Just add a good and positive message like - "And that's it. Payment is completed. It's that simple on Turbo UPI"

My (Entirely-Unsolicited) Thoughts on the most Casual Crue™'s 10th:

Ya know, my memory isn't so great anymore, but I remember my then best friend and most respected music authority resting pretty confidently in an argument about this sound, and those who peretuated it: that it was by nature/declaration substanceless, and therefore, those invested in it were either just superficial or.. idek anymore. Ingenuine, maybe?

I don't think I was even placating with him when I mostly went along with it - it did seem important to invest in more abrasive (read: edgy bs) pursuits. I thought I was resisting "nostalgia" and even invested most of my twenties trying to start an online culture/electronic music magazine in direct editorial opposition to regurgitation. Imo, though, any actual exposure to self-described "vaporwave" makes it very plain how utterly useless it is to cry nostalgia because - crucially - whatever form of it that may or may not be an established marker of this voice is completely devoid of the illness that has absolutely pervaded, destructively, throughout all manner of expression and exploitation in the past 10 years.

It is just not a constraining or negative force, here. I would propose, even, that it's been made, here, into the most powerful form of critique there possibly could be.

And the grief!!! and the mania!! In any sort of ... worldly-participatory context, it should not be some gargantuan leap for even the most cynical, repressed, bitter 50-something white music writer army to make the connections, here. Our tears are fucking digital, idiot.

...ANYway, sorry. I don't actually have any business talking about music, but I can express my big, soppy as hell appreciation for the nigh-inconceivable amount of quantitive life force for which this milestone is a handy opportunity to reflect.

Reviewer #1 (Public Review):

The manuscript by Wagstyl et al. describes an extensive analysis of gene expression in the human cerebral cortex and the association with a large variety of maps capturing many of its microscopic and macroscopic properties. The core methodological contribution is the computation of continuous maps of gene expression for >20k genes, which are being shared with the community. The manuscript is a demonstration of several ways in which these maps can be used to relate gene expression with histological features of the human cortex, cytoarchitecture, folding, function, development and disease risk. The main scientific contribution is to provide data and tools to help substantiate the idea of the genetic regulation of multi-scale aspects of the organisation of the human brain. The manuscript is dense, but clearly written and beautifully illustrated.

# Main comments

The starting point for the manuscript is the construction of continuous maps of gene expression for most human genes. These maps are based on the microarray data from 6 left human brain hemispheres made available by the Allen Brain Institute. By technological necessity, the microarray data is very sparse: only 1304 samples to map all the cortex after all subjects were combined (a single individual's hemisphere has ~400 samples). Sampling is also inhomogeneous due to the coronal slicing of the tissue. To obtain continuous maps on a mesh, the authors filled the gaps using nearest-neighbour interpolation followed by strong smoothing. This may have two potentially important consequences that the authors may want to discuss further: (a) the intrinsic geometry of the mesh used for smoothing will introduce structure in the expression map, and (b) strong smoothing will produce substantial, spatially heterogeneous, autocorrelations in the signal, which are known to lead to a significant increase in the false positive rate (FPR) in the spin tests they used.

## a. Structured smoothing

A brain surface has intrinsic curvature (Gaussian curvature, which cannot be flattened away without tearing). The size of the neighbourhood around each surface vertex will be determined by this curvature. During surface smoothing, this will make that the weight of each vertex will be also modulated by the local curvature, i.e., by large geometric structures such as poles, fissures and folds. The article by Ciantar et al (2022, https://doi.org/10.1007/s00429-022-02536-4) provides a clear illustration of this effect: even the mapping of a volume of *pure noise* into a brain mesh will produce a pattern over the surface strikingly similar to that obtained by mapping resting state functional data or functional data related to a motor task.

1. It may be important to make the readers aware of this possible limitation, which is in large part a consequence of the sparsity of the microarray sampling and the necessity to map that to a mesh. This may confound the assessments of reproducibility (results, p4). Reproducibility was assessed by comparing pairs of subgroups split from the total 6. But if the mesh is introducing structure into the data, and if the same mesh was used for both groups, then what's being reproduced could be a combination of signal from the expression data and signal induced by the mesh structure.<br /> 2. It's also possible that mesh-induced structure is responsible in part for the "signal boost" observed when comparing raw expression data and interpolated data (fig S1a). How do you explain the signal boost of the smooth data compared with the raw data otherwise?<br /> 3. How do you explain that despite the difference in absolute value the combined expression maps of genes with and without cortical expression look similar? (fig S1e: in both cases there's high values in the dorsal part of the central sulcus, in the occipital pole, in the temporal pole, and low values in the precuneus and close to the angular gyrus). Could this also reflect mesh-smoothing-induced structure?<br /> 4. Could you provide more information about the way in which the nearest-neighbours were identified (results p4). Were they nearest in Euclidean space? Geodesic? If geodesic, geodesic over the native brain surface? over the spherically deformed brain? (Methods cite Moresi & Mather's Stripy toolbox, which seems to be meant to be used on spheres). If the distance was geodesic over the sphere, could the distortions introduced by mapping (due to brain anatomy) influence the geometry of the expression maps?<br /> 5. Could you provide more information about the smoothing algorithm? Volumetric, geodesic over the native mesh, geodesic over the sphere, averaging of values in neighbouring vertices, cotangent-weighted laplacian smoothing, something else?<br /> 6. Could you provide more information about the method used for computing the gradient of the expression maps (p6)? The gradient and the laplacian operator are related (the laplacian is the divergence of the gradient), which could also be responsible in part for the relationships observed between expression transitions and brain geometry.

## b. Potentially inflated FPR for spin tests on autocorrelated data

Spin tests are extensively used in this work and it would be useful to make the readers aware of their limitations, which may confound some of the results presented. Spin tests aim at establishing if two brain maps are similar by comparing a measure of their similarity over a spherical deformation of the brains against a distribution of similarities obtained by randomly spinning one of the spheres. It is not clear which specific variety of spin test was used, but the original spin test has well known limitations, such as the violation of the assumption of spatial stationarity of the covariance structure (not all positions of the spinning sphere are equivalent, some are contracted, some are expanded), or the treatment of the medial wall (a big hole with no data is introduced when hemispheres are isolated).

Another important limitation results from the comparison of maps showing autocorrelation. This problem has been extensively described by Markello & Misic (2021). The strong smoothing used to make a continuous map out of just ~1300 samples introduces large, geometry dependent autocorrelations. Indeed, the expression maps presented in the manuscript look similar to those with the highest degree of autocorrelation studied by Markello & Misic (alpha=3). In this case, naive permutations should lead to a false positive rate ~46% when comparing pairs of random maps, and even most sophisticated methods have FPR>10%.

7. There's currently several researchers working on testing spatial similarity, and the readers would benefit from being made aware of the problem of the spin test and potential solutions. There's also packages providing alternative implementations of spin tests, such as BrainSMASH and BrainSpace (Weinstein et al 2020, https://doi.org/10.1101/2020.09.10.285049), which could be mentioned.<br /> 8. Could it be possible to measure the degree of spatial autocorrelation?<br /> 9. Could you clarify which version of the spin test was used? Does the implementation come from a package or was it coded from scratch?<br /> 10. Cortex and non-cortex vertex-level gene rank predictability maps (fig S1e) are strikingly similar. Would the spin test come up statistically significant? What would be the meaning of that, if the cortical map of genes not expressed in the cortex appeared to be statistically significantly similar to that of genes expressed in the cortex?

I do agree with what sherman had to say about how the relationships on the show The Outs challenged the popular image of the same sex relationships. I feel like in most of hollywood whenever they cast someone to be queer or any non hetero relationship it always so glamorized. Real relationships can be ugly beautiful and sometimes messy, I thought this show did kinda of capture that. sometimes it's just about sex especially when you're dating pool is very shallow. you can wind up in very bad or good places really quickly. Sherman I thought summed up a relationship of this show to another show that mirrored this show quite well,"It's a classic Sex and the City setup: a table, an issue, a difference of opinion. In Sex and the City, the varied experience of sexually liberated."(Sherman 259)This was true for the diner scene the show kind of gives that vibe but it just might be the the setting of new york city, It's just a different way of life there. This show I also though was taking a jab at the current film industry. they show that they can take the normal plot twist that usually happens in movies or primetime shows, but they don't they take the high rode to show that life isn't always that way. I think that this show challenges the assumptions of what queer people actually are like compared to how society sees them. This show portrays and cast these people as they are people who are jsut trying to figure out life like the rest of us and who we find love in comes from all different places and people. If I take this show in it's time it's was produced in 2012. Gay marriage had just been made legal i think recently during the time of this show. So I think that this says a lot. Compared to today where I think the queer community has taken leaps and bounds since then it's a lot more naturalized at least here in california. Maybe not so much in other states. But this show showed no matter you're sexual preference Were just people having people experiences

.Ng, E. (2013). A “Post-Gay” Era? Media Gaystreaming, Homonormativity, and the Politics of LGBT Integration. Communication, Culture & Critique, 6(2), 258–283. https://doi.org/10.1111/cccr.12013

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

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Referee #3

Evidence, reproducibility and clarity

The manuscript "Single molecule visualization of native centromeric nucleosome formation reveals coordinated deposition by kinetochore proteins and centromere DNA sequence" by Popchock and colleagues describes a new high-throughput single-molecule technique that combines both in vitro and in vivo sample sources. Budding yeast centromeres are genetically defined centromeres, which makes them ideal for studying short DNA segments at the single-molecule level. By flowing in whole cell lysates, Cse4 nucleosomes can form under near physiological conditions. Two analytical experiments were performed: endpoint and time-lapse. In the former case, nucleosomes were allowed to form within 90 minutes and the latter case, nucleosome formation was tracked for up to 45 minutes. In addition, well described genetic mutants were used to assess the stability of Cse4 nucleosomes, as well as different DNA sequences (this we particularly liked- well done). Overall, this is a very interesting technique with potential to be useful for studying any DNA-based effect, ranging from DNA repair to kinetochore assembly. This is strong and impactful work, and the potential this kind of microscopy has for solving kinetic problems in the field. We think it's worthy of publication after revising technical and experimental concerns that would elevate the ms significantly.

