Internet technology accelerates connections. It does so beyond the human beings evolved ability to cope with inputs. As a result it will accelerate the bad portions of humanity of which there are many we gloss over too often with our rose colored glasses. If we don't approach the world from a humanistic perspective, the bad will swamp us.

Read [[Pete Brown]] in Exploding Comma

how would ancestors have worked towards sovereignty if they were alive today

but this would force them to acknowledge their place as part of the US, does this create more negative feelings and legitimacy issues?

so maybe same end goal but more pragmatic way of getting there?

how does nationalism play a role in the divide on the sovereignty issue

why do they support it

how do they form unity for the cause amidst this much division

always a simmering thing?

I shouldn't be surprised honestly

risked their lives for their land

ITS THEIR LAND

destruction of indigenous land

Vocabulary learning - essential part of language learning.

We could include this in the lightbulb aside suggested above. Color temperature is now more meaningful a measure than wattage!

Move this up to the red and blue stars discussion?

Shall we mention that this is the Solar Constant? Maybe an aside about solar energy as a clean source of energy?

Should we use real stars?

Might be worth emphasizing here how counterintuitive this is. It wasn't really described until Kepler.

An aside would be good to describe why incandescent light bulbs are closer to blackbodies than fluorescent or LED bulbs thus confusing everyone!

Maybe it would be good to include the classic color temperature map here? That explains this much better than words, I think.

It might be worth emphasizing that the blackbody curve is not sharply peaked? Although Figure 9 is somewhat misleaing in that regard.

But there is arguably good reason for that. Since high temperatures are usually not approaching more than a few thousand K, red is hot. Blue is cool because that's the complimentary cone activation. This is made all the more evident because the red and blue colors of stars do not match the vivid reds and blues of our eye sensitivities.

Let's put the units in this equation.mK on the top?

Arguably, they do... it's just so low in intensity the practical upshot is that other productions of x-rays far outshine that (like cosmic ray collisions).

Do we need solid or object here? E.g. the CMB and stars are not solid. Arguably the CMB isn't even caused by an "object". Should we maybe say "opaque" objects instead?

Not just clouds, though clouds are perhaps the biggest contributor to albedo.

To the extent that objects reflect light, they are not behaving as blackbodies?

Maybe we can reword this: "This is why doctors recommend the application of sunblock if you are exposed to the Sun. Your skin can absorb UVA and UVB rays? Epidermis does absorb UVB.

dust that is opaque to visible light? Don't need to get into the details of Rayleigh scattering here, necessarily, but it can be confusing given the fact that IR light doesn't penetrate the atmosphere.

A good aside is to be had here about how this was the result of infrared light being absorbed by the material while visible light passes through! Otherwise the confusion is that visible light has a higher color temperature.

Might be good to mention that microwaves are often considered radio waves. Really the only reason they are distinguished is because we are biased towards degrees Kelvin so they act a bit like the low end of the infrared blackbodies.

Here might be a good place to have an aside about 5G paranoia.

Move up?

Add "Because of the photon-energy frequency relationship"

omit? Really it's a waveparticle, so we can just let the weirdness be?

Could we maybe use the actual values here in THz or something? Otherwise this seems misleading.

Oh, let's just mention Michelson and Morley here... maybe as an aside?

spicy! I guess this is true, but on the other hand this is the only wave at that time that was known which did not require a medium, so maybe we shouldn't be so harsh?

Hmm... I think I'd rather attribute this insight to Planck. Einstein didn't really seem to appreciate the particle implications, if I'm not mistaken. He just piggybacked on the E = hf formalism as a "threshhold" and showed that it could explain the weird results of the photoelectric effect

I would like an accounting of energy as follows: mechanical forms (kinetic and potential), wave forms, and mass-energy.

Shall we include a definition of energy? Ability to do work and work is a force that happens over a distance. Force is a nice conceptual point "push or pull" so students can get a sense for what energy is without appealing to vague understanding? Also removes the misconception about "subtle energies".

Funnily Iago does not incite suspicion in Lodovico, only Othello. Perhaps that emphasizes Iago is a delusional part of Othello, the inner darkness that arises, indicating Othello has a fatal flaw that differs from all other characters. Is it really because he represses something? If so what? Why is he weak in his convictions and easy to sway? What does that show? What does it say about how he sees Desdemona?

Ahh I see, the civility is based on being Iago, keeping one's passions, desires subdued -- he turns into a monster because he cannot accept his emotions and true self reflection by himself. Now that Iago has fished them out, he doesn't know how to deal with them. Like inferior function, repressing it only makes the inner darkness grow more dangerous.

Maybe this passage signifies the intertwining of politics and personal, and how they are inseperable, because human is inseperable to their emotions -- lest they be Iago?

Even the way he wants to kill her comes down to pride, justice, and his tightly held "Venetian morality" that comes from Iago's advice, all because he cannot trust his own morality and create his own convictions

Confusion and contradiction

Confirmation bias yet again, Iago has done none but plant the seeds (or rather, water the seeds of insecurity) that Othello has in him, and the rest is the human need for drama, for coherency, for understanding.

Confirmation bias! To provide an inkling of suspicion is to provide the basis of a narrative.

Advising against innocence, against not knowing, although Iago's advice that gives Othello a taste of new information is really what leads to his downfall.

Shows his reason being guided fully by physical emotion and anger, that even causes a seizure. He is not like Iago, as Iago has free will with the absence of emotion. Only reason, and that is why he is isolated from the rest, different. Juxtaposition between Othello (human) and Iago (reason, devil) and Desdemona (love, emotion) like tug of war

Shows that it is entirely Othello's choice to interpret Iago's words, that Iago is simply an inkling that knows none, and that it is man's tendency to suspect that causes the downfall.

I'm not sure this is a great fit here. Many Worlds does not really address the question of life in the Universe inasmuch as the interpretation relies on these branching probabilities being essentially independent paths on the landscape.

Might be worth mentioning that many of Bruno's ideas were wacky too?

Technically, it was direct proof that Venus went around the Sun. There is a little-appreciated "Tychonic" model that Galileo's interlocutors promoted :)

I like the story of getting better and better telescopes, but maybe we should avoid the spiciness of magnification being the thing that matters?

All this for another chapter?

Not sure this is necessary here. Maybe we can wait for chapters which discuss microscopy?

Perfer: "the apparent motion backwards in the path Mars takes across the sky can be explained entirely due to our perspective on the Earth"

Arguable. According to relativity, it is moving backwards.

Let's get an image for this.

Omit or just state as plain fact to be discussed later in the text: "Planets farther away from the Sun more more slowly than planets closer to the Sun". This fact is basically empirical anyway and we don't need Kepler's Laws to describe that.

Really -- ALL planets that undergo retrograde as well as why the Sun and the Moon do not. Mars may be the most dramatic example and the timing is such that epicycles can be falsified using Mars most easily, but I think we should be clearer that it's all planetary motion.

Need link

"could be included with the rest of the planets"??? I don't know that Copernicus actually concluded it was a planet.

I think we should say something slightly different. This was the first book in Europe that challenged the groupthink acceptance of Ptolemy and set the stage for Kepler and Galileo. It was a realization that maybe the ancients got things wrong.

I think we should include ideas that were cross-cultural about the emergence of life, the plurality of worlds, the stars being like the Sun, and deep time that are present in other cultures (Islamic, Indian, Chinese, Mesoamerican, Polynesian, etc.). Many of the ideas that ended up as scientific were built upon the colonial enterprise of collecting ideas like this and distilling them into the Enlightenment project.

This could probably translate into the first C of social change: consciousness of self. This is definitely a connection worth making in your philosophy.

I have reason to believe that electronic text is capable of existing in some manifestation alongside classical versions of text. It is possible to store absolutely anything, and it is impossible to lose the ability to reproduce something in one way or another nowadays. A number of samples of literature from bygone times are still unreadable without specially trained people or equipment. And both versions of the text are unarmed before fire.

These are the 6 things that need to be completed for this Module 3 Discussion! * Complete Learner Analysis Worksheet * Create 2 Personas * Share the Personas * Describe Challenges * Share Your Resources * Review 2 Peers' Personas

The naming and emphasizing of joy and play feels radical and revolutionary and healing - I also feel sad for how rare this seems to be named and prioritized. Related to research of joy and play, I am curious to learn how different people think and talk about and experience joy and play. I'm curious about the relationship between these three concepts: identity, belonging, and joy and play. I see so much potential for hope and healing in this update.

This is so powerful and seemingly so simple - it mirrors the User Experience focus of Instructional Design. I also believe this will be very challenging for some teachers to fully enact, as school systems focus so much on the power and role of the teacher; and this is not suggesting the power or role of the teacher is diminished, but shared with the students to encourage student to be more engaged in their own learning.

