LIFE Magazine November 20, 1964<br /> Show of Toughness in Moscow

Reviewer #5 (Public Review):

After reading the manuscript and the concerns raised by reviewer 2 I see both sides of the argument - the relative location of trigeminal nucleus versus the inferior olive is quite different in elephants (and different from previous studies in elephants), but when there is a large disproportionate magnification of a behaviorally relevant body part at most levels of the nervous system (certainly in the cortex and thalamus), you can get major shifting in location of different structures. In the case of the elephant, it looks like there may be a lot of shifting. Something that is compelling is that the number of modules separated but the myelin bands correspond to the number of trunk folds which is different in the different elephants. This sort of modular division based on body parts is a general principle of mammalian brain organization (demonstrated beautifully for the cuneate and gracile nucleus in primates, VP in most of species, S1 in a variety of mammals such as the star nosed mole and duck-billed platypus). I don't think these relative changes in the brainstem would require major genetic programming - although some surely exists. Rodents and elephants have been independently evolving for over 60 million years so there is a substantial amount of time for changes in each l lineage to occur.

I agree that the authors have identified the trigeminal nucleus correctly, although comparisons with more out groups would be needed to confirm this (although I'm not suggesting that the authors do this). I also think the new figure (which shows previous divisions of the brainstem versus their own) allows the reader to consider these issues for themselves. When reviewing this paper, I actually took the time to go through atlases of other species and even look at some of my own data from highly derived species. Establishing homology across groups based only on relative location is tough especially when there appears to be large shifts in relative location of structures. My thoughts are that the authors did an extraordinary amount of work on obtaining, processing and analyzing this extremely valuable tissue. They document their work with images of the tissue and their arguments for their divisions are solid. I feel that they have earned the right to speculate - with qualifications - which they provide.

https://site.xavier.edu/polt/typewriters/nabokov.jpeg via https://site.xavier.edu/polt/typewriters/typers.html

This photo, similar to others in the Carl Mydans series for LIFE Magazine is surely from his September 1958 photo series, though I couldn't find an original from the LIFE archive.

Nabokov, reading off of index cards in his zettelkasten, dictates to his wife Vera who is typing on what appears to be a 1949 or 1950 Henry Dreyfuss Royal Quiet De Luxe typewriter.

Notice metal strip on the back of the typewriter with small rectangular blocks. This is the Royal's tabulator set up which distinguishes the Quiet De Luxe model from the Arrow model.

The body styling of this typewriter changed in 1950 from Dreyfuss' original 1948 design. Because it's light gray it has to be from '49 or '50 as the '48 original was a black body with dark gray highlights and didn't have chrome across the front as this one does in an alternate angle.

eLife assessment

The authors further corroborated their model that Netrin signaling promotes survival and dissemination of non-proliferating ovarian cancer cells. These valuable results were found to be of significant potential interest to cancer biologists in as much as they address gaps in knowledge pertinent to the mechanisms underpinning ovarian cancer spread. In general, it was thought that solid experimental evidence was provided to support the role of Netrin signaling in fueling ovarian cancer progression.

Joint Public Review:

In this article, the authors employed modified CRISPR screens ["guide-only (GO)-CRISPR"] in the attempt to identify the genes which may mediate cancer cell dormancy in the high grade serous ovarian cancer (HGSOC) spheroid culture models. Using this approach, they observed that abrogation of several of the components of the netrin (e.g., DCC, UNC5Hs) and MAPK pathways compromise survival of non-proliferative ovarian cancer cells. This strategy was complemented by the RNAseq approach which revealed that number of the components of the netrin pathway are upregulated in non-proliferative ovarian cancer cells, and that their overexpression is lost upon disruption of DYRK1A kinase that has been previously demonstrated to play a major role in survival of these cells. Perampalam et al. then employed a battery of cell biology approaches to support the model whereby the Netrin signaling governs the MEK-ERK axis to support survival of non-proliferative ovarian cancer cells. Moreover, the authors show that overexpression of Netrins 1 and 3 bolsters dissemination of ovarian cancer cells in the xenograft mouse model, while also providing evidence that high levels of the aforementioned factors are associated with poor prognosis of HGSOC patients.

Strengths:

In this valuable study Perampalam et al. developed a CRISPR-based screening approach to identify key genes that are enriched in high grade serous ovarian cancer spheroids. This led to a discovery that Netrin signaling plays a prominent role in survival of ovarian cancer cells. During revision, the authors provide additional evidence to support their central claims and to this end, it was found that they now provide solid evidence to substantiate the proposed model. This work is anticipated to be of interest to cancer biologists specializing in ovarian cancer biology.

Author response:

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

Reviewer #1 (Public Review):

Summary:

Perampalam et al. describe novel methods for genome-wide CRISPR screening to identify and validate genes essential for HGSOC spheroid viability. In this study, they report that Netrin signaling is essential for maintaining disseminated cancer spheroid survival, wherein overexpression of Netrin pathway genes increases tumor burden in a xenograft model of ovarian cancer. They also show that high netrin expression correlates with poor survival outcomes in ovarian cancer patients. The study provides insights into the biology of netrin signaling in DTC cluster survival and warrants development of therapies to block netrin signaling for treating serous ovarian cancer.

Strengths:

- The study identifies Netrin signaling to be important in disseminated cancer spheroid survival

- A Novel GO-CRISPR methodology was used to find key genes and pathways essential for disseminated cancer cell survival

Thanks for the endorsement of our work and its importance to metastasis in ovarian cancer.

Weaknesses:

- The term dormancy is not fully validated and requires additional confirmation to claim the importance of Netrin signaling in "dormant" cancer survival.

- Findings shown in the study largely relate to cancer dissemination and DTS survival rather than cancer dormancy.

Much of the validation of dormancy and cell cycle arrest in HGSOC spheroids, as well as the culture model, have been published previously and hence was not repeated here.  I think this reviewer will appreciate the updated citations and explanations to better illustrate the state of knowledge.  We have also added new experiments that further emphasize the dormant state of spheroid cells in culture and xenografts, as well as patient derived spheroids used in this study.

Reviewer #1 (Recommendations for Authors):

(1) It is unclear what spheroid/adherent enrichment ratio is and how it ties into genes affecting cell viability. Why is an ER below 1 the criteria for selecting survival genes?

Our screen uses the ‘guide only’ comparison in each culture condition to establish a gene score under that specific condition.  A low adherent score captures genes that are essential under standard culture conditions where cells are proliferating and this can include genes needed for proliferation or other basic functions in cell physiology.  A low spheroid score identifies the genes that are most depleted in suspension when cells are growth arrested and this is an indication of cell death in this condition.  Since gene knock outs are first established in adherent proliferating conditions, essential genes under these conditions will already start to become depleted from the population before suspension culture.  By selecting genes with a ratio of <1 we can identify those that are most relevant to dormant suspension culture conditions.  Ultimately, the lowest enrichment ratio scores represent genes whose loss of function is dispensable in the initial adherent condition, but critical for survival in suspension and this is what we aimed to identify. We’ve updated Figure 1B to illustrate this and we’ve updated the explanation of the enrichment ratio on page 6, lines 144 to 147 of the results.

(2) The WB for phospho-p38 in figure 1A for OVCAR8 line does not show increased phosphorylation in the spheroid relative to the adherent. If anything, phospho-p38 appears to be reduced in the spheroid. Can the authors provide a better western blot?

We’ve updated this blot with a longer exposure, see Figure 1A.  Phosphorylation levels of p38 are essentially unchanged in OVCAR8 cells in suspension culture, although the overall levels of p38 may be slightly reduced in dormant culture conditions.

(3) How did the authors confirm dormancy apart from western blot for phospho-ERK vs phospho-p38? Authors should add EdU/BrdU staining and/or Ki67 staining to confirm dormancy.

Previous publications that appear as citations 7,10, and 33 in the reference list established the growth arrest state of these cells in suspension culture in the past.  This included measuring other known markers of dormancy and quiescence such as p27, p130, and reduced cyclin/cdk activity and 3H-thymidine incorporation. In addition, other associated characteristics of dormancy such as EMT and catabolic metabolism have been demonstrated in these culture conditions (see citation 11 and Rafehi et al. Endocr. Relat. Cancer 23;147-59).  We’ve added these additional citations to our descriptions of dormant spheroid culture to better clarify the status of these cells in our experiments (see page 6, lines 126-28).  To ensure that cells are growth arrested in the experiments shown in this paper, we have updated Figure 1A to include blots of p130 and Ki67 to further emphasize that spheroid cells are not proliferating as the quiescence marker (p130) is high and the proliferative marker (Ki67) is lost in suspension culture.

(4) Can the authors report spheroid volume over time in culture? How was viability measured?

We’ve updated the methods (see page 27, line 574) to better highlight the description of cell survival that answers both of these questions. At the ends of experimental time points in both the screen and viability assays we captured live cells by replating on adherent plasticware. We fixed and stained with crystal violet and photographed plates to illustrate the sizes of spheroids (shown in Fig. 2 Supplement 1E, Fig. 6C, and 7D). We subsequently extracted the dye and quantitated it spectrophotometrically to quantitatively compare biomass of viable cells between experiments irrespective of the relatively random shapes of spheroids. We found reattachment and staining in this manner to match traditional viability assays such as CellTiter-Glo in a previous paper (10). Furthermore, biomass never increases in culture and diminishes gradually over time in culture consistent with the non-proliferative state of these experiments. Double checks of this equivalency of viability and reattached biomass measurments, as well as demonstrating that biomass is lost over time, are shown in Fig. 2 Supplement 1E that compares reattached crystal violet staining measurements with CellTiter-Glo for DYRK1A knock out cells over time in culture. In addition, we include a comparison of crystal violet staining of reattached spheroids with trypan blue dye exclusion in Fig. 5G and H. In both cases reattachment and more direct viability assays demonstrate the same conclusion that Netrin signaling supports viability in dormant culture.

(5) Please show survival significance of Netrin signaling genes in recurrence/relapse free survival to claim importance in cancer dormancy.

