this one is the most straightforward translation yet imo

This is a really thoughtful point, and I appreciate that you didn’t just say AI can help, but also explained where it falls short. You describe the difference between “pattern” and “understanding” in a way that feels honest and grounded in what we’ve been learning. I wonder if you found any specific moment in the AI interrogation where the generated answer sounded convincing but you later realized it had no real historical basis. If you included a short example of that, it would make your argument even more meaningful and personal. But overall you’ve captured the ethical tension of using AI in history really well.

I really like how you explain the switch from “notes as storage” to “notes as a network.” The way you describe linking concepts actually helped me think about my own note system differently. I’m curious if you have a specific example of two ideas that didn’t seem connected at first but became linked once you used wikilinks. I think adding one concrete moment like that would make this even stronger, since you clearly worked hard to build an intentional structure instead of just tagging randomly. Still, you put the value of linking into words really clearly.

When I added YAML properties to my own notes, I began to understand that metadata is never neutral. A property like type or date might seem simple, but it decides how information is stored, sorted, and found. That small act of labeling defines what becomes visible in a database and what doesn’t. This connects to the idea of “dark data,” the information that stays invisible because it isn’t recorded within the system’s limits. Thinking through this process made me realize that data creation is interpretive work and it involves judgment, context, and responsibility.

This emphasis on reproducibility matters to history too. It suggests I should keep detailed logs: where I got a manuscript image, how I interpreted marginalia, what uncertainties remain. That way future readers or researchers can trace my reasoning or redo steps themselves.

Shows this notebook treats sources seriously and transparently. In my own project that’s important — I want to cite each manuscript image, each provenance trace, every secondary source, so readers can verify or explore further.

The open and editable public format makes the research living and dynamic. For medieval manuscripts it suggests I could update interpretations if I find new sources or corrections — it does not need to be fixed foreve

This statement shows the author’s commitment to transparency. It resonates with how I want to publish my own historical notebook: not just final conclusions, but the full process. For Dante manuscripts this means publishing not only text interpretations, but images, provenance notes, and gaps.

He works with histories of oppressed or non-elite groups, revealing structures often overlooked in dominant archives.

His research centers marginalized historical subjects, particularly enslaved people, bringing subaltern voices into visibility.

He invites historians, students, and the public to interact, showing an inclusive audience target.

The notebook is intended for a broad public audience, not limited to specialists.

His authority comes from transparent documentation of edits, allowing the public to verify his process.

His authority is reinforced through major scholarly achievements, showing credibility in historical research.

He presents himself as a scholar who values openness rather than closed, private scholarship.

He frames his identity as an open-scholarship researcher, showing his commitment to transparency in the research process.

McDaniel positions himself as an academic historian and professor, establishing who he is and the perspective he brings.

The child gets removed from the parents before investigation and gather evidence and make a decision about the child's future whenever he or she gets put in the foster care or placed for adoption.

Usually Mothers trauma is the cause of alcohol and drugs or when they refuse to leave their abuse partners, there's going to be no changes for her or her child

Poor Families don't get counseling even though trauma is the main issues.

Shows how the system pressure parents to improve quickly, even so trauma takes months or years to treat.

Trauma passes down generation when parents never get support to heal

shows how serious the situation has to be before the court acts

Con ADD también empezamos con la instancia del objeto que queremos manipular.

[Context] Explains where and when the incident happened

Where is this?

放在文末；但是图片是单独文件

Definition of their term--care poverty--focus away fom individual care. Structures.

Nation and confereradtion-level decisio making that takes, it seems as a starting point, an axiom (?) that

• state should provide care
• care should be affordable and accessible and high-quality

Clearly laying out the stakes involved in figuring out how to care for people within a society. Not just a "grand societal challenge" that impacts QOL and dignity but also: * labour market participation of family members nationl econommies legitimacy of political decision (?)

I'm glad you got to taste the Rye of my people from the great state of Indiana--the libertarian bootleggers who display Hoosier hospitality.

It is spicy alone but this is the best Rye for an old fashioned. .If you have pure Canadian maple syrup, then turn it into a maple old fashioned.

If you are at Indiana Beach with Channon them a diet Shasta cola is a great mixer with this rye.

Woolf indicates here that a speaker or a writer cannot force the audience to think a certain way. Rather, the best thing one can do is to present the truth openly including one's personal biases, limitations or opinions. Only then can the audience truly understand and come up with their own conclusion

Couldn't follow what he was saying in this lesson...

I wonder how executing thousands f officials affected the government and the people at the time.

It’s interesting that Zhu Yuanzhang became a future emperor survived the plague and famine as an orphan.

I find it interesting that the plague made people lose faith in the church because it couldn’t stop or explain the disease.

An interesting point is that Genghis Khans empire didn’t stop growing after his death. It kept expanding under his heirs.

I never knew this!

xxxx

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Reply to the reviewers

Manuscript number: RC-2025-03195R

Point-by-Point Response to Reviewers

We thank the reviewers for their thoughtful and constructive evaluations, which have helped us substantially improve the clarity, rigor, and balance of our manuscript. We are grateful for their recognition that our integrated ATAC-seq and RNA-seq analyses provide a valuable and technically sound contribution to understanding soxB1-2 function and regenerative neurogenesis in planarians.

We have carefully addressed the reviewers' major points as follows:

1. Direct versus indirect regulation by SoxB1-2:____ In the revision, we explicitly acknowledge the limitations of inferring direct regulation from our current datasets and have revised statements throughout the Results and Discussion to emphasize that our findings are correlative.
2. Evidence for pioneer activity:____ Although the pioneer role of SoxB1 transcription factors in well established in other systems, we agree that additional binding or motif data would be required to formally demonstrate SoxB1-2 pioneer function. Accordingly, we performed motif analysis and revised the text throughout to frame SoxB1-2's proposed role as consistent with, rather than demonstrating transcriptional activator activity.
3. Motif enrichment and downstream regulatory interactions:____ In response to Reviewer #1's suggestion, we have included a new motif enrichment analysis in the supplement to contextualize possible co-regulators within the SoxB1-2 network.
4. Data reproducibility and peak-calling consistency:____ We have included sample correlations ____and peak overlaps for ATAC-seq samples in the revision, providing a clearer assessment of reproducibility.
5. Clarification of co-expression and downstream targets:____ We included co-expression plots for soxB1-2 with mecom and castor in the supplemental materials. These plots were generated from previously published scRNA-seq data and demonstrate that cells expressing soxB1-2 also express mecom and __ __We appreciate the reviewers' recognition that our methods are rigorous and our data accessible. We have incorporated all major revisions suggested and believe have strengthened the manuscript's precision, interpretations, and conclusions. Below, we respond to each comment in detail.

Reviewer #1 (Evidence, reproducibility and clarity (Required)):

Summary

The authors of this interesting study take the approach of combining RNAi, RNA-seq and ATAC-seq to try to build a regulatory network surrounding the function of a planarian SoxB1 ortholog, broadly required for neural specification during planarian regeneration. They find a number of chromatin regions that differentially accessible (measured by ATAC-seq), associate these with potential genes by proximity to the TSS. They then compare this set of genes with those that are differentially regulated (using RNA-seq), after SoxB1 RNAi mediated knockdown. This allows them the authors some focus on potential directly regulated targets of the planarian SoxB1. Two of these downstream targets, the mecom and castor transcription factors are then studied in greater detail.

Major Comments

I have no suggestions for new experiments that fit sensibly with the scope of the current work. There are other analyses that could be appropriate with the ATAC-seq data, but may not make sense in the content of SoxB1 acting as pioneer factor.

I would like to see motif enrichment analysis under the set of peaks to see if SoxB1 is opening chromatin for a restricted set of other transcription factors to then bind. Much of this could be taken from Neiro et al, eLife 2022 (which also used ATAC-seq) and matched planarians TF families to likely binding motifs. This could add some breadth to the regulatory network. It could be revealing for example if downstream TF also help regulate other targets that SoxB1 makes available, this is pattern often seen for cell specification (as I am sure the authors are aware). Alternatively, it may reveal other candidate regulators.