I really appreciate the inclusion of both practitioners and researchers as equally important in this call. We should hold practitioners and researchers as equally important and encourage their collaboration - while acknowledging the growing number of practitioner researchers who truly are both. Additionally, this sentence is powerful in its naming of 'barriers rooted in biases and systems of oppression.' Only when we name these and illustrate them with real examples and show how people can use the UDL Guidelines 3.0 to address them will we begin to increase and ensure educational equity for more learners.

This sentence makes it clear the 'driver' behind this revision was seeking to ensure equity was more clearly supported by the UDL Guidelines. This seems to focus on making the guidelines work for learners as opposed to making the guidelines more consumable for instructors. This seems like a logical evolution. I believe educational equity can only be achieved when we focus on how learners experience our schools and other learning environments.

Här intressant: man kan neka en diagnos som troligen utförs pga. tecken på nedsatt kognitiv- eller utvecklingsförmåga.

Next to the xz debacle where a maintainer was psyops'd into backdooring servers, this is another new attack surface: AI tools make up software packages in what they generate which get downloaded. So introducing malware is a matter of creating malicious packages named the way they are repeatedly named by AI tools.

Note: This response was posted by the corresponding author to Review Commons. The content has not been altered except for formatting.

Learn more at Review Commons

Reply to the reviewers

__Reviewer #1 (Evidence, reproducibility and clarity (Required)):____ __ Deka and colleagues report that a non-canonical NFKb signaling operates in DCs in the context of inflammation and inhibits a tolerogenic mechanism driven by b-catenin-Raldh2. The following comments are made to clarify the findings presented.

1. The authors re-analyzed published scRNAseq data from DSS colitis to identify the expression of Relb and NFKB2 in myeloid cells. 1a- The authors are encouraged to expand this analysis to other published datasets.

We sincerely appreciate the comment from the knowledgeable reviewer. Unfortunately, we did not find any other publicly available scRNAseq dataset from DSS-treated mice. To circumvent this problem, we instead examined a previously published microarray-based bulk transcriptomic dataset obtained using FACS-sorted DCs isolated from the mouse colon (GSE58446, Muzaki et al. 2016; doi:10.1038/mi.2015.64). We consistently found an increased expression of Relb, and to some extent Nfkb2, mRNAs in intestinal DCs upon DSS treatment (Fig R1). Because microarray analysis lacks the quantitative attributes that scRNAseq offers, we provided this newly analysed dataset for reviewer's eyes and refrained from including this data in the manuscript per se. Of note, we have also provided our own experimental data directly demonstrating p100 processing in DC isolated from colitogenic gut. (Fig 1F)

Importantly, we could identify an additional scRNAseq dataset derived colitogenic human ulcerative colitis patients (GSE162335, Devlin et al. 2021, doi.org/10.1053/j.gastro. 2020.12.030). Interrogation of this dataset indeed confirmed that RELB and NFKB2 mRNAs were majorly expressed in intestinal DCs and not in intestinal macrophages and that IBD was associated with increased expression of multiple RelB-important genes in intestinal DCs. These analyses further supported the notion that heightened non-canonical NF-kB signalling in DCs could be fuelling aberrant gut inflammation. We have now incorporated this newly acquired data in the supplementary Figure S5A-S5C. (line# 456-460)

1b. Additionally, the expression of Relb and NFKB2 in other cells - especially other myeloid cells -should be explored and included, even if then the authors later choose to test their function in DCs.

Adhering to this brilliant suggestion, we have now further interrogated the mouse scRNAseq dataset (GSE148794 ; Ho et al., 2021) to compare macrophages and DCs for the expression of the non-canonical signal transducers. Indeed, we found a relatively insignificant level of Relb and Nfkb2 mRNAs in intestinal macrophages in comparison to intestinal DCs. Our data suggested that the non-canonical NF-kB pathway is likely to play a more prominent role in DCs than in macrophages in the gut. This new analysis has now been presented in the revised draft in Figure 1B. (revised text line#136-140) This comparison indeed proved useful in motivating subsequent in-depth analyses of the non-canonical NF-kB pathway in DCs in the context of experimental colitis.

1c. Please note that there is a transition from Fig 1A to Fig 1B to focus on DCs, which is not apparent from the figure.

Please find our response to #1b.

Please include scale bars for all histological analyses.

We thank the reviewer for alerting us. The scale bars were already included in the histological analyses; we have now appropriately highlighted them in this revised version for better visual clarity.

In Fig S1I, the authors show that loss of body weight upon DSS treatment in Nfkb2DCD11c is indistinguishable from control. Why is the starting weight at 110%? Please clarify.

We sincerely apologize for this inadvertent error. We have now rectified the axis label, representing the starting weight at day 0 as 100% (currently Figure S1J).

In Figure 2, please indicate the database/s used for the identification of top biological pathways.

We used "WikiPathways subset of cellular processes" available at www.gsea-msigdb.org/gsea/msigdb/mouse/collections.jsp?targetSpeciesDB=Mouse#M8 for the pathway enrichment analysis presented in Figure 2B. We also utilized a previously published RA-target gene set for the gene set enrichment analysis presented in Figure 2C (Balmer and Blomhoff, 2002; 10.1194/jlr.r100015-jlr200). While this information was included in the materials and methods section in the original draft, we have now included these descriptions in the figure legend for further clarity. (please see revised figure legends 2B and 2C)

The authors show a more significant expansion in Tregs upon DSS treatment when non-canonical NFKb is ablated in DCs. Is this at the expense of a reduction of specific Th cells? Can the authors also report the number of cells beyond the % of cells?

In response to the reviewer's comment, we have examined the abundance of Th17 cells in the colon of our knockout mice. As also observed earlier upon DC-specific ablation of NIK function (Jie et al., 2018), disruption of non-canonical NF-kB signaling in DCs in RelbDDC or Nfkb2DDC mice led to a reduced frequency of RoRgt+ Th17 cells in the LP (Figure S3F, new data). Our in vitro (Figure 2I) and in vivo (Figure 3F-G, 6B-6C) studies conclusively linked DC-intrinsic non-canonical NF-kB signaling to intestinal Treg via the RA pathway. Therefore, we conjectured that the observed decline in the Th17 compartment in our knockouts could be secondary to Treg expansion. We have now further discussed this point in the revised manuscript. (line#296-300)

As the reviewer suggested, in addition to the Treg frequency, we have also presented the number of intestinal FoxP3+ CD4 T cells in the supplement (Figure S3E). Our data revealed a similar increase in the total Treg numbers in the mouse colon upon ablation of the non-canonical NF-kB pathway in DCs. (line#296-300)

In figure 6A, it appears that not only the amount of beta-catenin expressed but also the percentage of beta-catenin positive MNL DCs is significantly expanded upon ablation of non-canonical NFkb. Please verify and if so, include.

We thank the reviewer for this very insightful comment. We have now catalogued MLN DCs into b-cateninlow and b-cateninhigh compartments. Indeed, we found a substantial more than two-fold increase in the frequency of b-cateninhigh DCs in RelbDDC mice. Accordingly, we have revised Figure 6A and emphasised this point in the text.

(line#428-430)

In analogy to comment #1 above, please expand the analyses in human samples to include the expression of Relb and Nfkb2 to other myeloid cells.

Adhering to the valuable suggestion by the reviewer, we have now analysed the scRNAseq dataset (SCP 259) comparing DCs, macrophages, and inflammatory and cycling monocytes present in the human gut for the expression of RELB and NFKB2 mRNA (Figure 7B). Consistent with our observation involving the mouse colon, we found that mRNAs encoding these non-canonical signal transducers were mostly expressed in DCs among various MNPs. This point has also been emphasized in the revised draft. (line#446-448)

Reviewer #1 (Significance (Required)):

Strengths of the manuscript include the conceptual novelty of the intersection between non-canonical NFkb and the tolerogenic b-catenin-Raldh2 axis. And additional strength is the methodical approach, which includes various immunological and biochemical assessments as well as genetic perturbations to dissect such relationships. While it remains unknown the relevant triggers for the non-canonical axis described, this study advances our mechanistic understanding on how activation of this axis overrides regulatory mechanisms in DCs. As such, this manuscript should be of broad interest to immunologists and in particular mucosal immunologists. We sincerely thank the reviewer for lauding our work as conceptually novel and methodical. The encouragement from the knowledgeable reviewer would certainly motivate us further to identify the relevant trigger of this pathway in the gut.

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

The following issues are noted.

- all animal strains and their provenance should be described and properly referenced (for example, there are at least two CD11c-Cre strains with different specificity). Along the same lines, the specificity of Cre recombination should be confirmed, at least in major cell types (DCs vs T effector or regulatory cells).