See Fig. 7 Supplement 1C where we include the recurrence free survival data. Netrin-1, and -3 high expressors also have a numerically shorter progression free survival but it is not statistically significant. Netrin-1 overexpression alone is also shown and it shows shorter survival with a P-value of 0.0735. Elevated survival of dormant cells in a residual disease state is expected to increase the chance of relapse and shorten this interval. Thus, this data is consistent with our model, but lacks statistical significance. 

There are many alternative ways to interpret what shorter progression free survival, or overall survival, may mean biologically. Since survival of dormant cells is but one of them, we also added new data to experimentally investigate the role of endogenous Netrin signaling in dormant residual disease in Fig. 6 and described on page 12, lines 266-87.  We used xenograft experiments to show OVCAR8 spheroids form and withdraw from the cell cycle equivalently to suspension culture following intraperitoneal injection.  Furthermore, loss of Netrin signaling due to receptor deletions compromises survival during this early window before disseminated lesions form.  This argues that Netrin signaling contributes to survival during this window of dormancy.  In addition, mice engrafted with mutant cells experience prolonged survival when Netrin signaling is blocked.  Together, these experiments further argue that Netrin signaling supports survival in the dormant, non-proliferative phase, and leads to reduced survival of mice.

(6) The authors show IHC staining of patient ascites derived HGSOC spheroids. However, no marker for dormancy is shown in these spheroids. Adding Ki67 staining or phospho-ERK vs phospho-p38 would be necessary to confirm cancer dormancy.

We have added new staining for Ki67 and p130 that compares these markers in HGSOC tumors where Ki67 is high and p130 is low with ascites derived spheroids where staining is the opposite. Importantly, expression of p130 is linked to cellular quiescence and is not found to accumulate in the nucleus of cells that are just transiting through G1.  This confirms that the ascites derived spheroids are dormant.  See Fig. 4A-E and described on page 9, lines 201-7.

(7) Overall, the findings are interesting in the context of cancer dissemination. There is not enough evidence for cancer dormancy and the importance of Netrin signaling in the survival of cancer dormancy. Overexpression of Netrin increases phosphorylation of ERK, leading one to expect an increase in proliferation. This suggests that Netrin breaks cancer cells out of dormancy, into a proliferative state.

We have found that the discovery of Netrin activation of MEK-ERK in growth arrested cells is counterintuitive to many cancer researchers.  However, this axis exists in other paradigms of Netrin signaling in axon outgrowth that are not proliferation related (see citation 26, Forcet et al. Nature 417; 443-7 as an example).  We have added Fig. 5D and descriptions on page 11, lines 244-52 to better clarify that Netrins CAN’T induce cell proliferation through ERK.  Addition of recombinant Netrin-1 can only induce ERK phosphorylation in suspension culture conditions and not in quiescent adherent conditions.  The small magnitude of ERK phosphorylation induced by Netrin-1 in suspension compared to treating adherent, quiescent cells with the same concentration of mitogenic EGF further emphasizes that this is not a proliferative signal.  Lastly, the new xenograft experiment in Fig. 6A-D (described on page 12, lines 266-81 demonstrates the growth arrested context in which Netrin signaling in dormant spheroids leads supports viability.

(8) If authors wish to claim cancer dormancy as the premise of their study, additional confirmatory experiments are required to support their claims. Alternatively, based on the current findings of the study, it would be best to change the premise of the article to Netrin signaling in cancer dissemination and survival of disseminated cancer spheroids rather than cancer dormancy.

I expect that this reviewer will agree that we have added more than sufficient explanations of background work on HGSOC spheroid dormancy from the literature, as well as new experiments that address their questions about dormancy in our experiments.

Reviewer #2 (Public Review):

Summary:

In this article, the authors employed modified CRISPR screens ["guide-only (GO)-CRISPR"] in the attempt to identify the genes which may mediate cancer cell dormancy in the high grade serous ovarian cancer (HGSOC) spheroid culture models. Using this approach, they observed that abrogation of several of the components of the netrin (e.g., DCC, UNC5Hs) and MAPK pathways compromise the survival of non-proliferative ovarian cancer cells. This strategy was complemented by the RNAseq approach which revealed that a number of the components of the netrin pathway are upregulated in non-proliferative ovarian cancer cells and that their overexpression is lost upon disruption of DYRK1A kinase that has been previously demonstrated to play a major role in survival of these cells. Perampalam et al. then employed a battery of cell biology approaches to support the model whereby the Netrin signaling governs the MEK-ERK axis to support survival of non-proliferative ovarian cancer cells. Moreover, the authors show that overexpression of Netrins 1 and 3 bolsters dissemination of ovarian cancer cells in the xenograft mouse model, while also providing evidence that high levels of the aforementioned factors are associated with poor prognosis of HGSOC patients.

Strengths:

Overall it was thought that this study is of potentially broad interest in as much as it provides previously unappreciated insights into the potential molecular underpinnings of cancer cell dormancy, which has been associated with therapy resistance, disease dissemination, and relapse as well as poor prognosis. Notwithstanding the potential limitations of cellular models in mimicking cancer cell dormancy, it was thought that the authors provided sufficient support for their model that netrin signaling drives survival of non-proliferating ovarian cancer cells and their dissemination. Collectively, it was thought that these findings hold a promise to significantly contribute to the understanding of the molecular mechanisms of cancer cell dormancy and in the long term may provide a molecular basis to address this emerging major issue in the clinical practice.

Thanks for the kind words about the importance of our work in the broader challenges of cancer treatment.

Weaknesses:

Several issues were observed regarding methodology and data interpretation. The major concerns were related to the reliability of modelling cancer cell dormancy. To this end, it was relatively hard to appreciate how the employed spheroid model allows to distinguish between dormant and e.g., quiescent or even senescent cells. This was in contrast to solid evidence that netrin signaling stimulates abdominal dissemination of ovarian cancer cells in the mouse xenograft and their survival in organoid culture. Moreover, the role of ERK in mediating the effects of netrin signaling in the context of the survival of non-proliferative ovarian cancer cells was found to be somewhat underdeveloped.

Experiments previously published in citation 7 show that growth arrest in patient ascites derived spheroids is fully reversible and that argued against non-proliferative spheroids being a form of senescence and moved this work into the dormancy field.  We have added extensive new support for our model systems and data to address the counterintuitive aspects of MEK-ERK signaling in survival instead of proliferation. 

Reviewer #1 Recommendations for Authors

(1) A better characterization of the spheroid model may be warranted, including staining for the markers of quiescence and senescence (including combining these markers with staining for the components of the netrin pathway)

See Figure 1A and page 6, lines 126-36 where we have added blots for Ki67 and p130 to better emphasize the arrested proliferative state of cells in our screening conditions.  We have also added these same controls for patient ascites-derived spheroids in Figure 4 and described on page 9, lines 203-7.  One realization from this CRISPR screen, and others in our lab, is that it identifies functionally important aspects of cell physiology and not necessarily ones that are easily explored using commercially available antibodies.  Netrin-1 and -3 staining of patient derived spheroids in Fig. 4, as well as cell line spheroids stained in Fig. 4 Supplement 1 further support the relevance of this pathway in dormant cancer cells because Netrins are expressed in the right place at the right time.  The Netrin-1 stimulation experiments in Fig. 5C were originally carried out to probe HGSOC cells for functionality of Netrin receptors since we couldn’t reliably detected them by blotting or staining with available antibodies.  This demonstrates that this pathway is active in the various HGSOC cell lines we’ve used and specifically, using OVCAR8 cells, we show it is only active in suspension culture conditions.

(2) In figure 1A it appears that total p38 levels are reduced in some cell lines in spheroid vs. adherent culture. The authors should comment on this.

These blots have been updated to be more clear.  Overall p38 levels may be reduced in some cell lines and when compared with activation levels of phosphorylated p38 it suggests the fraction of activated p38 is higher. OVCAR8 cells may be an exception where the overall activity level remains approximately the same.

(3) The authors should perhaps provide a clearer rationale for choosing to focus on the netrin signaling vs. e.g., GPCR signaling, and consider more explicit defining of "primary" vs. "tertiary" categories in Reactome gene set analysis.

We’ve updated Fig. 1E and the text on page7, lines 161-5 to illustrate which gene categories identified in the screen belong to which tiers of Reactome categories. It better visualizes why we have investigated the Axon guidance pathway that includes Netrin because it is a highly specific signaling pathway that scores similarly to the broader and less specific categories at the very top of the list. As an aside, the GPCR signaling and GPCR downstream signaling have proven to be fairly intractable categories.  As best we can tell the GPCR downstream signaling category is full of MAPK family members and likely represents some redundancy with MAPK further down.  

(4) In figure 3A-C, including factors whose expression did not appear to change between adherent and suspension conditions may be warranted as the internal control. Figure 3D-F may benefit from some sort of quantification.

The mRNA expression levels are normalized to GAPDH as an internal control. We have updated this figure and re-plotted it as fold change relative to adherent culture cells with statistical comparisons to indicate which are significantly upregulated in suspension culture.

The IHC experiments are now in Fig. 4D-F and show positive staining for Netrin-1 and -3.  Netrin-3 is easiest to see, while Netrin-1 is trickier because the difference with the no primary antibody control isn’t intensity, but the tint of the DAB stain.  We had to counter stain the patient spheroids with Hematoxylin in order for the slide scanner to find the best focal plane and make image registration between sections possible.  This unfortunately makes the Netrin-1 staining rather subtle.  For cell line spheroids in the Fig. 4, Supplement 1 we didn’t need the slide scanner and show negative controls without counter stain that are much more convincing of Netrin-1 detection and reassure us that our staining detects the intended target.  We’ve updated the labels in Fig. 4 and Fig. 4, Supplement 1 for this to be more intuitive.  Unfortunately, relying on the tint of the DAB stain leaves this as a qualitative experiment.

