispositifs concrets, des témoignages d'acteurs de terrain (notamment des Scops et des Scics) et une panoplie d'outils pédagogiques « clés en main » pour les enseignants.

L'objectif final est de transformer la société en intégrant ces principes dans le parcours scolaire et citoyen des individus.

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1. Cadre Institutionnel et Ambitions Éducatives

L'association L'ESPER, regroupant 41 organisations de l'éducation et de l'ESS, porte une vision politique et pédagogique forte pour le système éducatif français.

Vision et Plaidoyer

L'ESPER considère l'ESS comme un levier nécessaire pour transformer l'économie. Ses ambitions s'articulent autour de deux axes :

• Éducation à l'ESS : Faire comprendre un modèle de société basé sur la justice sociale et l'intérêt général. Un plaidoyer publié en août 2025 appelle d'ailleurs à l'intégration de l'ESS dans les programmes scolaires dès le collège.

• Éducation par l'ESS : Favoriser l'émancipation individuelle et collective par la mise en œuvre de projets concrets en classe, permettant aux élèves de découvrir la coopération par l'action.

La Semaine de l'ESS à l'école (SESSE)

Inscrite au calendrier de l'Éducation Nationale, cette semaine annuelle permet trois modes d'engagement :

1. Équipes éducatives : Valorisation de projets annuels ou organisation d'actions ponctuelles.

2. Acteurs de l'ESS : Accueil de classes dans leurs structures ou interventions directes en milieu scolaire.

3. Élèves/Étudiants : Montage de projets autonomes et sensibilisation de leurs pairs.

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2. Fondamentaux de l'Économie Sociale et Solidaire

L'ESS n'est pas une économie récente, mais elle s'est institutionnalisée, notamment via la loi Hamon du 31 juillet 2014.

Les 5 types de structures de l'ESS

| Type de structure | Caractéristiques principales | | --- | --- | | Associations | Groupements de personnes volontaires autour d'un projet non lucratif. | | Fondations | Affectation irrévocable de biens à une œuvre d'intérêt général. | | Coopératives | Entreprises où les associés partagent le pouvoir et les bénéfices. | | Mutuelles | Organismes à but non lucratif pratiquant la solidarité entre membres. | | Sociétés commerciales de l'ESS | Sociétés privées respectant les principes de l'ESS. |

Principes et Valeurs Cardinaux

Toutes ces organisations partagent un socle commun :

• Finalité d'intérêt général ou collectif.

• Lucrativité limitée : Les bénéfices sont prioritairement réinvestis dans le projet.

• Gestion démocratique : Application du principe « une personne, une voix », indépendamment du capital détenu.

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3. Retours d'Expérience et Témoignages d'Acteurs

L'Union Régionale des Scops et Scics (Occitanie)

Eugénie Bruni souligne l'importance de la promotion du modèle coopératif auprès des jeunes.

• Actions types : Interventions de 2 heures présentant l'histoire, les spécificités et des exemples concrets de coopératives.

• Impact : Ouverture des perspectives professionnelles pour les étudiants en montrant que la coopération est un modèle économique viable (4 558 sociétés coopératives en France générant 10,2 milliards d'euros de chiffre d'affaires).

• Conseils : Ne pas hésiter à solliciter les Unions Régionales qui disposent de délégués sur tout le territoire pour accompagner les projets.

La Scop Morasuti (Imprimerie, région AURA)

Témoignage de Damien sur une reprise d'entreprise à la barre du tribunal par les salariés.

• Le combat social : Transformation en Scop en juillet 2024. Le modèle a permis de supprimer les jours de carence et de rééquilibrer les salaires pour corriger les inégalités d'ancienneté.

• Engagement scolaire : Mise à disposition gratuite de chutes de matériaux pour les écoles et accompagnement technique (design, PAO) pour des projets d'exposition.

• Observation sur la démocratie : Les élèves sont souvent surpris par la double casquette « ouvrier et patron ». Damien explique : « Personne ne peut être d'accord avec tout... la démocratie, c'est aux voix. »

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4. Ressources et Outils Pédagogiques

L'ESPER propose des outils testés et adaptés pour différents niveaux (collège, lycée, supérieur).

Outils de sensibilisation "Clés en main"

| Outil | Objectif | Méthode | | --- | --- | --- | | Junior Coopérative | Initier à la méthodologie de projet. | Puzzle sur les étapes d'un projet et études de cas réels. | | Idées reçues sur l'ESS | Déconstruire les préjugés. | Débat mouvant à partir de cartes "Vrai/Faux". | | Filmographie ESS | Illustrer les réalités de l'ESS. | Sélection de documentaires avec guides pédagogiques. | | Fiches Pratiques | Organiser une intervention. | Guides logistiques pour les visites d'entreprises ou les interventions en classe. |

Recommandations pour les intervenants

• Adaptation : Simplifier le discours pour les collégiens en se concentrant sur les piliers (solidarité, partage des richesses, démocratie) plutôt que sur les détails juridiques.

• Interactivité : Utiliser des supports vidéo (ex: série "Ma boîte en Scop") et favoriser le dialogue.

• Préparation : Prévoir environ une heure d'échange préalable entre l'enseignant et l'intervenant pour cadrer l'action.

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5. Calendrier et Inscriptions

• Inscriptions : Ouvertes sur le site de L'ESPER. L'équipe salariée assure la mise en relation entre les établissements scolaires et les acteurs de l'ESS.

• 25 février 2026 : Second webinaire de préparation dédié à une présentation détaillée de l'ESS avec l'expert Hervé de Falvar.

• 23 au 28 mars 2026 : Déroulement de la Semaine de l'ESS à l'école. Valorisation des actions sur les réseaux sociaux et newsletters de L'ESPER.

Citation clé : « Le SS porte un modèle de société qui est basé notamment sur la démocratie, la justice sociale, l'intérêt général [...] pour aboutir à une société plus juste dans laquelle les individus sont émancipés individuellement mais également collectivement. »

État des Lieux Scientifique des Thérapies Manuelles : Entre Mythes et Réalités

Résumé Exécutif

Ce document de synthèse analyse l'état actuel des connaissances scientifiques concernant les thérapies manuelles (kinésithérapie, ostéopathie, chiropraxie, étiopathie), avec un accent particulier sur le mal de dos, principal motif de consultation.

Les points saillants sont les suivants :

• Le primat du mouvement : La science moderne démontre que le traitement le plus efficace contre la lombalgie est le mouvement actif.

Les thérapies passives ne doivent pas être utilisées de manière isolée.

• Obligations légales et déontologiques : Contrairement aux pseudomédecines, la kinésithérapie est encadrée par l'obligation d'utiliser des moyens conformes aux « données acquises de la science », un principe juridique ancré depuis l'arrêt Mercier de 1936.

• Déconstruction des mythes : Les concepts de « vertèbre déplacée » ou de « bassin décalé » sont des vues de l'esprit sans réalité anatomique.

La palpation manuelle, bien que rassurante, manque de fiabilité scientifique pour établir un diagnostic de texture ou de blocage.

• Risques et conséquences sociales : Au-delà de l'effet placebo ou contextuel, certaines manipulations (notamment cervicales) présentent des risques graves comme l'accident vasculaire cérébral (AVC).

De plus, ces pratiques peuvent parasiter les messages de santé publique et altérer la littératie en santé des patients.

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1. L'Évolution de la Science face au Mal de Dos

L'approche médicale de la lombalgie a radicalement changé au cours des trente dernières années, passant d'une logique de repos à une logique d'action.

Chronologie des changements de paradigme

• 1986 : Une étude du New England Journal of Medicine suggère que deux jours de repos au lit sont plus bénéfiques que sept jours.

• 1995 : Une étude pivot démontre que le groupe "témoin" (continuant à vivre normalement) récupère mieux que les groupes soumis à un repos strict ou à des exercices trop prudents.

• 2019 : La Haute Autorité de Santé (HAS) et l'Assurance Maladie lancent des recommandations officielles : « Le bon traitement, c'est le mouvement ».

Les thérapies passives isolées sont déclarées inefficaces sur l'évolution de la lombalgie.

Le bénéfice physiologique du mouvement

Contrairement aux idées reçues, des activités comme la course à pied améliorent la physiologie discale.

L'alternance de pressions et dépressions (environ 1 Hz) lors de la course permet d'hydrater les disques intervertébraux. Statistiquement, les coureurs de fond souffrent moins du dos que les autres sportifs.

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2. Cadre Juridique et Déontologique : La Science comme Obligation

La distinction entre kinésithérapie et thérapies alternatives repose sur un fondement juridique historique.

L'Arrêt Mercier (1936)

Ce tournant de la Cour de cassation a établi trois principes majeurs :

1. Le contrat de soins : Il existe un lien contractuel entre le soignant et le patient.

2. L'obligation de moyens : Le soignant n'a pas d'obligation de résultat (guérison), mais doit mettre en œuvre tous les moyens nécessaires.

3. Les données acquises de la science : Les moyens choisis doivent être conformes aux connaissances scientifiques actuelles.

Évolution des pratiques en kinésithérapie

Le code de déontologie impose aux kinésithérapeutes d'abandonner les pratiques invalidées. Par exemple :

• Bronchiolite : La kinésithérapie respiratoire pédiatrique n'est plus recommandée depuis 2019 pour les nourrissons sains, car le bénéfice est jugé insuffisant par rapport au caractère traumatisant du soin.

• Massage : Son usage est désormais limité (cicatrices, œdèmes) et n'est plus recommandé comme traitement de première intention pour le mal de dos.

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3. Analyse Critique des Thérapies Manuelles

Les limites de la palpation et du diagnostic manuel

La science démontre que le sens tactile des praticiens est sujet à l'illusion.

• Manque de fiabilité : Deux évaluateurs sont rarement d'accord sur la texture (dur/mou) ou le caractère « bloqué » d'un tissu.

• Précision anatomique : En palpant une structure évidente sous la peau, l'erreur moyenne est de 5 cm.

• Impossibilité mécanique : Il est impossible de mobiliser une seule vertèbre de façon isolée ; une manipulation en impacte au minimum trois.

Effet "Gate Control" et placebo

Les thérapies manuelles produisent un effet antalgique réel mais transitoire :

• Distraction sensorielle : Le système nerveux privilégie les sensations tactiles, de chaud ou de froid sur la douleur. C'est un effet à court terme (quelques minutes à quelques heures).

• Effet contextuel : Le rituel de la consultation, l'attention portée par le praticien et la régression naturelle vers la moyenne (la douleur diminue souvent d'elle-même au moment où l'on consulte) renforcent l'illusion d'efficacité.

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4. Histoire et Fondements des Pseudomédecines Manuelles

Les thérapies comme l'ostéopathie ou la chiropraxie reposent sur le vitalisme, une philosophie du XIXe siècle postulant l'existence d'une « force vitale » non physique.

| Discipline | Origine | Fondements Idéologiques | État actuel en Europe | | --- | --- | --- | --- | | Ostéopathie | A.T. Still (1874) | "Le corps est la pharmacie de Dieu". Flux sanguin synonyme de santé. | Branche "puriste" (Littlejohn) très présente, axée sur le crânio-sacré et le fluidique. | | Chiropraxie | D.D. Palmer (1895) | Système nerveux central comme maître du corps. Recours aux manipulations à haute vélocité (faire craquer). | Pratique restée proche des concepts originels, avec une forte présence sur les réseaux sociaux. | | Étiopathie | C. Trédaniel (Fr) | Recherche de l'origine de la pathologie dans l'ajustement articulaire. | Très similaire à l'ostéopathie, sans distinction scientifique réelle. |

Note sur l'exception américaine : Aux États-Unis, l'ostéopathie s'est médicalisée suite au rapport Flexner (1910). Les "DO" y sont des médecins généralistes qui ne pratiquent quasiment plus de thérapie manuelle, contrairement à la branche européenne restée mystique.

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5. Risques et Impacts Sociétaux

Sécurité et perte de chance

• Risques graves : Les manipulations cervicales peuvent provoquer des dissections de l'artère vertébrale, entraînant des AVC ou le syndrome de "Locked-in" (paralysie totale avec conscience préservée).

• Erreurs de diagnostic : Le recours direct à ces thérapies sans avis médical peut retarder la prise en charge de pathologies graves (ex: fractures non détectées).