We sincerely appreciate the reviewer's attention to these important details. We would like to point out that in our original draft, Table 1 in the Materials and Methods section provides information on the source and the identifier of all mouse strains used. In particular, we utilized CD11c-Cre mice with the identifier 008068 from the Jackson Laboratories. Alternately known as B6.Cg-Tg (Itgax-cre)1-1Reiz/J, this strain displays Cre-mediated recombination in more than 95% of conventional DCs while exhibiting only minor recombination in lymphocytes (low-activated T cells (www.jax.org/strain/008068). Importantly, our immunoblot analyses revealed efficient depletion of RelB in specifically splenic CD11c+ cells of RelbDDC mice with only a negligible reduction in CD11c- cells (Figure S1E). Our analyses involving Nfkb2DDC mice also assured of similar gene disruption specificity (Figure S1H). Notably, our results were consistent with those documented on RelbDDC and Nfkb2DDC strains earlier (Andreas et al., 2019). To further address the reviewer's concern pertaining to the T-cell compartment, we have now compared splenic CD4+ cells from Nfkb2fl/fl and Nfkb2DDC mice for the expression of p100 (Figure S1I, newly added in the revised draft). Our results confirmed that CD11c-Cre-driven ablation of the non-canonical NF-kB pathway did not perturb p100 expressions in T cells. Taken together, these allow us to emphasize that knockout phenotypes observed in our study were attributed to non-canonical NF-kB deficiency in DCs. We have accordingly modified the text to highlight gene deletion specificities in our knockouts. (line#166-167, 180-182)

- the DSS model is prone to "batch effects" of individual cages, and proper comparison between genotypes is possible only if mice of different genotypes (eg littermates) are housed together in the same cages. The authors should clearly confirm whether this was the case, and if not, key experiments should be repeated in this setting.

As mentioned in the materials and methods section of the original draft, littermate male mice of indicated genotypes were indeed cohoused for at least one week prior to experiments. We have now further emphasised this point in the legend of Figure 1.

- BMDCs represent a heterogeneous mixture of DCs and macrophages (Helft et al., Immunity 2015). These populations should be clearly defined and compared between genotypes, to make sure that they do not underlie the observed gene expression differences.

The knowledgeable reviewer has raised a very pertinent issue. We would like to emphasize that instead of generating BMDCs using GM-CSF alone following the protocol prescribed by Helft et al. (2015), we differentiated bone marrow cells to BMDCs using a cocktail of GM-CSF+IL4 adhering to the protocol published by Jin and Sprent (2018). Following the reviewer's suggestion, we have now compared BMDCs generated in these two protocols in our laboratory. As reported earlier (Jin and Sprent, 2018), unlike BMDCs generated using GM-CSF alone, BMDCs generated using the GM-CSF+IL4 cocktail did not contain CD115high macrophage-like cells (Figure S2C). (line#230-232) However, they displayed equivalent expressions of the DC marker CD135 on their surface. Moreover, when we compared BMDCs derived from Relbfl/fl and RelbDCD11c mice in flow cytometry analyses, we found comparable surface expression of CD135, assuring intact BMDC generation from bone marrow cells ex vivo in spite of the absence of RelB (Figure S2I). (line#266-268) These studies argue that macrophage-like cells did not contribute to the observed gene expression differences between WT and RelB-deficient BMDCs.

• the analysis of DCs in mutant strains (e.g. in Fig. 3) would benefit from a better definition of populations, e.g. resident vs migratory DCs in the MLN, the Notch2-dependent CD103+ CD11b+ DCs in the LP and MLN, etc. Again, this would be important to justify differences in gene expression (e.g. Fig. 3D).

We sincerely appreciate the comment from the knowledgeable reviewer. In a landmark paper from Prof. Fiona Powrie's group (Coombes et al., 2007), it was earlier demonstrated that CD103+ DCs present in the intestine migrate to local MLNs and play a key role in producing RA and supporting Tregs. While our BMDC data strongly supported a cell-intrinsic mechanism underlying Raldh2 upregulation upon non-canonical NF-kB deficiency (Figure 2F), our in vivo studies (Figure 3D-3E) did not entirely rule out also a possible expansion of RA-producing CD103+ DC compartment in our knockout mice. Although the proposition that non-canonical NF-kB signaling regulates the generation of specific intestinal DC subsets seems attractive, we must point out that previous studies showed a relatively unaltered frequency of CD103+ cells among steady-state migratory DCs in skin-draining lymph nodes (Döhler et al., 2017). Nevertheless, following the reviewer's suggestion, we now plan to perform advanced flow cytometry analyses to compare Relbfl/fl and RelbDCD11c mice for the frequency of CD103+CD11b-, CD103+CD11b+ and CD103-CD11b+ DCs in the intestine. To this end, we have already optimized our experimental protocol for staining intestinal DCs with anti-CD103 antibody (BD Bioscience). In the coming weeks, we are expecting to gather adequate numbers of littermate knockout mice to perform a side-by-side comparison. [NOTE: also the section - "Description of the planned revisions"]

• the analysis of b-catenin protein expression and cellular localization at the single-cell level (e.g. by IF) would greatly strengthen the mechanistic connection between NF-kB and Wnt/b-catenin pathways.

Adhering to the reviewer's suggestion, we have now performed immunofluorescence assay (IFA) to capture the impact of RelB deficiency on b-catenin expression and cellular localization. Because BMDCs pose challenges for IFA owing to their non-adherent nature, we instead examined mouse embryonic fibroblasts (MEFs), which provide for a genetically amenable model cell system. As presented below (Figure R2), our IFA data conclusively demonstrated an increased cellular abundance and nuclear localization of b-catenin in Relb-/- MEFs. While we are truly excited to find that our proposed mechanism is functional in another cell type, we feel that the inclusion of MEF data in the main manuscript, which describes DC-mediated immune controls, may cause significant distractions for the general audience. Accordingly, we have provided this data for the reviewer's eyes only.

Minor: - The reanalysis of previous single-cell data is in Figs. 1 and 7 are much less convincing or exciting than the new experimental data relegated to the supplements. The distribution of the results between main and experimental figures may be reconsidered in this light.

We concur with the knowledgeable reviewer that our scRNAseq analyses may have appeared less convincing in the original draft. In response to comments by reviewer-1 and reviewer-3, we have now added additional data panels (Figure 1B, Figure 7B and Figure 7G) and examined additional publicly available datasets (Figure S5). In the revised draft, these analyses helped us to more firmly establish a link between non-canonical NF-kB signaling in DCs to aberrant intestinal inflammation in mice and humans.

However, we slightly diverge that many key experimental datasets were relegated to the supplement. Except for the FITC-dextran experiment, data from all other experimental analyses were presented in the main text (Figure 1). To suitably manage space in our figure panels, we opted to present quantified data averaged from experimental replicates in the main text while providing representative raw data in the supplement. Besides, immunoblot analyses confirming DC-specific ablation of target genes in our knockouts were placed in the supplement. Notably, these knockout strains were also examined earlier (Andreas et al., 2019). Those studies, along with our own analyses (Figure S1E, S1H and S1I - additional data), confirmed the most efficient gene deletion in CD11c+ cells. While maintaining these data in the supplement for want of space, we have now cited this reference in the main text to emphasize that knockout phenotypes observed in our study were attributed to non-canonical NF-kB dysfunctions in DCs.

Reviewer #2 (Significance (Required)):

The manuscript by Deka et al. explores the role of the non-canonical NF-kB pathway, specifically of its key mediators RelB and NF-kB2, in dendritic cells (DCs) during intestinal inflammation. The key strength of the paper is the demonstration that DC-specific deletion of RelB or NF-kB2 leads to improved acute or chronic DSS colitis. It is also shown that reducing the dose of b-catenin rescues the phenotype of RelB deletion, providing an important genetic connection between NF-kB and Wnt/b-catenin pathways. As such, the work is novel, important and of potential significance to the field.

We express our deepest gratitude to the reviewer for his/her valuable time and insightful comments. We are indeed extremely excited that the knowledgeable reviewer finds our work novel, important and of potential significance to the field. These positive comments would inspire us to look further into potential interventions targeting the non-canonical NF-kB pathway in human ailments.

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

Summary:

This manuscript from Deka et al. investigates the role of dendritic cell noncanonical NFκB signaling on intestinal inflammation. Based on prior data showing altered DC function in intestinal inflammation, they interrogated existing scRNAseq data and found that DSS treatment (which yields chemical colitis) increased the expression of non-canonical NFkB family members in dendritic cells. This led to the generation of a DC-specific RelB deficient mouse and use of a DC specific NFkB2 deficient mouse, each of which showed varying degrees of protection from chemical colitis.