Major comments:

Statistics are highly recommended for all the data in the ms.

• At what rate is data collected in the TIRFM setup. For clarity for the reader, it is important to provide imaging details for time-lapse. What is the impact of photobleaching on the stability of the fluorophore signal? Please clarify.
• The power of single-molecule technique is precisely that such data can be made quantitative. Indeed, the Kaplan-Meyer graphs do show nice quantitative results. Unfortunately, in the text few quantitative measurements are reported. In fact, the Kaplan-Meyer graphs can be interpreted in a quantitative manner such as probability of residency time. Although in most cases the statistical significance between two conditions can be expected, this is not formally calculated and shown. What is the 50% survival time of Cse4 alone or with Ndc10, for instance? This manuscript would greatly benefit from a quantitative approach to the data, including a summary table of the results of the various conditions tested. Please add this important table.
• This reviewer would expect that the endpoint (90 min) would roughly reflect the occupancy results from time-lapse (45 min) experiments. Based on the data presented in Figures 1, 2, S1-3, this does not appear to be the case. 50% of Cse4-GFP and 70% Ndc10-mCherry colocalized with CEN3 DNA in the endpoint experiment, whereas in Fig 2C, ~30 and ~52 traces were positive for Cse4-GFP and Ndc10-mCherry, resp. with the former having drastically lower residency survival compared to Ndc10-mCherry. If indeed, 50% of Cse4-GFP makes it to the endpoint, about 50% of all traces should reach the end of the 45 minutes time-lapse window. Only about 1/3 of all positive Cse4-GFP traces can be seen at the end of the 45 min window. Could this be due to technical issues of photostability of GFP? Why does the colocalization of Cse4 signal with the DNA signal disappear so readily? Are Cse4 so unstable? Is the same true for canonical H3 nucleosomes? This unlikely true for nucleosomes in cells. Along the same lines, in Suppl Fig 3 there is a disconnect between residency survival and endpoint colocalization on either CEN3, CEN7, or CEN9. What could be the underlying mechanism between the discordance of endpoint results and time-lapse results? Could this be the result of experimental differences?
• What fraction of particles show colocalization between Cse4-GFP and Ndc10-mCherry? What fraction of occupancy time show colocalization between Cse4-GFP and Ndc10-mCherry? Altogether, understanding the limitation and benefits of endpoint analysis and time-lapse analysis in this particular experimental set-up is important to be able to interpret the results. Please clarify these points.
• Page 9, third sentence of third paragraph it is stated that the "results suggests that Scm3 helps promote more stable binding of Cse4 ...". This is indeed one possible explanation of the results, and this possibility is tested by overexpressing Psh1 or Scm3 by endpoint colocalization analysis. 1) Taking the concerns regarding the endpoint vs time-lapse results into account, wouldn't it be more accurate to compare either time-lapse results against each other or endpoint results? 2) Alternatively, more stable Cse4 particles are able to recruit Scm3, simply because of the increased binding opportunity of a more stable particle. In this scenario, just the residency time of Cse4 alone is the predicting factor in likelihood to associate with Scm3. To test the latter possibility, Cse4 stability would need to be altered. Please consider this experiment- should be relatively easy with the right mutant of either CSE4 or CDEII (see Luger or Wu papers).
• In Figure 1C and Supplemental Figure 5B, there appears to be foci that CEN3-ATTO-647 positive, but Cse4-GFP negative and visa verse. It seems logical that there are DNA molecules that didn't reconstitute Cse4 nucleosomes. But how can there be Cse4-GFP positive foci without a positive DNA signal? Is it possible that unlabeled DNA make it onto the flow chamber? If so, can these unlabeled DNA be visualized by Sytox Orange for instance to confirm that no spurious Cse4 deposition occurred? Please clarify.
• On page 10, at the end of the first paragraph, growth phenotype of pGAL-SCM3 and pGAL-PSH1 mutants were tested. On GAL plates, pGAL-PSH1 shows reduced growth, but not pGAL-SCM3. Wouldn't a more accurate conclusion be that Psh1 is limiting stable centromeric nucleosome formation, instead of Scm3?
• In the section where DNA was tethered at either one or both ends, an important control is missing. How does such a set-up impact nucleosome formation in general. Can H3 nucleosomes form on random DNA that is either tethered at one or both ends? Does this potentially affect the unwrapping potential/topology of AT-tract DNA? Please comment.

Minor comments

• Censored data points are not explained in the text.
• Number of particles tested should be reported in the main and supplemental figures, not just the legends for those readers who first skim the manuscript before deciding to read it.
• Typo on page 5, first line: "nucleosom" should be "nucleosome".
• Typo on page 9, second line: sentence is missing something "... is required for Scm3-dependent ..."
• It is unclear how the difference in Supplemental figure 5D was calculated.
• Figure 4C: why are there more Ndc10-mCherry foci observed in double tethered constructs vs single tethered constructs?
• For the display of individual traces as shown in Fig 2B, 3A, 4E, and 5E, it might be more informative if the z-normalized signal and the binary read-out are shown in separate windows to better appreciate how the z-normalized signal was interpretated.
• Page 17, fifth line of the second paragraph, it is stated that a conserved feature of centromeres is their AT-richness. This is most certainly true for the majority of species studied thus far, but bovine centromeres for instance are about 54% GC rich. Indeed, Melters et al 2013 Genome Biol showed that in certain clades centromeres can be comprised of GC-rich sequences. It might be worthwhile to nuance this statement.
• Page 17, last paragraph. Work by Karolin Luger and Carl Wu is cited in relationship to AT-rich DNA being unfavorable for canonical nucleosome deposition. A citation is missing here: Stormberg & Lyubchenko 2022 IJMS 23(19): 11385. Also, the first person to show that AT-tracts affect nucleosome positioning are Andrew Travers and Drew. This landmark work should be cited.
• Page 18, 9th line from the top, it is stated that yeast centromeres are sensitive to negative genetic drift. This reviewer is of the understanding that genetic drift is a statistical fluctuation of allele frequency, which can result in either gain or loss of specific alleles. Population size is a major factor in the potential power of genetic drift. The smaller a population, the greater the effect. Budding yeast is found large numbers, which would mean that drift only has limited predicted impact. Maybe the authors meant to use the term purifying selection?

Significance

This study developed an in vitro imaging technique that allows native proteins from whole cell lysates to associate with a specific DNA sequence that is fixed to a surface. By labeling proteins with specific fluorophore-tags colocalization provides insightful proximity data. By creating mutants, the assembly or disassembly of protein complexes on native or mutated DNAs can therefore be tracked in real time. In a way, this is a huge leap forward from gel shift EMSA assays that have traditionally been used to do comparative kinetics in biochemistry.

This makes this technique ideal for studying DNA binding complexes, and potentially, even RNA-binding complexes. This study shows both the importance of using genetic mutants, as well as testing the effects of the fixed DNA sequence. As many individual fixed DNA molecules can be tracked at one, it allows for high-throughput analysis, similar to powerful DNA curtain work from Eric Greene's lab. Overall, this is a promising new single-molecule technique that combines in vitro and ex vivo sample sources, and will likely appeal to a broad range of molecular and biophysics scientists.

I think when a bunch of people get together to figure something out, like finding those folks in the proposal, sending them good vibes, and sharing pictures, crowdsourcing can be pretty cool. But, you know, there are those internet trolls who just love to mess things up and invade people's privacy. Personally, I'm not totally sold on crowdsourcing because it's like a 50-50 chance, and that makes me feel a little nervous.