- In figure 4C-E the authors show that Netrin-1 stimulation induces ERK phosphorylation whereby it is argued that this is a "low-level" stimulation of ERK signaling required for the survival of ovarian cells in the suspension. This is however hard to appreciate, and it was thought that having adherent cells in parallel would be helpful to wage whether this indeed is a "low level" ERK activity. Moreover, the authors should likely include downstream substrates of ERK (e.g., RSKs) as well as p38 in these experiments. The control experiments for the effects of PD184352 on ERK phosphorylation also appear to be warranted. Finally, performing the experiments with PD184352 in the presence of Netrin-1 stimulation would also be advantageous.

We have added a new Netrin-1 stimulation experiment in Fig. 4D (described on page 11, line 244-52) that shows that Netrins can only activate  very low levels of ERK phosphorylation in suspension when proliferation is arrested. Netrin-1 stimulation of quiescent adherent cells where stimulation of proliferation is possible shows that Netrins are unable to activate ERK phosphorylation in this condition.  In contrast, we also stimulate quiescent adherent OVCAR8 cells with an equal concentration of EGF (a known mitogen) to offer high level ERK phosphorylation as a side by side comparison.  I think that this offers clear evidence that Netrin signaling is inconsistent with inducing cell proliferation.  We’ve also updated citations in the introduction to include citation 26 that offers a previously reported paradigm of Netrin-ERK signaling in axon outgrowth that is a non-cancer, non-proliferative context to remind readers that Netrins utilize MEK-ERK differently. 

We highlight Netrin-MEK-ERK signaling as key to survival for a number of reasons.  First, Netrin signaling in this paradigm does not fit the dependence receptor paradigm where loss of Netrin receptors protect against cell death.  Fig. 5B rules this out as receptor loss never offers a survival advantage, but clearly receptor deletions compromise survival in suspension culture.  Second, positive Netrin signaling is known to support survival by inactivating phosphorylation of DAPK1.  We’ve added this experiment as Fig. 5 Supplement 1D and show that loss of Netrin receptors doesn’t reduce DAPK1 phosphorylation in a time course of suspension culture.  Consequently, we conclude this isn’t the survival signal either.  Since MEK and ERK family members scored in our screen, we investigated their role in survival.  We now show two different MEK inhibitors with different inhibitory mechanisms to confirm that MEK inhibition induces cell death. In addition to the previous PD184352 inhibitor in our first submission, we’ve added Trametinib as well and this is shown in Fig. 5G.  Since it is surprising the MEK inhibition can kill instead of just arrest proliferation, we’ve also added another cell death assay in which we show trypan blue dye exclusion as a second look at survival.  This is now Fig. 5H.  Lastly, we include Trametinib inhibition of ERK phosphorylation in these assays in Fig. 5I.  While we leave open what takes place downstream of ERK, our model in Fig. 5J offers a very detailed look at the components upstream.

- Does inhibition of ERK prevent the abdominal spread of ovarian cancer cells? The authors may feel that this is out of the scope of the study, which I would agree with, but then the claims regarding ERK being the major mediator of the effects of netrin signaling should be perhaps slightly toned down.

We agree that loss of function xenograft experiments will enhance our discovery of Netrin’s role in dormancy and metastasis.  We have added a new Fig. 6 that uses xenografts with Netrin receptor deficient OVCAR8 cells (UNC5 4KO).  It demonstrates that two weeks following IP engraftment we can isolate spheroids from abdominal washes and that cells have entered a state of reduced proliferation as determined by lowered Ki67 expression as well as other proliferation inducing genes.  In the case of UNC5 4KO cells, there is significant attrition of these cells as determined by recovering spheroids in adherent culture (Fig.6C) and by Alu PCR to detect human cells in abdominal washes (Fig. 6D).  Lastly, xenografts of UNC5 4KO cells cause much less aggressive disease and significantly extend survival of these mice (Fig. 6E,F).  Not exactly the experiment that the reviewer is asking for, but a clear indication that Netrin signaling supports survival in xenograft model of dormancy.

- Notwithstanding that this could be deduced from figures 6D and F, it would be helpful if the number of mice used in each experimental group is clearly annotated in the corresponding figure legends. Moreover, indicating the precise statistical tests that were used in the figures would be helpful (e.g., specifying whether anova is one-way, two-way, or?)

We have added labels to what is now Fig. 8B to indicate the number of animals used for each genotype of cells.  We have also updated figure legends to include more details of statistical tests used in each instance.

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https://images.google.com/hosted/life/2bff56953d14c9d9.html

Nabokov, reflected in a mirror off camera, dictating his writing from index cards to his wife Vera who is typing on what appears to be a 1949 or 1950 Henry Dreyfuss Royal Quiet De Luxe typewriter.

Notice the chrome on the front of the machine which is sitting in its bottom case shell.

https://images.google.com/hosted/life/c835f121c2b6ce79.html

Nabokov dictating his writing from index cards to his wife Vera who is typing on what appears to be a 1949 or 1950 Henry Dreyfuss Royal Quiet De Luxe typewriter.

https://images.google.com/hosted/life/8d0b2f02ac27973e.html

Nabokov dictating his writing from index cards to his wife Vera who is typing on what appears to be a 1949 or 1950 Henry Dreyfuss Royal Quiet De Luxe typewriter.

Reviewer #2 (Public Review):

Summary:

The manuscript by Gitanjali Roy et al. applies deep transfer learning (DEGAS) to assign patient-level disease attributes (metadata) to single cells of T2D and non-diabetic patients, including obese patients. This led to the identification of a singular cluster of T2D-associated β-cells; and two subpopulations of obese- β-cells derived from either non-diabetic or T2D donors. The objective was to identify novel and established genes implicated in T2D and obesity. Their final goal is to validate their findings at the protein level using immunohistochemistry of pancreas tissue from non-diabetic and T2D organ donors.

Strengths:

This paper is well-written, and the findings are relevant for β-cell heterogeneity in T2D and obesity.

Weaknesses:

The validation they provide is not sufficiently strong: no DLK1 immunohistochemistry is shown of obese patient-derived sections. Additional presumptive relevant candidates from this transcriptomic analysis should be screened for, at the protein level.

eLife assessment

This is a useful study that used DEGAS, a deep transfer learning tool, to identify distinct pancreatic beta cell subpopulations that could be associated with type 2 diabetes (T2D) and/or obesity status. The data supporting the authors' findings is solid and demonstrates that DEGAS will be a helpful tool for analyzing cell-specific transcriptomic phenotypes. This study will be of interest to researchers studying the genetics of T2D.

Reviewer #1 (Public Review):

In this manuscript, Roy et al. used the previously published deep transfer learning tool, DEGAS, to map disease associations onto single-cell RNA-seq data from bulk expression data. The authors performed independent runs of DEGAS using T2D or obesity status and identified distinct β-cell subpopulations. β-cells with high obese-DEGAS scores contained two subpopulations derived largely from either non-diabetic or T2D donors. Finally, immunostaining using human pancreas sections from healthy and T2D donors validated the heterogeneous expression and depletion of DLK1 in T2D islets.

Strengths:

(1) This meta-analysis of previously published scRNA-seq data using a deep transfer learning tool.

(2) Identification of novel beta cell subclusters.

(3) Identified a relatively innovative role of DLK1 in T2D disease progression.

Weaknesses:

(1) There is little overlap of the DE list of bulk RNA-seq analysis in Figure 1D and 1E overlap with the DE list of pseudo-bulk RNA-seq analysis of all cells in Figure S2C.

(2) The biological meaning of "beta cells had the lowest scores compared to other cell types" is not clear.

(3) The figures and supplemental figures were not cited following the sequence, which makes the manuscript very difficult to read. Some supplemental figures, such as Figures S1C-S1D, S2B-S2E, S3A-S3B, were not cited or mentioned in the text.

(4) In Figure 7, the current resolution is too low to determine the localization of DLK1.

Author response:

Public Reviews:

Reviewer #1 (Public Review):

Summary:

In this manuscript, Roy et al. used the previously published deep transfer learning tool, DEGAS, to map disease associations onto single-cell RNA-seq data from bulk expression data. The authors performed independent runs of DEGAS using T2D or obesity status and identified distinct β-cell subpopulations. β-cells with high obese-DEGAS scores contained two subpopulations derived largely from either non-diabetic or T2D donors. Finally, immunostaining using human pancreas sections from healthy and T2D donors validated the heterogeneous expression and depletion of DLK1 in T2D islets.

Strengths:

(1) This meta-analysis of previously published scRNA-seq data using a deep transfer learning tool.

(2) Identification of novel beta cell subclusters.

(3) Identified a relatively innovative role of DLK1 in T2D disease progression.

We thank the reviewer for their constructive critiques and positive feedback. We hope to further apply deep transfer learning tools in future scRNA-seq meta-analyses.

Weaknesses:

(1) There is little overlap of the DE list of bulk RNA-seq analysis in Figure 1D and 1E overlap with the DE list of pseudo-bulk RNA-seq analysis of all cells in Figure S2C.

We thank the reviewer for this insightful thought and plan to perform additional analyses and comparisons to address this comment.

(2) The biological meaning of "beta cells had the lowest scores compared to other cell types" is not clear.

We agree with the reviewer and will amend this statement to clarify in the revised manuscript. In summary, the relatively lower T2D-DEGAS scores for beta cells overall compared to all other cell types (alpha cells, acinar cells, etc) reflects the fact that in T2D, beta cell-specific genes can be downregulated. This is also possibly due to beta cell loss in T2D and would be reflected in bulk islet RNAseq data. This affects the DEGAS model which is reflected in the scores of all cells in the scRNA-seq data (Fig 3A). For this reason, subsetting the beta cells and replotting them on their own (Fig 4B) is an important step to identify relative differences in DEGAS scores between different subsets of beta cells.

(3) The figures and supplemental figures were not cited following the sequence, which makes the manuscript very difficult to read. Some supplemental figures, such as Figures S1C-S1D, S2B-S2E, S3A-S3B, were not cited or mentioned in the text.