Thank you for this suggestion. We agree with the reviewers that this analysis should be done. We ran the motif enrichment analysis using the same methods as outlined in Neiro et al. eLife, 2022. We have included a new motif enrichment analysis in the supplement to contextualize possible co-regulators within the SoxB1-2 network.

Overall peak calling consistency with ATAC-sample would be useful to report as well, to give readers an idea of noise in the data. What was the correlation between samples?

__Excellent point. In response to this comment, we ran a Pearson correlation test on replicates within gfp and soxB1-2 RNAi replicates to get an idea of overall correlation between replicates. Additionally, we calculated percent overlap of peaks for biological replicates and between treatment groups. __

While it is logical to focus on downregulated genes, it would also be interesting to look at upregulated genes in some detail. In simple terms would we expect to see the representation of an alternate set of fate decisions being made by neoblast progeny?

This is also an important point that we considered but initially did not pursue it due to the lack of tools to test upregulated gene function. However, the reviewer is correct that this is straightforward to perform computationally. Thus, we have performed Gene Ontology analysis on the upregulated genes in all RNA-seq datasets (soxB1-2 RNAi, mecom RNAi, and castor RNAi). Both mecom and castor datasets did not reveal enrichment within the upregulated portion of the dataset. Genes upregulated after soxB1-2 RNAi were enriched for metabolic, xenobiotic detoxification, potassium homeostasis, and endocytic programs. Rather than indicating a shift toward alternative lineages, including non-ectodermal fates, these signatures are consistent with stress-responsive and homeostatic programs activated following loss of soxB1-2. We did not detect enrichment patterns strongly associated with alternative cell fates. We conclude that this analysis does not formally exclude potential shifts in lineage-specific transcriptional programs, but does support our hypothesis that soxB1-2 functions as a transcriptional activator.

Can the authors be explicit about whether they have evidence for co-expression of SoxB1/castor and SoxB1/mecom? I could find this clearly and it would be important to be clear whether this basic piece of evidence is in place or not at this stage.

We included co-expression plots for soxB1-2 with mecom and castor in the supplemental material. These plots were generated from previously published scRNA-seq data and demonstrate that cells expressing soxB1-2 also express mecom and castor. We have not done experiments showing co-expression via in situ at this time.

Minor comments

Formally loss of castor and mecom expression does mean these cells are absent, strictly the cell absence needs an independent method. It might be useful to clarify this with the evidence of be clear that cells are "very probably" not produced.

We agree that loss of castor and mecom expression does not formally demonstrate the physical absence of these cells, and that independent methods would be required to definitively confirm their loss. In response, we have revised our wording to indicate that castor- and mecom-expressing cells are very likely not being produced, rather than stating that they are absent.

Reviewer #1 (Significance (Required)):

Significance

Strengths and limitations.

The precise exploitation of the planarian system to identify potential targets, and therefore regulatory mechanisms, mediated by SoxB1 is an interesting contribution to the fi eld. We know almost nothing about the regulatory mechanisms that allow regeneration and how these might have evolved, and this work is well-executed step in that direction.

Advance

The paper makes a clear advance in our understanding of an important process in animals (neural specification) and how this happens in the context in the context during an example of animal regeneration. The methods are state-of-the-art with respect to what is possible in the planarian system.

Audience

This will be of wide interest to developmental biologists, particularly those studying regeneration in planarians and other regenerative systems,and those who study comparative neurodevelopment.

Expertise

I have expertise in functional genomics in the context of stem cells and regeneration, particularly in the planarian model system

Reviewer #2 (Evidence, reproducibility and clarity (Required)):

Review - Cathell, et al (RC-2025-03195)

Summary and Significance:

Understanding regenerative neurogenesis has been difficult due to the limited amount of neurogenesis that occurs after injury in most animal species. Planarians, with their adult neurogenesis and robust post-injury response, allow us to get a glimpse into regenerative neurogenesis. The Zayas laboratory previously revealed a key role for SoxB1-2 in maintenance and regeneration of a broad set of sensory and peripheral neurons in the planarian body. SoxB1-2 also has a role in many epidermal fates. Their previous work left open the tempting possibility that SoxB1-2 acts as a very upstream regulator of epidermal and neuronal fates, potentially acting as a pioneer transcription factor within these lineages. In the manuscript currently under review, Cathell and colleagues use ATAC-Seq and RNA-Seq to investigate chromatin changes after SoxB1-2(RNAi). With the experimental limitations in planarians, this is a strong first step toward testing their hypothesis that SoxB1-2acts as a pioneer within a set of planarian lineages. Beyond these cell types, this work is also important because planarian cell fates often rely on a suite of transcription factors, but the nature of transcription factor cooperation has been much less well understood. Indeed, the authors do show that loss of SoxB1-2 by RNAi causes changes in a number of accessible regions of the genome; many of these chromatin changes correspond to changes in gene expression of genes nearby these peaks. The authors also examine in more detail two genes that have genomic and transcriptomic changes after SoxB1-2(RNAi), mecom and castor. The authors completed RNA-Seq on mecom(RNAi) and castor(RNAi) animals, identifying genes downregulated after loss of either factor that are also seen in SoxB1-2(RNAi). The results in this paper are rigorous and very well presented. I will share two major limitations of the study and some suggestions for addressing them, but this work may also be acceptable without those changes at some journals.

Limitation 1:

The paper aims to test the hypothesis that SoxB1-2 is a pioneer transcription factor. Observation that SoxB1-2(RNAi) leads to loss of many accessible regions in the chromatin supports the hypothesis. However, an alternate possibility is that SoxB1-2 leads to transcription of another factor that is a pioneer factor or a chromatin remodeling enzyme; in either of these cases, the accessibility peak changes may not be due to SoxB1-2 directly but due to another protein that SoxB1-2 promotes. The authors describe how they can address this limitation in the future; in the meantime, is it known what the likely binding for SoxB1-2 would be (experimentally or based on homology)? If so, could the authors examine the relative abundance of SoxB1-2 binding sites in peaks that change after SoxB1-2(RNAi)? This could be compared to the abundance of the same binding sequence in non-changing peaks. Enrichment of SoxB1-2 binding sites in ATAC peaks that change after its RNAi would support the argument that chromatin changes are directly due to SoxB1-2.

We appreciate the feedback and agree that distinguishing between direct SoxB1-2 pioneer activity and indirect effects mediated through downstream regulators is an important consideration. While we did not perform a direct abundance analysis of potential chromatin-remodeling cofactors, we conducted a motif enrichment analysis following the approach of Neiro et al. (eLife, 2022), comparing control and soxB1-2(RNAi) peak sets. This analysis revealed that Sox-family motifs, particularly SoxB1-like motifs, were among the most enriched in regions that remain accessible in control animals relative to soxB1-2(RNAi) animals, consistent with a model in which SoxB1-2 directly contributes to establishing or maintaining accessibility at these loci. We have now included this analysis in the supplemental materials to further contextualize potential co-regulators and transcriptional partners within the SoxB1-2 regulatory network. We agree and acknowledge in the report that future studies assessing chromatin remodeling factor expression and abundance will be valuable to definitively separate direct and indirect pioneer activity.

Limitation 2:

The characterization of mecom and castor is somewhat preliminary relative to the deep work in the rest of the paper. I think this could be addressed with a few experiments. The authors could validate RNA-seq findings with ISH to show that cells are lost after reduction of either TF (this would support the model figure). The authors could also try to define whether loss of either TF causes behavioral phenotypes that might be similar to SoxB1-2(RNAi); this would be a second line of evidence that the TFs are downstream of key events in the SoxB1-2

pathway.

Thank you for this suggestion. We agree that additional validation of the mecom and castor RNA-seq results and further phenotypic characterization would strengthen this section. We are currently conducting in situ hybridization experiments to validate transcriptional changes in mecom and castor using the same experimental framework applied to soxB1-2 downstream candidates. We anticipate completing these studies within the next three months and will incorporate the results into future work.