Digital platforms for crowdsourcing, such as Wikipedia, are astounding innovations of our time. By tapping into the diverse knowledge and abilities of people worldwide, these platforms revolutionize how information is both created and disseminated. But it's not all smooth sailing, with hurdles like ensuring accuracy and addressing potential bias coming to the fore. The case where U.S. congressional staff were found editing Wikipedia pages exemplifies the tightrope walk between openness and the risk of misuse. This intriguing episode serves as a reminder of the ongoing transformation in the way we share information, and the vital role of ethical standards in the realm of digital information.

Wikipedia is probably the most notable mention when it comes to crowdsourcing platforms, especially given it's image as a database. However, wikipedia also shows off the negative possibilities with crowdsourcing on a database site, which happens to be misinformation and its ability to be spread easily.

I think it’s hard for men to be happy in civilization today because there’s so much pressure put on men and men kind of grow up in a different way than women. They’re kind of told not to be emotional to always be strong and kind of like to be robots and people don’t teach men how to be human and just be themselves and it’s OK to has different emotions. Everybody has emotions.

I think that this is a really good point. Technology has become an assumed skill that everyone is expected to know. It's supposed to be "easy" for people to pick up. In my opinion, applications are becoming increasingly more complicated with new updates that constantly change the layout and Terms of Use of the app. With the amount of applications that are sued in school, it seems impossible to stay up to date on these features. This can be very harmful and cause teachers and students to fall behind and struggle with completing assignments.

You might want to change the wording.

In their raw form, LLMs are very much not KGs, just abstract vectors representing text content. In fact, many of their failure modes come from not having ground truth factual data, like what you find in a KG.

But it's not hard to integrate an LLM with a KG, that makes both tools vastly more powerful, and that is obviously what's coming next.

It's more granular than this, and that's significant. It's not just pairing advertisers with customers, it's connecting particular ad verticals, formats, and inventories with customers with specific demographics, classifications, and interests.

That means potentially sensitive information about end users gets shared (anonymously, in theory) with advertisers who get to leverage that knowledge to manipulate them. It also means advertisers compete for access, and iterate with Platforms on how to most efficiently monetize the end users.

And, of course, the same is true of law enforcement, etc.

Glad to see you make explicit what you think is wrong here. This is an interesting framing. It's not what I would have said, but I think I like it.

Why is this bad? Just thinking out loud: by bundling the computation, you remove direct access to the data. By making the computation a black box, you hide its bias and side-effects. You can also hide a vast pipeline with many inputs and outputs by presenting a much simpler subset API to the public, as if that were the whole thing. This lets you hide your profit model and the asymmetry in how much value the user / company gets out of the product.

Love this point. It might also be worth mentioning that it's totally possible (and common, I assume) to join seemingly safe and innocuous KGs with private data / surveillance KGs. This works really well, and some of the mundane data might end up being the missing link that binds together the more controversial stuff and makes it useful.

This is true, but it's one sided and missing something very important.

Having powerful, well funded groups make products out of structured data also had several large, positive effects. The schemas became more practical for addressing the needs of real people. The volume, quality, and consistency of structured data on the web went up. The accessibility and usage of structured data went way up. Many useful products got built that probably never would have emerged without the corporate efforts.

You do a good job of highlighting many down sides to this, which are also true. But if you don't bring up the good sides, people will accuse you of cherry picking. If you tell both sides, they'll argue why the benefits outweigh the drawbacks.

So, I think it's worth disentangling the threads of not just what they did but how they did it. Funding products and product-oriented data curation was positive. But they had ulterior motives, which is why they designed the systems to be closed, proprietary, and unaccountable. It didn't have to be like that. Could we do it differently, avoid most of the harms, and still reap most of the benefits?

I like your vulgar data vision, but it doesn't address this key point. How do we get high quality useful tools without handing everything over to a rich corporation? We do need an effective model for organizing and funding the vulgar efforts so they can compete.

This is an interesting perspective. Web 2.0 has two sides. To users, they were reaping the benefits of the platforms to get things done. To platforms, this activity served as a source of data, validation, and ranking.

Usually you hear just perspective one. It's rare to see just perspective two, like you wrote here. To me, they're two sides of the same coin, and we should always emphasize both.

That said, there could be an interesting discussion about whether it's a "fair coin" given the power / value asymmetry here.

This strikes me as a little strange. I'm not familiar with the Semantic Web project specifically, tho, so it may be true.

It's just that a decentralized KG with custom schemas is not so different from a web of documents tied together with links. You still need some sort of third-party aggregator to find the right content. The big difference is you could go to a KG hub (like Freebase) instead of a Search engine and work with structured data instead of raw text. But this was still a third party.

Lol, lmao. It is truly right and just, our duty and our salvation, always and everywhere to clown on The Atlantic. (With only a slight side of term usage pet peeve.)

But also: perhaps it is fair to say that the pre-internet didn't feel like such a global commons, but an archipelago of local commons. How many hits did GameFAQs get, long ago? It was small fora first, and only then "platforming", and now perhaps a return to older audience sizes?

Even the global resources on the early internet look cliquey and nichey in retrospect because there were so few people using the web; just being an internet user used to carry a lot of signal, tell you a lot about a person, situate them within a club.

This is showcasing the belief that many of us share in that we are not prepared for bad things to happen to us. We see others experience bad things and may feel sorrow towards their situation, but we don't really know what it's like until it happens to us, and it is a truly shocking thing to happen when it does.

reply to u/drogers8 at https://www.reddit.com/r/antinet/comments/13eyg8p/extended_numbering_and_why_use_outline_of/

Based on my research, Scott Scheper was the one of the original source for people adopting the Academic Outline of Disciplines. I've heard him say before that he recommends it only as a potential starting place for people who are new to the space and need it as a crutch to get going. It's an odd suggestion as almost all of the rest of his system is so Luhmann-based. I suspect it's a quirk of how he personally started and once moving it was easier than starting over. He also used his own ZK for showing others, and it's hard to say one thing in a teaching video when showing people something else. Ultimately it's hard to mess up on numbering choices unless you're insistent on using only whole numbers or natural numbers. I generally wouldn't suggest complex numbers either, but you might find some interesting things within your system if you did. More detail: https://boffosocko.com/2022/10/27/thoughts-on-zettelkasten-numbering-systems/ The only reason to have any standardized base or standardized numbers would be if you were attempting to have a large shared ZK with others. If this is your intent, then perhaps look at the Universal Decimal Classification, though a variety of things might also work including Dewey Decimal.

Why assign formative assessments/activities ahead of midterm, etc.

More on "exposure before class"

Critique of Perusall as about right or wrong versus the social construction of knowledge.

I think mods should be paid at least a small amount. While it is true that most mods volunteer their time to moderate it is because they are passionate about the subject of the subreddit which they are moderating, but just because you enjoy the work you do doesn’t mean you shouldn’t be paid for it. Also, it’s not like Reddit needs to pay them a huge salary or anything; even just a small fee for moderators would be better than nothing

That's the reason we are seeing a growing fascination with how AI is revolutionizing content moderation. It's not just making the process smoother. It's also ramping up the precision in weeding out content that does not fit the bill. It's always on duty, ensuring businesses can trust it to keep their digital platforms clean and secure at any hour of the day.

I agree with most of what I've read so far, but hate these weird and needless intermissions. The way it's formatted: question -> "because it does" -> what seems to be a criticism of the question (although that's not inherently true), makes me feel pretty sus about why it's included especially when its utility in the context of the article isn't immediately apparent. There's definitely a possibility that it's not intended to psyop. Either way, I just want the facts and I can take it from there about what to conclude.

I really hate it when articles do this bologna. "It is because it is" - why include it? Statements of "it's obvious" have a goal just like every other statement.

In this generation, we have gotten used to the idea that SA can happen without fitting into the idealized rape genre. With that being said, like I mentioned before It causes people to be more likely to defend the perpetrator. To those people, un-ideal rape can seem like a grey area, more acceptable to defend. For example, someone could say "Well Stacy got super drunk and she was with greg, I heard greg was being touchy and she didn't like it, but I mean it's not like he raped her or anything, he was just being forward." When in reality, the factual story I have created as an example would be worded like this. "Stacy got drunk at a party with her friends, and started flirting with greg, she just wanted to flirt and chat. They were being a bit touchy, until greg began touching her more forwardly. Stacy kept moving his hand away, telling him to keep things PG. Greg listened for about 5 minutes then continued. Stacy said no, but he did not listen. She started to freak out, and became speechless until a friend came and grabbed her noticing her obvious discomfort. It is very easy for apologists to come up with excuses for this type of SA/SH.

Reviewer #1 (Public Review):

The authors introduce a computational model that simulates the dendrites of developing neurons in a 2D plane, subject to constraints inspired by known biological mechanisms such as diffusing trophic factors, trafficked resources, and an activity-dependent pruning rule. The resulting arbors are analyzed in terms of their structure, dynamics, and responses to certain manipulations. The authors conclude that 1) their model recapitulates a stereotyped timecourse of neuronal development: outgrowth, overshoot, and pruning 2) Neurons achieve near-optimal wiring lengths, and Such models can be useful to test proposed biological mechanisms- for example, to ask whether a given set of growth rules can explain a given observed phenomenon - as developmental neuroscientists are working to understand the factors that give rise to the intricate structures and functions of the many cell types of our nervous system.