We apologize and thank the reviewer for pointing out these errors. All of the annotated errors will be amended in the revised manuscript.

(4) In Figure 7, the current resolution is too low to determine the localization of DLK1.

We will include the original highest-resolution confocal images in our resubmission. We will also improve the color combination to improve visibility of colocalization of DLK1 with Insulin.

Reviewer #2 (Public Review):

Summary:

The manuscript by Gitanjali Roy et al. applies deep transfer learning (DEGAS) to assign patient-level disease attributes (metadata) to single cells of T2D and non-diabetic patients, including obese patients. This led to the identification of a singular cluster of T2D-associated β-cells; and two subpopulations of obese- β-cells derived from either non-diabetic or T2D donors. The objective was to identify novel and established genes implicated in T2D and obesity. Their final goal is to validate their findings at the protein level using immunohistochemistry of pancreas tissue from non-diabetic and T2D organ donors.

Strengths:

This paper is well-written, and the findings are relevant for β-cell heterogeneity in T2D and obesity.

We thank the reviewer for their constructive critiques and positive feedback. We believe this study can improve our understanding β-cell heterogeneity in the context of T2D and obesity.

Weaknesses:

The validation they provide is not sufficiently strong: no DLK1 immunohistochemistry is shown of obese patient-derived sections. Additional presumptive relevant candidates from this transcriptomic analysis should be screened for, at the protein level.

Thank the reviewer for this suggestion. We are planning to perform new immunostaining of DLK1 in human pancreas tissue sections from non-diabetic lean, non-diabetic obese, T2D lean, and T2D obese donors. We also note that Table S6 contains the patient metadata for the pancreas samples we show in the current manuscript. Two of the T2D donors have BMI > 30 (obese). However, the non-diabetic donors have BMI between 26-29. Our new planned studies should address the question of differential DLK1 expression / beta cell heterogeneity in the context of both diabetes and obesity.

handle time travel for you

https://typewriterchicago.com/

Run by Lucas Dul

Typewriter 101: The ULTIMATE TYPEFACE Guide (ft. Typewriter Chicago) by [[Just My Typewriter]]

featuring Typewriter Chicago's Lucas Dul

Ajouter un bouton : annuaire des acteurs en région avec lien vers la base de donnée + faire des liens de renvoi depuis chaque page acteur (agriculteur, collectivité) vers l'annuaire

Résumé de la vidéo [00:00:00][^1^][1] - [00:29:12][^2^][2]:

François Dubet discute du déclin de l'institution scolaire et des conflits de principes qui en découlent. Il aborde les changements dans la perception de l'école, l'impact de la logique utilitariste, et la transformation du rôle des enseignants dans une société où l'éducation est devenue un marché compétitif. Dubet souligne également le défi de concilier les objectifs contradictoires de l'éducation et plaide pour une réforme qui reconnaît la complexité de ces enjeux.

Points forts: + [00:00:00][^3^][3] Changements dans l'école * L'école vue comme un lieu de vie juvénile * L'envahissement de l'école par une logique utilitariste * La transformation de l'école en marché + [00:07:02][^4^][4] Rôle des enseignants * Les enseignants confrontés à de nouvelles attentes * La nécessité pour les enseignants de motiver et d'être motivés * La difficulté croissante du métier d'enseignant + [00:14:21][^5^][5] Objectifs contradictoires de l'éducation * Le désir d'une culture commune et la sélection des meilleurs * L'autonomie des élèves versus leur placement dans la société * La guerre des dieux de Weber et les désirs incompatibles + [00:21:01][^6^][6] Réforme de l'éducation * La nécessité d'une institution démocratique modeste * La réforme des systèmes scolaires indépendamment des lois de la mondialisation * L'appel à une école plus modeste et de meilleure qualité

Résumé de la vidéo [00:29:14][^1^][1] - [00:50:30][^2^][2]:

François Dubet discute du déclin de l'institution scolaire et des conflits de principes, en se concentrant sur la nécessité d'une négociation démocratique dans les écoles et l'importance de l'apprentissage et de l'intelligence. Il souligne que l'école doit rester un lieu d'apprentissage et non se transformer en un espace pour la culture juvénile. Dubet plaide pour une massification scolaire qui permet à tous d'accéder à l'éducation, tout en reconnaissant que cela n'a pas réduit les inégalités. Il propose une école modeste qui ne porte pas toute la responsabilité de la justice sociale et où l'échec scolaire n'est pas stigmatisé.

Points forts: + [00:29:14][^3^][3] Autonomie et contrôle dans l'éducation * La liberté et le contrôle doivent être équilibrés * Les droits des élèves sont importants, mais pas égaux à ceux des enseignants * La négociation démocratique est essentielle dans l'établissement scolaire + [00:32:12][^4^][4] Massification de l'éducation * La massification scolaire a augmenté le niveau général, sans réduire les inégalités * Les différences entre les types de baccalauréat sont devenues fondamentales * La nature de l'école a changé avec la massification + [00:38:11][^5^][5] Motivation et culture juvénile * La motivation est le principal défi pour les élèves * L'école doit rester centrée sur l'apprentissage et éviter d'adopter la culture juvénile * Les élèves veulent devenir plus intelligents et trouvent difficile de se motiver + [00:43:45][^6^][6] Réformisme et changement dans l'éducation * Le courage réside dans le réformisme plutôt que dans le radicalisme * Les changements doivent être pragmatiques et progressifs * L'école doit s'adapter aux nouvelles manières de travailler et aux conditions de travail

Résumé de la vidéo [00:00:20][^1^][1] - [00:31:07][^2^][2] : La vidéo présente une conférence de François Dubet sur le déclin de l'institution scolaire et les conflits de principes. Dubet explore l'évolution de l'école, son rôle dans la société et les défis auxquels elle est confrontée. Il discute de la manière dont l'école est perçue comme déclinante malgré son importance croissante dans la vie sociale et son rôle dans la détermination de l'avenir des individus.

Points forts : + [00:07:01][^3^][3] Thèse du déclin de l'institution scolaire * Paradoxe entre l'importance accrue de l'école et l'idée de son déclin * L'école comme institution de socialisation et son rôle historique * Influence de l'église sur l'éducation et la transition vers la laïcité + [00:20:11][^4^][4] L'école républicaine et ses principes * Principes sacrés de l'école : nation, raison, progrès * L'instituteur comme incarnation des valeurs républicaines * L'école comme sanctuaire protégé des influences extérieures + [00:27:49][^5^][5] Conception de l'élève et de l'éducation * Distinction entre l'élève (être de raison) et l'enfant (être de passion) * L'école s'adresse à l'élève, excluant les aspects non académiques de l'enfant * L'obéissance à la discipline scolaire comme moyen d'élévation vers la raison

Résumé de la vidéo [00:31:11][^1^][1] - [00:42:28][^2^][2]:

François Dubet discute du déclin de l'institution scolaire et des conflits de principes. Il aborde la perte de légitimité des institutions éducatives, l'impact de la modernité et du désenchantement, ainsi que les défis posés par la massification scolaire et l'intégration des problèmes sociaux dans l'école.

Points forts: + [00:31:11][^3^][3] Perte de légitimité de l'école * L'école ne fonctionne plus comme avant * Les principes sacrés perdent de leur influence + [00:34:01][^4^][4] Défis de la modernité * La notion d'école de la nation est remise en question * L'école est vue comme un moyen d'acquérir du capital humain + [00:35:00][^5^][5] Impact des médias et de la culture * Les médias remettent en cause le monopole culturel de l'école * L'école doit rivaliser avec les médias pour l'attention des élèves + [00:38:02][^6^][6] Massification scolaire et intégration des problèmes sociaux * L'école doit faire face à une diversité croissante d'élèves * Les problèmes sociaux entrent dans l'école avec la massification

Sunset Strolls and Scenic Drives: Capturing Towns County Summer Beauty

eLife assessment

ProtSSN is a valuable approach that generates protein embeddings by integrating sequence and structural information, demonstrating improved prediction of mutation effects on thermostability compared to sequence-only models. The work is currently incomplete as it lacks a thorough comparison against other recent top-performing methods that also incorporate structural data, such as SaProt, EVE-based models, and GEMME. Providing a comprehensive analysis benchmarking ProtSSN against these state-of-the-art structure-based approaches would significantly strengthen the evidence supporting the utility of ProtSSN's joint sequence-structure representations.

Reviewer #1 (Public Review):

Summary:

The authors introduce a denoising-style model that incorporates both structure and primary-sequence embeddings to generate richer embeddings of peptides. My understanding is that the authors use ESM for the primary sequence embeddings, take resolved structures (or use structural predictions from AlphaFold when they're not available), and then develop an architecture to combine these two with a loss that seems reminiscent of diffusion models or masked language model approaches. The embeddings can be viewed as ensemble-style embedding of the two levels of sequence information, or with AlphaFold, an ensemble of two methods (ESM+AlphaFold). The authors also gather external datasets to evaluate their approach and compare it to previous approaches. The approach seems promising and appears to out-compete previous methods at several tasks. Nonetheless, I have strong concerns about a lack of verbosity as well as the exclusion of relevant methods and references.

Advances:

I appreciate the breadth of the analysis and comparisons to other methods. The authors separate tasks, models, and sizes of models in an intuitive, easy-to-read fashion that I find valuable for selecting a method for embedding peptides. Moreover, the authors gather two datasets for evaluating embeddings' utility for predicting thermostability. Overall, the work should be helpful for the field as more groups choose methods/pretraining strategies amenable to their goals, and can do so in an evidence-guided manner.

Considerations:

Primarily, a majority of the results and conclusions (e.g., Table 3) are reached using data and methods from ProteinGym, yet the best-performing methods on ProteinGym are excluded from the paper (e.g., EVE-based models and GEMME). In the ProteinGym database, these methods outperform ProtSSN models. Moreover, these models were published over a year---or even 4 years in the case of GEMME---before ProtSSN, and I do not see justification for their exclusion in the text.