Parasitage du message médical

Le "vernis médical" utilisé par ces disciplines (mots tels que « diagnostic », « anamnèse », « consultation ») crée une confusion chez les patients :

• Atteinte à la littératie en santé : En ancrant des concepts erronés (vertèbre déplacée, jambe plus courte), les praticiens créent une dépendance et une peur de bouger (kinésiophobie).

• Facteurs sociaux : Le principal facteur de persistance d'une lombalgie n'est pas mécanique, mais lié à l'insatisfaction au travail ou à des problèmes sociétaux. Les thérapies manuelles, en se focalisant sur le "crack and go", ignorent cette complexité.

Conclusion

Si les thérapies manuelles offrent un soulagement temporaire et un confort relationnel, elles ne constituent pas une solution de fond au mal de dos.

La science préconise une approche centrée sur l'éducation thérapeutique, la gestion de la motivation et, impérativement, le mouvement actif du patient.

eLife Assessment

This valuable study presents a technically sophisticated intravital two-photon calcium imaging approach to characterize Ca²⁺ dynamics in distinct populations of meningeal macrophages in awake, freely behaving mice. These data are solid and suggest that meningeal macrophage calcium activity is tightly linked to anatomical sub-compartments, with potential implications for migraine and neuroinflammatory processes. Despite these strengths and broad relevance to neuroimmunology, several technical and interpretational issues limit the study, which could be addressed to strengthen this manuscript.

Reviewer #1 (Public review):

Summary:

This study presents a technically sophisticated intravital two-photon calcium imaging approach to characterize meningeal macrophage Ca²⁺ dynamics in awake mice. The development of a Pf4Cre:GCaMP6s reporter line and the integration of event-based Ca²⁺ analysis represent clear methodological strengths. The findings reveal niche-specific Ca²⁺ signaling patterns and heterogeneous macrophage responses to cortical spreading depolarization (CSD), with potential relevance to migraine and neuroinflammatory conditions. Despite these strengths, several conceptual, technical, and interpretational issues limit the impact and mechanistic depth of the study. Addressing the points below would substantially strengthen the manuscript.

Strengths:

The use of chronic two-photon Ca²⁺ imaging in awake, behaving mice represents a major technical strength, minimizing confounds introduced by anesthesia. The development of a Pf4Cre:GCaMP6s reporter line, combined with high-resolution intravital imaging, enables long-term and subcellular analysis of macrophage Ca²⁺ dynamics in the meninges.

The comparison between perivascular and non-perivascular macrophages reveals clear niche-dependent differences in Ca²⁺ signaling properties. The identification of macrophage Ca²⁺ activity temporally coupled to dural vasomotion is particularly intriguing and highlights a potential macrophage-vascular functional unit in the dura.

By linking macrophage Ca²⁺ responses to CSD and implicating CGRP/RAMP1 signaling in a subset of these responses, the study connects meningeal macrophage activity to clinically relevant neuroimmune pathways involved in migraine and other neurological disorders.

Weaknesses:

The manuscript relies heavily on Pf4Cre-driven GCaMP6s expression to selectively image meningeal macrophages. Although prior studies are cited to support Pf4 specificity, Pf4 is not an exclusively macrophage-restricted marker, and developmental recombination cannot be excluded. The authors should provide direct validation of reporter specificity in the adult meninges (e.g., co-labeling with established macrophage markers and exclusion of other Pf4-expressing lineages). At minimum, the limitations of Pf4Cre-based labeling should be discussed more explicitly, particularly regarding how off-target expression might affect Ca²⁺ signal interpretation.

The manuscript offers an extensive characterization of Ca²⁺ event features (frequency spectra, propagation patterns, synchrony), but the biological significance of these signals is largely speculative. There is no direct link established between Ca²⁺ activity patterns and macrophage function (e.g., activation state, motility, cytokine release, or interaction with other meningeal components). The discussion frequently implies functional specialization based on Ca²⁺ dynamics without experimental validation. To strengthen the conceptual impact, a clearer framing of the study as a foundational descriptive resource, rather than a functional dissection, would improve alignment between data and conclusions.

The GLM analysis revealing coupling between dural perivascular macrophage Ca²⁺ activity and vasomotion is technically sophisticated and intriguing. However, the directionality of this relationship remains unresolved. The current data do not distinguish whether macrophages actively regulate vasomotion, respond to mechanical or hemodynamic changes, or are co-modulated by neural activity. Statements suggesting that macrophages may "mediate" vasomotion are therefore premature. The authors should reframe these conclusions more cautiously, emphasizing correlation rather than causation, and expand the discussion to explicitly outline experimental strategies required to establish causality (e.g., macrophage-specific Ca²⁺ manipulation).

The authors conclude that synchronous Ca²⁺ events across macrophages are driven by extrinsic signals rather than intercellular communication, based primarily on distance-time analyses. This conclusion is not sufficiently supported, as spatial independence alone does not exclude paracrine signaling, vascular cues, or network-level coordination. No perturbation experiments are presented to test alternative mechanisms. The authors can either provide additional experimental evidence or rephrase the conclusion to acknowledge that the source of synchrony remains unresolved.

A major and potentially important finding is that the dominant macrophage response to CSD is a persistent decrease in Ca²⁺ activity, which is independent of CGRP/RAMP1 signaling. However, this phenomenon is not mechanistically explored. It remains unclear whether Ca²⁺ suppression reflects macrophage inhibition, altered viability, homeostatic resetting, or an anti-inflammatory program. Minimally, the discussion should be more deeply engaged with possible interpretations and implications of this finding.

The pharmacological blockade of RAMP1 supports a role for CGRP signaling in persistent Ca²⁺ increases after CSD, but the experiments are based on a relatively small number of cells and animals. The limited sample size constrains confidence in the generality of the conclusions. Pharmacological inhibition alone does not establish cell-autonomous effects in macrophages. The authors should acknowledge these limitations more explicitly and avoid overextension of the conclusions.

Reviewer #2 (Public review):

Using chronic intravital two-photon imaging of calcium dynamics in meningeal macrophages in Pf4Cre:TIGRE2.0-GCaMP6 mice, the study identified heterogeneous features of perivascular and non-perivascular meningeal macrophages at steady state and in response to cortical spreading depolarization (CSD). Analyses of calcium dynamics and blood vessels revealed a subpopulation of perivascular meningeal macrophages whose activity is coupled to behaviorally driven diameter fluctuations of their associated vessels. The analyses also investigated synchrony between different macrophage populations and revealed a role for CGRP/RAMP1 signaling in the CSD-induced increase, but not the decrease, in calcium transients.

This is a timely study at both the technical and conceptual levels, examining calcium dynamics of meningeal macrophages in vivo. The conclusions are well supported by the findings and will provide an important foundation for future research on immune cell dynamics within the meninges in vivo. The paper is well written and clearly presented.

I have only minor comments.

(1) Please indicate the formal definition of perivascular versus non-perivascular macrophages in terms of distance from the blood vessel. This information is not provided in the main text or the Methods. In addition, please explain how the meningeal vasculature was imaged in the main text.

(2) Similarly, the method used to induce acute CSD (pin prick) is not described in the main text and is only mentioned in the figure legends and Methods. Additional background on the neurobiology of acute CSD, as well as the resulting brain activity and neuroinflammatory responses, could be helpful.

Reviewer #3 (Public review):

Summary:

The authors of this report wish to show that distinct populations of meningeal macrophages respond to cortical spreading depolarization (CSD) via unique calcium activity patterns depending on their location in the meningeal sub-compartments. Perivascular macrophages display calcium signaling properties that are sometimes in opposition to non-perivascular macrophages. Many of the meningeal macrophages also displayed synchronous activity at variable distances from one another. Other macrophages were found to display calcium signals in response to dural vasomotion. CSD could induce variable calcium responses in both perivascular and non-perivascular macrophages in the meninges, in part due to RAMP1-dependent effects. Results will inform future research on the calcium responses displayed by macrophages in the meninges under both normal and pathological conditions.

Strengths:

Sophisticated in vivo imaging of meningeal immune cells is employed in the study, which has not been performed previously. A detailed analysis of the distinct calcium dynamics in various subtypes of meningeal macrophages is provided. Functional relevance of the responses is also noted in relation to CSD events.

Weaknesses:

The specificity of the methods used to target both meningeal macrophages and RAMP1 is limited. Additional discussion points on the functional relevance of the two subtypes of meningeal macrophages and their calcium responses are warranted. A section on potential pitfalls should be included.

Author response:

Public Reviews:

Reviewer #1 (Public review): 

Strengths:

(1) The use of chronic two-photon Ca²⁺ imaging in awake, behaving mice represents a major technical strength, minimizing confounds introduced by anesthesia. The development of a Pf4Cre:GCaMP6s reporter line, combined with high-resolution intravital imaging, enables long-term and subcellular analysis of macrophage Ca²⁺ dynamics in the meninges.

(2) The comparison between perivascular and non-perivascular macrophages reveals clear niche-dependent differences in Ca²⁺ signaling properties. The identification of macrophage Ca²⁺ activity temporally coupled to dural vasomotion is particularly intriguing and highlights a potential macrophage-vascular functional unit in the dura.

(3) By linking macrophage Ca²⁺ responses to CSD and implicating CGRP/RAMP1 signaling in a subset of these responses, the study connects meningeal macrophage activity to clinically relevant neuroimmune pathways involved in migraine and other neurological disorders.

Thank you for recognizing the strengths in our work.

Weaknesses: 

(1) The manuscript relies heavily on Pf4Cre-driven GCaMP6s expression to selectively image meningeal macrophages. Although prior studies are cited to support Pf4 specificity, Pf4 is not an exclusively macrophage-restricted marker, and developmental recombination cannot be excluded. The authors should provide direct validation of reporter specificity in the adult meninges (e.g., co-labeling with established macrophage markers and exclusion of other Pf4-expressing lineages). At minimum, the limitations of Pf4Cre-based labeling should be discussed more explicitly, particularly regarding how off-target expression might affect Ca²⁺ signal interpretation.

We acknowledge that PF4 is not an exclusively macrophage-restricted marker. Yet, among meningeal immunocytes, it is almost exclusively expressed in macrophages (1, 2). Furthermore, in the adult mouse meninges, Pf4^Cre-based reporter lines label nearly all dural and leptomeningeal macrophages and almost no other cells (3, 4). This Cre line has also been used to target border-associated macrophages (2, 4). Moreover, a recent study suggests that the bacterial artificial chromosome used to generate the Pf4^Cre line does not affect meningeal macrophage activity (4). Nonetheless, while we already discussed PF4 expression in meningeal megakaryocytes, in a revised version, we plan to discuss the possibility that a very small population of other meningeal immune cells may also be labeled.

(2) The manuscript offers an extensive characterization of Ca²⁺ event features (frequency spectra, propagation patterns, synchrony), but the biological significance of these signals is largely speculative. There is no direct link established between Ca²⁺ activity patterns and macrophage function (e.g., activation state, motility, cytokine release, or interaction with other meningeal components). The discussion frequently implies functional specialization based on Ca²⁺ dynamics without experimental validation. To strengthen the conceptual impact, a clearer framing of the study as a foundational descriptive resource, rather than a functional dissection, would improve alignment between data and conclusions.

In our discussion, we indicated that “the exact link between the distinct Ca²⁺ signal properties of meningeal macrophage subsets observed herein and their homeostatic function remains to be established”. In a revised version, we plan to further acknowledge that this is primarily a descriptive study that provides a foundational landscape of Ca²⁺ dynamics in meningeal macrophages.

(3) The GLM analysis revealing coupling between dural perivascular macrophage Ca²⁺ activity and vasomotion is technically sophisticated and intriguing. However, the directionality of this relationship remains unresolved. The current data do not distinguish whether macrophages actively regulate vasomotion, respond to mechanical or hemodynamic changes, or are co-modulated by neural activity. Statements suggesting that macrophages may "mediate" vasomotion are therefore premature. The authors should reframe these conclusions more cautiously, emphasizing correlation rather than causation, and expand the discussion to explicitly outline experimental strategies required to establish causality (e.g., macrophage-specific Ca²⁺ manipulation). 

In the results section, we indicated that our data suggest that dural perivascular macrophages are functionally coupled to locomotion-driven dural vasomotion, either responding to it or mediating it. Furthermore, in our discussion, we discussed the possibilities that 1) macrophages sense vascular-related mechanical changes and 2) macrophage Ca²⁺ signaling may regulate dural vasomotion. Moreover, we explicitly state that studying causality will require an experimental approach that has yet to be developed, enabling selective manipulation of dural perivascular macrophages.