Overall, they do a very nice job identifying a mechanism by which noncanonical NFκB signaling in dendritic cells contributes to intestinal inflammation via transcriptional regulation of Axin1, downregulation of β-catenin, restraint of Raldh2 synthesis, impaired retinoic acid synthesis and subsequent decrease in protective Tregs, IgA+ B cells, and microbial dysbiosis. The importance of this pathway is well supported by their focused targeting of β-catenin. After pharmacologic inhibition of β-catenin showed restoration of Raldh2 abundance, they made a DC-specific β-catenin haploinsufficiency RelBDCD11c mouse which showed impaired Raldh2 activity with restoration of colonic Tregs and fecal sIgA. When challenged with DSS, the protective phenotype seen with the RelBDCD11c was lost and the colitis phenotype returned to that of the Relbfl/fl control, further solidifying the role of β-catenin, Raldh2 and RA on intestinal inflammation. Additionally, the discussion provides a robust mechanistic explanation for the phenotypic differences between the RelB and Nfkb2 genotypes, drawing on the authors' deep knowledge of the non-canonical NFκB pathway.

Major comments:

1. Although they propose a novel mechanism by which dendritic cells can contribute to intestinal inflammation, it is in a model of acute epithelial injury that accentuates the contribution of the innate immune system. Would recommend including a discussion of the limitations of this model.

We most sincerely thank the knowledgeable reviewer for raising this important issue. We argue that while erosive epithelial injury initiates colitis in the DSS model, T cells were shown to aggravate intestinal pathologies, particularly at DSS doses used in our study (Kim et al., 2006; doi: 10.3748/wjg.v12.i2.302). Furthermore, our chemically-induced colitis model offered a convenient tool for genetically dissecting the DC-intrinsic role of the non-canonical NF-kB pathway in the intestine. However, we agree entirely that no single animal model fully captures the clinical complexities of human IBD and that other models of experimental colitis should also be employed in the future to assess the generalisability of the proposed DC mechanism in regulating intestinal inflammation. In particular, future studies ought to examine composite knockout strains in the T-cell transfer model of experimental colitis to establish further the role of non-canonical NF-kB signaling in DCs in alleviating intestinal inflammation. As suggested by the reviewer, we have now articulated this point in the discussion section. (line# 553-557)

The human work (Figure 7) shows solid evidence of heightened non-canonical NFκB signaling in DCs via abundance of RELB and NFKB2 along with a few RelB important genes, however, the RA-specific pathway identified in the mouse work is not strongly corroborated by the human data. There is demonstration of one β-activated gene (CCND1) showing decreased expression in IBD patients, however no other gene along with RA pathway was clearly identified to be differentially expressed as one would predict from the mouse work.

We sincerely thank the knowledgeable reviewer for articulating this deficiency in our analyses of single-cell RNA-seq data derived from IBD patients (SCP259, Smillie et al., 2019). We would like to clarify that many well-known b-catenin target genes, including MYC, were not detectable in this dataset. Nevertheless, to address the reviewer's concern, we subjected this dataset to GSEA using a previously published list of RA target genes (Balmer et al., 2002). Our analyses revealed a significant enrichment of RA targets among genes that were downmodulated in DCs derived from inflamed colonic tissues of IBD patients as compared to those from non-inflamed tissues (Figure 7G, newly added in the revised version). We have now discussed this data in the result section. (line#470-475) These studies further substantiated the inverse correlation between noncanonical NF-kB signalling and the RA pathway in DCs in the inflamed human gut.

Minor comments: 1. Their NFκB2DCD11c mouse underwent a regimen of chronic DSS treatment after acute DSS treatment only displayed subtle phenotypic changes. Was the same chronic colitis regimen also tested in the RelBDCD11c ?

Indeed, we also examined RelbDCD11c mice in the chronic DSS treatment regime. As compared to Relbfl/fl mice, these knockout mice displayed significantly less bodyweight changes upon chronic DSS challenge. Because RelbDCD11c mice readily showed acute DSS phenotype, we did not further pursue investigations involving this strain in the chronic DSS settings and rather focused on Nfkb2DCD11c mice to illustrate chronic DSS phenotypes.

In the introduction, it was stated that patients with UC have a marked reduction in intestinal DCs. If DCs (particularly non-canonical NFκB signaling) promote inflammation, how do you explain a decrease in this cell type in patients with active disease?

Depending on the expression of immunogenic or tolerogenic factors, DCs may both promote or subdue inflammation in the colon. We have now revisited the relevant reference published by Magnusson et al., (2016). Indeed, the authors noted a marked reduction in the intestine of the CD103+ DC subset, which has been majorly linked to tolerogenic RA synthesis. While it is generally thought that aberrant inflammation promotes the death of mononuclear phagocytes in the intestine, it seems that either a contraction of the tolerogenic DC compartment or downmodulation of tolerogenic pathways in DCs incites gut inflammation in IBD patients. We have now revised the text in the introduction section to clarify this point. (line#81-83)

The focus on retinoic acid is interesting, however may be oversimplifying the role of non-canonical NFκB in DCs on the mucosal immune system. It must also be mentioned that there is crosstalk between the non-canonical and canonical NFκB signaling systems, for example Nfkb2 is capable of functioning as a IkB protein and inhibiting RelA-p50 (from the last author's prior work - Basak et al, Cell, 2007). Thus would include some mention of possible effects on the canonical system that contribute to intestinal inflammation.

We thank the reviewer for raising this important point. As mentioned in the introduction section of our original draft, the canonical NF-kB pathway in DCs aggravates experimental colitis mice (Visekruna, A. et al. 2015). Indeed, Nfkb2-dependent crosstalk was shown to modulate inflammatory RelA activity in a variety of cell types (Basak et al., 2007; Shih et al., 2009; Chawla et al., 2021). Although such cross-regulatory RelA controls by non-canonical NF-kB signaling are yet to be established in DCs, our studies involving RelB-deficient cells confirmed an essential role of p100-mediated RelB regulations in DC functions. We admit that further studies are required to determine if, independent of RelB, p100 directs immunogenic DC attributes via also RelA or another factor. We have now elaborated on p100-mediated crosstalks in the discussion section. (line#561-562)

In the single-cell DSS data they analyzed, there was a distinct DC population seen with DSS colitis treatment. Although they are categorized as cDC2s, what genes separate them from the other DC populations?

We curated a list of genes from Brown et al., (2019) to categorize cDC1 and cDC2 subsets in our study. We would like to clarify that the list was provided in Supplementary Table 1 in our original draft. In view of the reviewer's comment, we have now referred to this Table in the legend of Supplementary Figure 1 and also in the main text. (line#153)

Why was the RNAseq work on BMDCs (that identified RA metabolism as a top-ranking differentially expressed pathway) done only on Nfkb2-/- BMDCs and not RelB-/-? RelB-/- had a more pronounced protected phenotype in the cell type-specific knockout and is a cleaner target (does not have the IkB capability of Nfkb2).

We broadly agree with the knowledgeable reviewer that comparing WT and Relb-/- BMDCs for global gene expressions could have been worthwhile. We would like to clarify that we initially utilized a dataset derived using Nfkb2-/- BMDCs already available in the laboratory. These analyses were instrumental in developing a notion that non-canonical NF-kB signalling could be modulating Radh2 expression in DCs. Because previous studies involving germline Relb-/- mice suggested a role of RelB in the nonhematopoietic niche in instructing myeloid development (Briseño et al., 2017), we focused our subsequent analyses on BMDCs generated using bone marrow cells from cell type-specific knockouts. Indeed, we could confirm elevated Raldh2 expressions in BMDCs generated from both RelbDDC and Nfkb2DDC mice. Taken together, our studies suggested that Nfkb2-encoded p100 controlled Raldh2 expressions in DCs by providing RelB:p52 and less so as a regulator of the RelA activity. Although we admit that further studies are required to determine if, independent of RelB, p100 directs immunogenic DC attributes via also RelA or another factor. We have now deliberated this point in the discussion section. (line#566-567)

Reviewer #3 (Significance (Required): As a physician-scientist who clinically cares for patients with inflammatory bowel disease, and scientifically studies signaling within innate immune cells, this manuscript does a rigorous job of identifying a mechanism by which canonical NFκB signaling in dendritic cells contributes to intestinal inflammation. This study would be very informative for both basic and translational researchers as it identifies a clear pathway by which the innate immune system contributes to intestinal inflammation, and opens up room for inquiry into triggers of non-canonical NFκB in IBD and modulation of the RA pathway as a potential novel therapeutic target.

We are humbled that the knowledgeable reviewer finds our work to be informative for basic and translational research. These encouragements would undoubtedly motivate us further to identify the relevant trigger of this pathway in the gut and explore potential interventions.