Secondly, related to the comparison of other models, there is no section in the methods about how other models were used, or how their scores were computed. When comparing these models, I think it's crucial that there are explicit derivations or explanations for the exact task used for scoring each method. In other words, if the pre-training is indeed an important advance of the paper, the paper needs to show this more explicitly by explaining exactly which components of the model (and previous models) are used for evaluation. Are the authors extracting the final hidden layer representations of the model, treating these as features, and then using these features in a regression task to predict fitness/thermostability/DDG etc.? How are the model embeddings of other methods being used, since, for example, many of these methods output a k-dimensional embedding of a given sequence, rather than one single score that can be correlated with some fitness/functional metric? Summarily, I think the text lacks an explicit mention of how these embeddings are being summarized or used, as well as how this compares to the model presented.

I think the above issues can mainly be addressed by considering and incorporating points from Li et al. 2024[1] and potentially Tang & Koo 2024[2]. Li et al.[1] make extremely explicit the use of pretraining for downstream prediction tasks. Moreover, they benchmark pretraining strategies explicitly on thermostability (one of the main considerations in the submitted manuscript), yet there is no mention of this work nor the dataset used (FLIP (Dallago et al., 2021)) in this current work. I think a reference and discussion of [1] is critical, and I would also like to see comparisons in line with [1], as [1] is very clear about what features from pretraining are used, and how. If the comparisons with previous methods were done in this fashion, this level of detail needs to be included in the text.

To conclude, I think the manuscript would benefit substantially from a more thorough comparison of previous methods. Maybe one way of doing this is following [1] or [2], and using the final embeddings of each method for a variety of regression tasks---to really make clear where these methods are performing relative to one another. I think a more thorough methods section detailing how previous methods did their scoring is also important. Lastly, TranceptEVE (or a model comparable to it) and GEMME should also be mentioned in these results, or at the bare minimum, be given justification for their absence.

[1] Feature Reuse and Scaling: Understanding Transfer Learning with Protein Language Models<br /> Francesca-Zhoufan Li, Ava P. Amini, Yisong Yue, Kevin K. Yang, Alex X. Lu<br /> bioRxiv 2024.02.05.578959; doi: https://doi.org/10.1101/2024.02.05.578959

[2] Evaluating the representational power of pre-trained DNA language models for regulatory genomics<br /> Ziqi Tang, Peter K Koo<br /> bioRxiv 2024.02.29.582810; doi: https://doi.org/10.1101/2024.02.29.582810

Reviewer #2 (Public Review):

Summary:

To design proteins and predict disease, we want to predict the effects of mutations on the function of a protein. To make these predictions, biologists have long turned to statistical models that learn patterns that are conserved across evolution. There is potential to improve our predictions however by incorporating structure. In this paper, the authors build a denoising auto-encoder model that incorporates sequence and structure to predict mutation effects. The model is trained to predict the sequence of a protein given its perturbed sequence and structure. The authors demonstrate that this model is able to predict the effects of mutations better than sequence-only models.

As well, the authors curate a set of assays measuring the effect of mutations on thermostability. They demonstrate their model also predicts the effects of these mutations better than previous models and make this benchmark available for the community.

Strengths:

The authors describe a method that makes accurate mutation effect predictions by informing its predictions with structure.

Weaknesses:

It is unclear how this model compares to other methods of incorporating structure into models of biological sequences, most notably SaProt (https://www.biorxiv.org/content/10.1101/2023.10.01.560349v1.full.pdf).

ProteinGym is largely made of deep mutational scans, which measure the effect of every mutation on a protein. These new benchmarks contain on average measurements of less than a percent of all possible point mutations of their respective proteins. It is unclear what sorts of protein regions these mutations are more likely to lie in; therefore it is challenging to make conclusions about what a model has necessarily learned based on its score on this benchmark. For example, several assays in this new benchmark seem to be similar to each other, such as four assays on ubiquitin performed at pH 2.25 to pH 3.0.

Ajouter des parties thématiques sur webinaires faits (acceptabilité territoriale, sujet 2 manquant, sujet 3, etc.) : - Comment favoriser une meilleure acceptabilité des projets : https://www.youtube.com/@methan-action9015

Drive slower when there is a heavy traffic or bad weather

Move to the right if someone behind you wants to drive faster

Diamond shape signs means that the truck has dangerous loads such as gas or explosives

Drivers must move over and slow down for emergency and road work vehicles

Stationary emergency vehicles or tow trucks

Stopped road work vehicles

Fines for traffic violations in a work zone can be 1000 or more

Anyone convicted of assaulting a highway worker faces fines of up to $2,000 and imprisonment for up to one year.

https://www.phillytypewriter.com/parts-mfg.html#/

James Norris does 3D printing of replacement parts for typewriter restoration projects.

I take this to mean that with games, we have control. However, I don't understand how other art forms lack agency. Unless I have the definition of 'agency' wrong. I believed art to be fully in the hands of the artist and they can send whatever message they wish. What does this line mean? Or does it mean that the control is given fully to the observer/ audience?

This reminds me of something I read a while ago online, about likes on an Instagram post. If you were to go out one day and one person complements you or your outfit, that one compliment would probably make your day. If you post something on Instagram and it gets 10 likes, you probably would be upset. At least most people would be.

Nowadays, people including myself, just randomly like posts on Instagram. Especially if they are posted by people I follow, I will like it without really paying attention to it. I despise snakes and if a celebrity I follow were to post their pet snake, I would probably like it and scroll away really quickly. But in real life if a friend were to show me a their snake, I would very obviously show that I do not like their snake.

Sometimes people online like things to just like things. Sometimes a post moved them, sometimes it did not. I think one sure way to tell is if they comment. I only comment if a post really moves me. Unless it is a friend's post on instagram in which case I will comment "so beautiful heart eyes emoji". 99.999% of the time, I do mean it but there are times when I don't.

This is something we discussed in the first day of lecture. A lot of the time in college, even if we take a class because we find it interesting, instead of actually learning from the class, we treat it like a game of some sort. Just trying to earn the highest score possible by looking up answers for homework instead of working on the problems. In a math class, our goal may be to become a mathematician by learning and improving our math skills, but when deadlines approach, we opt for looking up answers to the homework questions designed to help us learn. Which might give us the highest score/grade, but now our goals are "collapsed down to scoring systems".

The dialogue around this idea brings up the concept of mindfulness and intention again, saying that with video games, you have the choice to take a break from them or switch to another game, but in a gamified reality, we cannot take a step back from life. In a way, I think that it it up to each individual to ask themselves these types of questions C. Thi Nguyen asks himself, such as "was that worthwhile? was that interesting?" etc. Society perhaps was not as "gamified," but humanity has always "funneled" our values down one "particular pre-established path" in a way. Humans are social and certain things are socially acceptable and some are deemed frowned upon. Nothing will be universally agreed upon, but social pressure itself, not just gamification, has contributed to this issue.

I take this to mean that with games, we have control. However, I don't understand how other art forms lack agency. Unless I have the definition of 'agency' wrong. I believed art to be fully in the hands of the artist and they can send whatever message they wish. What does this line mean? Or does it mean that the control is given fully to the observer/ audience?

Very similar to what was said earlier about how point systems can water down our complex and multi layered goals. This is just another example of how point systems cause us to be played instead of playing them.

This reminds me of something I read a while ago online, about likes on an Instagram post. If you were to go out one day and one person complements you or your outfit, that one compliment would probably make your day. If you post something on Instagram and it gets 10 likes, you probably would be upset. At least most people would be.

Nowadays, people including myself, just randomly like posts on Instagram. Especially if they are posted by people I follow, I will like it without really paying attention to it. I despise snakes and if a celebrity I follow were to post their pet snake, I would probably like it and scroll away really quickly. But in real life if a friend were to show me a their snake, I would very obviously show that I do not like their snake.

Sometimes people online like things to just like things. Sometimes a post moved them, sometimes it did not. I think one sure way to tell is if they comment. I only comment if a post really moves me. Unless it is a friend's post on instagram in which case I will comment "so beautiful heart eyes emoji". 99.999% of the time, I do mean it but there are times when I don't.

This is something we discussed in the first day of lecture. A lot of the time in college, even if we take a class because we find it interesting, instead of actually learning from the class, we treat it like a game of some sort. Just trying to earn the highest score possible by looking up answers for homework instead of working on the problems. In a math class, our goal may be to become a mathematician by learning and improving our math skills, but when deadlines approach, we opt for looking up answers to the homework questions designed to help us learn. Which might give us the highest score/grade, but now our goals are "collapsed down to scoring systems".

https://www.phillytypewriter.com/#/

https://typewriters.co.uk/

https://americanhistory.si.edu/collections/nmah_1335701

The typewriter used on Murder, She Wrote, starring Angela Landsbury, was a black Royal standard, probably a 1940s KMM.

https://www.theguardian.com/world/article/2024/jun/24/delhi-heat-stroke-clinic-first-ram-manohar-lohia-hospital

Thousands of citations already. Called "the monster" in big tech. Save billions of $$$ at Amazon by applying DML to online experimentation such as A/B testing.

Tree-based methods such as random forest and boosting have been one of the most successful out-of-box machine learning methods for structured/tabular data.

Last year's R25 program had many examples of using tidycensus to explore the Census and ACS data.

Optional.

Something or someone regarded or presented as primary evidence in support of an argument or proposition.

to cause (someone) to make a mistake

(of something regarded as unpleasant) continuing without pause or interruption

take care to avoid or keep away from: steer clear of fatty food.

assert something as a position in an argument

use (something) to maximum advantage

the action of receiving something or the fact of its being received

without problems or bother

[no object] increase and then decrease sharply; reach a peak: oil prices would spike and fall again.

become subject to (something unwelcome or unpleasant) as a result of one's own behaviour or actions: I will pay any expenses incurred.

the amount of money taken by a business in a particular period

highlights a significant moment in the history of hypertext, marking the development of Lynx, one of the earliest web browsers that utilized hypertext links to connect documents across the internet, laying the groundwork for the World Wide Web as we know it today.