(4) The authors conclude that synchronous Ca²⁺ events across macrophages are driven by extrinsic signals rather than intercellular communication, based primarily on distance-time analyses. This conclusion is not sufficiently supported, as spatial independence alone does not exclude paracrine signaling, vascular cues, or network-level coordination. No perturbation experiments are presented to test alternative mechanisms. The authors can either provide additional experimental evidence or rephrase the conclusion to acknowledge that the source of synchrony remains unresolved. 

Thank you for this suggestion. In the revision, we will indicate that the source of synchrony remains unresolved.

(5) A major and potentially important finding is that the dominant macrophage response to CSD is a persistent decrease in Ca²⁺ activity, which is independent of CGRP/RAMP1 signaling. However, this phenomenon is not mechanistically explored. It remains unclear whether Ca²⁺ suppression reflects macrophage inhibition, altered viability, homeostatic resetting, or an anti-inflammatory program. Minimally, the discussion should be more deeply engaged with possible interpretations and implications of this finding. 

While we propose that the decrease in macrophage calcium signaling following CSD could indicate that a hyperexcitable cortex dampens meningeal immunity, in the revised version, we plan to elaborate on the possible implications of this finding.

(6) The pharmacological blockade of RAMP1 supports a role for CGRP signaling in persistent Ca²⁺ increases after CSD, but the experiments are based on a relatively small number of cells and animals. The limited sample size constrains confidence in the generality of the conclusions. Pharmacological inhibition alone does not establish cell-autonomous effects in macrophages. The authors should acknowledge these limitations more explicitly and avoid overextension of the conclusions. 

We plan to acknowledge these limitations.

Reviewer #2 (Public review): 

Using chronic intravital two-photon imaging of calcium dynamics in meningeal macrophages in Pf4Cre:TIGRE2.0-GCaMP6 mice, the study identified heterogeneous features of perivascular and non-perivascular meningeal macrophages at steady state and in response to cortical spreading depolarization (CSD). Analyses of calcium dynamics and blood vessels revealed a subpopulation of perivascular meningeal macrophages whose activity is coupled to behaviorally driven diameter fluctuations of their associated vessels. The analyses also investigated synchrony between different macrophage populations and revealed a role for CGRP/RAMP1 signaling in the CSD-induced increase, but not the decrease, in calcium transients.

This is a timely study at both the technical and conceptual levels, examining calcium dynamics of meningeal macrophages in vivo. The conclusions are well supported by the findings and will provide an important foundation for future research on immune cell dynamics within the meninges in vivo. The paper is well written and clearly presented.

Thank you.

I have only minor comments. 

(1) Please indicate the formal definition of perivascular versus non-perivascular macrophages in terms of distance from the blood vessel. This information is not provided in the main text or the Methods. In addition, please explain how the meningeal vasculature was imaged in the main text. 

We did not measure the exact distance of the perivascular macrophages from the blood vessels, but defined them as such based on previous data showing that these cells reside along the abluminal surface and maintain tight interactions with mural cells (5). We plan to provide this information in the revised manuscript.

(2) Similarly, the method used to induce acute CSD (pin prick) is not described in the main text and is only mentioned in the figure legends and Methods. Additional background on the neurobiology of acute CSD, as well as the resulting brain activity and neuroinflammatory responses, could be helpful.

We plan to add the method for inducing CSD (i.e., a pinprick in the frontal cortex) to the Results section and provide more background in the Introduction section.

Reviewer #3 (Public review):

Strengths: 

Sophisticated in vivo imaging of meningeal immune cells is employed in the study, which has not been performed previously. A detailed analysis of the distinct calcium dynamics in various subtypes of meningeal macrophages is provided. Functional relevance of the responses is also noted in relation to CSD events.

Thank you for recognizing the strengths of our paper

Weaknesses:

(1) The specificity of the methods used to target both meningeal macrophages and RAMP1 is limited. Additional discussion points on the functional relevance of the two subtypes of meningeal macrophages and their calcium responses are warranted. A section on potential pitfalls should be included. 

We plan to address these issues in the revision

References

(1) H. Van Hove et al., A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci 22, 1021-1035 (2019).

(2) F. A. Pinho-Ribeiro et al., Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion. Nature 615, 472-481 (2023).

(3) G. L. McKinsey et al., A new genetic strategy for targeting microglia in development and disease. Elife 9,  (2020).

(4) H. J. Barr et al., The circadian clock regulates scavenging of fluid-borne substrates by brain border-associated macrophages. bioRxiv,  (2025).

(5) H. Min et al., Mural cells interact with macrophages in the dura mater to regulate CNS immune surveillance. J Exp Med 221,  (2024).

Le Puy 就是一个很好的例子。你还记得大教堂里那个非凡的“发烧石”，这块黑色石头，那到底是什么？显然，在他们建造大教堂之前，它就已经存在......大教堂建在这些尖塔之一的侧面......这些火山地，必定是权力所在。这是一种治疗石，他们称之为热结石。那几乎可以确定是凯尔特人的，非常古老，那大概是一座古老的德鲁伊神殿......远在基督徒到来之前。于是基督徒来了。当地人用这种石头是因为它有效，他们从中获得了治愈，所以他们（基督徒）不得不在大教堂里建造它......所以他们知道这里是权力所在，必须有一座大教堂。某个时候，有人从十字军东征中带着一尊母亲的雕像出现，可能是伊西斯，也许是伊西斯。当然，这应该属于大教堂。这是其中一部分。所以，这个地方的体验又增加了一层。一切都关乎这个地方。（2006 年 11 月 6 日）

身体作为方法：田野调查中的身体感受（"被吸引"）是认知工具，而非需要消除的偏见--身体的退化的反击

层积作为能动性：历史层积不是压迫的遗迹，而是抵抗的资源——女性朝圣者通过重新激活古老层积，在父权结构中创造自主意义

最表层：中世纪黑圣母雕像 + 哥特式建筑 ↓ 第二层：罗马高卢时期的墨丘利神庙（Mercury） ↓ 第三层：凯尔特时期的 healing spring（治愈泉水崇拜） ↓ 最深层：史前火山岩地貌本身被视为神圣（Dolmens）

"他几乎总是发现那里存在某种崇拜：罗马崇拜、凯尔特崇拜，早在基督徒之前……基督教在欧洲相对来说是较新的，这些地方早已被占据……罗马崇拜、希腊崇拜已经在欧洲传播了很长很长时间。但基督教后来覆盖了所有这些，将圣人基督教化，或改变传说以确立自身……" 异教元素 基督教转化 例子 大地女神（Mother Earth--圣母玛利亚 <br /> 黑圣母的深色=大地、丰饶

泉水/井崇拜 --圣井、洗礼池

太阳神崇拜--圣徒节日对应冬至/夏至<br /> 圣诞节=冬至，复活节=春分

罗马神庙--教堂建在原地 <br /> 巴黎圣母院地下有罗马神庙

凯尔特圣林--教堂庭院保留古树 许多教堂旁的"神圣橡树"

史前 大地母神（被压抑） <br /> 女性身体经验：生育、月经、更年期 凯尔特 女祭司（被抹去） <br /> 女性社群：知识传递、疗愈实践 罗马 国家宗教（男性神祇）<br /> 家庭崇拜：家神、祖先、日常仪式 基督教 父权教会 <br /> 圣母/女圣人崇拜：女性重新占领神圣空间

不是完全背离基督教的信仰背景，而呈现一种连续性，只是角度的改变。选取mm是因为可以把她们过去的宗教经历和新发现的灵性体验所结合--连续性

eLife Assessment

This study provides valuable evidence that hepatic DHHC7-dependent palmitoylation is a physiologically relevant regulator of systemic metabolism, and that loss of DHHC7 disrupts Gαi palmitoylation, activates cAMP-PKA-CREB signaling, and increases hepatic transcription and secretion of Prg4. The identification of Prg4 as a hepatokine that is elevated in vivo, together with some in vitro evidence for its interaction with GPR146, represents a conceptually novel contribution to the field. However, the evidence linking these mechanisms to systemic lipolysis, liver-adipose tissue crosstalk, and whole-body metabolic physiology remains incomplete, as the phenotypic analyses rely on a limited set of experiments and do not yet fully support claims regarding adipose tissue dysfunction or altered lipid flux.

Reviewer #1 (Public review):

Summary:

In this study, the authors' aim was to determine whether hepatic palmitoylation is a physiologically relevant regulator of systemic metabolism. The data demonstrate that loss of DHHC7 in hepatocytes disrupts Gαi palmitoylation, enhances cAMP-PKA-CREB signaling, and drives transcriptional upregulation and secretion of Prg4. The KO mice display increased body weight, fat mass, and plasma cholesterol, but at 12 weeks on HFD, do not exhibit insulin resistance. The potential mechanism underlying the metabolic phenotype was examined by assessing adipocyte signaling and by exploring whether Prg4 acts through GPR146. Through this pathway, the authors intend to link DHHC7-dependent palmitoylation to the regulation of hepatokines that exert systemic metabolic effects.

Strengths:

(1) Hepatic palmitoylation in systemic metabolic regulation is largely unexplored. The authors demonstrate the role of DHHC7 in vivo using a successful liver-specific knockout mouse model that causes HFD-dependent obesity without insulin resistance.

(2) Several studies were performed on chow and HFD, as well as male and female mice.

(3) Plasma proteomics identified Prg4 as a circulating factor elevated in KO mice. Prg4 overexpression phenocopied the KO mice.

(4) There is solid mechanistic data supporting the hypothesis that hepatic DHHC7 loss selectively increases Prg4 secretion as a hepatokine.

(5) There is convincing evidence for the DHHC7 mechanism in liver: DHHC7 controls cAMP-PKA-CREB via Gαi palmitoylation. The authors recognize that the palmitoylation change is causative rather than correlated, and this needs to be more fully explored in the future.

(6) Strong in vitro data support that Prg4 acts through adipocyte GPR146 via its SMB domain

Weaknesses:

(1) The assessment of liver and adipose tissue responses to DHH7 loss is insufficient to support claims that it alters systemic lipolysis. In this new mouse model, liver histology is necessary, especially given the cholesterol increase in the KO. As this is a newly established mouse line, common assessments of the liver during HFD feeding would be important for interpreting the phenotype.

(2) The data show DHH7 loss causes adipose tissue dysfunction and alterations in lipid metabolism. Beyond that, I suggest not stating more regarding the phenotype of the DHH7 mice for this work. A thorough analysis would be needed to determine which factor drives the obesity and changes in energy balance in the mice. For example, the KO mice had lower oxygen consumption (but no change in CO2 production, which is also usually similarly altered), suggesting a CNS component could drive obesity. However, since the data are not normalized for lean mass and there is no information about locomotor activity, this analysis is incomplete. RER may be informative if available. A broad conservative description of the KO phenotype would be more accurate since Pgr4 has many paracrine targets and likely has autocrine signaling in the liver.

(3) Most references to lipolysis or lipolysis flux systemically would be inaccurate. To suggest a suppression of lipolysis, serum NEFA would need to be measured, and in vivo or in vitro lipolysis assays performed to test the effect of DHH7 loss or the specificity of PGR4 action on adipocytes in vivo. To demonstrate adipose tissue dysfunction, analysis of lipogenesis markers, canonical markers for insulin sensitivity, and mitochondrial dysfunction should be performed/measured.

(4) Line 179: The experiment was performed in brown adipocytes to show that Prg4 does not affect p-CREB Figure S8 under the heading: "DHHC7 controls hepatic PKA-CREB activity through Gαi palmitoylation to regulate Prg4 transcription." Unless repeated using liver lysate, the conclusions stated in the text throughout the paper should be revised.

(5) It appears that the serum and liver proteomics were only assessed for factors that increased in KO mice? Were proteins that were significantly decreased analyzed?

(6) The beige adipocyte culture method is unclear. The methods do not describe the fat pad used, and the protocol suggests the cells would be differentiated into mature white adipocytes. If they are beige cells, a reference for the method, gene expression, and cell images could support that claim.

(7) The use of tamoxifen can confound adipocyte studies, as it increases beigeing and weight gain even after a brief initiation period. Both groups were treated with Tam, but another way to induce Cre would be ideal.