Overall, my reaction to this work is that this is just one instantiation of many models that the author could have built, given their stated goals. Would other models behave similarly? This question is not well explored, and as a result, claims about interpreting these models and using them to make experimental predictions should be taken warily. I give more detailed and specific comments below.

Line 109. After reading the rest of the manuscript, I worry about the conclusion voiced here, which implies that the model will extrapolate well to manipulations of all the model components. How were the values of model parameters selected? The text implies that these were selected to be biologically plausible, but many seem far off. The density of potential synapses, for example, seems very low in the simulations compared to the density of axons/boutons in the cortex; what constitutes a potential synapse? The perfect correlations between synapses in the activity groups is flawed, even for synapses belonging to the same presynaptic cell. The density of postsynaptic cells is also orders of magnitude of, etc. Ideally, every claim made about the model's output should be supported by a parameter sensitivity study. The authors performed few explorations of parameter sensitivity and many of the choices made seem ad hoc.

Many potentially important phenomena seem to be excluded. I realize that no model can be complete, but the choice of which phenomena to include or exclude from this model could bias studies that make use of it and is worth serious discussion. The development of axons is concurrent with dendrite outgrowth, is highly dynamic, and perhaps better understood mechanistically. In this model, the inputs are essentially static. Growing dendrites acquire and lose growth cones that are associated with rapid extension, but these do not seem to be modeled. Postsynaptic firing does not appear to be modeled, which may be critical to activity-dependent plasticity. For example, changes in firing are a potential explanation for the global changes in dendritic pruning that occur following the outgrowth phase.

Line 167. There are many ways to include activity -independent and -dependent components into a model and not every such model shows stability. A key feature seems to be that larger arbors result in reduced growth and/or increased retraction, but this could be achieved in many ways (whether activity dependent or not). It's not clear that this result is due to the combination of activity-dependent and independent components in the model, or conceptually why that should be the case.

Line 183. The explanation of overshoot in terms of the different timescales of synaptic additions versus activity-dependent retractions was not something I had previously encountered and is an interesting proposal. Have these timescales been measured experimentally? To what extent is this a result of fine-tuning of simulation parameters?

Line 203. This result seems at odds with results that show only a very weak bias in the tuning distribution of inputs to strongly tuned cortical neurons (e.g. work by Arthur Konnerth's group). This discrepancy should be discussed.

Line 268. How does the large variability in the size of the simulated arbors relate to the relatively consistent size of arbors of cortical cells of a given cell type? This variability suggests to me that these simulations could be sensitive to small changes in parameters (e.g. to the density or layout of presynapses).

The modeling of dendrites as two-dimensional will likely limit the usefulness of this model. Many phenomena- such as diffusion, random walks, topological properties, etc - fundamentally differ between two and three dimensions.

The description of wiring lengths as 'approximately optimal' in this text is problematic. The plotted data show that the wiring lengths are several deviations away from optimal, and the random model is not a valid instantiation of the 2D non-overlapping constraints the authors imposed. A more appropriate null should be considered.

It's not clear to me what the authors are trying to convey by repeatedly labeling this model as 'mechanistic'. The mechanisms implemented in the model are inspired by biological phenomena, but the implementations have little resemblance to the underlying biophysical mechanisms. Overall my impression is that this is a phenomenological model intended to show under what conditions particular patterns are possible. Line 363, describing another model as computational but not mechanistic, was especially unclear to me in this context.

I'm curious about what specifically they're referring to and where that quote comes from. If it's from the book, it has no real meaning. If it's a reference to a quote from a person in a position of "the elite" then that's at least potentially a different story but the meaning would still need to be evidenced. Otherwise, it take a giant leap of assumption for the reader to go from one contextless quote to a conclusion.

I really like this statement from Bo Burnham, it's humorous but true. I agree that social media can be seen as a huge bubble, encompassing all sorts of emotions and influences. Whether these are positive or negative depends entirely on how individuals choose to use and interact with the platform.

I completely agree with this. I think with social media there is a disconnect from the online you and the in person you. You can be as selective as you want with your online identity in a way that you can't do so much in person. Even though we all pretty much do this online, it can still feel very real. There is constant comparison with our online selves and others on live selves to our real life self which can create a lot of isolation and self-worth issues. I think we are starting to see the negative impacts of social media really emerging. I am starting to also see some more push back online and a sort of exhaustion when it comes to things like filters. I hope there will be a greater movement against this sort of stuff.

It's true that social media has both positive and negative effects on our lives. While it can connect us with people around the world, it can also create a sense of loneliness and overstimulation. The paragraph highlights the fact that social media can intensify the struggles that kids already face. It's important to recognize these challenges and work towards finding a balance in our use of technology.

This was a really interesting quote to read. I can not personally speak to this experience and I have never heard this thought process, so it's really eye opening to see just how harmful lesbian stereotyping can be.

I find this very interesting. I suspected that there might be some way for social media to control what is being posted so that their platform is safer. However, people will always find ways around it, like the "unalive" example or just changing the letters to a special character that resembles it. Personally, I don't think this helps... since even throughout the day, there are negative things that we see and this isn't really any exception. I can't speak for people experiencing this, but I feel like these things don't really affect me but I have seen these algorithms at work before, I just don't think it's effective yet.

reply to u/ruthlessreuben at https://www.reddit.com/r/Zettelkasten/comments/w5yz0n/comment/ihxojq0/?utm_source=reddit&utm_medium=web2x&context=3

u/ruthlessreuben, as a historian, you're likely to appreciate some variations which aren't as Luhmann-centric. Try some of the following:

• Victor Margolin: https://www.youtube.com/watch?v=Kxyy0THLfuI
• Thomas, Keith. “Diary: Working Methods.” London Review of Books, June 10, 2010. https://www.lrb.co.uk/the-paper/v32/n11/keith-thomas/diary.
• S. D. Goitein used a (non-Luhmann-esque) zettelkasten to write many things including the magisterial A Mediterranean Society: The Jewish communities of the Arab World as Portrayed in the Documents of the Cairo Geniza (1967–1993). Incidentally he took 1/3 less notes and had 1/3 more output than Luhmann: https://boffosocko.com/2023/01/14/s-d-goiteins-card-index-or-zettelkasten/.

The following note taking manuals (or which cover it in part) all bear close similarities to Luhmann's system, but were written by historians and related to the ideas of "historical method":

• Barzun, Jacques. The Modern Researcher. Boston : Houghton Mifflin Co., 1992. http://archive.org/details/modernresearcher00barz_1.
• Dow, Earle Wilbur. Principles of a Note-System for Historical Studies. New York: Century Company, 1924.
• Goutor, Jacques. The Card-File System of Note-Taking. Approaching Ontario’s Past 3. Toronto: Ontario Historical Society, 1980. http://archive.org/details/cardfilesystemof0000gout.
• Langlois, Charles Victor, and Charles Seignobos. Introduction to the Study of History. Translated by George Godfrey Berry. First. New York: Henry Holt and company, 1898. http://archive.org/details/cu31924027810286.

Although she's a sociologist, you might also appreciate Beatrice Webb's coverage which also has some early database collection flavor:

Webb, Sidney, and Beatrice Webb. Methods of Social Study. London; New York: Longmans, Green & Co., 1932. http://archive.org/details/b31357891.

It’s almost like he’s saying compared to Rome and old renaissance painters who captured a view point from which no one had ever seen ,making it grander , New York’s view points from tall building onto city’s isn’t all that its made to be because everyone can look from that view point (down onto other) and that this belief that you are higher then others is just another sale. Or just another lie to make you feel good about yourself. “ ITSD HARD TO BE DOWN WHEN YOUR UP” said a poster in a building

This seems valid and resonable

Yeah, it is a subjective question. Part of the subjectiveness: values make a difference. If no one gives a shit about climate change and species extinction, then I bet everything looks rosier. So it's easier to blame people for caring

reply to u/jordynfly at https://www.reddit.com/r/Zettelkasten/comments/13b0b5c/comment/jjcu3cn/?utm_source=reddit&utm_medium=web2x&context=3

I'm curious what your area of research is? What are you studying with respect to Zettelkasten?

Caveat notetarius. Note collections are highly idiosyncratic to the user or intended audience, thus quality will vary dramatically on the creator's needs and future desires and potential uses. Contemporaneous, very simple notes can be valuable for their initial sensemaking and quite often in actual practice stop there.

Ultimately, only the user can determine perceived quality and long term value for themselves. Future generations of historians, anthropologists, scholars, and readers, might also find value in notes and note collections, but it seems rare that the initial creators have written them with future readers and audiences in mind. Often they're less useful as the external reader is missing large swaths of context.