Regarding behavioral phenotypes, we performed preliminary screening for robust behavioral responses, including mechanosensory responses, but did not observe overt defects. However, the lack of established, standardized behavioral assays in planarians presents a current limitation; such assays need to be developed de novo, and predicting specific behavioral phenotypes in advance remains challenging. We fully agree that functional behavioral assays represent an important next step and are actively exploring strategies to systematically develop and implement them going forward.

Other questions or comments for the authors:

Is it known how other Sox factors work as pioneer TFs? Are key binding partners known? I wondered if it would be possible to show that SoxB1-2 is co-expressed with the genes that encode these partners and/or if RNAi of these factors would phenocopy SoxB1-2. This is likely beyond the scope of this paper, but if the authors wanted to further support their argument about SoxB1-2 acting as a pioneer in planarians, this might be an additional way to do it.

In other systems, Sox pioneer factors often act together with POU family transcription factors (for example, Oct4 and Brn2) and PAX family members such as Pax6. In planarians, a POU homolog (pou-p1) is expressed in neoblasts and may represent an interesting candidate co-factor for future investigation in the context of SoxB1-2 pioneer activity. We have also previously examined the relationship between SoxB1-2 and the POU family transcription factors pou4-1 and pou4-2. Although RNAi of these factors does not fully phenocopy soxB1-2 knockdown, pou4-2(RNAi) results in loss of mechanosensation, suggesting that downstream POU factors may contribute to aspects of neural function regulated by SoxB1-2 (McCubbin et al. eLife 2025). We agree that co-expression and functional interaction studies with these candidates would be highly informative, and we view this as an exciting future direction beyond the scope of the current manuscript.

This paper is one of few to use ATAC-Seq in planarians. First, I think the authors should make a bigger deal of their generation of a dataset with this tool! Second, it would be great to know whether the ATAC-Seq data (controls and/or RNAi) will be browsable in any planarian databases or in a new website for other scientists. I believe that in addition to the data being used to test hypotheses about planarians, the data could also be a huge hypothesis generating resource in the planarian community, so I would encourage the authors to both self-promote their contribution and make plans to share it as widely and usably as possible.

Thank you very much for this encouraging feedback. We appreciate the suggestion and have strengthened the text to emphasize the significance of generating this ATAC-seq resource for the planarian field. We agree that these datasets represent a valuable community resource and are committed to making all control and soxB1-2(RNAi) ATAC-seq data publicly accessible.

Reviewer #2 (Significance (Required)):

This paper's strengths are that it addresses an important problem in regenerative biology in a rigorous manner. The writing and presentation of the data are excellent. The paper also provides excellent datasets that will be very useful to other researchers in the fi eld. Finally, the work is one of, if not the first to examine how the action of one transcription factor in planarians leads to changes in the cellular and chromatin environment that could then be acted upon by subsequent factors. This is an important contribution to the planarian fi eld, but also one that will be useful for other developmental neuroscientists and regenerative biologists.

I described a couple of limitations in the review above, but the strengths outweigh the weaknesses.

Reviewer #3 (Evidence, reproducibility and clarity (Required)):

The authors investigated the role of soxB1-2 in planarian neural and epidermal lineage specification. Using ATAC-seq and RNA-seq from head fragments after soxB1-2 RNAi, they identified regions of decreased chromatin accessibility and reduced gene expression, demonstrating that soxB1-2 induces neural and sensory programs. Integration of the datasets yielded 31 overlapping candidate targets correlating ATAC-seq and RNA-seq. Downstream analyses of transcription factors that had either/or differentially accessible regulatory region or showed differential expression (castor and mecom) implicated these transcription factors in mechanosensory and ciliary modules. The authors combined additional techniques, such as in situ hybridization to support the observations based on the ATACseq/RNAseq data. The manuscript is clearly written as well as data presentation in the main and supplementary figures. The major claim of the manuscript is that SoxB1-2 is likely a pioneer transcription factor that alters the accessibility of the chromatin, which if true, would be one of the first demonstrations of direct transcriptional regulation in planarians. As described below, I am not certain that this interpretation of the data is more valid than alternative interpretations.

Major comments

1. Direct vs. indirect regulation. The current analysis does not distinguish between direct and indirect soxB1-2 targets, therefore, this analysis cannot indicate whether soxB1-2 functions as a pioneer transcription. ATAC-seq and RNA-seq, as performed here, do not determine whether reduced accessibility or downregulation of gene expression represents a change within existing cells or a reduction in the proportion of specific cell types in the libraries produced. This limitation should be explicitly recognized where causal statements are made. In fact, several pieces of information strongly suggest that indirect effects are abundant in the data: (1) the observed loss of accessibility and gene expression in late epidermal progenitors likely represent indirect effects, indicating that within the timeframe of the experiment, it is impossible (using these techniques) to distinguish between the scenarios. (2) The finding that castor knockdown reduces soxB1-2 expression likely reflects population loss rather than direct regulation, given overlapping expression domains. This further illustrates the difficulty in inferring directionality from such datasets. In order to provide evidence for a more direct association between soxB1-2 and the differentially accessible chromatin regions, a sequence(e.g., motif) analysis would be required. Other approaches to infer direct regulation would have been useful, but they are not available in planarians to the best of my knowledge.

We agree that distinguishing between direct SoxB1-2 pioneer activity and indirect chromatin changes mediated by downstream factors is an important consideration. As suggested, examining the enrichment of SoxB1-2 binding motifs in regions that lose accessibility following soxB1-2(RNAi) can provide supporting evidence for direct regulation.

While we did not conduct a direct abundance analysis of all potential chromatin-remodeling cofactors, we performed a motif enrichment analysis following the methodology of Neiro et al. (eLife, 2022), comparing control-specific and soxB1-2(RNAi)-specific accessible peak sets. Consistent with a direct role for SoxB1-2 in chromatin regulation, Sox-family motifs, particularly SoxB1-like motifs, were among the most significantly enriched in regions that maintain accessibility in control animals relative to soxB1-2(RNAi) animals.

Evidence for pioneer activity. The authors correctly acknowledge that they do not present direct evidence of soxB1-2 binding or chromatin opening. However, the section title in the Discussion could be interpreted as implying otherwise. The claim of pioneer activity should remain explicitly tentative until supported (at least) by motif or binding data.

We have performed suggested motif analysis and changed the language in this section to better fit the data.

Replication and dataset comparability. Both ATAC-seq and soxB1-2 RNA-seq were performed on head fragments, but the number of replicates differ between assays (ATAC-seq n=2 per group, RNA-seq n=4-6). This is of course acceptable, but when interpreting the results, it should be taken into consideration that the statistical power is different when using data collected using different techniques and having a varied number of replicates.

Thank you for raising this important point regarding replication and comparability across datasets. We agree that the differing number of biological replicates between the ATAC-seq and RNA-seq experiments results in different statistical power across assays. We have now clarified this consideration in the manuscript text.

Minor comments

"Thousands of accessible chromatin sites". Please state the number of peaks and the thresholds for calling them. Ensure consistency between text (264 DA peaks) and Figure 1 legend (269 DA peaks).

__We have clarified specific peak numbers and will include the calling parameters in the methods section. Additionally, we will fix the discrepancies between differential peaks. __

Specify the y-axis normalization units in all coverage plots.

We have specified this across plots.

Clarify replicate numbers consistently in the text and figure legends.

We have identified and corrected discrepancies in the figure legends vs text and correct them and ensured they are included consistently across datasets.

Referees cross commenting

The reviews are highly consistent. They recognize the value of the work, and raise similar points. The main shared view is that the current data do not distinguish direct from indirect effects, and claims about pioneer activity should be softened, and further analysis of the differentially accessible peaks could strengthen the link between SoxB1-2 and the chromatin changes.

-I don't think that it's necessary to further characterize experimentally mecom or castor (as suggested), but of course that it could have value.