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

Summary:

This manuscript from Deka et al. investigates the role of dendritic cell noncanonical NFκB signaling on intestinal inflammation. Based on prior data showing altered DC function in intestinal inflammation, they interrogated existing scRNAseq data and found that DSS treatment (which yields a chemical colitis) increased expression of non-canonical NFkB family members in dendritic cells. This led to the generation of a DC specific RelB deficient mouse and use of a DC specific NFkB2 deficient mouse, each of which showed varying degrees of protection from chemical colitis. Overall, they do a very nice job identifying a mechanism by which noncanonical NFκB signaling in dendritic cells contributes to intestinal inflammation via transcriptional regulation of Axin1, downregulation of β-catenin, restraint of Raldh2 synthesis, impaired retinoic acid synthesis and subsequent decrease in protective Tregs, IgA+ B cells, and microbial dysbiosis. The importance of this pathway is well supported by their focused targeting of β-catenin. After pharmacologic inhibition of β-catenin showed restoration of Raldh2 abundance, they made a DC specific β-catenin haploinsufficiency RelBCD11c mouse which showed impaired Raldh2 activity with restoration of colonic Tregs and fecal sIgA. When challenged with DSS, the protective phenotype seen with the RelBCD11c was lost and the colitis phenotype returned to that of the Relbfl/fl control, further solidifying the role of β-catenin, Raldh2 and RA on intestinal inflammation. Additionally, the discussion provides a robust mechanistic explanation for the phenotypic differences between the RelB and Nfkb2 genotypes, drawing on the authors' deep knowledge of the non-canonical NFκB pathway.

Major comments:

1. Although they propose a novel mechanism by which dendritic cells can contribute to intestinal inflammation, it is in a model of acute epithelial injury that accentuates the contribution of the innate immune system. Would recommend including a discussion of the limitations of this model.
2. The human work (Figure 7) shows solid evidence of heightened non-canonical NFκB signaling in DCs via abundance of RELB and NFKB2 along with a few RelB important genes, however the RA specific pathway identified in the mouse work is not strongly corroborated by the human data. There is demonstration of one β-activated gene (CCDN1) showing decreased expression in IBD patients, however no other gene along with RA pathway was clearly identified to be differentially expressed as one would predict from the mouse work.

Minor comments:

1. Their NFκB2CD11c mouse underwent a regimen of chronic DSS treatment after acute DSS treatment only displayed subtle phenotypic changes. Was the same chronic colitis regimen also tested in the RelBCD11c ?
2. In the introduction, it was stated that patients with UC have a marked reduction in intestinal DCs. If DCs (particularly non-canonical NFκB signaling) promote inflammation, how do you explain a decrease in this cell type in patients with active disease?
3. The focus on retinoic acid is interesting, however may be oversimplifying the role of non-canonical NFκB in DCs on the mucosal immune system. It must also be mentioned that there is crosstalk between the non-canonical and canonical NFκB signaling systems, for example Nfkb2 is capable of functioning as a IkB protein and inhibiting RelA-p50 (from the last author's prior work - Basak et al, Cell, 2007). Thus would include some mention of possible effects on the canonical system that contribute to intestinal inflammation.
4. In the single cell DSS data they analyzed, there was a distinct DC population was seen with DSS colitis treatment. Although they are categorized as cDC2s, what genes separate them from the other DC populations?
5. Why was the RNAseq work on BMDCs (that identified RA metabolism as a top ranking differentially expressed pathway) done only on Nfkb-/- BMDCs and not RelB-/-? The RelB-/- had a more pronounced protected phenotype in the cell type specific knockout, and is a cleaner target (does not have the IkB capability of Nfkb2).

Significance

As a physician scientist who clinically cares for patients with inflammatory bowel disease, and scientifically studies signaling within innate immune cells, this manuscript does a rigorous job of identifying a mechanism by which canonical NFκB signaling in dendritic cells contributes to intestinal inflammation. This study would be very informative for both basic and translational researchers as it identifies a clear pathway by which the innate immune system contributes to intestinal inflammation, and opens up room for inquiry into triggers of non-canonical NFκB in IBD and modulation of the RA pathway as a potential novel therapeutic target.

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

The following issues are noted.

• all animal strains and their provenance should be described and properly referenced (for example, there are at least two CD11c-Cre strains with different specificity). Along the same lines, the specificity of Cre recombination should be confirmed, at least in major cell types (DCs vs T effector or regulatory cells).
• the DSS model is prone to "batch effects" of individual cages, and proper comparison between genotypes is possible only if mice of different genotypes (eg littermates) are housed together in the same cages. The authors should clearly confirm whether this was the case, and if not, key experiments should be repeated in this setting.
• BMDCs represent a heterogeneous mixture of DCs and macrophages (Helft et al., Immunity 2015). These populations should be clearly defined and compared between genotypes, to make sure that they do not underlie the observed gene expression differences.
• the analysis of DCs in mutant strains (e.g. in Fig. 3) would benefit from better definition of populations, e.g. resident vs migratory DCs in the MLN, the Notch2-dependent CD103+ CD11b+ DCs in the LP and MLN, etc. Again, this would be important to justify differences in gene expression (e.g. Fig. 3D).
• the analysis of b-catenin protein expression and cellular localization at single-cell level (e.g. by IF) would greatly strengthen the mechanistic connection between NF-kB and Wnt/b-catening pathways.

Minor:

• the reanalyses of previous single-cell data in Figs. 1 and 7 are much less convincing or exciting than the new experimental data relegated to the supplements. The distribution of the results between main and experimental figures may be reconsidered in this light.

Significance

The manuscript by Deka et al. explores the role of the non-canonical NF-kB pathway, specifically of its key mediators RelB and NF-kB2, in dendritic cells (DCs) during intestinal inflammation. The key strength of the paper is the demonstration that DC-specific deletion of RelB or NF-kB2 lead to improved acute or chronic DSS colitis. It is also shown that reducing the dose of b-catenin rescues the phenotype of RelB deletion, providing an important genetic connection between NF-kB and Wnt/b-catenin pathways. As such, the work is novel, important and of potential significance to the field.

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 #1

Evidence, reproducibility and clarity

Deka and colleagues report that a non-canonical NFKb signaling operates in DCs in the context of inflammation and inhibits a tolerogenic mechanism driven by b-catenin-Raldh2. The following comments are made to clarify the findings presented.

1. The authors re-analyzed published scRNAseq data from DSS colitis to identify the expression of Relb and NFKB2 in myeloid cells.
   • a. The authors are encouraged to expand this analysis to other published datasets.
   • b. Additionally, the expression of Relb and NFKB2 in other cells - especially other myeloid cells -should be explored and included, even if then the authors later choose to test their function in DCs.
   • c. Please note the there is a transition from Fig 1A to Fig1B to focus on DCs, which is not apparent from the figure.
2. Please include scale bars for all histological analyses.
3. In Fig S1I, the authors show that loss of body weight upon DSS treatment in Nfkb2deltaCD11c is indistinguishable from control. Why is the starting weight at 110%? Please clarify.
4. In Figure 2, please indicate the database/s used for identification of top biological pathways.
5. The authors show a more significant expansion in Tregs upon DSS treatment when non-canonical NFKb is ablated in DCs. Is this at the expense of a reduction of specific Th cells? Can the authors also report the number of cells, beyond the % of cells?
6. In figure 6A, it appears that not only the amount of beta-catenin expressed, but also the percentage of beta-catenin positive MNL DCs is significantly expanded upon ablation of non-canonical NFkb. Please verify and if so, include.
7. In analogy to the comment #1 above, please expand the analyses in human samples to include the expression of Relb and Nfkb2 to other myeloid cells.

Significance

Strengths of the manuscript include the conceptual novelty of the intersection between non-canonical NFkb and the tolerogenic b-catenin-Raldh2 axis. And additional strength is the methodic approach, which includes various immunological and biochemical assessments as well as genetic perturbations to dissect such relationships. While it remains unknow the relevant triggers for the non-canonical axis described, this study advances our mechanistic understanding on how activation of this axis overrides regulatory mechanisms in DCs. As such, this manuscript should be of broad interest to immunologists and in particular mucosal immunologists.

From what I understand, Tasks are not the top-level futures, but rather any Future that's being executed.

So there may be: async { async { async { }.await }.await }.await Where each async block is a Future, that's been wrapped by a Task on .await, and will drive to completion, be it returning right away, or hanging and calling .wake() on it's parent when it's done.