For my own personal notes, I consider high quality notes to be well-sourced, highly reusable, easily findable, and reasonably tagged/linked. My favorite, highest quality notes are those that are new ideas which stem from the combination of two high quality notes. With respect to subjectivity, some of my philosophy is summarized by one of my favorite meta-zettels (alt text also available) from zettelmeister Umberto Eco.

Anecdotally, 95% of my notes are done digitally and in public, but I've only got scant personal evidence that anyone is reading or interacting with them. I never write them with any perceived public consumption in mind (beyond the readers of the finished pieces that ultimately make use of them), but it is often very useful to get comments and reactions to them. I'm only aware of a small handful of people publishing their otherwise personal note collections (usually subsets) to the web (outside of social media presences which generally have a different function and intent).

Intellectual historians have looked at and documented external use cases of shared note collections, commonplace books, annotated volumes, and even diaries. There are even examples of published (usually posthumously) commonplace books, waste books, etc., but these are often for influential public and intellectual figures. Here Ludwig Wittgenstein's Zettel, Walter Benjamin's Arcades Project, Vladimir Nabokov's The Original of Laura, Roland Barthes' Mourning Diary, Georg Christoph Lichtenberg's Waste Books, Ralph Waldo Emmerson, Ronald Reagan's card index commonplace, Stobaeus' Anthology, W. H. Auden's A Certain World, and Robert Southey’s Common-Place Book come quickly to mind not to mention digitized scholarly collections of Niklas Luhmann, W. Ross Ashby, S.D. Goitein, Jonathan Edwards' Miscellanies, and Aby Warburg's notes. Some of these latter will give you an idea of what they may have thought quality notes to have been for them, but often they mean little if nothing to the unstudied reader because they lack broader context or indication of linkages.

I think this idea needs to be revolutionalized and be spread. While worksheets, standardized testing, same narrow curriculum might make things efficient, it makes some students settle down lower then where they are and get bored, and makes other students feel as if they do not fit and are delayed. While it's so hard to change a whole system, providing options for representation and expression and engagement, even in little increments, will make students feel that they aren't just a number who needs to reach an educational milestone at one particular date.

This is a great point and one that is easily forgotten. It's a common saying and it's true, that when we plan for neuro-divergent learners, we are not just benefitting those students but all of the students in the classroom. I think giving students options for the kind of work they complete, and how they complete it, can result in increased engagement, learning, and satisfaction in students.

I remember wanting to do that, when I learned about this style of vector component notation originally. I didn't find any advantage of thinking about it that way, but also, it's not obvious to me that there isn't one that I just haven't found.

Circling back around to this after a mention by Tim Bushell at Dan Allosso's Book Club this morning. Nicole van der Hoeven has been using it for a while now and has several videos.

Though called Napkin, which conjures the idea of (wastebook) notes scribbled on a napkin, is a card-based UI which has both manual and AI generated tags in a constellation-like UI. It allows creating "stacks" of notes which are savable and archivable in an outline-esque form (though the outline doesn't appear collapsible) as a means of composition.

It's got a lot of web clipper tooling for saving and some dovetails for bringing in material from Readwise, but doesn't have great data export (JSON, CSV) at the moment. (Not great here means that one probably needs to do some reasonably heavy lifting to do the back and forth with other tools and may require programming skills.)

At present, it looks like just another tool in the space but could be richer with better data dovetailing with other services.

agreed, It's not that hard to be a kind person, and that sticks with people. Those are the types of people I enjoy hanging out with, and just being respectful with people goes a long way.

It's really impressive that this kind of tissue-specific knockout in just a few cells works well enough to see a measurable effect. I imagine the knockout efficiency must be very high!

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Reviewer #3 (Public Review):

This manuscript describes interesting experiments on how information from the two eyes is combined in cortical areas, sub-cortical areas, and perception. The experimental techniques are strong and the results are potentially quite interesting. But the manuscript is poorly written and tries to do too much in too little space. I had a lot of difficulty understanding the various experimental conditions, the complicated results, and the interpretations of those results. I think this is an interesting and useful project so I hope the authors will put in the time to revise the manuscript so that regular readers like myself can better understand what it all means.

Now for my concerns and suggestions:

The experimental conditions are novel and complicated, so readers will not readily grasp what the various conditions are and why they were chosen. For example, in one condition different flicker frequencies were presented to the two eyes (2Hz to one and 1.6Hz to the other) with the flicker amplitude fixed in the eye presented to the lower frequency and the flicker amplitude varied in the eye presented to the higher frequency. This is just one of several conditions that the reader has to understand in order to follow the experimental design. I have a few suggestions to make it easier to follow. First, create a figure showing graphically the various conditions. Second, come up with better names for the various conditions and use those names in clear labels in the data figures and in the appropriate captions. Third, combine the specific methods and results sections for each experiment so that one will have just gone through the relevant methods before moving forward into the results. The authors can keep a general methods section separate, but only for the methods that are general to the whole set of experiments.

I wondered why the authors chose the temporal frequencies they did. Barrionuevo et al (2014) showed that the human pupil response is greatest at 1Hz and is nearly a log unit lower at 2Hz (i.e., the change in diameter is nearly a log unit lower; the change in area is nearly 2 log units lower). So why did the authors choose 2Hz for their primary frequency? And why did the authors choose 1.6Hz which is quite close to 2Hz for their off frequency? The rationale behind these important decisions should be made explicit.

By the way, I wondered if we know what happens when you present the same flicker frequencies to the two eyes but in counter-phase. The average luminance seen binocularly would always be the same, so if the pupil system is linear, there should be no pupil response to this stimulus. An experiment like this has been done by Flitcroft et al (1992) on accommodation where the two eyes are presented stimuli moving oppositely in optical distance and indeed there was no accommodative response, which strongly suggests linearity.

Figures 1 and 2 are important figures because they show the pupil and EEG results, respectively. But it's really hard to get your head around what's being shown in the lower row of each figure. The labeling for the conditions is one problem. You have to remember how "binocular" in panel c differs from "binocular cross" in panel d. And how "monocular" in panel d is different than "monocular 1.6Hz" in panel e. Additionally, the colors of the data symbols are not very distinct so it makes it hard to determine which one is which condition. These results are interesting. But they are difficult to digest.

The authors make a strong claim that they have found substantial differences in binocular interaction between cortical and sub-cortical circuits. But when I look at Figures 1 and 2, which are meant to convey this conclusion, I'm struck by how similar the results are. If the authors want to continue to make their claim, they need to spend more time making the case.

Figure 5 is thankfully easy to understand and shows a very clear result. These perceptual results deviate dramatically from the essentially winner-take-all results for spatial sinewaves shown by Legge & Rubin (1981); whom they should cite by the way. Thus, very interestingly the binocular combination of temporal variation is quite different than the binocular combination of spatial variation. Can the pupil and EEG results also be plotted in the fashion of Figure 5? You'd pick a criterion pupil (or EEG) change and use it to make such plots.

My main suggestion is that the authors need to devote more space to explaining what they've done, what they've found, and how they interpret the data. I suggest therefore that they drop the computational model altogether so that they can concentrate on the experiments. The model could be presented in a future paper.

Reviewer #1 (Public Review):

People can perform a wide variety of different tasks, and a long-standing question in cognitive neuroscience is how the properties of different tasks are represented in the brain. The authors develop an interesting task that mixes two different sources of difficulty, and find that the brain appears to represent this mixture on a continuum, in the prefrontal areas involved in resolving task difficulty. While these results are interesting and in several ways compelling, they overlap with previous findings and rely on novel statistical analyses that may require further validation.

Strengths<br /> 1. The authors present an interesting and novel task for combining the contributions of stimulus-stimulus and stimulus-response conflict. While this mixture has been measured in the multi-source interference task (MSIT), this task provides a more graded mixture between these two sources of difficulty

2. The authors do a good job triangulating regions that encoding conflict similarity, looking for the conjunction across several different measures of conflict encoding

3. The authors quantify several salient alternative hypothesis and systematically distinguish their core results from these alternatives

4. The question that the authors tackle is of central theoretical importance to cognitive control, and they make an interesting an interesting contribution to this question

Concerns<br /> 1. It's not entirely clear what the current task can measure that is not known from the MSIT, such as the additive influence of conflict sources in Fu et al. (2022), Science. More could be done to distinguish the benefits of this task from MSIT.

2. The evidence from this previous work for mixtures between different conflict sources make the framing of 'infinite possible types of conflict' feel like a strawman. The authors cite classic work (e.g., Kornblum et al., 1990) that develops a typology for conflict which is far from infinite, and I think few people would argue that every possible source of difficulty will have to be learned separately. Such an issue is addressed in theories like 'Expected Value of Control', where optimization of control policies can address unique combinations of task demands.