We thank all three reviewers for their positive assessment of the value of our work aiming to elucidate mechanisms by which SoxB1-2 programs planarian stem cells. In the revision, we have improved the presentation and carefully edited conclusions about the function of SoxB1-2. Performing motif analysis and GO annotation of upregulated genes has strengthened our observation that SoxB1-2 acts as an activator and has revealed putative binding sites.

The preliminary revision does not yet include further characterization of mecom and castor downstream genes. In response to Reviewer #2, we appreciate that additional validation of the mecom and castor RNA-seq results and further phenotypic characterization would strengthen this section. Although we are currently conducting in situ hybridization experiments to validate transcriptional changes in mecom and castor using the same experimental framework applied to soxB1-2 downstream candidates, we also reconsidered, as we did in our first revision, whether this is necessary or better suited for future investigations.

In the revision, we noted that our Discussion points were not balanced and that we emphasized the mecom and castor results in a manner that distracted from the major focus of the work, likely contributing to the impression that additional experimental evidence was required. Therefore, we have revised the section accordingly and streamlined the Discussion to avoid repetitive statements and to focus on the insights gained into the mechanism of SoxB1-2 function in planarian neurogenesis. We remain open to including these additional experiments if the reviewers or handling editors consider them essential; however, we agree that their inclusion is not absolutely necessary.

Reviewer #3 (Significance (Required)):

General assessment. The study offers valuable observations by combining chromatin and transcriptional analysis of planarian neural differentiation. The integration with in situ validation convincingly demonstrates effects on neural tissues and provides a solid resource for future functional work. However, mechanistic interpretation remains limited, partly because of technical limitations of the system. The data support an important role for soxB1-2 in neural and epidermal lineage regulation, but not direct binding or chromatin-opening activity. The authors have previously published analysis of soxB1-2 in planarians, so the addition of ATAC-seq data contributes to solving another piece of the puzzle.

__Advance. __

This is one of the first studies to couple ATAC-seq and RNA-seq in planarian tissue to dissect regulatory logic during regeneration. It identifies new candidate regulators of sensory and epidermal differentiation and identifies soxB1-2 as a likely upstream factor in ectodermal lineage networks. The work extends previous studies on soxB1-2 activity and neural cell production by integrating chromatin and transcriptional layers. In that respect the results are very solid, although the study remains correlative at the mechanistic level.

Audience.

This work will potentially interest researchers interested in regeneration and transcriptional networks. The datasets and gene lists will be valuable references for follow-up studies on planarian ectodermal lineages, and therefore will appeal to this community.

Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

Learn more at Review Commons

Referee #3

Evidence, reproducibility and clarity

The authors investigated the role of soxB1-2 in planarian neural and epidermal lineage specification. Using ATAC-seq and RNA-seq from head fragments after soxB1-2 RNAi, they identified regions of decreased chromatin accessibility and reduced gene expression, demonstrating that soxB1-2 induces neural and sensory programs. Integration of the datasets yielded 31 overlapping candidate targets correlating ATAC-seq and RNA-seq. Downstream analyses of transcription factors that had either/or differentially accessible regulatory region or showed differential expression (castor and mecom) implicated these transcription factors in mechanosensory and ciliary modules. The authors combined additional techniques, such as in situ hybridization to support the observations based on the ATACseq/RNAseq data. The manuscript is clearly written as well as data presentation in the main and supplementary figures. The major claim of the manuscript is that SoxB1-2 is likely a pioneer transcription factor that alters the accessibility of the chromatin, which if true, would be one of the first demonstrations of direct transcriptional regulation in planarians. As described below, I am not certain that this interpretation of the data is more valid than alternative interpretations.

Major comments

1. Direct vs. indirect regulation. The current analysis does not distinguish between direct and indirect soxB1-2 targets, therefore, this analysis cannot indicate whether soxB1-2 functions as a pioneer transcription. ATAC-seq and RNA-seq, as performed here, do not determine whether reduced accessibility or downregulation of gene expression represents a change within existing cells or a reduction in the proportion of specific cell types in the libraries produced. This limitation should be explicitly recognized where causal statements are made. In fact, several pieces of information strongly suggest that indirect effects are abundant in the data: (1) the observed loss of accessibility and gene expression in late epidermal progenitors likely represent indirect effects, indicating that within the timeframe of the experiment, it is impossible (using these techniques) to distinguish between the scenarios. (2) The finding that castor knockdown reduces soxB1-2 expression likely reflects population loss rather than direct regulation, given overlapping expression domains. This further illustrates the difficulty in inferring directionality from such datasets. In order to provide evidence for a more direct association between soxB1-2 and the differentially accessible chromatin regions, a sequence (e.g., motif) analysis would be required. Other approaches to infer direct regulation would have been useful, but they are not available in planarians to the best of my knowledge.
2. Evidence for pioneer activity. The authors correctly acknowledge that they do not present direct evidence of soxB1-2 binding or chromatin opening. However, the section title in the Discussion could be interpreted as implying otherwise. The claim of pioneer activity should remain explicitly tentative until supported (at least) by motif or binding data.
3. Replication and dataset comparability. Both ATAC-seq and soxB1-2 RNA-seq were performed on head fragments, but the number of replicates differ between assays (ATAC-seq n=2 per group, RNA-seq n=4-6). This is of course acceptable, but when interpreting the results, it should be taken into consideration that the statistical power is different when using data collected using different techniques and having a varied number of replicates.

Minor comments

"Thousands of accessible chromatin sites". Please state the number of peaks and the thresholds for calling them. Ensure consistency between text (264 DA peaks) and Figure 1 legend (269 DA peaks). Specify the y-axis normalization units in all coverage plots. Clarify replicate numbers consistently in the text and figure legends.

Referees cross commenting

The reviews are highly consistent. They recognize the value of the work, and raise similar points. The main shared view is that the current data do not distinguish direct from indirect effects, and claims about pioneer activity should be softened, and further analysis of the differentially accessible peaks could strengthen the link between SoxB1-2 and the chromatin changes.

• I don't think that it's necessary to further characterize experimentally mecom or castor (as suggested), but of course that it could have value.

Significance

General assessment. The study offers valuable observations by combining chromatin and transcriptional analysis of planarian neural differentiation. The integration with in situ validation convincingly demonstrates effects on neural tissues and provides a solid resource for future functional work. However, mechanistic interpretation remains limited, partly because of technical limitations of the system. The data support an important role for soxB1-2 in neural and epidermal lineage regulation, but not direct binding or chromatin-opening activity. The authors have previously published analysis of soxB1-2 in planarians, so the addition of ATAC-seq data contributes to solving another piece of the puzzle.

Advance. This is one of the first studies to couple ATAC-seq and RNA-seq in planarian tissue to dissect regulatory logic during regeneration. It identifies new candidate regulators of sensory and epidermal differentiation and identifies soxB1-2 as a likely upstream factor in ectodermal lineage networks. The work extends previous studies on soxB1-2 activity and neural cell production by integrating chromatin and transcriptional layers. In that respect the results are very solid, although the study remains correlative at the mechanistic level.

Audience. This work will potentially interest researchers interested in regeneration and transcriptional networks. The datasets and gene lists will be valuable references for follow-up studies on planarian ectodermal lineages, and therefore will appeal to this community.

Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

Learn more at Review Commons

Referee #2

Evidence, reproducibility and clarity

Review - Cathell, et al (RC-2025-03195)

Summary and Significance:

Understanding regenerative neurogenesis has been difficult due to the limited amount of neurogenesis that occurs after injury in most animal species. Planarians, with their adult neurogenesis and robust post-injury response, allow us to get a glimpse into regenerative neurogenesis. The Zayas laboratory previously revealed a key role for SoxB1-2 in maintenance and regeneration of a broad set of sensory and peripheral neurons in the planarian body. SoxB1-2 also has a role in many epidermal fates. Their previous work left open the tempting possibility that SoxB1-2 acts as a very upstream regulator of epidermal and neuronal fates, potentially acting as a pioneer transcription factor within these lineages. In the manuscript currently under review, Cathell and colleagues use ATAC-Seq and RNA-Seq to investigate chromatin changes after SoxB1-2(RNAi). With the experimental limitations in planarians, this is a strong first step toward testing their hypothesis that SoxB1-2 acts as a pioneer within a set of planarian lineages. Beyond these cell types, this work is also important because planarian cell fates often rely on a suite of transcription factors, but the nature of transcription factor cooperation has been much less well understood. Indeed, the authors do show that loss of SoxB1-2 by RNAi causes changes in a number of accessible regions of the genome; many of these chromatin changes correspond to changes in gene expression of genes nearby these peaks. The authors also examine in more detail two genes that have genomic and transcriptomic changes after SoxB1-2(RNAi), mecom and castor. The authors completed RNA-Seq on mecom(RNAi) and castor(RNAi) animals, identifying genes downregulated after loss of either factor that are also seen in SoxB1-2(RNAi). The results in this paper are rigorous and very well presented. I will share two major limitations of the study and some suggestions for addressing them, but this work may also be acceptable without those changes at some journals.

Limitation 1:

The paper aims to test the hypothesis that SoxB1-2 is a pioneer transcription factor. Observation that SoxB1-2(RNAi) leads to loss of many accessible regions in the chromatin supports the hypothesis. However, an alternate possibility is that SoxB1-2 leads to transcription of another factor that is a pioneer factor or a chromatin remodeling enzyme; in either of these cases, the accessibility peak changes may not be due to SoxB1-2 directly but due to another protein that SoxB1-2 promotes. The authors describe how they can address this limitation in the future; in the meantime, is it known what the likely binding for SoxB1-2 would be (experimentally or based on homology)? If so, could the authors examine the relative abundance of SoxB1-2 binding sites in peaks that change after SoxB1-2(RNAi)? This could be compared to the abundance of the same binding sequence in non-changing peaks. Enrichment of SoxB1-2 binding sites in ATAC peaks that change after its RNAi would support the argument that chromatin changes are directly due to SoxB1-2.

Limitation 2:

The characterization of mecom and castor is somewhat preliminary relative to the deep work in the rest of the paper. I think this could be addressed with a few experiments. The authors could validate RNA-seq findings with ISH to show that cells are lost after reduction of either TF (this would support the model figure). The authors could also try to define whether loss of either TF causes behavioral phenotypes that might be similar to SoxB1-2(RNAi); this would be a second line of evidence that the TFs are downstream of key events in the SoxB1-2 pathway.

Other questions or comments for the authors:

Is it known how other Sox factors work as pioneer TFs? Are key binding partners known? I wondered if it would be possible to show that SoxB1-2 is co-expressed with the genes that encode these partners and/or if RNAi of these factors would phenocopy SoxB1-2. This is likely beyond the scope of this paper, but if the authors wanted to further support their argument about SoxB1-2 acting as a pioneer in planarians, this might be an additional way to do it. This paper is one of few to use ATAC-Seq in planarians. First, I think the authors should make a bigger deal of their generation of a dataset with this tool! Second, it would be great to know whether the ATAC-Seq data (controls and/or RNAi) will be browsable in any planarian databases or in a new website for other scientists. I believe that in addition to the data being used to test hypotheses about planarians, the data could also be a huge hypothesis generating resource in the planarian community, so I would encourage the authors to both self-promote their contribution and make plans to share it as widely and usably as possible.

Significance

This paper's strengths are that it addresses an important problem in regenerative biology in a rigorous manner. The writing and presentation of the data are excellent. The paper also provides excellent datasets that will be very useful to other researchers in the field. Finally, the work is one of, if not the first to examine how the action of one transcription factor in planarians leads to changes in the cellular and chromatin environment that could then be acted upon by subsequent factors. This is an important contribution to the planarian field, but also one that will be useful for other developmental neuroscientists and regenerative biologists.

I described a couple of limitations in the review above, but the strengths outweigh the weaknesses.

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Referee #1

Evidence, reproducibility and clarity

Summary

The authors of this interesting study take the approach of combing RNAi, RNA-seq and ATAC-seq to try to build a regulatory network surrounding the function of a planarian SoxB1 ortholog, broadly required for neural specification during planarian regeneration. They find a number of chromatin regions that differentially accessible (measured by ATAC-seq), associate these with potential genes by promity to the TSS. They then compare this set of genes with those that are differentially regulated (using RNA-seq), after SoxB1 RNAi mediated knockdown. This allows them the authors some focus on potential directly regulated targets of the planarian SoxB1. Two of these downstream targets, the mecom and castor transcription factors are then studied in greater detail.

Major Comments.

I have no suggestions for new experiments that fit sensibly with the scope of the current work. There are other analyses that could be appropriate with the ATAC-seq data, but may not make sense in the content of SoxB1 acting as pioneer factor.

I would like to see motif enrichment analysis under the set of peaks to see if SoxB1 is opening chromatin for a restricted set of other transcription factors to then bind. Much of this could be taken from Neiro et al, eLife 2022 (which also used ATAC-seq) and matched planarians TF families to likely binding motifs. This could add some breadth to the regulatory network. It could be revealing for example if downstream TF also help regulate other targets that SoxB1 makes available, this is pattern often seen for cell specification (as I am sure the authors are aware). Alternatively, it may reveal other candidate regulators. Overall peak calling consistency with ATAC-sample would be useful to report as well, to give readers an idea of noise in the data. What was the correlation between samples? While it is logical to focus on downregulated genes, it would also be interesting to look at upregulated genes in some detail. In simple terms would we expect to see the representation of an alternate set of fate decisions being made by neoblast progeny? Can the authors be explicit about whether they have evidence for co-expression of SoxB1/castor and SoxB1/mecom? I could find this clearly and it would be important to be clear whether this basic piece of evidence is in place or not at this stage.

Summary

The authors of this interesting study take the approach of combing RNAi, RNA-seq and ATAC-seq to try to build a regulatory network surrounding the function of a planarian SoxB1 ortholog, broadly required for neural specification during planarian regeneration. They find a number of chromatin regions that differentially accessible (measured by ATAC-seq), associate these with potential genes by promity to the TSS. They then compare this set of genes with those that are differentially regulated (using RNA-seq), after SoxB1 RNAi mediated knockdown. This allows them the authors some focus on potential directly regulated targets of the planarian SoxB1. Two of these downstream targets, the mecom and castor transcription factors are then studied in greater detail.

Major Comments.

N suggestions for new experiments that fit sensibly with the scope of the current work. There are other analyses that could be appropriate with the ATAC-seq data but may not make sense in the content of SoxB1 acting as pioneer factor. Overall, the study is executed very well, methods are sound, data and analysis well-presented and narrated, and the results placed in context. The experiments are clearly reproducible and can be built on, all data is accessible to others. Motif enrichment analysis under the set of peaks to see if SoxB1 is opening chromatin for a restricted set of other transcription factors to then bind. Much of this could be taken from Neiro et al, eLife 2022 (which also used ATAC-seq) and matched planarians TF families to likely binding motifs. This could add some breadth to the regulatory network. It could be revealing for example if downstream TF also help regulate other targets that SoxB1 makes available, this is pattern often seen for cell specification (as I am sure the authors are aware). Alternatively, it may reveal other candidate regulators. Overall peak calling consistency with ATAC-sample would be useful to report as well, to give readers an idea of noise in the data. What was the correlation between samples? While it is logical to focus on downregulated genes, it would also be interesting to look at upregulated genes in some detail. In simple terms would we expect to see the representation of an alternate set of fate decisions being made by neoblast progeny? Can the authors be explicit about whether they have evidence for co-expression of SoxB1/castor and SoxB1/mecom? I could find this clearly and it would be important to be clear whether this basic piece of evidence is in place, or not, at this stage.

Minor comments.

Formally loss of castor and mecom expression does mean these cells are absent, strictly the cell absence needs an independent method. It might be useful to clarify this with the evidence of be clear that cells are "very probably" not produced.