(8) Evidence for the lack of the glucose phenotype is incomplete. One reason could be due to the IP route of glucose administration, which has a large impact on glucose handling during a GTT. To confirm the absence of a glucose tolerance phenotype, an OGTT should be performed, as it is more physiological. In addition, the mice should be fed for 16 weeks. Prg4 affects immune cells, changing how adipose tissue expands, and 12 weeks of HFD feeding is often not long enough to see the effects of adipose tissue inflammation spilling over into the system.

(9) There may be liver-adipose tissue crosstalk in KO mice, but this was not fully assessed in this study and would be difficult to determine in any setting, given the diverse cell types that are targets of Pdg4. The crosstalk claim is unnecessary to share the basic premises; there is the DHH7 mechanism/phenotype and the Pgr4 mechanism/phenotype, and while there is no Pgr4 adipose direct mechanism, the paper can be successfully reframed.

(10) Although the DHH7 loss on the chow diet did not result in a phenotype, did the Pgr4 increase in the KO mice on chow? This would determine whether either i) the expression of Pgr4 is dependent on HFD/obesity, or ii) circulating Pgr4 has effects only in an HFD condition. The receptors may also change on HFD, especially in adipocytes.

Impact:

This work would significantly contribute to the study of liver metabolism, provided it includes data describing the liver. The role of Pgr4 in adipocytes and other cell types is of substantial value to the field of metabolism. By reframing the paper and conducting some key experiments, its quality and impact can be increased.

Reviewer #2 (Public review):

In the current report, Sun and Colleagues sought to determine the liver-specific role that DHHC7, a DHHC palmitoyltransferase protein, plays in regulating whole-body energy balance and hepatic crosstalk with adipose tissues. The authors generated an inducible, liver-specific DHHC7 knockout mouse to determine how altered palmitoylation in hepatocytes alters hepatokine production/secretion, and in turn, systemic metabolism. The ablation of DHHC7 was found to alter the production of proteoglycan 4 (Prg4), a hepatokine previously linked to metabolic regulation. The authors propose that the change in Prg4 production is mediated by the loss of Gαi palmitoylation, due to DHHC7 ablation, thereby augmenting cAMP-PKA-CREB signaling in hepatocytes, which alleviates the 'brake' on Prg4 production. The authors further propose that Prg4 overexpression leads to excessive binding to GPR146 on adipocytes, which in turn suppresses PKA-mediated HSL activation, promoting impairments in lipolysis, leading to obesity. The report is interesting and generally well-written, but it appears to have some clear gaps in additional data that would aid in interpretation. The addition of confirmatory culture studies would be incredibly helpful for testing the hypotheses being explored. My comments, concerns, and/or suggestions are outlined below in no particular order.

(1) Figures: All data should be presented in dot-boxplot format so the reader knows how many samples were analyzed for each assay and group. n=3 for some assays/experiments is incredibly low, particularly when considering the heterogeneity in responsiveness to HFD, food intake, etc....

(2) Figure 1E-F: It is unclear when the food intake measure was performed. Mice can alter their feeding behavior based on a myriad of environmental and biological cues. It would also be interesting to show food intake data normalized to body mass over time. Mice can counterregulate anorexigenic cues by altering neuropeptide production over time. It is not clear if this is occurring in these mice, but the timing of measuring food intake is important. Additionally, the VO2 measure appears to be presented as being normalized to total body mass, when in fact, it would probably be more accurate to normalize this to lean body mass. Normalizing to total body mass provides a denominator effect due to excessive adiposity, but white fat is not as metabolically active as other high-glucose-consuming tissues. If my memory serves me right, several reports have discussed appropriate normalizations in circumstances such as this.

(3) Figure 1J-N: It is not all that surprising that fasting glucose and/or TGs were found to be similar between groups. It is well-established that mice have an incredible ability to become hyperinsulinemic in an effort to maintain euglycemia and lipid metabolism dynamics. A few relatively easy assays can be performed to glean better insights into the metabolic status of the authors' model. First, fasting insulin concentrations will be incredibly helpful. Secondly, if the authors want to tease out which adipose depot is most adversely affected by ablation, they could take an additional set of CON and KO mice, fast them for 5-6 hours, provide a bolus injection of insulin (similar to that provided during an insulin tolerance test), and then quickly harvest the animals ~15 minutes after insulin injections; followed by evaluating AKT phosphorylation. This will really tell them if these issues have impairments in insulin signaling. The gold-standard approach would be to perform a hyperinsulinemic-euglyemic clamp in the CON and KO mice. I now see GTT and ITT data, but the aforementioned assays could help provide insight.

(4) Figure 3A: This looks overexposed to me.

(5) Figures 3-4: It appears that several of these assays could be complemented with culture-based models, which would almost certainly be cleaner. The conditioned media could then be used from hepatocyte cultures to treat differentiated adipocytes.

(6) Figure 4: It is unclear how to interpret the phospho-HSL data because the fasting state can affect this readout. It needs to be made clear how the harvest was done. Moreover, insulin and glucagon were never measured, and these hormones have a significant influence over HSL activity. I suspect the KO mice have established hyperinsulinemia, which would likely affect HSL activity. This provides an example of why performing some of these experiments in a dish would make for cleaner outcomes that are easier to interpret.

Reviewer #3 (Public review):

Summary:

In the current manuscript, Sun et al aimed to determine the metabolic function of hepatocyte DHHC7, one of the key enzymes in protein palmitoylation. They generated inducible liver-specific Dhhc7 knockout mice and discovered that Dhhc7-LKO mice are more prone to gain weight and develop adipose expansion and obesity. Via unbiased proteomic analysis, they identified PRG4 as one of the top secreted factors in the liver of Dhhc7-LKO mice. Hepatic overexpression of PRG4 recapitulates the obesity phenotype observed in Dhh7-LKO mice. At the mechanistic level, PRG4, once secreted from the liver, can bind to GPR146 on adipocytes and inhibit PKA-HSL signaling and lipolysis. Taken together, their findings suggest a novel pathway by which the liver communicates with adipose tissue and impacts systemic metabolism.

Strengths:

(1) The systemic metabolic homeostasis depends on coordination among metabolically active tissues. Thus, active communication between the liver and adipose tissue when facing nutritional challenges (such as high-fat diet feeding) is crucial for achieving metabolic health. The concept that the liver can communicate with adipose tissue and impact the lipolysis process via secreted hepatokines is quite significant but remains poorly understood.

(2) Hepatocyte Dhhc7 knockout mice developed a significant obesity phenotype, which is associated with adipose expansion.

(3) Unbiased proteomic analysis identified PRG4 as one of the top secreted factors in the liver of Dhh7-LKO mice. Hepatic overexpression of PRG4 recapitulates the obesity phenotype observed in Dhh7-LKO mice.

(4) In vitro cell-based assay showed that PRG4 can bind to adipocyte GPR146, inhibit PKA-mediated HSL phosphorylation, and subsequently, the lipolysis process.

Weaknesses:

(1) Lack of a causal-effect study to generate evidence directly linking hepatocyte DHH7 and PRG4 in driving adipose expansion and obesity upon HFD feeding.

(2) Lack of direct evidence to support that PRG4 inhibits adipocyte lipolysis via GPR146. A functional assay demonstrating adipocyte lipolysis is required.

(3) The conclusion is largely based on the correlation evidence.

Author response:

Public reviews:

Reviewer #1 (Public review):

Weaknesses:

(1) The assessment of liver and adipose tissue responses to DHH7 loss is insufficient to support claims that it alters systemic lipolysis. In this new mouse model, liver histology is necessary, especially given the cholesterol increase in the KO. As this is a newly established mouse line, common assessments of the liver during HFD feeding would be important for interpreting the phenotype.

We will add the data of the liver histology in the revised version.

(2) The data show DHH7 loss causes adipose tissue dysfunction and alterations in lipid metabolism. Beyond that, I suggest not stating more regarding the phenotype of the DHH7 mice for this work. A thorough analysis would be needed to determine which factor drives the obesity and changes in energy balance in the mice. For example, the KO mice had lower oxygen consumption (but no change in CO2 production, which is also usually similarly altered), suggesting a CNS component could drive obesity. However, since the data are not normalized for lean mass and there is no information about locomotor activity, this analysis is incomplete. RER may be informative if available. A broad conservative description of the KO phenotype would be more accurate since Pgr4 has many paracrine targets and likely has autocrine signaling in the liver.

We will add the data of CO2 production, locomotor activity and RER in the revised version.

(3) Most references to lipolysis or lipolysis flux systemically would be inaccurate. To suggest a suppression of lipolysis, serum NEFA would need to be measured, and in vivo or in vitro lipolysis assays performed to test the effect of DHH7 loss or the specificity of PGR4 action on adipocytes in vivo. To demonstrate adipose tissue dysfunction, analysis of lipogenesis markers, canonical markers for insulin sensitivity, and mitochondrial dysfunction should be performed/measured.

We will measure the serum NEFA to test the effect of DHHC7. We will analyze the lipogenesis markers, canonical markers for insulin sensitivity, and mitochondrial dysfunction.

(4) Line 179: The experiment was performed in brown adipocytes to show that Prg4 does not affect p-CREB Figure S8 under the heading: "DHHC7 controls hepatic PKA-CREB activity through Gαi palmitoylation to regulate Prg4 transcription." Unless repeated using liver lysate, the conclusions stated in the text throughout the paper should be revised.

The figure S8 is to demonstrate that Prg4 has no impact on forskolin induced CREB phosphorylation at Ser133, and provide the evidence that the prg4 acts on the upstream of adenylyl cyclase. We will revise the description.

(5) It appears that the serum and liver proteomics were only assessed for factors that increased in KO mice? Were proteins that were significantly decreased analyzed?

We are analyzing the decreased proteins in the following project.

(6) The beige adipocyte culture method is unclear. The methods do not describe the fat pad used, and the protocol suggests the cells would be differentiated into mature white adipocytes. If they are beige cells, a reference for the method, gene expression, and cell images could support that claim.

We will add a reference for the method, gene expression, asn cell images.

(7) The use of tamoxifen can confound adipocyte studies, as it increases beigeing and weight gain even after a brief initiation period. Both groups were treated with Tam, but another way to induce Cre would be ideal.

We will use the Doxycycline-inducible systems in the future.

(8) Evidence for the lack of the glucose phenotype is incomplete. One reason could be due to the IP route of glucose administration, which has a large impact on glucose handling during a GTT. To confirm the absence of a glucose tolerance phenotype, an OGTT should be performed, as it is more physiological. In addition, the mice should be fed for 16 weeks. Prg4 affects immune cells, changing how adipose tissue expands, and 12 weeks of HFD feeding is often not long enough to see the effects of adipose tissue inflammation spilling over into the system.

We will perform the OGTT and feed the mice for 16 weeks in the future.

(9) There may be liver-adipose tissue crosstalk in KO mice, but this was not fully assessed in this study and would be difficult to determine in any setting, given the diverse cell types that are targets of Pdg4. The crosstalk claim is unnecessary to share the basic premises; there is the DHH7 mechanism/phenotype and the Pgr4 mechanism/phenotype, and while there is no Pgr4 adipose direct mechanism, the paper can be successfully reframed.

We will reframe the paper.

(10) Although the DHH7 loss on the chow diet did not result in a phenotype, did the Pgr4 increase in the KO mice on chow? This would determine whether either i) the expression of Pgr4 is dependent on HFD/obesity, or ii) circulating Pgr4 has effects only in an HFD condition. The receptors may also change on HFD, especially in adipocytes.

We will test the Prg4 in the KO mice on chow diet.

Reviewer #2 (Public review):

(1) Figures: All data should be presented in dot-boxplot format so the reader knows how many samples were analyzed for each assay and group. n=3 for some assays/experiments is incredibly low, particularly when considering the heterogeneity in responsiveness to HFD, food intake, etc.

We will present the data in dot-boxplot format.

(2) Figure 1E-F: It is unclear when the food intake measure was performed. Mice can alter their feeding behavior based on a myriad of environmental and biological cues. It would also be interesting to show food intake data normalized to body mass over time. Mice can counterregulate anorexigenic cues by altering neuropeptide production over time. It is not clear if this is occurring in these mice, but the timing of measuring food intake is important. Additionally, the VO2 measure appears to be presented as being normalized to total body mass, when in fact, it would probably be more accurate to normalize this to lean body mass. Normalizing to total body mass provides a denominator effect due to excessive adiposity, but white fat is not as metabolically active as other high-glucose-consuming tissues. If my memory serves me right, several reports have discussed appropriate normalizations in circumstances such as this.

We will see how to be more accurate to normalize.