3. Wouldn't a region that represented each conflict source separately still show the same pattern of results? The degree of Stroop vs Simon conflict is perfectly negatively correlated across conditions, so wouldn't a region that *just* tracks Stoop conflict show these RSA patterns? The authors show that overall congruency is not represented in DLPFC (which is surprising), but they don't break it down by whether this is due to Stroop or Simon congruency (I'm not sure their task allows for this).

4. The authors use a novel form of RSA that concatenates patterns across conditions, runs and subjects into a giant RSA matrix, which is then used for linear mixed effects analysis. This appears to be necessary because conflict type and visual orientation are perfectly confounded within the subject (although, if I understand, the conflict type x congruence interaction wouldn't have the same concern about visual confounds, which shouldn't depend on congruence). This is an interesting approach but should be better justified, preferably with simulations validating the sensitivity and specificity of this method and comparing it to more standard methods.

A chief concern is that the same pattern contributes to many entries in the DV, which has been addressed in previous work using row-wise and column-wise random effects (Chen et al., 2017, Neuroimage). It would also be informative to know whether the results hold up to removing within-run similarity, which can bias similarity measures (Walther et al., 2016, Neuroimage).

Another concern is the extent to which across-subject similarity will only capture consistent patterns across people, making this analysis very similar to a traditional univariate analysis (and unlike the traditional use of RSA to capture subject-specific patterns).

5. Finally, the authors should confirm all their results are robust to less liberal methods of multiplicity correction. For univariate analysis, they should report the effects from the standard p < .001 cluster forming threshold for univariate analysis (or TFCE). For multivariate analyses, FDR can be quite liberal. The authors should consider whether their mixed-effects analyses allow for group-level randomization, and consider (relatively powerful) Max-Stat randomization tests (Nichols & Holmes, 2002, Hum Brain Mapp).

• Quote
  • "Assembly theory was developed to capture my intuition that complex molecules can’t just emerge into existence because the combinatorial space is too vast,"
  • Author
    • Lee Cronin

This experience made me understand that it's important to think carefully and not just follow what everyone else is doing. That way, we can avoid being tricked by scams or spreading wrong information.

I have participated in helping content go viral just by interacting with it like reposting, commenting, liking, sharing, etc. It's crazy that you can really help kickstart a post or video go viral by literally just seeing it and adding to the views or simply liking it.

This is definitely a feedback loop in play, as already LLMs emulate bland SEO optimised text very well because most of the internet is already full of that crap. It's just a bunch of sites, and mostly other sources that serve as source of K though, is it not? So the feedback loop exposes to more people that they shouldn't see 'the internet' as the source of all truth? And is this feedbackloop not pointing to people simply stopping to take this stuff in (the writing part does not matter when there's no reader for it)? Unless curated, filtered etc by verifiable human actors? Are we about to see personal generative agents that can do lots of pattern hunting for me on my [[Social Distance als ordeningsprincipe 20190612143232]] en [[Social netwerk als filter 20060930194648]]

Personal websites like mine since mid 90s fit this. #openvraag what incentives are there actually for people now to start their own site for online interaction, if you 'grew up' in the silos? My team is largely not on-line at all, they use services but don't interact outside their own circles.

reply to rogerscrafford at tk

Fine furniture comes at a fine price. 🗃️🤩 I suspect that it won't sell for quite a while and one could potentially make an offer at a fraction of that to take it off their hands. It might bear considering that if one had a practice large enough to fill half or more, then that price probably wouldn't seem too steep for the long term security and value of the contents.

On a price per card of storage for some of the cheaper cardboard or metal boxes you're going to pay about $0.02-0.03 per card, but you'd need about 14 of those to equal this and those aren't always easy to stack and access regularly. With this, even at the full $1,900, you're looking at storage costs of $0.10/card, but you've got a lot more ease of use which will save you a lot of time and headache as more than adequate compensation, particularly if you're regularly using the approximately 20,400 index cards it would hold. Not everyone has the same esthetic, but I suspect that most would find that this will look a lot nicer in your office than 14 cheap cardboard boxes. That many index cards even at discount rates are going to cost you about $825 just in cards much less beautiful, convenient, and highly usable storage.

Even for some of the more prolific zettelkasten users, this sort of storage is about 20 years of use and if you compare it with $96/year for Notion or $130/year for Evernote, you're probably on par for cost either way, but at least with the wooden option, you don't have to worry about your note storage provider going out of business a few years down the line. Even if you go the "free" Obsidian route, with computers/storage/backups over time, you're probably not going to come out ahead in the long run. It's not all apples to apples comparison and there are differences in some of the affordances, but on balance and put into some perspective, it's probably not the steep investment it may seem.

And as an added bonus, while you're slowly filling up drawers, as a writer you might appreciate the slowly decreasing wine/whiskey bottle storage over time? A 5 x 8 drawer ought to fit three bottles of wine or as many fifths of Scotch. It'll definitely accommodate a couple of magnums of Jack Daniels. 🥃🍸🍷My experience also tells me that an old fashioned glass can make a convenient following block in card index boxes.

I think that I see this most often out of all the ‘gaming’ in these algorithms. I believe that it’s just the easiest way to do it because you don’t need any information, it’s just to promote interaction with whatever is in the link.

I just read a reading about design strategy employed by most websites and applications, which indicates that most recommendation algorithms still use the gender binary framework because it's represented by the majority of the audience. However, this approach is obviously biased and unfair by neglecting the diversity of sexuality and users' identity.

I don't think it's the users fault, but yes when you pay more attention to content you hate, you will get more of that. This has happened to me before and you just have to ignore the content you hate.

This has implications for instructional designers and is one of the main reasons why a teacher of record should participate in the design of a course to the fullest extent possible. It isn't just about "buy in". It's about authenticity, authority, and teacher agency.

Author Response

Reviewer 1 (Public Review):

In this paper, Reato, Steinfeld et al. investigate a question that has long puzzled neuroscientists: what features of ongoing brain activity predict trial-to-trial variability in responding to the same sensory stimuli? They record spiking activity in the auditory cortex of head-fixed mice as the animals performed a tone frequency discrimination task. They then measure both overall activity and the synchronization between neurons, and link this ’baseline state’ (after removing slow drifts) of cortex to decision accuracy. They find that cortical state fluctuations only affect subsequent evoked responses and choice behavior after errors. This indicates that it’s important to take into account the behavioral context when examining the effects of neural state on behavior.

Strengths of this work are the clear and beautiful presentation of the figures, and the careful consideration of the temporal properties of behavioral and neural signals. Indeed, slowly drifting signals are tricky as many authors have recently addressed (e.g. Ashwood, Gupta, Harris). The authors are well aware of the difficulties in correlating different signals with temporal and cross-correlation (such as in their ’epoch hypothesis’). To disentangle such slow trends from more short-lived state fluctuations, they remove the impact of the past 10 trials and continue their analyses with so-called ’innovations’ (a term that is unusual, and may more simply be replaced with ’residuals’).

The terms ‘innovations’ and ‘residuals’ are sometimes used interchangeably. We used innovations because that’s how they were introduced in the signal processing literature (i.e., Kailath, T (1968). ”An innovations approach to least-squares estimation–Part I: Linear filtering in additive white noise.” IEEE transactions on automatic control). We try to be explicit in the text about the formal definition of this quantity, to avoid problems with terminology.

I do wonder if this throws out the baby with the bathwater. If the concern is statistical confound, the ’session permutation’ method (Harris) may be better suited. If the concern is that short-term state fluctuations are more behaviorally relevant (and obscured by slow drifts), then why are the results with raw signals in the supplement (Suppfig 8) so similar?

The concern was statistical confound, although this concern is ameliorated when using a mixed model approach and focusing on fixed effects. However, our approach allowed us to assess the relative importance of slow versus single-trial timescales in the predictive relationship between cortical state (and arousal) and behavior, revealing that, in the conditions of our experiment, only the fast timescales are relevant. Because of this, we think that the baby wasn’t thrown out with the bathwater as, qualitatively, no new phenomenology was revealed when the slow components of the signals were included. In hindsight, it is true that the results we obtained suggest that maybe the effort we made to isolate the fast component of the signals was unjustified. However, this can only be known after both options have been tried, as we did. Moreover, we started using innovations based on the results in Figure 2 where, as we show, the use of innovations does make a difference, even at the level of fixed effects in a mixed model. We agree that we could have used the ‘session permutation’ method, but given the depth at which we have explored this issue in the manuscript already, and the clarity of the results, we think that adding a third method would only make reading the manuscript more difficult without adding any substantially new content.

While the authors are correct that go-nogo tasks have drawbacks in dissociating sensitivity from response bias, they only cursorily review the literature on 2AFC tasks and cortical state. In particular, it would be good to discuss how the specific method - spikes, EEG (Waschke), widefield (Jacobs) and algorithm for quantifying synchronization may affect outcomes. How do these population-based measures of cortical state relate to those described extensively with slightly different signals, notably LFP or EEG in humans (e.g. work by Saskia Haegens, Niko Busch, reviewed in https://doi.org/10.1016/j.tics.2020.05.004)? This review also points out the importance of moving beyond simple measures of accuracy and using SDT, which would be an interesting improvement for this paper too.