Significance

Strengths and limitations.

The precise exploitation of the planarian system to identify potential targets, and therefore regulatory mechanisms, mediated by SoxB1 is an interesting contribution to the field. We know almost nothing about the regulatory mechanisms that allow regeneration and how these might have evolved, and this work is well-executed step in that direction.

Advance

The paper makes a clear advance in our understanding of an important process in animals (neural specification) and how this happens in the context in the context during an example of animal regeneration. The methods are state-of-the-art with respect to what is possible in the planarian system.

Audience

This will be of wide interest to developmental biologists, particularly those studying regeneration in planarians and other regenerative systems, and those who study comparative neurodevelopment.

Expertise

I have expertise in functional genomics in the context of stem cells and regeneration, particularly in the planarian model system

The medium (local TV news with videos) shows us the emotional resonance and community pride. Further reinforces one of our news values we studied in this class, human interest.

Shows prominence (President of the United States) and conflict. This quote that I picked out highlights political reactions and the symbolic weight of an American pope.

Frames him as a continuity candidate in his anticipated papacy. Reinforces Pope Francis’ progressive legacy.

The primary sources included are family, who know Prevost personally obviously. There are many local voices, and clergy. Missing voices are critics or those raising concerns about his record, keeping the tone celebratory.

Shows timeliness and usualness, giving precise detail to dramatize the election process.

News values highlighted here...proximity to Chicago as well as impact (with international pastoral work).

A local reporter for FOX 32 Chicago. The outlet’s regional focus shapes the narrative toward community pride and local identity.

The headline immediately points to local pride and historic significance. Frames the story as global, but more Chicago-centered. (makes sense since it's a Chicago news outlet)

Positions Leo as progressive. Big focus on institutional reform. Signals a continuation of Francis' modernization efforts during his papacy.

Sources include other media outlets and his social posts. Missing voices are LGBTQ Catholics themselves. This echoes the gap in perspective.

Shows timeliness (immediate reaction after election) and impact (symbolic message watched globally).

Highlights core news values we discussed in class, such as prominence and proximity. It stresses both his historic role and local Chicago identity.

A political reporter for The Hill, which often focuses on U.S. politics and policy. This suggests the coverage leans toward political implications of his papacy.

The headline frames the story as biographical and explanatory. It's connecting immediately to his U.S. roots and historic election as the new pope.

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Childhood and personal photos create intimacy and human interest. The tabloid storytelling from the New York Post tries to make us, as readers, feel like we can relate to him and his background.

Introduces conflict and controversy...shows how US and foreign politics plus scandals complicate his image.

Frames Prevost as a more progressive and reform-minded leader. Highlights his values of inclusivity and modernization.

News values of prominence and impact. Stresses the sheer scale of his newly elected position.

Emphasizes both American identity and missionary work in Peru. The New York Post, similar to the many other news sources I have looked at, frame him as both historic and humble.

Two reporters writing for the New York Post, a tabloid known for sensational and accessible storytelling. The Post shapes the narrative toward human interest and some interesting controversy to readers as well.

The headline is a bit conversational and tabloid-style...framing the story as a personal introduction of a friend rather than a formal announcement.

Positions his election as a national moment of unity despite U.S. divisions.

Frames the new pope, Prevost, as balanced but conservative in terms of doctrine. Shows us the tension between reformist and traditional elements as readers.

While this personal account is valuable when describing Prevost, it only shows one side of the story. There are still missing voices such as critics of him or the Catholic church, as well as survivors of the abuse scandals over the years that have been covered up in the church. The frame is narrow and focused largely on admiration and celebration of this historic event.

Broad appeal for Pope Leo. Framed for both American historic novelty and Latin American ties.

She is a CBS News correspondent. CBS is signaling mainstream U.S. coverage. CBS tends to emphasize national pride here in the US and broad appeal. The narrative fostered by CBS is leaning toward the American identity.

The headline frames the story as explanatory and accessible to all. CBS is answering public curiosity about this historic event.

The photo that The New York Times chose to add provides some authority and formality, while also visually reinforcing his Vatican status already. NYT blends analysis with visual legitimacy.

Frames him as cautious and reserved, contrasting with Francis’ outspoken style. Shows off a different leadership tone.

Same quote as my other annotation. Sources include the clergy and academics who praise him. However, there are missing voices here in this narrative. Seems to be a recurring issue with all the pieces of media I have consumed. There are no critics outside of the Catholic church, so it truly narrows the perspective.

Shows prominence (papal candidate), impact (potential leader of 1.4 billion Catholics), and conflict (between conservative and progressive groups).

Experienced NYT journalist reporting from Rome adds credibility. The Times’ reputation for analytical depth suggests a focus on global politics and institutional context. Helpful to look at all different perspectives from people around the world.

The headline frames the story as speculative and historic, emphasizing novelty and suspense about an American pope coming to the global Catholic forefront.

The photo reinforces human interest and proximity to ordinary people like you and me. This photo helps to visually frame him as compassionate and accessible to normal everyday Catholics.

Frames him as a bridge-builder, reinforcing the narrative of moderation and continuity with Francis.

The source puts more of an emphasis on Prevost's personality and pastoral style. Missing voices in this article include critics of the Catholic church, critics of Prevost, or survivors of abuse scandals, which narrows the frame to mainly admiration.

Shows conflict and impact, framing his election as politically and ideologically significant.

Underscores the total unusualness of a U.S. pope. It stresses the political concerns about having American influence intersect with the papacy.

A single journalist writing for The Guardian, known for progressive leanings...the coverage may emphasize reformist or different human-interest angles. Something to watch for...

Headline positions him as approachable and balanced. It shapes the narrative around personality traits rather than just institutional power.

CNN uses strong visuals such as this picture to capture the emotion and scale of electing a new pope. The medium (photos on this digital news article) amplifies the celebratory mood and dramatic atmosphere of the conclave.

Brings up conflict and institutional crisis. Frames his leadership as one that will be tested early by unresolved scandals from over the years.

Clothing is very symbolic. The quote here is suggesting continuity with tradition and subtle changes from Francis’ simpler style.

Sources include political leaders from Peru and other nations, as well as Vatican analysts. Missing voices are critics of the Catholic church or survivors of abuse scandals, which CNN notes but doesn’t quote directly.

Shows some of the news values we talked about in class such as timeliness (fast election), prominence (global leader), and impact (affects 1.4 billion Catholics).

Frames him as bridging Western influence with global inclusivity. Also addresses fears of U.S. dominance in papal politics.

Multiple reporters across Rome and London. CNN uses their global reach and intent to cover the story from several different angles for added credibility.

The headline highlights the rarity of this historic and national moment. The story CNN is framing is both global and American.

This page explains Alfred Nobel's life and legacy. I wonder what he would think about the invention of AI. Would he deem it ethical? Would he think that it is worthy of a Nobel Prize (a prize in his name)?

This article discuss the comparison of how AI is similar to the consulting firm McKinsey. How people are going to soon rely on AI for advice/descioin making. How AI is taking over the ability the McKinsey has of consolidating strategic decisions for companies.

Neofunctionalization is when a duplicated gene evolves a new function after duplication, while subfunctionalization is when the two gene copies divide the original function between them

a scientific classification group of organisms, from the species level up to a kingdom

talks about what causes the differences

A nonsynonymous substitution changes the amino acid sequence of a protein, while a synonymous substitution does not

a set of concepts and categories in a subject area or domain that shows their properties and the relations between them.

the rapid diversification of a single ancestral species into a multitude of new species that are adapted to different ecological niches, often triggered by new resources, empty habitats, or key adaptations

The article builds a descriptive narrative and quotes to convey the celebratory atmosphere. As a digital news product, it relies on vivid language and visuals.

Introduces news values of conflict and impact. Shows how his election intersects with broader ideological battles in American Catholicism.

Leo received admiration from clergy and locals. Missing voices here include critics or those skeptical of his leadership. To me, this tilts the narrative here toward praise.