(3) Figure 1J-N: It is not all that surprising that fasting glucose and/or TGs were found to be similar between groups. It is well-established that mice have an incredible ability to become hyperinsulinemic in an effort to maintain euglycemia and lipid metabolism dynamics. A few relatively easy assays can be performed to glean better insights into the metabolic status of the authors' model. First, fasting insulin concentrations will be incredibly helpful. Secondly, if the authors want to tease out which adipose depot is most adversely affected by ablation, they could take an additional set of CON and KO mice, fast them for 5-6 hours, provide a bolus injection of insulin (similar to that provided during an insulin tolerance test), and then quickly harvest the animals ~15 minutes after insulin injections; followed by evaluating AKT phosphorylation. This will really tell them if these issues have impairments in insulin signaling. The gold-standard approach would be to perform a hyperinsulinemic-euglyemic clamp in the CON and KO mice. I now see GTT and ITT data, but the aforementioned assays could help provide insight.

We have the data for evaluating AKT phosphorylation and will add it in the revised version.

(4) Figure 3A: This looks overexposed to me.

We will replace it with short exposed one.

(5) Figures 3-4: It appears that several of these assays could be complemented with culture-based models, which would almost certainly be cleaner. The conditioned media could then be used from hepatocyte cultures to treat differentiated adipocytes.

We will perform the cell culture experiments for Figures 3-4

(6) Figure 4: It is unclear how to interpret the phospho-HSL data because the fasting state can affect this readout. It needs to be made clear how the harvest was done. Moreover, insulin and glucagon were never measured, and these hormones have a significant influence over HSL activity. I suspect the KO mice have established hyperinsulinemia, which would likely affect HSL activity. This provides an example of why performing some of these experiments in a dish would make for cleaner outcomes that are easier to interpret.

We will perform some experiments in cell culture dish.

Reviewer #3 (Public review):

Weaknesses:

(1) Lack of a causal-effect study to generate evidence directly linking hepatocyte DHH7 and PRG4 in driving adipose expansion and obesity upon HFD feeding.

We will perform the causal-effect study to demonstrate the hypothesis.

(2) Lack of direct evidence to support that PRG4 inhibits adipocyte lipolysis via GPR146. A functional assay demonstrating adipocyte lipolysis is required.

We will add the direct evidence in the revised version.

(3) The conclusion is largely based on the correlation evidence.

We will perform the experiment to strengthen the conclusion base on the a causal-effect study.

AI agents as kompromat collectors

Hi – this is the initial draft for selecting the covariates. The updated analysis plan can be accessed from the menu.

The greater the width of the band gap, the more suitable a semiconductor material is for operation at room temperature. Reducing a detector’s physical size also improves its performance at room temperature because the detector will contain fewer electrons. Fewer electrons means less thermionic noise.

To reduce the thermionic noise(where electron in the semiconductor might have sufficient thermal energy to climb to the conduction band) which deteriorates the detector resolution.

Intrinsic layer has the property that, in thermal equilibrium, the number of conduction band electrons per unit volume, is equal to the number of valence band holes. The intrinsic region presents a larger volume in which photons can produce electron hole pairs, increased quantum efficiency.

Analyse de la Rhétorique Complotiste : Mécanismes, Discours et l'Allégorie du « Mouton »

Ce document de synthèse analyse les recherches et les réflexions de Loïc Massaia, vulgarisateur pour le projet Utopia, concernant la rhétorique employée dans les milieux complotistes.

Il détaille les structures argumentatives, les fonctions psychologiques du discours et l'usage spécifique de l'insulte « mouton » comme outil de distinction sociale et de clôture du débat.

Synthèse

L'analyse de la rhétorique complotiste révèle un système de communication visant moins à établir une vérité qu'à asseoir un ascendant sur l'auditoire.

Cette rhétorique se caractérise par une structure circulaire (tautologique) et un recours systématique à l'essentialisme.

L'usage de termes comme « mouton » remplit une triple fonction : une attaque ad personam pour éviter le débat de fond, une accusation de complicité passive, et un mécanisme de distinction permettant de renforcer l'estime de soi du locuteur.

En s'affranchissant des règles du « débat sain », le discours complotiste s'établit comme un système fermé où la conclusion (l'existence d'un complot) est déjà contenue dans les prémisses.

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1. Définition et Catégorisation de la Rhétorique Complotiste

Le document propose de définir la rhétorique comme l'ensemble des moyens mis en œuvre dans un discours pour convaincre, briller, manipuler ou obtenir un ascendant sur autrui.

Une définition complémentaire la décrit comme la « négociation de la différence entre les individus sur une question donnée ».

Dans le cadre du complotisme, les expressions récurrentes peuvent être classées selon quatre dimensions principales :

| Dimension | Exemples de phrases types | Objectif recherché | | --- | --- | --- | | Accusatoire | « Journalopes », « Merdias », « On ne vous dit pas tout » | Discréditer les sources d'information officielles. | | Incitatoire | « Faites vos propres recherches », « Réveillez-vous » | Pousser l'interlocuteur à adopter la même conclusion par une illusion d'autonomie. | | Négation du hasard | « Coïncidence ? Je ne crois pas », « Tout est lié » | Refuser la contingence au profit d'un dessein caché. | | Surconfiance et Distinction | « Tous des moutons », « On avait raison » | Se placer au-dessus de la « masse » ignorante. |

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2. Analyse Structurelle de l'Argumentation

Le Modèle de Toulmin

Pour évaluer la solidité d'un argument, le document mobilise le modèle de Toulmin, qui identifie les composants d'une argumentation optimale :

1. Données : Les informations de base.

2. Conclusion : Ce que l'on veut démontrer.

3. Justifications : Le lien logique entre données et conclusion.

4. Fondement : Ce qui rend la justification solide et acceptée.

5. Réfutation : L'intégration des limites et des conditions qui pourraient contredire l'argument.

La défaillance du discours complotiste

L'analyse montre que le discours complotiste omet généralement la réfutation.

Par exemple, l'argument consistant à dire que le gouvernement est une secte parce qu'il lutte contre les dérives sectaires (pour étouffer la dissidence) s'effondre si l'on introduit d'autres facteurs de distinction entre État et secte.

Circularité et Essentialisme

Le discours complotiste est décrit comme un système fermé ou une tautologie.

Il repose sur l'essentialisation : on décrète que la « nature » profonde d'une entité (le gouvernement, les élites) est malveillante.

Dès lors, toute action de cette entité, même positive en apparence, est interprétée comme une preuve supplémentaire de sa malveillance.

Le complot existe nécessairement au départ pour expliquer les faits qui servent ensuite à prouver l'existence du complot.

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3. L'Allégorie du « Mouton » : Origines et Usages

L'expression « tous des moutons » est un idiotisme animalier présent dans plusieurs langues (français, italien, anglais, polonais).

Origine Littéraire

L'image du mouton qui suit aveuglément remonte notamment à Rabelais (l'épisode des moutons de Panurge), où les animaux sautent à l'eau et meurent simplement parce que le premier a sauté.

Cela souligne une dimension « naturelle » ou essentialiste de l'animal : le besoin de suivre.

Fonctions dans le discours complotiste

1. L'identification du comploteur : S'il y a des moutons, il y a nécessairement un « berger » ou un « maître » (le comploteur).

2. L'accusation de complicité : Les non-complotistes sont jugés idiots, mais aussi complices par leur passivité.

3. Le besoin de distinction : Se déclarer « non-mouton » permet de s'extraire de la masse. Selon les travaux d'Anthony Lantian (2015), l'adhésion aux théories du complot serait un moyen de rehausser une estime de soi initialement basse en se sentant détenteur d'un savoir supérieur.

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4. La Rhétorique comme Rupture du Débat

L'usage de l'insulte « mouton » est qualifié d'argument ad personam.

Théorisée par Schopenhauer, cette tactique consiste à attaquer l'individu plutôt que ses arguments pour mettre fin à une discussion que l'on ne peut pas gagner sur le fond.

Violation des règles de la controverse honorable

En s'appuyant sur les travaux de Levi Hedge (XIXe siècle), le document identifie trois règles fondamentales d'un débat sain systématiquement violées par la rhétorique complotiste :

• Règle n°4 : Interdiction des attaques personnelles.

• Règle n°5 : Interdiction d'accuser l'adversaire de mobiles cachés.

• Règle n°7 : La vérité doit être le but, non la victoire. L'usage du ridicule ou de la raillerie (traiter l'autre de mouton) est une violation de cette règle.

Toutefois, le document souligne que ces dérives ne sont pas l'apanage des complotistes ; elles se retrouvent fréquemment dans tout débat public où l'objectif des participants est de « gagner » plutôt que de chercher la vérité.

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5. Perspectives Critiques

En conclusion, le document invite à une réflexion sur la nature même de la critique du complotisme.

Si l'on définit la rhétorique complotiste comme étant « par nature » une tautologie basée sur un essentialisme, on court le risque de produire soi-même un discours fermé et essentialiste.

Cette mise en abyme suggère que l'analyse du complotisme doit elle-même rester vigilante quant à ses propres structures argumentatives pour ne pas tomber dans les travers qu'elle dénonce.

Briefing : Devenir parent, un grand défi — Analyse des obstacles systémiques, médicaux et sociaux

Résumé exécutif

Ce document synthétise les échanges d'une table ronde consacrée aux défis majeurs de l'accès à la parentalité.

L'analyse révèle un décalage profond entre l'injonction sociétale à la natalité et la réalité des parcours « atypiques » (infertilité, handicap, adoption).

Les parents et futurs parents font face à une triple épreuve :

1. Des préjugés tenaces : Une stigmatisation de l'infertilité masculine et une négation de la compétence parentale des personnes handicapées.

2. Une faillite de l'accompagnement : Un manque d'information neutre et de formation du personnel médical, poussant parfois les individus vers des dérives idéologiques ou des pseudo-sciences.

3. Des barrières systémiques violentes : Des procédures administratives d'adoption exténuantes et une surveillance intrusive des services sociaux pouvant mener à des traumatismes familiaux graves (placements abusifs).

Malgré ces obstacles, l'esprit critique et l'engagement associatif émergent comme des outils de résilience essentiels pour naviguer dans ces systèmes complexes.

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1. L'infertilité : Entre réalités biologiques et mythes sociaux

L'infertilité est souvent perçue à tort comme une problématique essentiellement féminine.

Les données scientifiques et les témoignages personnels rectifient cette vision.

Répartition des causes d'infertilité

Selon Marjorie Whitfield (chercheuse à l'Inserm), la responsabilité de l'infertilité est équitablement répartie :

• Un tiers des cas est d'origine féminine.

• Un tiers des cas est d'origine masculine.

• Un tiers des cas est d'origine mixte (impliquant les deux partenaires).

Le poids des préjugés masculins

L'infertilité masculine est particulièrement sujette à des amalgames psychologiques et sociaux :

• Confusion avec l'impuissance : La société confond souvent la capacité à procréer (production de spermatozoïdes) et la virilité ou la performance sexuelle. Un homme stérile peut avoir une fonction sexuelle normale.

• Atteinte à la virilité : Pour beaucoup, l'incapacité à concevoir est vécue comme une défaillance du « contrat » de virilité.

• Déni de paternité : Dans les cas de recours à un donneur, le préjugé social tend à nier le rôle de père au profit de la seule génétique.

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2. Parentalité et handicap : Un parcours d'obstacles discriminatoire

Le témoignage de Leitha met en lumière un système de santé et un encadrement social profondément « validocentrés », où le handicap est systématiquement perçu comme un frein, voire un danger.

La stigmatisation médicale

Les professionnels de santé manifestent souvent une incompréhension totale face au désir de grossesse d'une personne handicapée :

• Invisibilisation de la sexualité : Étonnement des soignants face à la conception (« Comment avez-vous fait ? »).

• Orientation systématique vers l'IVG : Des patientes se voient proposer l'interruption volontaire de grossesse par défaut, sans que leur choix ou leur projet parental ne soit envisagé.

• Manque de matériel adapté : Absence de tables d'examen gynécologique ou d'instruments permettant la prise en charge de personnes en fauteuil roulant, menant à des violences gynécologiques.

La suspicion des services sociaux

Une fois parents, les personnes handicapées subissent une surveillance disproportionnée :

• Injonctions contradictoires : Les services sociaux imposent des cadres rigides et changeants, sans offrir de solutions concrètes aux difficultés quotidiennes liées au handicap.