Hypertext changed how we read and write stories. Instead of reading in a straight line from start to finish, like a regular book, hypertext lets us jump around to different parts of the story. This makes reading more like exploring, where you can choose different paths and discover new things.

後ろに「を」があったほうがよさそうです。

後ろに「を」があったほうがよさそうです。

「他の文では「クエリ」と書いていて表記が揺れています。

compute 'now/, when fetch

batch with spark for slow change feature

I'd slightly reword this. Something like: While 90% of past clients have secured interviews within 2 weeks, and landed their dream offer in less than 4 months, this program does not come with a guarantee that you'll secure a job within that timeframe.

I would move this entire about section further up on the page just underneath the first pricing tables.

I would beef up these ideas more and move them down into the pricing table.

The perfect blend of feedback, support and guidance

Love this section... what if you turned it into a mini timeline? As soon as you join... in 2 weeks... in 1 month ... in 2 months ... in 3-4 months

I would break down here what exactly is included in the program. How many group calls? Which courses? Which templates? What does the 1:1 support look like? What is the format of each inclusion? Is there a private podcast? Make it super clear for people to see what they get.

Can you somehow break down the program into or modules so people can picture how they're going to progress through your framework?

I would move this section towards the top of the page because it includes brands your clients would be aspiring to land a role at, right?

The 16-week job search strategy program that will give you the clarity and confidence to not only land the RIGHT interviews but secure that DREAM role.

90% of clients secured their dream offer in less than 4 months.

LOVE THIS!

I would switch each of these ideas up so they don't sound like they're going to do all the work, but rather turn them into a partnership. Let's...

What will land you that dream leadership role? Your Inevitable Edge

This section is great because it speaks to the obstacles between them and that dream role. I'd just mix up the introduction... something like: But what stands between you and the leadership role that stretches you into your next level of growth is not only the state of the market, but the hamster wheel of every seemingly neverending job search. ...

Can you lead with that dream future here? And really paint a picture of what it would feel like to already have that dream role. Something like: Imagine waking up to the role you've been working towards for the past few years. And what expects you is... (tangible things they're aspiring to).

I feel like this offer promise could be punchier. Something like: The perfect blend of accountability, feedback and personalised support to land you the leadership role of your dreams quicksmart.

Even in an unpredictable job market and if you're tried unsuccessfully for months.

Coming from a total outsider's perspective here... the person you're describing on the sales page seems pretty fed up with their current job and if I had to guess, I'd say they want to make a move quicker than in the next 4 months. I know that's a totally realistic timeline and you need to set the right expectations, but I'd start with your AMAZING tagline you introduce further down on the sales page: What if you could switch the status of your next leadership role from eventual to inevitable? This statement leads with hope rather than timelines people might not want to accept, and that put them off right away.

亚马逊词库搭建

Can be used to identify ground truth problems in our study

这个objects是指的什么？

https://www.youtube.com/playlist?list=PLJtHauPh529XYHI5QNj5w9PUdi89pOXsS

Typewriter 101

Again don't worry about syntaxes. Focus on concepts of data wrangling, which are universal among many languages (SQL, Python, Julia).

Tidyverse is not the only choice. data.table package is a popular framework for data wrangling as well.

Don't be overwhelmed by syntax. GenAI tools such as GitHub Copilot and ChatGPT alleviate lots of programming details. More important to grasp the tasks and workflow.

Significado

bigrafías

narrativas autobiográficas

Significado de religiosidad popular

Metodología con énfasis epistemológico

DOI: 10.1016/j.celrep.2021.108899

Resource: (Alomone Labs Cat# AGA-014, RRID:AB_2340938)

Curator: @Naa003

SciCrunch record: RRID:AB_2340938

What is this?

DOI: 10.1016/j.celrep.2021.108899

Resource: (Alomone Labs Cat# AGA-014, RRID:AB_2340938)

Curator: @Naa003

SciCrunch record: RRID:AB_2340938

What is this?

Tema del párrafo.

Idea principal del párrafo

Tema del párrafo.

Idea principal del párrafo.

This fisrt ine is definitily art.

Unable to clone

This a form of media bias because the term sore is exaggerated and meant to cause the reader to be fearful of future events related to gas prices. In the Allsildes link, this is an example of a spin in media biases.

This is an example of media bias because it's opinion presented as fact. According to Allslides, "How to spot 16 types of media bias", states that the world could *indicate a subjective statement. "A subjective statement is one that is based on personal opinions, assumptions, beliefs, tastes, preferences, or interpretations. It reflects how the writer views reality, what they presuppose to be the truth".

But this is in fact what is now quite clearly possible today. Using employees as frontline moderators and enforcers of unevenly applied ToS is officially an old school brute force tactic. There are only two viable techniques now IMHO... 1) is AI assisted pre-moderation, and 2) is community driven meta-moderation (e.g. semi-random, community self-moderation).

Résumé de la vidéo [00:00:00][^1^][1] - [00:22:03][^2^][2]:

Cette vidéo explore l'apprentissage à travers les lentilles des neurosciences et de la sociologie, discutant de la manière de développer l'intelligence chez les enfants. Les experts débattent de l'efficacité des méthodes d'apprentissage, de l'utilité des tests de QI, et de l'importance de la plasticité cérébrale.

Points forts: + [00:00:00][^3^][3] Introduction au débat * Présentation du thème sur le développement de l'intelligence des enfants * Discussion sur les différentes formes d'intelligence et les méthodes pour les cultiver + [00:01:30][^4^][4] Les intervenants et leurs contributions * Présentation des experts en neuropsychologie et en sociologie * Exploration de leurs travaux sur l'intelligence et l'apprentissage + [00:04:02][^5^][5] L'évolution des recherches sur l'intelligence * Réflexion sur les travaux d'Alfred Binet et l'évolution de la mesure de l'intelligence * Discussion sur l'impact de l'éducation sur le développement de l'intelligence + [00:07:03][^6^][6] Définition et mesure de l'intelligence * Débat sur la nature de l'intelligence et les limites des tests de QI * Importance de la plasticité cérébrale et de l'environnement dans le développement de l'intelligence + [00:10:08][^7^][7] La perspective sociologique sur l'intelligence * Analyse de l'influence des déterminants sociaux sur l'apprentissage * Évaluation de l'impact des pratiques éducatives familiales sur le développement cognitif + [00:17:01][^8^][8] L'importance de l'environnement dans le développement cognitif * Examen de la manière dont l'environnement façonne le cerveau et l'intelligence * Discussion sur l'importance des stimulations précoces et de l'éducation adaptée

Résumé de la vidéo [00:22:05][^1^][1] - [00:44:46][^2^][2]:

Cette partie de la vidéo explore l'impact des neurosciences et de la sociologie sur l'apprentissage, en mettant l'accent sur la capacité du cerveau à se développer et à compenser les dysfonctionnements à travers des stimulations adaptées. Elle souligne l'importance de la rééducation et de la remédiation pour surmonter les troubles d'apprentissage et insiste sur le rôle crucial des attentes des enseignants et des parents dans la réussite scolaire des enfants.

Points forts: + [00:22:05][^3^][3] La plasticité cérébrale * Capacité du cerveau à se développer malgré les dysfonctionnements * Importance des stimulations adaptées pour la rééducation * Exemples de rééducation visuelle chez les enfants + [00:25:08][^4^][4] Les troubles d'apprentissage * Difficultés à lire et à compter ne sont pas une fatalité * Importance de la prise en charge spécifique pour restaurer les fonctions * Réflexion sur la prise en charge des troubles chez les jeunes adultes + [00:27:02][^5^][5] Facteurs influençant la réussite scolaire * Complexité des facteurs contribuant à la réussite scolaire * Rôle des compétences émotionnelles et de la personnalité de l'enfant * Influence des méthodes d'enseignement et de la structure du système éducatif + [00:31:02][^6^][6] La socialisation et l'éducation familiale * Impact des pratiques éducatives familiales sur les dispositions scolaires * Importance de la persévérance et de la régularité inculquées par les familles * Distinction entre les pratiques éducatives des milieux populaires et aisés + [00:35:54][^7^][7] Développement de la métacognition chez l'enfant * L'enfant doit apprendre à apprendre et comprendre comment il apprend * Importance de la métacognition pour la réussite scolaire * Influence des attentes des enseignants sur les performances des élèves + [00:42:31][^8^][8] L'importance des compétences cognitives et émotionnelles * Corrélation entre les compétences cognitives et la réussite scolaire * Rôle des compétences émotionnelles dans l'apprentissage * Nécessité d'une approche globale intégrant tous les acteurs éducatifs

Résumé de la vidéo 00:44:49 - 01:07:21 : La vidéo explore l'impact des facteurs sociaux et émotionnels sur l'apprentissage, en soulignant que le succès scolaire ne dépend pas uniquement du QI. Elle discute de l'importance de la régulation des émotions et de l'empathie dans le développement des compétences cognitives et sociales des enfants. Un programme éducatif axé sur la philanthropie est présenté comme un moyen d'améliorer l'estime de soi et les compétences sociales, tout en questionnant l'efficacité des technologies éducatives et l'équilibre entre théorie et pratique dans l'enseignement.