Shows several news values we discussed in class such as impact (saving lives), human interest (helping poor communities), and usualness (hands-on gestures unusual for a pope).

Frames him as an individual with dual identity. Bridges the US and Latin America. This quote frames Prevost as both a global and local (to the US) figure...appealing to multiple audiences.

AP News chooses to use two different reporters. One of the is based in Peru, while the other one in Rome. They choose to use a blend of local and global perspectives when crafting their story. The outlet’s reputation for straight reporting suggests a focus on factual storytelling with human detail.

The headline immediately comes out and frames the man as compassionate and saintly. These traits emphasis human interest and the moral character of Pope Leo, rather than the institutional power of the role.

The medium is print/digital text through Vatican News. This piece of media is formal and official. Unlike other multimedia news, it conveys authority through structured chronology rather than emotional visuals or someone's opinion.

Highlights his administrative power, showing how he became central to Church governance. Shows Pope Leo in a qualified light...like he is the right guy for this job.

Shows Leo's human interest and proximity to marginalized communities. This quote reinforces the narrative surrounding him of being a compassionate individual who's dedicated to service.

Shows Pope Leo in an intellectual and spiritual light. This article does a good job framing him as highly educated and well-rounded.

This quote emphasizes the pure uniqueness and continuity. The quote stresses his identity as both a religious “first” and part of a broader trend of non-European popes.

This source, Vatican News, is the Vatican’s own media outlet. To me, this suggests institutional bias toward presenting the Pope positively and avoiding controversy. Especially since they are the ones dictating what message is portrayed.

The headline frames the piece as official and factual, signaling a formal biographical record rather than investigative journalism.

My views on how social media can be a very cruel and toxic environment have been reinforced. This class just showcased the various ways on how social media can affect peoples mental health, behavior, and views. People who do this to others at the cost of just making jokes or trolling.

Of course, I would change the way people interact with one another. Ideally, everyone should be kind and respectful, thinking about the impact of their words before they post. This would make social media a more uplifting environment, as it should be. It should be focused on connection, community, information, and entertainment. Hate speech and negativity has no place.

The hyperlink shows how the BBC uses audio-visual storytelling to expand emotional impact far beyond written print. The medium shapes the message by letting audiences see and hear him directly.

Highlights conflict and institutional crisis within the church. This frames him not only as a unifier but also as someone facing credibility challenges.

The article positions him as socially engaged, aligning with global climate change discourse. The metaphor “from words to action” frames urgency and moral responsibility we have.

Personal sources humanize him, but missing voices include critics outside the Church hierarchy or lay Catholics who may disagree with his positions.

Shows timeliness (live event), prominence (global religious leader), and human interest (crowd emotion). These values make a story like this with Pope Leo, newsworthy.

This stresses dual identity. He has American roots and Latin American ties. This frames him as a bridge figure across the two continents, North and South America.

The dual authorship signals BBC wants to highlight both global and regional angles of this massive story.

The headline frames the story as a warm introduction to the world. It invites the readers to see him (Leo) as both a person and a global leader. It sets a tone of discovery, and excitement, rather than controversy.

There seems to be a dilemma about which route composition studies should take moving forward.

These kind of titles grab your attention for a quick glance, but usually, (personally) the interest fizzles within the first couple paragraphs

i believe the word "test" add urgency to this as well. I feel like it implies to the audience that there's a right and wrong answer.

this is what I think of as the meat of different persuading papers. I want to include issues and information that are not usually seen by the public eye, bringing light and attention to them. I believe these kind of shock value issues bring in a lot of interest and can incite different emotions in the reader

take the audience's preexisting passion for something, and correlate it with the information you're trying to share to spark interest.

the more passion you have in something, the more interesting it becomes to you. Unless you can convince others to share that interest, they will not share the same passion

The Simple View of Reading allows children to understand what they read and improves their individual word-reading skill.

children will be able to take that next step with the support and extensive opportunities given.

Both of these work hand in hand with each other and can benefit at the same time.

Many writers often won't find or learn morphological rules and will often rely on their orthographic patterns instead.

Morphology is the study of the form of different words and word structure.

spellings and pronunciations are different all around the world and take time to learn.

Many people who still mispronounce their words while on social media or texting surprisingly have good literacy skills.

This is very important. Children as a whole can benefit more with the use of these tools and techniques.

There are a wide variety of systems that people worldwide must understand their own native writing.

It's important to understand one's true native writing system and language in order to further develop themselves.

What is required out of young students in order to further develop their reading and writing skills.

It's important for children to be introduced to these learning environments at a young age.

Did it really show this? OK we can check this in the appendix -- but it might be good to present a bit more side-by-side comparison.

OK I checked the appendix and I couldn't find any mention of the temporal data leakage issue. It mentioned other issues that I interpreted as more about fitting a model on one time period and expecting it to pertain to another period, but that's not 'leakage'.

Let's put a table of the relative ratings here (human vs AI, for each category etc), especially for this subset

iirc this overlaps the human evaluation

this was raised by the authors themselves, and they had an approach to accounting for it

Did the model really mention this? If so, awesome. (Although I'm a bit concerned about whether our evaluations entered it's corpus because I on't think it did so in the last version)

you didn't mention this one for the LLM

is this the same as something the LLM identified? Maybe better to present the exact language in parallel (for human vs llm)?

I would want to look at this correspondence between human and LLM critiques more closely. (Can also ask LLMs to check that)

Relative to other papers or relative to other ratings categories? I don't think we showed summary statistics or plots for the overall set of evaluations to compare this to know if it is 'relatively high'.

Or maybe you meant 'relative to the human evaluations'?

I thought we asked it for 'reasoning for each rating'?

It's not clear to me how the prompt use here is different from the prompt used on the rest of the papers.

I find the collection of data by Meta that is not essential to their services to be extremely problematic, as shown with the advertisements branded towards "Jew Haters." By targeting people with ads based on their beliefs, it can foster a more hateful society, especially on a social media platform which already struggles with moderation and making sure there is not too much toxicity.

in my opinion, in order to solve these obstacles, the company need to have a lot of money. Im also curious about how the first obstacle and its solution would work because why do people not leave when the ads are introduced since they didn't want it. How do creator make users so obsessed with their website.

I actually didn't see this in the discussion! Looked through it in some detail

While the idea was quite beneficial in brining more affordable technology to children, I think the laptop also played into ideas of colonialism. The idea based off profiting from children from under developed areas, and the the laptop being so cheap would probably also need cheap labor from third world countries.

We can still observe the ideology of white supremacy existing in today's society. Even though most people acknowledge the history of the past, the current protection measures for the indigenous people seem to remain superficial. The so-called cultural protection merely involves establishing museums or commemorative days. However, in reality, fewer and fewer people are using the Native American language because they need to integrate into the white society.

One source that stood out to me was the StackOverflow study (t29) about how programming languages differ between wealthy and developing countries. The most interesting detail I learned from that article is that Python and R—two languages I always hear people hype up—are barely used in poorer countries. Meanwhile, older languages like PHP and Android development stay extremely common there. The study explains that it’s not because developers in those countries “prefer” outdated tech, but because the global tech industry is shaped around Silicon Valley’s needs. That really clicked for me. It shows how something as simple as a programming language choice is actually influenced by economics and access, not just technical preference. It made me rethink the whole idea that tech is some neutral, equal-opportunity field.

White Man's Burden is a metaphor for white protagonist helping people of color like a mentor. It is a sign of western imperialism. In some books, author focuses on the goodness of the white characters meanwhile the minority characters are just there for the development of plot, ignoring minorities' culture.

IIRC this echoes the human evaluation (although one of the evaluators had a particular detailed suggestion for this)

This suggests/confirms that the model does not have access to the latest 'news' about the publication (in Management Science)

Seems to miss the issue of MHT, and some very surprising heterogeneity suggests spurious estimates.

Also, divergence from the PAP, although I'm not sure it had access to the PAP

Maybe make these either folded or one paper per chapter in the Quarto?