• Le « signalement » par défaut : Des inquiétudes infondées ou des préjugés sur la capacité de protection de l'enfant peuvent mener à des procédures de placement.

• Traumatismes familiaux : Des enfants sont parfois retirés à leurs parents durant plusieurs années sur la base de suspicions de danger jamais étayées par des faits.

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3. Les entraves administratives et législatives

L'accès à la parentalité est également conditionné par des mécanismes bureaucratiques lourds qui peuvent décourager les candidats.

| Type de parcours | Nature des obstacles identifiés | | --- | --- | | Adoption | Délais d'agrément longs (5 ans), enquêtes sociales intrusives (voisinage, famille), tests psychologiques obsolètes (ex: test de Rorschach), et fermetures de pays étrangers suite à des évolutions législatives françaises (ex: Mariage pour tous). | | PMA | Délais rallongés pour les personnes handicapées (examens supplémentaires), limitation du nombre de tentatives prises en charge, et coût élevé des démarches à l'étranger. | | Suivi Social | Surveillance psychosociale non demandée, sentiment d'être « jugé à la loupe » contrairement aux parents biologiques sans difficultés apparentes. |

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4. Le danger du manque d'information et de l'isolement

Le déficit d'accompagnement par les structures officielles crée un vide dangereux que comblent des organisations aux agendas variés.

• Dérives idéologiques : En l'absence de ressources publiques pour accompagner les grossesses avec handicap, des associations anti-IVG deviennent parfois les seules détentrices d'informations pratiques, utilisant cette aide pour manipuler psychologiquement les futures mères.

• Pseudo-médecines : Le désir de parentalité est un marché lucratif pour des cures ou formations miracles promettant de « booster » la fertilité sans base scientifique.

• Isolement psychologique : La culpabilité, souvent induite par le discours médical (« Vous ne pouvez pas faire ça à un enfant »), isole les parents et fragilise leur santé mentale.

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5. Le rôle crucial de l'esprit critique

L'esprit critique est présenté comme un levier fondamental pour reprendre le pouvoir sur son parcours de parent.

1. Filtrer l'information : Apprendre à vérifier les sources et à ne pas accepter la parole médicale comme une vérité absolue, surtout lorsqu'elle est empreinte de jugements de valeur.

2. Désamorcer la culpabilité : Comprendre les mécanismes systémiques permet de réaliser que l'échec ou la difficulté n'est pas une faute individuelle mais le résultat d'un manque de soutien.

3. Créer des ressources : Face à l'absence de structures adaptées, l'engagement associatif (comme la création de sites de ressources neutres) permet de briser l'isolement et de proposer un accompagnement basé sur l'expérience et les preuves (EBM - Evidence-Based Medicine).

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Conclusion : Une question de dignité et de droits

Les parcours de Sylvain Rozier et de Leitha démontrent que devenir parent, lorsqu'on s'écarte de la norme biologique ou sociale, est un acte de résistance.

Malgré la dureté des épreuves — 11 ans de combat pour l'un, des années de bataille judiciaire pour l'autre — l'issue positive de ces parcours souligne la nécessité urgente d'une réforme de l'accompagnement de la parentalité :

• Formation des personnels soignants et sociaux aux enjeux du handicap.

• Neutralité et accessibilité de l'information médicale.

• Soutien logistique plutôt que surveillance répressive.

« La parentalité est un chemin semé d'embûches [...] mais sur des parcours atypiques, on est vraiment à un autre niveau d'embûches qui isolent. » — Marjorie Whitfield.

L'Esprit Critique au Cœur de l'Enquête Privée Spécialisée : Analyse des Pratiques de Benoît Judde

Ce document de synthèse analyse les interventions de Benoît Judde, détective privé spécialisé, concernant l'évolution de la profession de détective en France, le cadre juridique des dérives sectaires et l'utilisation de l'esprit critique comme outil méthodologique fondamental pour l'administration de la preuve.

Synthèse

La profession de détective privé en France, désormais strictement réglementée et contrôlée par le ministère de l'Intérieur (CNAPS), s'est transformée en un auxiliaire de fait pour la défense des intérêts privés et le système judiciaire.

Benoît Judde, spécialisé dans les faits de manipulation et les dérives sectaires, démontre que l'efficacité de l'enquêteur repose sur une maîtrise rigoureuse du cadre juridique et sur l'application de l'esprit critique.

Cette approche, adossée aux psychologies cognitive et sociale expérimentales, permet de transformer des phénomènes subjectifs comme la « sujétion psychologique » en éléments de preuve objectifs, circonstanciés et recevables en justice.

Le passage récent (2024) de la sujétion psychologique au statut d'infraction autonome renforce la nécessité d'une expertise technique capable de caractériser les manœuvres de manipulation sans tomber dans le biais de confirmation.

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1. Le Cadre Légal et Déontologique de la Profession

La profession de détective privé, officiellement dénommée « agent de recherche privée », est définie par le Code de la sécurité intérieure (CSI).

Définition et Prérogatives

Selon l'article L621-1 du CSI, le détective est un professionnel libéral dont la mission consiste à recueillir des informations ou des renseignements destinés à des tiers, en vue de la défense de leurs intérêts.

• Anonymat d'enquête : C’est la seule profession parajuridique autorisée à enquêter sans révéler sa qualité, son identité réelle ou l’objet de sa mission. Contrairement aux commissaires de justice (huissiers), le détective peut agir sous une identité fictive.

• Recevabilité des preuves : Les rapports de détective doivent être « détaillés, circonstanciés et précis » (DCP) pour être recevables devant les tribunaux, selon une jurisprudence de la Cour de cassation datant de 1962.

Régulation et Formation

La profession est passée d'un état de « freestyle » à un encadrement strict :

• Contrôle du CNAPS : Le Conseil national des activités privées de sécurité (sous tutelle du ministère de l'Intérieur) délivre trois agréments distincts (personne physique, structure juridique, carte professionnelle), renouvelables tous les 5 ans après enquête de moralité approfondie.

• Formation obligatoire : Un niveau Bac+3 (licence professionnelle) est requis. Il n'existe que quatre écoles en France (deux universités et deux écoles privées), formant environ 120 nouveaux professionnels par an.

• Déontologie : Les détectives sont soumis au secret professionnel et à une obligation de conseil. Ils doivent notamment vérifier la légitimité de la demande pour éviter de servir des projets de vengeance ou des recherches malveillantes.

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2. L'Enquête Spécialisée dans les Dérives Sectaires

Le champ d'action des détectives est vaste (recherche de personnes, contrefaçon, fraude à l'assurance), mais la spécialisation de Benoît Judde porte sur la manipulation mentale.

Les Critères de la MIVILUDES

Pour objectiver une dérive sectaire, l'enquêteur s'appuie sur le référentiel de la Mission interministérielle de vigilance et de lutte contre les dérives sectaires (MIVILUDES), qui identifie 10 critères principaux.

| Catégorie d'atteinte | Exemples de sous-critères | | --- | --- | | Atteintes aux personnes | Rupture avec l'environnement d'origine, perte d'esprit critique, embrigadement des enfants, privation de sommeil ou de nourriture. | | Atteintes aux biens | Exigences financières disproportionnées, endettement, travail dissimulé (ex: détournement du concept de woofing). | | Vie sociale et démocratique | Discours antisocial, trouble à l'ordre public, détournement des circuits économiques. |

Collaboration Interdisciplinaire

L'enquêteur travaille en binôme avec un psychologue (spécialisé en psychologie scientifique, cognitive et sociale) pour valider la réalité de l'emprise.

Cette collaboration permet d'apporter une « parole psychologique » crédible que le juriste ou le détective ne peut formuler seul, notamment pour qualifier le préjudice ou la sujétion devant un juge.

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3. Évolutions Législatives Récentes (Loi de 2024)

Le cadre juridique français a récemment évolué pour faciliter la répression des dérives sectaires, rendant le rôle de la preuve plus complexe et crucial.

• Autonomie de la sujétion psychologique : Auparavant liée à l'abus de faiblesse (nécessitant de prouver un état de faiblesse préalable et un préjudice), la « mise en état de sujétion psychologique » est devenue une infraction autonome en 2024.

Il suffit désormais de prouver l'utilisation de techniques de pression ou de manipulation altérant le jugement.

• Détournement de traitement médical : Une nouvelle infraction punit le fait de provoquer une personne à abandonner un traitement médical thérapeutique ou prophylactique (vaccination) au profit de pratiques pseudo-scientifiques.

• L'Escroquerie et la Cybermalveillance : Dans le domaine numérique, 95 % des arnaques reposent sur l'ingénierie sociale (manipulation humaine) plutôt que sur des failles purement techniques.

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4. L'Esprit Critique comme Méthodologie d'Enquête

Pour Benoît Judde, l'esprit critique n'est pas une posture intellectuelle mais un outil de travail permettant d'éviter le biais de confirmation et d'assurer l'objectivité du rapport.

Les Trois Piliers de la Manipulation

L'enquêteur analyse les situations à travers trois mécanismes identifiés par la psychologie expérimentale :

1. L'automanipulation : Utilisation des biais cognitifs naturels des individus.

2. La soumission librement consentie : Techniques comme le « pied dans la porte » (obtenir un petit engagement pour en obtenir un plus grand) ou la « porte au nez » (demander l'excessif pour obtenir le raisonnable).

3. La soumission à l'autorité : Référence à l'expérience de Milgram. La manipulation réussit si l'autorité est perçue comme légitime (ex: port d'une blouse, titre de « frère de Jésus », etc.).

L'Objectivité de la Preuve

• Recours à la technologie : Utilisation de caméras cachées lors d'infiltrations pour fournir une preuve brute et incontestable, évitant ainsi la faillibilité de la mémoire humaine ou les accusations de partialité.

• Nécessité et proportionnalité : L'enquêteur doit justifier que l'atteinte à la vie privée (infiltration, surveillance) était strictement indispensable à la manifestation de la vérité et proportionnée à l'enjeu (droit à la preuve vs droit à la vie privée).

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5. Conclusion : Vers un Continuum de Sécurité

Le document souligne que l'État ne peut assurer seul la surveillance de tous les risques, particulièrement dans les domaines complexes des dérives sectaires et thérapeutiques.

• Synergie Public-Privé : Le détective privé intervient là où la police ne peut plus agir (disparitions non inquiétantes, enquêtes pré-pénales pour consolider une plainte).

• Auxiliaire de Justice : En apportant des éléments basés sur un consensus scientifique (psychologie expérimentale), le détective aide le magistrat à fonder sa décision sur des faits plutôt que sur des témoignages contradictoires.

• Complémentarité : L'objectif n'est pas une « américanisation » du système, mais une validation réciproque où le secteur privé complète l'action régalienne en fournissant une expertise technique et de terrain spécifique.

Synthèse Clinique : Comprendre et Accompagner la Cooccurrence TSA-TDAH (ODHD)

Résumé Exécutif

Ce document propose une analyse approfondie de la cooccurrence entre le Trouble du Spectre de l'Autisme (TSA) et le Trouble du Déficit de l'Attention avec ou sans Hyperactivité (TDAH), un profil souvent désigné sous l'acronyme anglo-saxon « ODHD ».

Longtemps ignorée par les classifications officielles (notamment avant le DSM-5 en 2013), cette double problématique est aujourd'hui reconnue comme une entité clinique à part entière, et non une simple addition de symptômes.

Les points clés de cette analyse incluent :

• Prévalence élevée : Plus de 40 % des individus avec un TSA présentent un TDAH associé.

• Complexité clinique : La combinaison des deux troubles entraîne une sévérité accrue des symptômes, une fatigue majeure (burnout autistique) et des profils sensoriels complexes.

• Prise en charge spécifique : L'approche doit être multidisciplinaire, privilégiant la psychoéducation et une pharmacologie prudente, tout en évitant le recours systématique aux antipsychotiques.

• Changement de paradigme : Il est crucial de passer d'une vision centrée sur le symptôme à une vision axée sur le fonctionnement global et la qualité de l'environnement.

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1. Analyse du Diagnostic et Prévalence

1.1 Évolution des Classifications

Avant 2013, le DSM-5 interdisait formellement le double diagnostic TSA et TDAH. Pourtant, la pratique clinique révélait déjà des patients présentant des caractéristiques marquées des deux troubles. Depuis la levée de cette interdiction, la littérature scientifique et l'expérience de terrain confirment une imbrication fréquente.