This website was quite interesting to me because they offer different types of engagements type across different platforms. It's crazy how they offer a "Like" bot for post which I find pretty funny. One thing I found really interesting was their way of marketing. They are selling you this product/service in hopes of you buying into the dream of becoming famous. I can see how this can help different pages in certain scenarios. I feel that the idea of buying fake interactions defeats the purpose of authenticity and in a way you are buying a fake reality.

biggest differences between USA and China: - changing public opinion beyond borders - participates in international space to spread own agenda - economic practices to build economic footprint

ssh -R 80:localhost:3000 serveo.net

I find the idea of botting and buying fake followers to be very interesting. I never understood why people would want to buy fake followers if their interactions are going to be poorly ratios. However, I understand that it can create a perception of "clout" but long term wouldn't that hurt their branding/account. I have followed the rise and fall of many musicians and seen many industry plant go through struggles that are created by this fake perception. An artist could have 3 million followers but can't get 5000 views on their music videos. I wonder what the return on investment would be for buying fake followers and how common it is across different industries.

For the mention of the "Gender Pay Gap Bot" on Twitter, it's intriguing to see technology being used as a tool for political activism and social change. While the bot undoubtedly sheds light on an important issue, one wonders about the accuracy and impact of its data, as well as the potential for backlash from targeted companies. It raises questions about the ethical boundaries of using bots for advocacy and the broader implications for online activism in the digital age.

Crazy how open everybody is. In my country, if people spoke this freely about drugs use, the police would raid their homes and put them in jail.

actually that is what is called a sane country

"sane countries" would ban only the actual bad drugs: alcohol, tobacco, fentanyl, methadone, oxycodone, krokodil, all chemotherapy drugs for cancer, all vaccines, pasteurized milk, ... also, all legal drugs would have zero taxes for the next 1 million years to say "sorry for our war on drugs".

but well, "sane" is a very subjective thing: my paradise is your hell. thats why we need tribalism: every tribe has his own rules, and if i dont like my tribe, i can move to a different tribe. tribalism aka "small countries"

Balanced life of moderation, is more like the proper choice, action, or feeling. Our behavior is virtuous when it is appropriately expressed. The appropriateness of this expression depends on the setting , our social status, our social role and whether or not we are performing a certain behavior.

I think this social media platform makes it spread out quickly by simply commenting and sharing. Also, the hashtag of it make it unique and fun. Everyone want to use the hashtag and join this conversation.

They were trying to cross Gave de Pau, which is located in south western France. They had to wait until the next day to create a passage since it was not crossable.

GATES, LAURA DOYLE. “Telling Stories, Naming Names: ‘Heptaméron’ 43.” Renaissance and Reformation / Renaissance et Réforme, vol. 20, no. 4, 1996, pp. 27–38. JSTOR, http://www.jstor.org/stable/43445122. Accessed 31 Mar. 2024.

The statement highlights a nuanced perspective within the ethics of care regarding the relationship between particular moral claims and universalize judgments. It suggests that while some advocates of the ethics of care prioritize the validity of individual moral claims, even if they conflict with universalize moral requirements, others argue for a reconciliation between care and justice, friendship, loyalty, and impartiality. This perspective acknowledges the potential for conflict between the principles of care and the demands of universality but also proposes the possibility of integrating care norms into universal judgments to resolve such conflicts. Ultimately, this discussion underscores the complexity of moral deliberations and the ongoing debate within the ethics of care regarding the interplay between particularity and universality in ethical reasoning.

A key aspect of the ethics of care, which challenges the perspective of dominant moral theories regarding abstract reasoning in moral problem-solving. It suggests that prioritizing abstract reasoning, often advocated by dominant moral theories, may not necessarily lead to better outcomes in ethical decision-making. Instead, the ethics of care emphasizes the importance of contextual understanding and interpersonal relationships in moral deliberations. By rejecting the notion that abstract reasoning alone can achieve impartiality and avoid bias, the ethics of care advocates for a more holistic approach that considers the unique circumstances and relational dynamics involved in moral dilemmas.

The statement contrasts rationalist approaches to morality by emphasizing the significance of certain emotions, including sympathy, empathy, sensitivity, and responsiveness. It suggests that these emotions are not only valuable in facilitating the implementation of rational dictates but also in providing insights into moral judgments and recommendations. By advocating for the cultivation of these moral emotions, the statement suggests a broader understanding of morality that incorporates both rational and emotional dimensions, thereby enriching ethical discourse and decision-making processes.

The statement underscores the universal need for care, particularly during the early stages of life. It emphasizes that the prospects for human progress and flourishing are intrinsically linked to the quality of care provided to those who require it, highlighting the pivotal role of care in shaping individuals and societies. Furthermore, it asserts that the ethics of care places significant moral emphasis on the obligation to meet the needs of those who are dependent, emphasizing the ethical imperative to respond to vulnerability and dependency with compassion and responsibility. The statement articulates the essential nature of care for all individuals, especially during their formative years, suggesting that care is indispensable for personal development and societal advancement.

The statement suggests that the ethics of care is occasionally regarded as a viable alternative to established moral theories like Kantian ethics, utilitarianism, or Aristotelian virtue ethics. Furthermore, it posits that the ethics of care is often viewed as a subset or variation of virtue ethics. Additionally, it emphasizes the unique focus of the ethics of care on moral considerations that are frequently overlooked in other moral frameworks, asserting their significance as being on par with, if not surpassing, the considerations typically central to justice-based or utility-based moralities. The statement outlines the perception of the ethics of care as a potential substitute for traditional moral theories such as Kantian ethics, utilitarianism, or Aristotelian virtue ethics, indicating its perceived relevance in contemporary moral discourse.

The statement highlights the relatively recent emergence of the ethics of care, which has gained prominence in moral philosophy over the past few decades. While some scholars have attempted to replace the term "care" with alternatives such as "the ethic of love" or "relational ethics," the discourse consistently gravitates back to "care" as the most preferred term, despite lingering dissatisfactions with it. The assertion underscores the novelty of the ethics of care within the realm of moral philosophy, indicating its emergence within the past few decades.

While we are independent individuals with our own goals and motivations in life, we are much more than that. We develop our own relationships with others as we are dependent on others to an extent. An extent that is undermined in dominant moral theories.

Moral theories in legislature have been the cause of several issues that have impacted groups of people like women. In a society bound to these moral values of marriage the rights of women are taken away.

When we limit morality to abstract rules we fail to account for the basic needs of our society. Morals have no basis in objective truth and therefore should not have legislature power.

Moral theories do not account for more than half the picture of this approach. Even the universal norms one would consider to be important to discuss are then left out as a result to moral conformity and therefore results in the failure to understand the ethics of care.

Human dependence on others is universal and by constraining this abstract approach would leave it far more ambiguous than it should be.

J. Kaiser doesn't admonish against on writing only on one side of cards, but does show examples of how to use them thusly when necessary.

This is similar to the idea of edge notched cards, but is done visually instead of cutting the cards. It's also seen in the Pile of Index Card method which uses a variety of marks on gridded cards.

It shouldn't matter whether or not one has tabs in front of or behind sections of cards about which they are labeling, but a determination should be made at the start and followed religiously for ease of use.

Kaiser suggest placing tabbed cards in front of their related sections.

While Kaiser recommends against the need to re-arrange physical cards from one drawer to another, which creates the need to refamiliarize oneself with their new locations, the same idea applies to switching from one digital note taking application to another as a similar switch of user interface functionality may cause additional overhead and stress thereby preventing quick use of the system itself.

does this fit in with his prior definitions of these things?

Luhmann's topical index was a form of a central register as he concatenated words on cards rather than having a separate card for each word.

The equivalent of an alphabetical register of company (firm) names within card index for business would be a register of author names in a bibliographical file.

This is a restatement that a particular system should be customized to its users.

There is potential that a system could be applied universally, but it requires a very large amount of data and metadata to suit the needs of a greater number of people and use cases. It also requires a reasonable amount of work in practical use to make it operate as expected.

The Mundaneum was likely close on paper and Google comes close to this, but still isn't perfect.

quote via ¶76 and 92

Placing call numbers or location numbers on items to be filed allows them to be separated from other items while placing cross-references or links allows them to be brought back together again. These two affordances allow for divergence as well as convergence of items or ideas.

Cross references in Kaiser's card system are broadly similar to links from one item to another as a means of helping to associate them or "bringing these materials together again when required."

While some sources (which? Kaiser implies that there are some, though they may have been based on anecdotal evidence) apparently recommend to use one number for each firm, Kaiser admonishes users to stay away from this rule as not all firms will also take up space within each particular category. He recommends using consecutive numbering within each category so that there are no gaps. This lack of any gaps will reveal in the future when things may be missing from one's system.

Commendable usually means it's applaudable / worthy of high praise. However, Rabelais states the tripes were not of that sort, resulting in Grangousier restricting his wife from eating too many.