Points forts : + [00:44:49][^1^][1] Influence des facteurs sociaux sur l'apprentissage * L'importance de l'environnement familial et de la régulation des émotions * L'impact des problèmes personnels sur la capacité d'apprentissage * La nécessité de développer l'empathie et les compétences émotionnelles + [00:45:53][^2^][2] Rôle de l'empathie et des comportements prosociaux * L'empathie nécessite de faire attention aux autres et de comprendre leurs problèmes * Développer l'altruisme peut améliorer les compétences cognitives * Le programme "l'école de la philanthropie" vise à développer ces compétences chez les enfants + [00:50:15][^3^][3] Adéquation des programmes scolaires avec la réalité * Difficulté à évaluer l'éco-responsabilité des programmes * Nécessité d'adapter l'éducation aux contraintes écologiques et technologiques * Importance de l'équilibre entre expérimentation pratique et fondements théoriques + [00:53:47][^4^][4] Intégration des nouvelles technologies dans l'éducation * Défis de l'application des technologies éducatives dans les écoles * Potentiel des tablettes et applications pour personnaliser l'apprentissage * Importance de maintenir les compétences humaines face à l'intelligence artificielle

Résumé de la vidéo [01:07:23][^1^][1] - [01:29:51][^2^][2] : Cette partie de la vidéo aborde l'importance de l'écriture manuelle dans l'apprentissage, les défis posés par l'utilisation croissante des technologies numériques dans l'éducation, et la nécessité de différencier les méthodes d'enseignement pour répondre aux besoins individuels des élèves. Les intervenants discutent également des concepts de neurodiversité et de l'importance de reconnaître les rythmes d'apprentissage variés chez les enfants.

Points saillants : + [01:07:23][^3^][3] L'écriture manuelle et la mémoire * L'écriture manuelle active la mémoire gestuelle en plus de la mémoire visuelle * La perte de la pratique de l'écriture manuelle due à la technologie est un sujet de préoccupation * Importance de la conscience dans les décisions éducatives + [01:09:01][^4^][4] L'importance de l'écriture dans les écoles * Les enseignants valorisent l'écriture manuelle pour le développement des élèves * Différenciation des méthodes d'enseignement pour les élèves avec ou sans troubles spécifiques * Les contraintes pratiques influencent la quantité d'écriture dans les classes + [01:13:02][^5^][5] Les troubles d'apprentissage et les diagnostics * Démocratisation des termes liés aux troubles d'apprentissage et risque de surdiagnostic * Importance de distinguer les difficultés temporaires des troubles permanents * Nécessité d'éduquer les enseignants sur la variabilité des rythmes d'apprentissage + [01:17:02][^6^][6] Neurodiversité et individualité dans l'apprentissage * Reconnaissance de la neurodiversité et des différences individuelles dans l'utilisation du cerveau * Tendance à étudier les différences plutôt que les moyennes dans la recherche neuroscientifique * Acceptation croissante de l'idée que les enfants n'apprennent pas tous de la même manière ni au même rythme

Résumé de la vidéo [01:29:54][^1^][1] - [01:30:41][^2^][2]:

La partie 5 de la vidéo aborde le thème de l'apprentissage à travers les neurosciences et la sociologie. Elle conclut avec une invitation au prochain débat sur l'intelligence des plantes et comment elles s'adaptent au monde.

Points forts: + [01:29:54][^3^][3] L'éducation des dyslexiques * Discussion sur l'éducation adaptée aux dyslexiques * Lutte contre l'échec scolaire * Importance de la découverte et du goût de l'effort + [01:30:14][^4^][4] Prochain débat sur l'intelligence des plantes * Exploration de l'intelligence végétale * Réflexion sur d'autres formes d'intelligence * Adaptation des plantes au monde

yess

lmao sure

oh no

oh!

oh this is barristen selmy

oh i was right!

renly?

hating jon is crazy like he's so sweet

no i kinda get her

aww

:(

he's the one killed by theon...

umm

aww

LMAO PLS

i don't like you theon but you're right

LIAR

yes you got it

YESS

supersinly sweet in a way but atleast she can rest now

YES CAT

she dont gaf

dont be grateful yet

lmao

he shouldnt have to do this

man she really is loosing it

https://www.youtube.com/watch?v=4MUsSFo-0hg cambridge dictionary schema project for unemployment

the word test: Make people listen to verbs commonly used in the workplace.

insérer " $$\text{la différence }(g_{t}-\bar{g})$$" avant "sera très souvent négatif" (code Latex : (g_{t}-\bar{g}))

remplacer g par $$\bar{g}$$ (code Latex \bar{g})

remplacer g par $$\bar{g}$$

insérer $$\bar{g}$$

Est-il possible de noter le t sous forme d'indice? $$ g_{t} $$

Merci de réécrire comme suit : "Des mesures d’accompagnement (atténuation et solidarité) ont été prévues. Elle comprennent :"

How does the platform help extract my strengths? I can do 100 things, what are the networks hot needs I could focus in on.

"align with", nothing's perfect :D in life

ok, I kinda buy it. fix formatting.

more positve language. "While we strive for great matches, we understand that differences may arise. We stay ahead of this with our white glove onboarding and robust matching algos. In the event of a mis-match, we'll get ahead of that and provide you with several alternative partners and faciliate the handover. As partnership experts we'll help craft messaging to ensure optimal optics"

This can be framed in a more positive way. something along the lines of "We're honing in our process and tooling to ensure automation and AI is leveraged safely and ethically. In the mean time, we prefer a bespoke white glove experience to ensure optimal customer experience and growth opportunities for the platform and comunity"

Is this fee/cut disclosed at any time?

How do you stay unbiased. What are the firewalls inplace?

And you have the network to reach into new sectors and the credibility to pull in SMEs from there. You cant be everywhere, be humble about it.

If affiliate link is not facilitating payments, then I agree this is the entire process. Otherwise, that's only the dealflow "matchmaking'"

I don't understand why I'm notifying affiliate labs. The platform would take it's cut and distribute payment accordingly. OR are you trying to emphasize a P2P angle?

Is there an onboarding provided by affiliate labs? I may know I need an AWS provider, but what services should they have competency in?

Are SPIFS disclosed? What's the criteria? How are new partners identified?

I'd like to know more about the handover. Presuming it will be different based on the service provider.

This is the onboarding phase

Ahmet Davutoğlu Türkiye'nin ekonomik gücünün en yüksek olduğu dönemde, Batı'ya ve doğuya jeopolitik açılımın gerçekleştiği en yoğun dönemde Türkiye'nin etki alanının genişlemesini kendi ideolojik görüşleri yönünde kullandı. Neo-Osmanlıcılık cumhuriyet Türkiye'sinde uygulanma alanı bulmayan ve altyapısı olmayan bir düşünceydi. Keza Osmanlı İmparatorluğunun son döneminde bile bu düşünce saraydan halka kadar birçok kişi tarafından tartışılmış fakat vazgeçilerek milliyetçi bir politika izlenmiştir. Ahmet Davutoğlu bir akademisyen olarak jeopolitik ile özel ilgilendi fakat tıpkı Ratzel'in düşüncelerini kendi çıkarları için kullanan düşünürler gibi o da farklı bir şey yapmadı. Ayrıca bugün Türkiye'de yaklaşık 12 milyon yabancı nüfusun bulunmasının temel aktörüdür. Suriye iç savaşından itibaren sığınmacıları özellikle kabul etmiş ve bunun devamında Türkiye'yi daha islamist bir çizgiye sokmayı hedefledi. Fakat neredeyse tüm dünyada bilinen önemli bir yanılgı var. Cumhuriyet kurulduğundan beri Türkler milliyetçi bir çizgide yetiştirildi ve sığınmacı fikri bunun da vesilesiyle oldukça zararlı bir sonuca sebep oldu. Türkler yeryüzünde müslümanlığa en büyük altın çağını yaşatmış bir millet olsa da günümüzde islam kurallarına sıcak bakmayan en büyük müslüman kitleyi temsil ederler (küçük bir azınlık grup hariç). Bu yüzden Suriye, Afganistan, Pakistan gibi ülkelerden gelen toplulukların yaptığı davranışlar ve temsil ettiği düşünceler toplumun genelinde çok ciddi rahatsızlıklara yol açtı. Türkiye kimlik bazında %90 müslüman bir nüfusa sahip olsa da şeriat isteyenlerin oranı %10'u bulmaz. Hatta Türkiye'de "aşırı sağ" günümüze kadar aşırı cumhuriyetçi, laik, militarist kesimin temsil ettiği grubu ifade ederken; islamcı, muhafazakar kesim daha merkez sağ hatta kimi zaman sol kesimi ifade etti. Günümüzde bu bir değişim içindedir. Fakat en kısa tabiriyle Davutoğlu 85 milyon içinde küçük bir azınlığa hitap eden bir politikayı Türkiye'nin dış politikası olarak sürdürdü ve başarısız bir siyasetçi olarak tarihe karıştı. *

Davutoğlu, "alan" bakımından genişleyen bir Türkiye değil "isamcı etkinin tüm topluma sirayet etmesi gayretiyle müslüman nüfusu ülke içine alıp ülke dışında da çeşitli tampon bölgeler yaratma" hevesinde olan yani pek Ratzel'e uymayan pratiğe sahip olan birisidir.

(Yabancı halkların Türkiye'ye gelmesi hakkında: Suriye iç savaşı sırasında gelen savaş mağdurlarının yanı sıra Türkiye çok uzun bir süre "açık sınır" politikası izleyerek milyonlarca resmi ve özellikle neredeyse tamamı gayrıresmi kişiyi hiçbir kayıt ve resmi prosedür olmadan kabul etti. Bu iki durumun karıştırılmaması oldukça önemlidir. Çünkü kayıt dışı birçok insan suç işlemiş, sınır dışı edilmiş ve kaçak yollarla tekrar Türkiye'ye girerek çalışmaya devam etmiştir. Keza "savaş mağduru" olarak nitelendirilen bazı kesimlerin dini bayramlarda Suriye'deki yakınlarını ziyaret edip sonra Türkiye'ye tekrar dönmeleri Türk halkının ciddi tepkisine yol açmıştır. Hatta modern Türkiye'de birçok kitlesel hastalığın yok edilmesinden sonra gelen kayıtsız birçok kişinin bazı hastalıkları tekrar yaymaya başladığı görüldü. Üstelik bu gelen kitle çok ciddi bir şeriat politikası yürütmeye başlayınca Türkiye'de çok ciddi bir göçmen karşıtlığı başladı. Bunun en temel sebebi "mantık" sorunudur. Türkiye 85 milyon bir ülke olarak genç bir nüfusa sahiptir. Dolayısıyla halkın önemli bir bölümü kayıtsız göçmen almanın, iş kollarına dahil edilmesinin mantıksız olduğunu ifade etmektedir (Bu oran iktidar partisini destekleyen kesimde dahi %80'e varan oranlara sahiptir). Özellikle 2016 da yaşanan darbe girişiminden sonra ekonomik açıdan kriz yaşayan Türkiye'nin son 5 yılda milyonlarca kayıtsız/kaçak nüfus alması tepkilerin yoğunluğunu daha da artırdı.) Şuan Türkiye'de ara sıra gündeme gelen fakat gelecekte Türkiye'nin en büyük problemi olacağı düşünülen ve araştırmaya ihtiyaç duyulan en önemli konu bu göç konusudur. Çünkü çok net ifade edilebilir ki Türkiye'de süre gelen göç hikayesi tarihte eşi benzeri görülmemiş bir süreçle işlemektedir. Batı dünyasında tüm prosedürlerle kayıt altına alınmış sığınmacılara karşı çıkılması ile Türkiye'de göçmenlere/kaçaklara karşı çıkılması kesinlikle aynı durum değildir. Dolayısıyla araştırmacılara tavsiyem şudur: Türkiye'deki göç sorununa tüm teorilerden, göç tarihinden, günümüzdeki eleştirilerden bağımsız bir şekilde, şahsına münhasır bir şekilde araştırma yapılmalı. Aksi taktirde ulaşacağınız sonuç pek de sağlıklı olmayacaktır.

muestra

what is this?