1.2 Statistiques de Cooccurrence

Les données actuelles mettent en évidence une asymétrie dans la comorbidité :

• TSA avec TDAH : Plus de 40 % des personnes autistes répondent également aux critères du TDAH.

• TDAH avec TSA : Environ 13 % à 20 % des personnes TDAH présentent des traits autistiques associés.

1.3 L'importance du Diagnostic Différentiel

Il est impératif de distinguer l'origine des symptômes pour éviter un empilement erroné de diagnostics. Par exemple :

• Les difficultés sociales du TDAH sont souvent liées à l'impulsivité ou l'inattention, tandis que dans le TSA, elles relèvent de la cognition sociale.

• Les troubles attentionnels du TSA sont souvent la conséquence d'une hyper-sensorialité ou d'intérêts restreints plutôt que d'un mécanisme TDAH intrinsèque.

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2. Manifestations Cliniques et Impacts Fonctionnels

L'association des deux troubles (ODHD) crée un tableau singulier où les symptômes s'influencent mutuellement, augmentant la sévérité globale.

| Domaine de fonctionnement | Impact de la cooccurrence TSA + TDAH | | --- | --- | | Fonctions Exécutives | Difficultés plus marquées (inhibition, flexibilité, attention) ; profil proche du TDAH isolé mais plus sévère. | | Cognition Sociale | Difficultés sociales accrues, contact visuel moindre et peu d'amélioration spontanée avec le temps. | | Sensorialité | Cumul des hypersensibilités ; profil sensoriel complexe et particulièrement intense. | | Santé Mentale | Risque accru de troubles dépressifs, troubles du sommeil, épuisement majeur et burnout autistique. | | Adaptation | Précarité économique plus importante et difficultés psychosociales majeures. |

2.1 La Question du "Trouble" vs "Fonctionnement"

Un point crucial de l'analyse est la distinction entre avoir un fonctionnement neurodivergent et présenter un trouble. Le trouble n'apparaît que lorsqu'il y a une répercussion fonctionnelle négative. Cette répercussion est étroitement liée à la qualité environnementale (par exemple, la personnalité d'un enseignant ou l'adaptation d'un poste de travail).

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3. Stratégies Thérapeutiques et Accompagnement

3.1 La Psychoéducation : Le Pilier Central

La psychoéducation doit être « sextuple » (incluant l'enfant, les parents et la fratrie). Ses objectifs sont de :

• Donner du sens aux symptômes.

• Mettre fin aux idées reçues et aux préjugés (notamment ceux des soignants).

• Réduire l'auto-stigmatisation et la culpabilité.

• Limiter le "masking" (suradaptation permanente), qui est une cause majeure d'épuisement et de burnout.

3.2 Approche Médicamenteuse (Méthylphénidate)

Le recours au méthylphénidate est possible mais nécessite une expertise clinique fine :

• Sensibilité accrue : Les patients TSA sont souvent hyper-sensibles aux substances (perception fine des changements corporels).

• Posologie : Il est recommandé de commencer par des doses très faibles (ex: 5 mg) et d'augmenter de manière très progressive.

• Vigilance : Surveiller l'augmentation potentielle des stéréotypies ou de l'irritabilité.

• Critique des pratiques : Le document dénonce comme une « hérésie » l'usage de première intention des antipsychotiques (type Haldol ou Risperdal) en France, au détriment du méthylphénidate.

3.3 La "Thérapie de Mamie" et Médiations Corporelles

L'hygiène de vie et le corps sont des leviers fondamentaux :

• Hygiène de vie : Régime méditerranéen, sommeil de qualité et régulation de l'exposition aux écrans.

• Activité physique : Présente une efficacité majeure prouvée par la littérature pour la régulation du TDAH.

• Régulation émotionnelle : Utilisation d'outils de cohérence cardiaque (ex: RespiRelax) pour agir sur le système nerveux autonome.

• Médiations alternatives : La musicothérapie et la danse-thérapie sont particulièrement efficaces car elles passent par les fréquences et le corps plutôt que par le langage verbal.

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4. Neurodiversité : Forces et Perspectives Évolutionnistes

Il est essentiel de ne pas réduire l'individu à ses symptômes mais de reconnaître les forces inhérentes à ces profils.

• Forces du TDAH : Empathie, créativité (issue des stratégies d'adaptation développées), curiosité, enthousiasme, intuition et rapidité.

• Forces du TSA : Précision, sérieux, honnêteté, respect des horaires et sens du détail.

• Lecture évolutionniste : La persistance des troubles du neurodéveloppement (TND) dans l'évolution humaine suggère leur utilité sociale. Par exemple, le TDAH pour l'exploration et la résolution de problèmes rapides, et le TSA pour la vigilance et l'expertise technique au sein d'un groupe.

Vers des environnements inclusifs

Le projet « Atipy Friendly » illustre la transition nécessaire vers une société (notamment l'université) capable de s'adapter à la singularité de ces fonctionnements, plutôt que d'exiger une suradaptation systématique des personnes concernées.

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Conclusion

Le profil TSA-TDAH (ODHD) nécessite une attention particulière et une coordination accrue entre les professionnels (psychomotriciens, pédopsychiatres, éducateurs).

L'enjeu n'est pas seulement de traiter des symptômes, mais de répondre aux besoins spécifiques de la personne pour favoriser son autonomie et sa qualité de vie, tout en valorisant les forces liées à sa neurodivergence.

Note de Synthèse : Réalités et Idées Reçues sur le Trouble Déficitaire de l'Attention avec ou sans Hyperactivité (TDAH)

Résumé Exécutif

Ce document synthétise les interventions d'experts — Franck Ramus (chercheur au CNRS), Magalie Laviel Guida (psychologue et orthophoniste) et Clément Freze (patient et illusionniste) — lors d'une table ronde consacrée au TDAH.

Les points clés à retenir sont les suivants :

• Définition Officielle : Le TDAH est un trouble neurodéveloppemental caractérisé par une inattention persistante et/ou une hyperactivité-impulsivité, impactant négativement le fonctionnement social, scolaire ou professionnel.

• Augmentation des Diagnostics : Il ne s'agit pas d'une "épidémie" mais d'une meilleure connaissance du trouble par les professionnels et le public, ainsi que d'une meilleure intégration dans les formations médicales.

• Origine et Histoire : Contrairement aux idées reçues, le TDAH n'est pas une invention de "Big Pharma" ; il est décrit par la médecine depuis la fin du XVIIIe siècle, bien avant la synthèse des premiers traitements.

• Prise en Charge : Le traitement pharmacologique (méthylphénidate) est efficace et non addictif, mais il doit s'insérer dans une approche pluridisciplinaire incluant les Thérapies Cognitivo-Comportementales (TCC), la psychomotricité et l'activité physique.

• Enjeux Sociaux : La France souffre d'un retard de diagnostic dû à une influence persistante de la psychanalyse et à des inégalités d'accès aux soins selon le milieu socio-économique.

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I. Définition et Cadre Clinique du TDAH

Le TDAH est classé par l'Organisation mondiale de la santé (OMS) dans la 11e version de la Classification internationale des maladies (CIM-11) parmi les troubles neurodéveloppementaux.

Les Deux Catégories de Symptômes

1. Inattention : Difficulté à maintenir sa concentration, distractibilité.

2. Hyperactivité et Impulsivité : Besoin de mouvement incessant, difficulté à inhiber les comportements inappropriés.

Bien que souvent combinées, ces catégories peuvent se manifester isolément.

Par exemple, le trouble de l'attention sans hyperactivité (TDA) est souvent plus discret et détecté tardivement par le biais des performances scolaires ou professionnelles.

Comorbidités Fréquentes

Le TDAH se présente rarement seul. Les experts soulignent la fréquence des troubles associés :

• Troubles neurodéveloppementaux : Autisme (TSA), dyslexie, troubles du langage, troubles de la coordination motrice.

• Troubles psychiatriques : Dépression, troubles anxieux généralisés, trouble bipolaire, trouble borderline.

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II. Déconstruction des Idées Reçues

La table ronde s'est attachée à invalider plusieurs mythes persistants dans l'opinion publique et certains milieux médicaux.

| Idée Reçue | Réalité Scientifique et Clinique | | --- | --- | | Diagnostic à la mode | L'augmentation des cas reflète une meilleure formation des professionnels et une sensibilisation accrue de la société. | | Invention de "Big Pharma" | Le trouble est décrit dès le XVIIIe et XIXe siècles (ex: cas de Mozart). Les médicaments n'ont été synthétisés qu'à partir des années 1940. | | Simple manque de volonté | Le TDAH est un trouble des fonctions cognitives (planification, régulation) et non un trait de caractère ou de la paresse. | | Faute des parents | Le comportement de l'enfant n'est pas causé par une "éducation défaillante" ; au contraire, le stress des parents est souvent une réaction au trouble de l'enfant. | | Disparition à l'âge adulte | Bien que les symptômes puissent s'atténuer ou repasser sous un seuil clinique, le trouble peut persister toute la vie. |

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III. Diagnostic et Parcours de Soins

Le Processus Diagnostique

Le diagnostic doit être posé par une équipe pluridisciplinaire et validé par un médecin (psychiatre ou pédopsychiatre). Il repose sur :

• Une batterie de tests évaluant les fonctions cognitives (planification, attention sélective et soutenue).

• Des examens médicaux complémentaires pour exclure d'autres pathologies (EEG, ECG, IRM, prises de sang).

• L'identification d'un impact négatif direct sur la vie quotidienne.

L'Opposition Psychanalytique en France

La France se distingue par une résistance culturelle forte issue de la psychanalyse, qui tend à interpréter le TDAH exclusivement sous l'angle de causes affectives ou relationnelles (ex: complexe d'Œdipe).

Cette approche engendre des retards de diagnostic et des erreurs d'orientation thérapeutique.

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IV. Stratégies Thérapeutiques

Approche Pharmacologique

Le méthylphénidate (Ritaline) est le traitement de première intention.

• Efficacité : Très élevée pour une grande proportion de patients.

• Sécurité : Molécule non addictive. Les effets secondaires (perte d'appétit, léger retard de croissance) sont modérés et gérables par un suivi médical.

• Usage : Permet souvent de briser le cercle vicieux de l'échec pour instaurer un cercle vertueux de réussite sociale et scolaire.

Thérapies Non Médicamenteuses

• TCC et Thérapie ACT : Travaillent sur l'acceptation des émotions, la régulation du comportement et la modification des schémas de pensée automatiques.

• Remédiation Cognitive : Travail spécifique sur la planification et l'organisation des tâches.

• Orthophonie : Intervient sur la pragmatique de la communication (respect des tours de parole, continuité thématique).

• Activité Physique : Le sport aide à canaliser l'hyperactivité, sécrète des endorphines et facilite le sommeil.

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V. Impacts Environnementaux et Sociaux

L'École comme Révélateur

Le milieu scolaire, par son exigence d'immobilité et de concentration prolongée, agit comme un révélateur des symptômes du TDAH.

Un enfant qui grimperait aux arbres en plein air pourrait ne pas être perçu comme "troublé", mais il devient "inadapté" dans une salle de classe.

Le Biais de Genre

Il existe un écart de diagnostic entre les sexes :

• Les garçons manifestent plus souvent une hyperactivité externe, jugée gênante, ce qui mène à un diagnostic rapide.

• Les filles peuvent présenter des symptômes plus "sages" ou intériorisés, ou être victimes de critères diagnostiques historiquement basés sur des comportements masculins.

Conséquences Socio-économiques

Le TDAH non traité a un impact négatif mesurable sur :

• La stabilité professionnelle (difficulté à garder un emploi).

• La gestion financière (achats impulsifs, oublis administratifs).

• La santé mentale globale (risque accru de harcèlement scolaire, anxiété, troubles du sommeil).

Conclusion

Le TDAH est une réalité clinique documentée nécessitant une approche scientifique et bienveillante.

L'accès au diagnostic reste inégal, dépendant fortement du milieu socio-économique et de la proximité avec des professionnels formés aux troubles neurodéveloppementaux (plateformes TND, associations de patients).

La réussite de la prise en charge repose sur la collaboration entre le patient, sa famille, les médecins et le corps enseignant.

父亲对所有我欢喜的鸡毛蒜皮的轻蔑, 让我对这个世界不敢再欢喜起来。

This BBC article reports on how false COVID‑19 cures and myths spread rapidly on social media. It’s a perfect example of misinformation because the people sharing these claims believed them to be true — there was no deliberate intent to deceive. An attentive reader can identify misinformation by noticing the lack of scientific evidence, the reliance on viral posts rather than expert sources, and the sensational tone of the claims. The article also contrasts these myths with verified medical guidance, making it clear that the falsehoods spread accidentally, not maliciously.