We thank the reviewer for pointing us towards the oscillation-based brain-state literature in humans. We have expanded the paragraph in the discussion where we compare our results with previous work in order to (i) elaborate on the literature on 2AFC tasks, (ii) specifically address the literature linking alpha power in the pre-stimulus baseline and psychophysical performance, and (iii) mention different methods for assessing desynchronization. Our view is that absence of lowfrequency power is a robust measure which can be assessed using different types of signals (spikes, imaging, LFP, EEG). That said, the relationship between desynchronization and behavior appears subtle and variable, specially within discrimination paradigms. These issues are discussed in the paragraph starting in line 527 in the text.

Regarding the use of SDT, we had already established that our main finding could be expressed as a significant interaction between FR/Synch and the stimulus-strength regressor, when predicting choice after errors (Supplementary Fig. 4A in original manuscript), which is equivalent to a cortical state-dependent increase in d′ after the mice made a mistake. In order to consider a possible effect of cortical state on the ‘criterion’ (i.e., an effect on the bias of the mice towards either response spout), we re-run this GLMM but adding the cortical state regressors as main effects. The results show that the FR-Synch predictor is only significantly greater than zero as an interaction after errors (p = 0.0025). As a main effect, it’s not significantly different from zero neither after errors (p = 0.28), nor after correct trials (p = 0.97). We have included this analysis as Figure 3-figure supplement 1B (replacing the previous Supplementary Fig. 4A) and commented on them in the text (lines 222-225).

Reviewer 2 (Public Review):

The relationship between measures of brain state, behavioral state, and performance has long been speculated to be relatively simple - with arousal and engagement reflecting EEG desynchronization and improved performance associated with increases in engagement and attention. The present study demonstrates that the outcome of the previous trial, specifically a miss, allows these associations to be seen - while a correct response appears less likely to do so. This is an interesting advance in our understanding of the relationship between brain state, behavioral state, and performance.

This is probably just a typo, but we would like to clarify that the relevant outcome in the previous trial is not a miss, but an incorrect choice in an otherwise valid trial (i.e., a trial with a response within the allowed response window).

While the study is well done, the results are likely to be specific to their trial structure and states exhibited by the mice. To examine the full range of arousal states, it needs to be demonstrated that animals are varying between near-sleep (e.g. drowsiness) and high-alertness such as in rapid running. The fact that the trials occurred rapidly means that the physiological and neural variables associated with each trial will overlap with upcoming trials - it takes a mouse more than a few seconds to relax from a previous miss or hit, for example. Spreading the rapidity of the trials out would allow for a broader range of states to be examined, and perhaps less cross-talk between adjacent trials. The interpretation of the results, therefore, must be taken in light of the trial structure and the states exhibited by the mice.

We thank the reviewer for the positive assessment of our work and also for raising this point in particular. This motivated us to look more carefully at this issue, with results that, we believe, strengthen our study.

good belief to have

Thinking about big ML models and how they can be more like tools than total machines (a distinction without great linguistic provenance but with obvious immediate utility)

Afterward, student leaders typically announce the election results to the school. For example, the lead teacher at SHS indicated the below after receiving the election results.

"We will share these detailed results and insights (including the anonymous data you mention below) with the student leaders, and they will showcase them to the entire school in a presentation. Having this level of detail will help significantly in highlighting how the core values of Sage Hill School are very much in harmony with the core values of the individual students. This will without question strengthen our sense of community even further and encourage future participation in these events."

This was in response to the 'election results' email format (the email for SHS, to which the lead teacher responded, is pasted below). The intention for this email is to inspire schools to share the results (e.g., at a school assembly) in a way that promotes effective giving more widely.

"Dear SHS charity elections team,

Thank you for running a charity election at Sage Hill School! Giving What We Can has reviewed your school's survey data, and we are excited to share the election results below.

Election Results 1st place: SCI Foundation -- $712 -- 185 votes 2nd place: Clean Air Task Force -- $0 -- 100 votes 3rd place: GiveDirectly -- $0 -- 71 votes Results, SHS.png

The winning charity in your school's election is the SCI Foundation, and the $712 gift can help protect 1,780 children from schistosomiasis. If student leaders are interested in reflecting on student takeaways from the event, they are welcome to view the anonymous data (password: GWWCSHS23). Students overwhelmingly indicated they "voted for a cause they believe in" and "thought critically about what makes a charity effective," and a selection of anonymous student takeaways are listed below.

1. It made me want to be conscious about how I help others.
2. I’ve opened my perspective to the lives others lead and how a few dollars can impact someone enormously.
3. It’s made me think about the cost effectiveness of charities.
4. It made me better understand how even a small amount of money can truly make a difference.
5. This has reminded me that we must think about and help others, not just ourselves.
6. It made me think more critically on how exactly I could use my money to help others.
7. I will continue to donate to foundations for a good cause due to the charity elections. I’ve seen a glimpse of where donations go and how they impact others.
8. I learned to think more specifically about how a charity helps people, and if a charity's money is really being used well.
9. It made me think about getting the best way to help others and benefit the world.
10. It makes me want to do more for the world.

Additionally, there were several students who indicated an interest in the following opportunities. - Taking a leadership role in a charity election next year (48 students) - Participating in a student group related to world poverty (57 students) - Participating in a student group related to improving the long-term future (54 students) - Making a donation to one of the charities in the election (50 students)

Thank you for making a difference for your school community, as well as those directly benefiting from the charities on the ballot! Please let us know if there is anything else that would be useful in bringing closure to the event.

All our best, Charity Elections team Giving What We Can"

reply to ctietze at https://forum.zettelkasten.de/discussion/2560/zettel-feedback-functor-yeah-just-that#latest

Kudos on tackling the subject area, especially on your own. I know from experience it's not as straightforward as it could/should be. I'll refrain from monkeying with the perspective/framing you're coming from with overly dense specifics. As an abstract mathematician I'd break this up into smaller pieces, but for your programming perspective, I can appreciate why you don't.

If you want to delve more deeply into the category theory space but without a graduate level understanding of multiple various areas of abstract mathematics, I'd recommend the following two books which come at the mathematics from a mathematician's viewpoint, but are reasonably easy/intuitive enough for a generalist or a non-mathematician coming at things from a programming perspective (particularly compared to most of the rest of what's on the market):

• Ash, Robert B. A Primer of Abstract Mathematics. 1st ed. Classroom Resource Materials. Washington, D.C.: The Mathematical Association of America, 1998.
  • primarily chapter 1, but the rest of the book is a great primer/bridge to higher abstract math in general)
• Spivak, David I. Category Theory for the Sciences. MIT Press, 2014.
  • Spivak had a free draft prepublication version at https://arxiv.org/abs/1302.6946; There's also an open courseware version of his MIT course with a free .pdf textbook (with a 2013 date, but ostensibly a copy of the final published version from 2014) at https://ocw.mit.edu/courses/18-s996-category-theory-for-scientists-spring-2013/

You'll have to dig around a bit more for them (his website, Twitter threads, etc.), but John Carlos Baez is an excellent expositor of some basic pieces of category theory.

For an interesting framing from a completely non-technical perspective/conceptualization, a friend of mine wrote this short article on category theorist Emily Riehl which may help those approaching the area for the first time: https://hub.jhu.edu/magazine/2021/winter/emily-riehl-category-theory/?ref=dalekeiger.net

One of the things which makes Category Theory difficult for many is that to have multiple, practical/workable (homework or in-book) examples to toy with requires having a reasonably strong grasp of 3-4 or more other areas of mathematics at the graduate level. When reading category theory books, you need to develop the ability to (for example) focus on the algebra examples you might understand while skipping over the analysis, topology, or Lie groups examples you don't (yet) have the experience to plow through. Giving yourself explicit permission to skip the examples you have no clue about will help you get much further much faster.

I haven't maintained it since, but here's a site where I aggregated some category theory resources back in 2015 for some related work I was doing at the time: https://cat.boffosocko.com/course-resources/ I was aiming for basic/beginner resources, but there are likely to be some highly technical ones interspersed as well.

violence being a part of hip-hop culture

I have the original PocketBook InkPad color and I generally like it. Most of the improvements in V2 would be welcome (albeit well short of prompting me to upgrade), but dropping the microSD card slot is a bad move. The article suggests that this may have been done to increase the tablet's water resistance, but I will take the SD card over being able to submerge my e-reader in 2 meters of water.

Meg Wolitzer

I like how they associate the fear they once had to public speak with a good thought process. Speaking from personal experience the one thing I can't do in front of other people is sing, and that's because I know my singing is bad. But public speaking has always come easier, probably because it's easy to make yourself seem like a confident person over a decent singer.