Whitaker, Thomas R. “The Drinkers and History: Rabelais, Balzac, and Joyce.” Comparative Literature, vol. 11, no. 2, 1959, pp. 157–64. JSTOR, https://doi.org/10.2307/1768645. Accessed 31 Mar. 2024.

In this line the Monk is calling for Pincocrates to come to his side.

Vine-tree syrup in this line is used to describe the venom of his breathe being subdued.

https://www.naturalmedicinalherbs.net/herbs/a/acer-circinatum=vine-maple.php

it seems as if the character cannot locate his feeling for as to why he may be experiencing the mental suffering he is detailing in this excerpt. It can also be noticed how emotionally sensitive the character is, when the smallest of disturbances will cause grand commotion internally. All of the different emotions he feels such as vexed, displeased, or even weeping show the true nature of deep and complex the emotions of humans can truly be. With the severity of sensitivity one possesses to experience such a wide variety of emotions internally is what seems to be the presenting idea here.

Homer who is the poet who wrote both the Odyssey and the Iliad which offer a world of Greek mythology insightfulness. What the speaker has alluded to Homer is that their viewpoints differ greatly. Similarly to that of a interpretation that is normal. Homer's writing may have failed to anticipate his viewpoint. The speaker believes so strongly and confidently in his viewpoint that compares the writing of Homer and he imagined emotion that would be illicted when reading his work. He goes on to show how truly different and unique his viewpoint is that it is so orginal to what Homer had thought.

This passage underscores the importance of considering learning theories and the broader socio-cultural context when designing learning environments. While learning theories provide valuable insights into fostering learning outcomes such as self-direction and motivation, socio-cultural perspectives, including activity theory, emphasize the need to account for the larger context in which learning occurs. By aligning with social constructivism and related theories, activity theory offers a framework for understanding how learners navigate and operate within social learning processes. This suggests that effective learning environment design requires a multifaceted approach that draws on learning theories and socio-cultural considerations to create experiences grounded in theory and relevant to their context.

The authors make a compelling case for using personas and scenarios in learning design. While learner and context analysis seem to be standard components of the instructional design process, the authors argue that traditional approaches to these analyses can be overly broad and fail to capture the nuances of individual learners' experiences. Personas and scenarios can situate learning designs within those specific contexts and lived experiences. Designers can better understand their needs, challenges, and perspectives by creating realistic representations of target learners, leading to more learner-centered and contextually relevant designs.

This passage highlights the core tenet of activity theory—learning and consciousness are profoundly interconnected and situated within a broader socio-cultural context. By considering the larger context and culture in which learning occurs, activity theory provides a framework for understanding how learners construct meaning and develop understanding through their interactions with the world and others around them. This holistic perspective on learning is a strength of activity theory and seems to set it apart from other learning theories that may focus more narrowly on individual cognitive processes.

I feel this is really important, as these materials are meant for the user/learner. I wonder if teaching experience helps with this aspect of LXD? I know as a teacher myself, I would often shaped assignments based on my student cohort, and would often change or discard those which consistently didn't meet student needs.

John Hartley's chapter on "Pushing Back: Social Media as an Evolutionary Phenomenon" offers a thought-provoking perspective on the role of social media in shaping societal dynamics. Hartley explores how social media platforms serve as catalysts for social change, allowing individuals and groups to challenge established norms and power structures. His analysis sheds light on the transformative potential of social media as a tool for grassroots activism and political mobilization.

This sentence shows how the use of personas influenced the designers to create learning materials that were appropriate and beneficial for the target users. The designers could incorporate elements that addressed those specific needs by empathizing with the personas and understanding their challenges, such as low digital literacy skills. This demonstrates the practical impact of using personas in the design process—it leads to the creation of learning resources tailored to the learners' actual needs and abilities.

Ah, the importance of creating engaging and emotionally resonant personas for designers. It is cool that the authors suggest we use techniques like narrative tension and surprising elements to become more memorable for understanding and empathizing with the users. It is also interesting how the authors connect this to the fundamental human desire for stories and meaning-making. This suggests that well-crafted personas tap into this innate craving, making them powerful instruments in the design process.

By Creating personas, we are making these fiction characters likable and able to create empathy with our readers.

This is an important factor to consider when navigating conflict, especially conflict that involves ethical breaches. A student may have had their data used without their consent, or a student's information may have been accidentally taken without use. It is important for the instructional/learning designer to first determine what happens, and they must serve as someone that the student can trust in this situation. Fair treatment should be paramount and a learning designer should never dismiss a learner's real concerns, feelings, or motivations for feeling the way that they do. It is also important to set a clear role of the learning designer, so that students and instructors involved in the course are not thrown into more disarray due to the confusing actions of the learning designer. It is very important to curate learning experiences that are enjoyable to the learner.

This is a new and important impact to the learner. Information that was once stored in a paper setting that could be easily stored and destroyed is now in a digital format. Furthermore, student data is utilized for learning analytics, in which school organizations or districts use student data to improve or understand how students learn. Is this process ethical? Is using learner's information without their consent in order to better their learning a sacrifice that is okay to make? Those are the questions worth asking in a 21st century learning environment.

This is absolutely an important aspect to consider for learners. When conducting a learner analysis, it's important to not just look at the surface level conditions of access (whether a student can or cannot access technology), but at the deeper dimensions of why. As the article points out, it is not as simple as "Student A does not have a computer." Student A may have a computer that she shares with her entire family, and Student B may have a computer that is old or faulty. Access issues are oftentimes more complex than the surface level, which this article does a wonderful job at pointing out.

All of the learner characteristics are important; however, I feel as though "who is the learner/who are the learners" is the most important question that a learning or instructional designer should ask before creating a persona, developing a training plan, or doing anything involving designing curriculum that others will use. The learner identity determines who you are catering to and what the learner will be doing. It is the heart and soul of the entire project that you are building. A learner's identity determines their age, their socioeconomic background, their race, and who they are as a person. It is key to understanding the learner's needs.

This aspect of the article is extremely helpful to me as someone who created a learning persona for students in Kindergarten, this article assisted me in understanding how to create a persona for young learners. A young learner who has not been to school before would not know as much as a student who has been to school; therefore, there is an expectation that depending upon grade level and skill level, that a learner's material and understanding of the subject would change. A learner at the beginning of Kindergarten would have different needs than a learner in first grade; therefore, this thought process allowed me to understand what to ask of my learners and their needs.

BRUH

thats crazy

ok hypocrite

so like equally good and bad

wait so is the king like on the western side

white supremacy

Curlec

Curlec

“the practice of doing something (such as hiring a person who belongs to a minority group) only to prevent criticism and give the appearance that people are being treated fairly.”

Can I join the group ?

DOI: 10.1158/2767-9764.CRC-23-0090

Resource: The Cancer Genome Atlas (RRID:SCR_003193)

Curator: @scibot

SciCrunch record: RRID:SCR_003193

What is this?

I believe that games offer a belief of escapism. When you're playing a game, you are leaving the problems of the physical world to work towards goals in an otherwise imaginary landscape. While in this landscape, the escapism is few and far between, because the game still fits within the rules that are prompted by our real world and society that we exist in, pitting us against a computer, fellow gamers, or even oneself to get to the highest score possible be it kills, progress, time to achievement.

I find this point to be incredibly engaging because it shows how people are so easily manipulated into engaging with, and trying to attain, a number that is given intrinsic value. In the same way that people are pit against one another to get the highest number of capital in their bank account, attain the highest credit score, and kill the most zombies in a video game. Putting value onto numbers creates a trap for the people who engage with them. Our society of capitalism invites competition, and does not function without it. The easiest way to demonstrate competition in a tangible way is by associating a number with it, so, within schools, deans and administrations are prompted to offer an exact score to prove that you have won the competition. It's a game that we all compete in whether or not we actively work to participate in it.

For me, physical and virtual gaming mediums, while competitive, are generally things that I engage in to enjoy a fun shared experience with friends and family. I think that games have an amazing engagement in getting people to feel a visceral connection to this medium that otherwise does not affect the world around us; but it manipulates people into a position of immense engagement with this unsubstantial medium.

Biofilm formation is the process by which microorganisms attach to a surface and create a community. Here, bacterial cell is transition from planktonic (free-swimming) to the biofilm mode of growth, using innovative microfluidic techniques.

Mutation rate is defined as the frequency of new mutations occurring in a single gene of bacteria over time. Here, mutation rates influence bacterial responses to challenges, including host immune defenses and antibiotic treatments.

The dilution rate represents the flow of medium per unit of time over the volume of culture in the bioreactor. Here, it is a key controlling factor that determines the concentration of nutrients in the culture medium.