If Barbara Ann Kipfer were to make You Choose, how would she do it?

What kinds of episodes can I put into Her Best Friends?

Knowing just 'A' way of war, and which the vessels represent people, carcasses, and life bypassed for the destructive path they're now hoping another civilization takes off their hands, is very cunning indeed. But, instruction is only generational, whereas the conflict of promise eternal. The plague brought on by the explorer/settler was only poor management of mankind-like decision burdening civilization now.

As much an accusation of terror with power, than the message they were intent on, even oppressing in superiority. Excuse the broken adlibs

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SciCrunch record: RRID:IMSR_JAX:030600

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (Cell Signaling Technology Cat# 14074, RRID:AB_2650491)

Curator: @scibot

SciCrunch record: RRID:AB_2650491

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (ARP American Research Products Cat# 03-GP-K20, RRID:AB_1541036)

Curator: @scibot

SciCrunch record: RRID:AB_1541036

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (BD Biosciences Cat# 566490, RRID:AB_2869771)

Curator: @scibot

SciCrunch record: RRID:AB_2869771

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (BD Biosciences Cat# 610181, RRID:AB_397580)

Curator: @scibot

SciCrunch record: RRID:AB_397580

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (Agilent Cat# EC 3.2.1.17, RRID:AB_2341231)

Curator: @scibot

SciCrunch record: RRID:AB_2341231

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (Thermo Fisher Scientific Cat# BMS145, RRID:AB_10597738)

Curator: @scibot

SciCrunch record: RRID:AB_10597738

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (BD Biosciences Cat# 552848, RRID:AB_394489)

Curator: @scibot

SciCrunch record: RRID:AB_394489

What is this?

DOI: 10.1016/j.stem.2026.01.006

Resource: (Thermo Fisher Scientific Cat# 17-5791-82, RRID:AB_2716944)

Curator: @scibot

SciCrunch record: RRID:AB_2716944

What is this?

DOI: 10.1016/j.jbc.2026.111278

Resource: (ATCC Cat# CRL-4031, RRID:CVCL_K278)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_K278

What is this?

DOI: 10.1016/j.jbc.2026.111278

Resource: (RRID:CVCL_0498)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0498

What is this?

DOI: 10.1016/j.isci.2026.115000

Resource: (RRID:CVCL_0042)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0042

What is this?

DOI: 10.1016/j.isci.2026.114999

Resource: (KCB Cat# KCB 200848YJ, RRID:CVCL_0546)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0546

What is this?

DOI: 10.1016/j.isci.2026.114999

Resource: (RRID:CVCL_0291)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0291

What is this?

DOI: 10.1016/j.isci.2026.114996

Resource: RRID:IMSR_JAX:000664

Curator: @areedewitt04

SciCrunch record: RRID:IMSR_JAX:000664

What is this?

DOI: 10.1016/j.expneurol.2026.115681

Resource: RRID:IMSR_JAX:000664

Curator: @areedewitt04

SciCrunch record: RRID:IMSR_JAX:000664

What is this?

DOI: 10.1016/j.celrep.2026.116976

Resource: (RRID:CVCL_0063)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1016/j.celrep.2026.116976

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

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0493

What is this?

DOI: 10.1016/j.celrep.2026.116970

Resource: (IMSR Cat# JAX_005557,RRID:IMSR_JAX:005557)

Curator: @areedewitt04

SciCrunch record: RRID:IMSR_JAX:005557

What is this?

DOI: 10.1016/j.celrep.2026.116970

Resource: (ICLC Cat# HTL04003, RRID:CVCL_0312)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0312

What is this?

DOI: 10.1016/j.celrep.2026.116970

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

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0132

What is this?

DOI: 10.1016/j.celrep.2026.116970

Resource: (RRID:CVCL_0291)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0291

What is this?

DOI: 10.1016/j.celrep.2026.116970

Resource: (BCRJ Cat# 0110, RRID:CVCL_0317)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0317

What is this?

DOI: 10.1016/j.celrep.2026.116970

Resource: (RRID:CVCL_0062)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0062

What is this?

DOI: 10.1016/j.celrep.2026.116958

Resource: (RRID:CVCL_0063)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1016/j.ccell.2026.01.014

Resource: (RRID:CVCL_0063)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1016/j.ccell.2026.01.014

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

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0493

What is this?

DOI: 10.1016/j.ccell.2026.01.014

Resource: (NCBI_Iran Cat# C558, RRID:CVCL_0152)

Curator: @areedewitt04

SciCrunch record: RRID:CVCL_0152

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_55100

Curator: @scibot

SciCrunch record: RRID:BDSC_55100

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_8209

Curator: @scibot

SciCrunch record: RRID:BDSC_8209

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_7019

Curator: @scibot

SciCrunch record: RRID:BDSC_7019

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_7023

Curator: @scibot

SciCrunch record: RRID:BDSC_7023

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_56555

Curator: @scibot

SciCrunch record: RRID:BDSC_56555

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_6355

Curator: @scibot

SciCrunch record: RRID:BDSC_6355

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_2017

Curator: @scibot

SciCrunch record: RRID:BDSC_2017

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_30126

Curator: @scibot

SciCrunch record: RRID:BDSC_30126

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_83123

Curator: @scibot

SciCrunch record: RRID:BDSC_83123

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_52215

Curator: @scibot

SciCrunch record: RRID:BDSC_52215

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_6332

Curator: @scibot

SciCrunch record: RRID:BDSC_6332

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_81024

Curator: @scibot

SciCrunch record: RRID:BDSC_81024

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_32571

Curator: @scibot

SciCrunch record: RRID:BDSC_32571

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_56198

Curator: @scibot

SciCrunch record: RRID:BDSC_56198

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_28984

Curator: @scibot

SciCrunch record: RRID:BDSC_28984

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_44621

Curator: @scibot

SciCrunch record: RRID:BDSC_44621

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_5073

Curator: @scibot

SciCrunch record: RRID:BDSC_5073

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_28909

Curator: @scibot

SciCrunch record: RRID:BDSC_28909

What is this?

DOI: 10.15252/embr.202051716

Resource: RRID:BDSC_63819

Curator: @scibot

SciCrunch record: RRID:BDSC_63819

What is this?

DOI: 10.1091/mbc.E25-05-0228

Resource: RRID:Addgene_55158

Curator: @scibot

SciCrunch record: RRID:Addgene_55158

What is this?

DOI: 10.1088/2057-1976/ae34b3

Resource: PhysioNet (RRID:SCR_007345)

Curator: @scibot

SciCrunch record: RRID:SCR_007345

What is this?

DOI: 10.1084/jem.20251065

Resource: protein simple Cat# DM-002, RRID:AB_3095298

Curator: @scibot

SciCrunch record: RRID:AB_3095298

What is this?

DOI: 10.1084/jem.20251065

Resource: (Millipore Cat# MAB1501, RRID:AB_2223041)

Curator: @scibot

SciCrunch record: RRID:AB_2223041

What is this?

DOI: 10.1084/jem.20251065

Resource: (protein simple Cat# DM-001, RRID:AB_3095297)

Curator: @scibot

SciCrunch record: RRID:AB_3095297

What is this?

DOI: 10.1084/jem.20251065

Resource: (Abcam Cat# ab18251, RRID:AB_2210057)

Curator: @scibot

SciCrunch record: RRID:AB_2210057

What is this?

DOI: 10.1084/jem.20251065

Resource: (Molecular Probes Cat# A-21207, RRID:AB_141637)

Curator: @scibot

SciCrunch record: RRID:AB_141637

What is this?

DOI: 10.1084/jem.20251065

Resource: (AdipoGen Cat# AG-25B-0020, RRID:AB_2490454)

Curator: @scibot

SciCrunch record: RRID:AB_2490454

What is this?

DOI: 10.1084/jem.20251065

Resource: (Sigma-Aldrich Cat# F3165, RRID:AB_259529)

Curator: @scibot

SciCrunch record: RRID:AB_259529

What is this?

DOI: 10.1084/jem.20251065

Resource: GraphPad Prism (RRID:SCR_002798)

Curator: @scibot

SciCrunch record: RRID:SCR_002798

What is this?

DOI: 10.1084/jem.20251065

Resource: None

Curator: @scibot

SciCrunch record: RRID:Addgene_167018

What is this?

DOI: 10.1084/jem.20251065

Resource: RRID:Addgene_12259

Curator: @scibot

SciCrunch record: RRID:Addgene_12259

What is this?

DOI: 10.1084/jem.20251065

Resource: FASTX-Toolkit (RRID:SCR_005534)

Curator: @scibot

SciCrunch record: RRID:SCR_005534

What is this?

DOI: 10.1084/jem.20251065

Resource: RRID:Addgene_112895

Curator: @scibot

SciCrunch record: RRID:Addgene_112895

What is this?

DOI: 10.1084/jem.20251065

Resource: RRID:Addgene_73957

Curator: @scibot

SciCrunch record: RRID:Addgene_73957

What is this?

DOI: 10.1084/jem.20251065

Resource: LIMMA (RRID:SCR_010943)

Curator: @scibot

SciCrunch record: RRID:SCR_010943

What is this?

DOI: 10.1084/jem.20251065

Resource: (JCRB Cat# IFO50038, RRID:CVCL_0007)

Curator: @scibot

SciCrunch record: RRID:CVCL_0007

What is this?

DOI: 10.1084/jem.20251065

Resource: (RRID:CVCL_0063)

Curator: @scibot

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1084/jem.20250641

Resource: University of Chicago Functional Genomics Core Facility (RRID:SCR_019196)

Curator: @scibot

SciCrunch record: RRID:SCR_019196

What is this?

DOI: 10.1084/jem.20250641

Resource: University of Chicago Integrated Light Microscopy Core Facility (RRID:SCR_019197)

Curator: @scibot

SciCrunch record: RRID:SCR_019197

What is this?

DOI: 10.1084/jem.20250641

Resource: Emory University NIH Tetramer Core Facility (RRID:SCR_026557)

Curator: @scibot

SciCrunch record: RRID:SCR_026557

What is this?

DOI: 10.1084/jem.20250641

Resource: University of Chicago Human Tissue Resource Center Core Facility (RRID:SCR_019199)

Curator: @scibot

SciCrunch record: RRID:SCR_019199

What is this?

DOI: 10.1084/jem.20250607

Resource: UTHealth Houston Center for Advanced Microscopy Core Facility (RRID:SCR_025962)

Curator: @scibot

SciCrunch record: RRID:SCR_025962

What is this?

DOI: 10.1083/jcb.202510018

Resource: MATLAB (RRID:SCR_001622)

Curator: @scibot

SciCrunch record: RRID:SCR_001622

What is this?

DOI: 10.1083/jcb.202510018

Resource: (Santa Cruz Biotechnology Cat# sc-2354, RRID:AB_628490)

Curator: @scibot

SciCrunch record: RRID:AB_628490

What is this?

DOI: 10.1083/jcb.202510018

Resource: (Abcam Cat# ab9132, RRID:AB_307033)

Curator: @scibot

SciCrunch record: RRID:AB_307033

What is this?

DOI: 10.1083/jcb.202510018

Resource: Fiji (RRID:SCR_002285)

Curator: @scibot

SciCrunch record: RRID:SCR_002285

What is this?

DOI: 10.1083/jcb.202510018

Resource: (Roche Cat# 11814460001, RRID:AB_390913)

Curator: @scibot

SciCrunch record: RRID:AB_390913

What is this?

DOI: 10.1083/jcb.202507190

Resource: (Frontier Institute Cat# PSD95-Go, RRID:AB_2920798)

Curator: @scibot

SciCrunch record: RRID:AB_2920798

What is this?

DOI: 10.1083/jcb.202507190

Resource: (Frontier Institute Cat# PSD95-GP, RRID:AB_2571612)

Curator: @scibot

SciCrunch record: RRID:AB_2571612

What is this?

DOI: 10.1083/jcb.202507190

Resource: None

Curator: @scibot

SciCrunch record: RRID:AB_2895276

What is this?

DOI: 10.1083/jcb.202507190

Resource: (Frontier Institute Cat# Nlgn3-GP, RRID:AB_2571814)

Curator: @scibot

SciCrunch record: RRID:AB_2571814

What is this?