Good it noted the Winsorizing -- something Reiley emphasized.

At a first look (and from my memory) this seems like an extremely useful and plausible report!

Core Themes: Key idea; monarchy as national symbol

Core Themes: Explains how monarchy adapted historically

We observe that capitalism seems to lack the long-term resilience needed to address social crises, as its power is highly decentralized and there are many different stakeholders who benefit from it. This results in the situation where, when a social crisis occurs, such as a major epidemic, the government finds it difficult to organize people to unite and work together.

After reading this part, I realized that many decisions made by social media platforms are actually determined and driven by capitalism. The platform does not make choices that harm users at will, but is driven by competition, profit, and growth pressure, even if these choices may affect the user experience.

During Winter break of last year, I actually had an experience very related to this. I created my own business selling my paintings via art prints, and in a way became a business owner. I have to agree that in order to succeed in a business (driving up sales), you have to compete with other people doing similar ideas, their prices, and if things become large, hire more people too help you because it can be very difficult for one person to do everything at one. Overall I can say that I lost a lot of sleep over this, and that capitalism plays a big part in businesses.

Public funding is something that I can relate to, as my dad had invested in many Kickstarter companies and then tested their products for them. I find this a good idea, and it helps smaller companies share their ideas and products with the world, and the people who first invested in the product get it first. However, when investing in Kickstarter, you must be cautious because once you invest that money, you can either get the product back or just lose your money because the company failed.

For awhile, I had no idea why companies would always let themselves be bought out or sold when another party is trying to buy them, because in many cases it seemed like a bad idea with worse consequences. But now I family understand the concept that companies accept because they are required to make as much money as possible for their shareholders, and not accepting an offer like that would be cheating them out of money. This puts a lot of different things about company acquisitions into perspective for me, and maybe it took me a little too long to figure this out but hey, better late than never. This whole system of shareholders required business to make the most money whenever the opportunity arises however doesn’t always seem good though.

This article explains how companies, businesses, apps, etc. use this tactic where they first are nice to the users,(giving them perks) often at a loss of their own profits, then after building that mutual trust between the users and company, they pivot to prioritize themselves through ads and shareholders. Now that I apply it to the own apps/businesses I have used, I find this very true. Amazon for example, when you first sign up will often give you free prime, then immediately charge you after the trial has ended. Even social media sites such as Instagram and Facebook make you have to constantly keep up with the people you know lives, making it seem that if you leave, you will be behind on what others are doing. I find this tactic very sly in what they are doing, and this is why it is good to be informed so you don't fall too deep into the rabbit hole.

After reading this part, I have a clearer understanding that the relationship between workers and employers is actually a mutually beneficial one, shaped by market rules. Workers sell their labor to employers, while the output becomes the property of the employers. This reflects the common work structure in modern capitalist society. Although wage labor is the most common form of employment, the differences in treatment and social class among different positions also make this system more complicated.

I found this definition by Merriam Webster and the first section of this chapter very interesting because they were explaining what capitalism is and the definition of capitalism. I always hear about capitalism but I have never taken the time to really research the meaning, I knew the main idea of it but I found it helpful to get very clarify and clear meaning of capitalism. It is an interesting concept that people can get screwed in and people can do extremely well in.

This source discusses the definition of capitalismm and how the private ownership of companies and economic systems are usually manipulated for personal profit.

This is a Wikipedia page about the 1989 handheld Nintendo console the Game Boy. I’ll use this as a jumping off point to try to explain why video games, mainly in the 80’s, 90’s, and early 2000’s, was viewed primarily as a masculine or male hobby. After the 1983 video game crash, Nintendo was having a troubled time marketing and selling their home console the Nintendo Famicon to American companies and retailers. After many failed attempts to convince retkairrs to hold their product, Nintendo decided to market the famicon in the US not as a game console, but as a toy, which is what lead to the release of the Nintendo Entertainment System in the US with the zappinator and Rob the robot. But, if you know anything about toys, then you’d know that toys are one of the most gendered marketed products out their, so when Nintendo was marketing the NES as a toy to the US, they decided to market it as a “boy toy” since that was viewed as more lucrative. Even after the NES and Game Boy and as other consoles entered the scene, that original mattering for the NES lead to the general idea of gaming as a male dominated hobby.

I think this is the best option for users to be able to make a difference on meta's sites. Facebook and Instagram both rely on users, they would be nothing without the users using the sites and creating everything about the cites. Without users there is no content or social media site at all. If users can all vote to leave a site and do it in an organized way, that could actually hurt meta and make a difference. This would be really hard to coordinate though.

Honestly, this chapter made me realize how invisible the role of English is in programming. I always took it for granted that terms like if, while, or return were “universal,” but they’re only universal because English basically colonized the coding world. It makes me think about how much harder programming must be for people who don’t speak English well. We talk a lot in tech about making things “accessible,” but the foundation of programming itself is already biased toward one language.

The part about Silicon Valley deciding what technologies the rest of the world uses also stood out to me. It feels weird that a whole country’s developers might rely on “outdated” languages just because the global tech trends are controlled by one region. It reminds me of how fashion or music trends spread — people follow whatever the cultural “center” is doing, even if it doesn’t fit their own needs.

One question I have is: would programming look totally different today if the early pioneers weren’t mostly English-speaking? Like, if the first mainstream languages came from Brazil or Japan, would we all be learning those instead? It makes me wonder how many innovations never spread just because they weren’t born in the “right” place.

This paragraph shows that VWIL gives men and women different treatment; the programs are unequal.

This paragraph basically means that the state has no set policy for diversity. Giving education advantages to only men is unfair; that isn't equal protection.

This is only a part of the project though

Last sentence seems relevant to the grant application language

"reliably identifies" feels too strong ... or at least I haven't seen the evidence yet.

I don't understand 'anchored in the PDF of each paper' -- maybe LLM wrote this?

OBSERVATION: Unthank notes that any man is entitled to run for public office regardless of their background, and that theft is less frequent than in his hometown, possibly due to the lower poverty rate.

INTERPRETATION: Unthank's experience living in New York was extremely pleasant, safe, and a large step up from his life in Ireland, with less discrimination, poverty, and crime taking place.

CONTEXT: The tertiary source describes the Protestants as very well-off, especially compared to their Catholic counterparts who would migrate to the US en masse in the following decade. They are described as predominantly being educated property-owners, making their transition into becoming citizens smooth and largely free of distress. This is corroborated by Unthank's account of his experience living in a safe area of the city where crime and suffering are at a minimum.

CONTEXT: The tertiary source gives context behind Unthank's experiences as a Protestant Irish immigrant to the US. Additionally, Unthank's experience gives context behind the privilege of living in the US as an educated white male at the time and why so many Protestants were drawn there from Ireland with the promise of better living.

This study demonstrates the impact of weather on reading during driving, offering new insights for cognitive theory by showing how environmental factors shape language processing while in motion.

Task performance changed over time, with slight accuracy gains and increasingly slower responses in rain, suggesting accumulating perceptual fatigue, while stable frequency effects showed that lexical familiarity consistently aided recognition throughout the task.

Overall, the findings show that rainy conditions slow drivers' processing of written information, underscoring the need for adaptive, weather-responsive signage and intelligent transportation systems that enhance visibility, support real-time traffic sign recognition, and improve safety under adverse environmental conditions.

The lack of interaction between weather and word frequency indicates that rain likely disrupts early visual encoding equally for all words, producing independent, additive effects that occur before later lexical frequency processes can engage.

Adverse weather like rain, fog, snow, and wind impairs visibility and affects drivers’ cognitive functioning, raising accident risk by up to 13% and making it harder to process fast-moving road signs. Because so much written information is read while we’re in motion, understanding how people recognize words under these conditions matters. Yet research shows the visual word recognition system is highly resilient—people can read distorted, rotated, or altered text with only small costs, thanks to flexible letter-detection mechanisms that tolerate substantial visual degradation unless disruptions are extreme.