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?????

This is a very thin and partly confusing para for such an important core result. Pls rewrite and use more space if necessary. We can discuss this next week.

Color codes are inconsistent between Fig 5 and Fig. 6. (confusion between life time extension and material efficieny). pls correct.

Maybe: Technology improvements are not sufficient to reach climate targets in the housing sector In any case: sufficiently at the end of the heading deludes the reader to ignore the qualifier sufficiently.

which don't distinguish between

is invisible in aggregated national models

3.65 billion m2 floor space. In MFA stock is often measured as weight (tons). Pls make sure the reader always know the stock is here measured as floor space.

in yearly time steps as part of a dynamic...

The regions.... remain

Don't make the East one region, and btw Potsdam and Berlin are growing.

I do not understand this sentence

Improving material efficiency

based on a

the analysis uses a novel.....

Résumé de la vidéo [00:00:00][^1^][1] - [00:21:08][^2^][2]:

Cette vidéo présente une discussion avec Mathieu Cassotti, professeur en psychologie du développement à l'Université Paris Cité, sur le rôle de la psychologie dans la lutte contre le réchauffement climatique. Il explore les raisons pour lesquelles les gens ne changent pas leurs comportements malgré la conscience des conséquences du réchauffement climatique et comment la psychologie peut aider à surmonter ces obstacles.

Points forts: + [00:00:00][^3^][3] La contradiction entre conscience et action * Reconnaissance de l'écart entre le discours et les actions * Importance de comprendre les blocages psychologiques * La psychologie comme outil pour faciliter le changement + [00:02:47][^4^][4] Le biais technologique face aux défis écologiques * La tendance à croire que la technologie résoudra les problèmes écologiques * La nécessité de changer les comportements plutôt que de compter uniquement sur la technologie * L'impact des activités humaines sur l'environnement + [00:08:19][^5^][5] Le climatoscepticisme et son influence * La désinformation et les climatosceptiques sur les réseaux sociaux * L'augmentation du scepticisme après l'exposition à des arguments climatosceptiques * La difficulté de revenir à un niveau de croyance initial même après le démenti des fausses informations + [00:12:41][^6^][6] L'importance de la connaissance du fonctionnement du cerveau * Apprendre aux gens comment leur cerveau réagit aux informations émotionnelles * La prise de conscience des biais et des stratégies du cerveau pour éviter l'action * L'éducation des adultes sur le fonctionnement du cerveau pour favoriser le changement collectif + [00:16:37][^7^][7] Les mécanismes de coping et leur impact sur l'action * Les stratégies de coping comme moyen de réguler les émotions négatives * La réévaluation cognitive pour éviter de changer les comportements * L'importance de passer à l'action individuellement et collectivement pour un impact significatif

Résumé de la vidéo [00:21:10][^1^][1] - [00:42:03][^2^][2]:

La vidéo présente une discussion sur l'enseignement de la psychologie pour contribuer à la sauvegarde de la planète. Elle aborde les défis émotionnels des activistes, l'importance de l'éducation des enfants et des adolescents dans la résolution de problèmes environnementaux, et la nécessité d'innover dans les comportements et les politiques pour un impact écologique positif.

Points forts: + [00:21:10][^3^][3] Les défis des activistes * Confrontation à l'inaction malgré leurs efforts * Sentiment d'isolement et frustration * Difficulté à mobiliser et à être entendus + [00:24:00][^4^][4] L'éducation et l'action * Importance de l'information et de la compréhension du fonctionnement du cerveau * Nécessité d'impliquer les enfants et les adolescents dans la conception de solutions * Encouragement à l'innovation et à la créativité dès le jeune âge + [00:31:02][^5^][5] Modules d'enseignement sur la psychologie de la transition écologique * Développement de modules pour sensibiliser aux enjeux écologiques * Intégration des sciences humaines et sociales dans l'éducation écologique * Évaluation de l'impact des modules sur les comportements et les actions + [00:40:17][^6^][6] Le collectif et la politique * L'importance de la coopération et de l'action collective * La nécessité d'impliquer les politiques dans la formation écologique * Réflexion sur les leviers politiques pour soutenir la transition écologique

Résumé de la vidéo [00:42:05][^1^][1] - [00:47:07][^2^][2] :

La partie 3 de la vidéo aborde l'importance de l'enseignement de la psychologie et des compétences psychosociales pour favoriser la coopération et résoudre les problèmes complexes, notamment en matière d'écologie. Mathieu Cassotti souligne la nécessité d'innover dans l'éducation pour préparer les citoyens à collaborer et à comprendre les émotions et les perspectives des autres. Il critique la tendance actuelle à se concentrer sur les connaissances fondamentales au détriment des compétences sociales et de la coopération.

Points forts : + [00:42:05][^3^][3] Innovation en éducation * Nécessité de sortir du cadre traditionnel * Proposer des approches innovantes * Réfléchir à des solutions aux problèmes complexes + [00:42:34][^4^][4] Coopération dès le jeune âge * Importance de la coopération pour résoudre les problèmes * Développement des compétences psychosociales et émotionnelles * Respect et travail en groupe comme compétences clés + [00:43:01][^5^][5] Changement de paradigme éducatif * Transition vers l'apprentissage du savoir-être ensemble * Liberté pédagogique pour innover dans l'enseignement * Critique de la société compétitive au détriment de la coopération + [00:44:32][^6^][6] Évaluation des compétences mathématiques * Questionnement sur l'importance relative des mathématiques * Possibilité d'évaluer les compétences mathématiques collectivement * Comparaison avec les classements PISA et leur impact

continuação

Nouveau lien: https://www.iec.ch/blog/150th-anniversary-father-international-standardization

La "mégamachine" est le nom donné à une forme d'organisation sociale qui fonctionne comme une machine de machines et permet la réalisation de projets sociétaux (Son exemple est la construction des pyramides égyptiennes). Voir, de Bruno Chaudet, Lewis Mumford, machines et mégamachines : un auteur et des notions à convoquer en information-communication organisationnelle (Revue française des sciences de l'information et de la communication, 2020 - https://journals.openedition.org/rfsic/9032). Briet, qui n'est pas citée dans cet article, est une des rares en France à citer Mumford.

Avec sa femme Georgette (1899 - 1988), militant pour la lecture publique et parmi les fondateurs de l'UFOD en 1932.

Dans les années 1950, il forme à la physique nucléaire les officiers français chargés de développer l'arme atomique.

... associé au projet Manhattan.

(1) pick out は 取り出す という意味もありますが、ここは 見分ける / 明らかにする のニュアンスを採用した方が日本語としては自然に感じます。

（「取り出す」だと何か抽出してるっぽいので

https://ejje.weblio.jp/content/pick+out

(2) 「より良い」というより「（さっきと比べて）良くなってきている」みたいな表現の方が自然かと

(3) nits. 「 the most significant earthquakes」なので、「最も大きな」というより「最も重要な」では（どのみちマグニチュードが大きな地震を「重要」と定義してるっぽいので、あまり違わないですが...）

まとめると、以下はどうでしょうか

この地図は良くなってきてはいますが、最も重要な地震がどの点なのか見分けるのは、まだ難しいです。

あるいは

この地図は良くなってきてはいますが、最も重要な地震がどの点なのか見分けるのは、未だ困難です。

(1)

一般的に近くプレートの境界線の近く

「近く」が1個余分なようです。

(2) 1文が長いので分けた方が良さそう。

地震は一般的にプレートの境界線付近で発生します。この地図に含まれる長い期間の地震活動によって、これらの境界の正確な位置がわかります。

よう

併せて -> 合わせて　?

あるいは「あわせて」という言葉を使わずに

マグニチュードが大きい地震ほどより大きな点で地図上に表示されます

などはどうでしょうか。

24時間内

あるいは

24時間以内

ここは（実践編だけで1冊になるので章番号が変わって）4章になるのでは。

図番号が違うようです（図5-7）

Yes, just ask for it. This may apply well in college, but I am not sure about high school, especially in specific education system..

Hmm. That's not entirely true. Studying in a group helps a lot in clarifying concepts when the students teach each-other. Simply co-working doesn't produce much effect except increasing accountability.

i mean, you're LIVING with a person. it's obvious that it will influence you.

That is why you need a second brain.

Use obsidian.md for notetaking

E.g. <br> Q: How is Cato the Younger stoic? <br> E: He chose to commit s*icide instead of surrendering to Caesar.<br> C: Cato the Younger is disciplined and follows his principles. He'd rather die than live a degraded life <br>

Note: I may not be right,

Why "normal" note-taking is useless.