Synthetic promoters act as genetic switches, allowing precise manipulation of bacterial behavior through of control gene expression. Here, the authors used synthetic promoters to build a population-control circuit in bacteria, enabling precise regulation of cell density through quorum sensing mechanisms.

The variability in observable characteristics among individual bacterial cells that contribute to the overall regulation and behavior of the bacterial population.

A lysis buffer is a solution used to break open bacterial cells and release their contents, particularly for extracting genetic material for various laboratory analyses. Here, they use it to get rid of all cells within the segment.

In a chemostat, fresh medium periodically replaces a portion of the bacterial culture, removing some bacteria. However, if biofilms develop, they protect bacteria from washout, leading to domination of the culture by biofilm-derived bacteria over time.

Can this claim be quantified without deferring to a figure?

The class representations of cell type 1 and cell type K are not very well differentiated.

You provide a clear explanation of how you generate the pseudospectra in the methods, but I question the use of "ideal" in describing them. I get that you mean idealized, but it sounds as if they are perfect and in no way subjective which is misleading.

Could you please clarify if this test was done by using manual segmentation as ground truth? If not, what was the source of ground truth data used to compute F1-scores?

An F1-score of 0.7 is not generally seen as very high. Could emphasize more strongly in your discussion the power of your approach (combining the instance segmentation with class maps for classification) given that this seems to be a non-trivial segmentation problem.

Typo? Do you mean "...change in the sFlt-1/PIGF-2 ratio" ?

Considering the importance of using the sFlt-1/PIGF ratio as a marker for preeclampsia (the only FDA-approved immunoassay to assess preeclampsia risk is based on the sFlt-1/PIGF ratio), do you believe the BAC/APOL-G1 model is a better model for preeclampsia?

Given the results of your work, is there a reason where one would prefer to use the Alb/APOL-G1 model?

You mention this later in the discussion but I would include a sentence conveying why you didn’t test APOL1-G2 variants since your introduction refers to both APOL1 high-risk variants (G1 and G2) and to evidence of preeclampsia development in APOL1-G2 transgenic mice (citation 16). E.g. “We did not study APOL1-G2 variants because we did not observe physical preeclampsia phenotypes in these transgenic lines.”

In an attempt to better understand the cell types and molecular mechanisms implicated in preeclampsia, Yoshida et al. analyzed pregnant female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses – novel IVF-derived preeclampsia mouse models – for physical biomarkers of preeclampsia and performed single-nucleus RNA-seq to identify differentially expressed genes and impacted cell-cell interactions.

When testing physical biomarkers of preeclampsia, the authors found that female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses had higher systolic blood pressure and smaller body weight, while just the female mice carrying BAC/APOL-G1 fetuses had a higher sFlt-1/PIGF-2 ratio. Elevated blood pressure and sFlt-1 levels and lower PIGF levels are phenotypes/markers clinically associated with preeclampsia.

Single-nucleus RNA-sequencing of placenta was conducted and differentially expressed genes were identified between APOL1-G1 and APOL1-G0 or APOL1-G1 and wild type mice. Inflammatory pathways and autoimmune disease pathways that were identified when comparing human preeclampsia RNA-seq data and a normal control were also implicated in the BAC/APOL1-G1 vs. BAC/APOL1-G0 DEG analysis results (e.g. pathogen induced cytokine storm signaling pathway and HIFI⍺ pathway).

The authors then performed cell-cell interaction analyses (Seurat) and found 31 shared activated and 4 shared deactivated pathways in BAC/APOL1-G1 placentas compared to BAC/APOL-G0 and wild type placentas. One of the identified shared activated pathways was the osteopontin/Spp1 signaling pathway which was found to be most upregulated in vascular endothelia – the cell type with the highest APOL1 expression.

Lastly, the authors attempted to determine the impact of maternal monocytes and decidual cells by APOL-G1 placentas and found upregulated signals to monocytes associated with the Cd44 receptor and upregulated expression of Ccl2 – supporting their hypothesis that APOL1-G1 induced preeclampsia in female mice activates maternal monocytes.

But please, for the love of Zeus, do NOT use this password for anything. This password is made to demonstrate the point. As password, it is known already and absolutely worthless for any practical purpose. You are supposed to make your own password.

Change: Providing examples on what would fit each category could be productive because students will be able to clearly compare the different levels of work.

Change: Perhaps having a class discussion about what the students deem to be exemplary vs satisfactory v unsatisfactory. Allowing the students to be in the conversation about what defines each category will prompt accountability. Student being involved in this conversion also limits the amount of gray area between student may be confused on in terms on what differs from each grade.

Question: Would you say there is a certain number of columns that is too much? What is the sweet spot?

Connect: I remember in middle school ELA, we were given the rubric to self grade our work and then the teacher would grade our work with the same rubric. Student conferences were then held to discuss the differences and similarities.

Connect: In my placement, the students are currently working on their ELA Performance Task for the unit. In the ESL class, the rubrics are available in both Spanish and English to make sure students are able to fully understand the requirements.

Confirm: I think this also goes back to the required reading for this week and confirms how making sure the format of the rubric is easily read. Choosing phrases that are not to wordy so the students is not immediately overwhelmed with how long the rubric is.

I agree that few things are more damaging than an abusive teacher, particularly for young or vulnerable learners. You must bring your best to your students and show them the respect and empathy you would want to receive in return. This is not just about your in-person interactions but also the digital ones. Students who enter your Canvas shell should feel that they are heard and understood.

Professor, what is your input on the radio vs newspaper debate?

I don't understand why the broadcasters had to bear the cost of the new services. That doesn't really seem fair.

I understand why radio has surpassed newspaper, anytime there is breaking news you have to wait to print the story but with radio you can report right then and there.

Hey Kouji, I really enjoyed reading your Leadership Vision Board. You did an amazing job of relating an experience you had (created 38 original images for a short story) to your desired career path in animation. I also appreciate how you incorporated the Seven C’s of great leadership into how you plan to attain your goals.

Do you need this phrase? "maritime" is a powerful word. If we hear it too much it becomes heavy.

the ship has a role and is a place? This strains logic. What do you mean?

Maybe a touch more about the Minden? This blurb refers to "resilience" and "patriotism" without mentioning why.

It was for lifelong learners, not undergrads.

Is Lacy suggesting that Adler was suggesting it DID? Or is this similar to my own objections about the "your betters" language Adler used?

Is this relevant only as a Catholic perspective? Even if it began there, did Adler's attack on Dewey's vocational approach contribute to the GBI?

Would it be possible to recreate this in MPLS or St. Paul? Would the Library systems be able to help? The Freedom Library?

From Martin, The Meaning of a Liberal Education, 1926

Trace the history of this product of Peter Cooper's largess in a post.

Check out the Erskine bio he cites.

While technically correct writing, this sentence is hart do read.

How to transition between the two sentences? Maybe a semicolon or combining them.

For a time, I though that abductive reasoning was regarding correlation equal causation. This debunking of abductive reasoning has added greater clarity.

murder is the only solution to overpopulation. blame pacifism. blame civilization.<br /> but it takes real intelligence to see murder as solution ...

The example provided about a stronger syllogism helps my identify what to consider when creating one.

https://research.ibm.com/blog/retrieval-augmented-generation-RAG

PK indicates that folks using footnotes in AI are using rag methods.

The overall collaborative nature of the production of I love Lucy goes to show how the collective efforts of a group of media processionals is in creating one of the most successful shows in television history.

It's interesting to see how Oppenheimer's involvement in labor negotiations reflected a larger shift in the industry, with the creation of the Writers guild of America.

Oppenheimer's approach to script writing and his advocacy on maintaining consistent character voices really underscores his major role in creating the perfect tone for the show.

I thinks its really interesting that a show as successful as I love Lucy lacks in its credit to the showrunner.

The term show-runner came int being as a important role in tv production. They play a pivotal role in making sure the creative and practical aspects of the show are in order.

I love Lucy is held in high regard for its significant cultural impact, being the first show to depict an interracial couple. The show also helped pioneer new techniques in film making/film industry.

The unique birth of Lucille's character's child held a huge cultural significance as it helped audiences blur the line between the fictional tv show and reality

this explains to the audience what the scene looks like. it also points out that the room would be comfortable if it wasn't a numerous amount of indestructible contradictions of the room.

This is interesting! I don't think I've ever had a teacher do this, but the interactive process of creating a rubric would've definitely made me feel more confident in the word I was producing for a big assignment.

Having students give their own input into what they think creates good and poor work for their assignment will definitely help them understand what they need to do to get credit for good work.

As a student it is definitely helpful to understand exactly what your teacher is looking for. It's nice to know that the rubrics truly help the students understand this and they can continue to apply the qualities of a good essay to other assignments.