Somehow I've always been disappointed with the two dimensional aspects of the pseudo-diagrams on prior books and articles in the space. If you go with something conceptual, perhaps try to capture a multidimensional systems/network feel? It's difficult to capture the ideas of serendipity and combinatorial complexity at play, but I'd love to see those somehow as the "sexier" ideas over the drab ideas people have when they think of their mundane conceptualizations of "just" notes.

Another idea may be to not go in the direction of the dot/line network map or "electronics circuit board route", but go back to the older ideas of clockworks, pneumatics, and steampunk...

By way of analogy, there's something sort of fun and suggestive about a person operating a Jacquard Loom to take threads (ideas) and fashioning something beautiful (https://photos.com/featured/jacquard-loom-with-swags-of-punched-print-collector.html) or maybe think, "How would John Underkoffler imagine such a machine?"

Now that I'm thinking about it I want a bookwheel (https://en.wikipedia.org/wiki/Bookwheel) next to my zettelkasten wheel!

make sure you don't pick a question and realize later that it's impossible to research or just really boring

Definitely agree with this! There is a curriculum development class that just talked about the importance of designing a lesson plan backwards. Having an end goal in mind is how we should be structure lesson plans and it's interesting to see how this applies to to technology as well. I have definitely gotten distracted by the "sparkle" before and really only had it just to use the tool, but if we backwards design, we can mitigate this problem.

This is such an important thing to think about. As teachers it's not just about giving a lesson and having the students listen. It's about being creative and coming up with lessons that engage the students. As a teacher you also have to think about where your students are with what you're teaching them. These are both very important things to keep in mind when you do teach to your students. Having lessons that aren't taught in a way that gets students attention won't be effective to have your students really learn what is being taught to them.

This feels like a major takeaway for the article. We can all hypothesize and discuss as much as we want, but who of us has access to whats really going on? We only know what these platforms disclose, or what is leaked, which certainly is just the tip of the iceberg. It’s hard to collectively fix a problem that impacts us all when the cause is kept secret.

I see so much of this online and it really concerns me. I feel like children are too young to consent to having information about them online. Parents might think something they are posting online is cute but there is likely not input from the child whether or not they want that shared. This is more recent, so it makes me wonder what the consequences -if any- could be later down the road. I've seen parents post their kids having a meltdown and treating it like it's funny, which just seems like it would create distrust from the child in the future.

This direct quote from Hockley-Harrison shows how not all sustainable options are equal, composting being a great example since it is inherently still just waist. she continues on with "Doing a little research ...at the very least, your cupcakes aren’t releasing greenhouse gases from the landfill." solidifying the fact that composting , while still better, does no better then just tossing it.

I'd imagine it's a MUST. Otherwise replica may receive content it just removed and happily keep on storing it. Keeping such 'blacklist' is an ellegant solution. Such lists are ever-growing however and perhaps could be trimmed in some way. E.g., after everybody who's been holding the content signed that it's been removed. Although even then nothing stops somebody from uploading the newly deleted content.

I guess another solution would be not to delete somebody's content but to depersonalize that somebody. So content stays intact, signed by that somebody, however any personal information of that somebody gets removed, leaving only their public key. That would require for personal information to be stored in one mutable place that is not content-addressed.

This article emphasises how this event affected other people. It mentioned many of the children who suffered and their statements, a pervious school shooting survivor and their perspective on the event. It focuses on guns, not esplishily saying that guns are bad and the cause of all this, but they sure are making us feel bad about it.

I mean, the last few quotes are just of children being scared and sad. "I don't want to be an only child", "son has been left traumatized" its true, yes, being in a school shooting is definitely traumatizing, especially if it affects you directly, but it's got a very guilt trippy vibe.

Big Big jump in descriptions? Idk emotions? It goes from light and floaty, "she was loved and appreciated", then snaps to "Hale came to school with two AR weapons", boom, big emotion, big contrast.

It's done on purpose, its an attention grabber, same as the hero turns out to be a villain. Obviously we already know what Hale did, but after six quotes(paragraphs) of Campbell describing Hale as a child and a student, someone who was loved, just a little girl, and that little girl brought 2 big guns to that school and murdered 6 people. It's like the climax of the story.

It's very easy to think that the reason this shooting happened was because something happened in the elementary school while Hale was attending, that made them do this, and that the reason was because of them being trans. But that's not necessarily the case.

Something did probably happen to them, but they didn't target any certain person during the shooting, so it is probably directed at the place and not the people there. We see that Hale shot the door open, so obviously it's an emotionally fueled action. One of the quotes somewhere idk I don't remember, but one of the quotes from a teacher said that they just shot anyone in front of them, regardless of who they were, child or adult.

This statement just tells us how difficult it is to change the church and how difficult it is to still be accepted into the church because of their sexuality. It's cool to see that they are finally being accepted into the church and how the church is changing to accommodate for things they haven't accepted in the past.

The directors explain what Alis is based on and why a participatory methodology was important from the very start of the film

imaginative start pulls you into the story

This reminds me of Sylvia Rivera and what I learned about her in another class. She was an activist who saw the bigger picture it wasn't just about being accepted. It was about the people who were struggling the most, the ones that need help. She wanted those voices to get heard. And I feel like Julio Salgado is trying the same to give them these voice he doesn't want to silence anybody but rather give them a voice and make them have a space to share their stories.

This is something I didn't know, but really highlights how dire the internet privacy situation is. In our increasingly connected social climate via the internet, privacy should be something we value and protect. It's very disappointing that there are no procedures in place that allow people to safely use modern technology as they were able to in the past. Also, I feel that internet browsing data is oftentimes more personal than just phone calls and have an even greater need for privacy protection.

I have a hard time understanding the privacy policies myself and I know a lot of other people do too – so it's common for people to skip it and just accept it. Companies do this so their users become unaware of what information is taken from them.

This was interesting to read as I did not know Maine passed a law that protects users personal information but I think it is a great thing. More states should pass always that protect our personal information because there is so much information that can be collected about someone through the information on their phones and it is scary to think about it. Pretty much every app you have installed on your phone has access to all of your data and is using it which is crazy. Up until we talked about it in this class I never realized just how much information on my phone is being tracked by companies and how many people have ahold of all my data and it is scary to think about it. Creating laws that help protect our personal information is great that way you have the choice of giving out your date or not.

I think it's great that Maine passed this law - definitely did not expect Maine to be the one that did it but okay. I feel like there is so much information that someone could collect about you and you don't realize to what extent it goes to. Companies should not have access to this information without asking you first because that is an invasion of privacy, especially from something you pay for. It is an opt-in choice but a way that a company can go around this is to just have a really long privacy policy or something that people won't read

This is so shocking to me. How is this information not sensitive or private? How does congress not recognize that? Also, even if they recognize it, how will it be enforced? It's so frustrating because it just feels more impossible to regulate the more I learn about it

I think this suggests that it is physically possible for humanity to construct a worldwide civilization that is capable of providing basic needs for all human beings while also protecting the environment and other forms of life on the planet. The author emphasizes the importance of recognizing the interconnectivity of all life forms in the biosphere and suggests that it is essential for a successful civilization to prioritize the protection and livelihood of all beings.

Rightfully so... these claims are not coming out of thin air history has proven that being realistic is important. I wouldn't call it pessimism because there is actual proof that life is not a thing to be optimistic about overall. Optimism is just used as a way to get through life it's not reality.

So in this case, the best way to create a utopia is to accept that utopias must start somewhere, it's not productive to debate endlessly

This is very interesting and true. I never looked at dystopian projects like this, I always just thought of it as something on the extreme side of the spectrum.

yes but it really isn't that easy. i understand where they are coming from. is it plausible? yes, absolutely. however it's extremely difficult when you look at how that would need a structural overhaul of society and those with the funds and power to make this happen choose not to everyday. we are left with the ability to make personal decisions that does help but is insufficient. i just think it's important to acknowledge that rather than saying we should just change civilization now

I think it's really good that people are being taught about this in schools and not just having to either learn the hard way or hope their friends/family would inform them. I especially think it's great that they will cover how you are tracked on apps and websites.

It’s kind of alarming how many websites ask you if you want to allow data tracking across other websites. It may seem surprising that you are being shown so much web content (ads, search results, etc.) that is related to something you were just thinking about or searching, but with the amount of data you provide even subconsciously, that is really not surprising at all.

reply to u/After-Cell at https://www.reddit.com/r/antinet/comments/12noly2/rebinding_a_book_for_more_margin_space/

The historical practice of "interleaved books" was more popular in a bygone era. If you search you can find publishers that still make bibles this way, but it's relatively rare now.

Given the popularity and ease of e-books and print on demand, you could relatively easily and cheaply get an e-book and reformat it at your local print shop to either print with larger margins or to add blank sheets every other page to have more room for writing your notes. For some classic texts (usually out of copyright) you can "margin shop" for publishers that leave more marginal space or find larger folio editions (The Folio Society, as an example) for your scribbles if you like.

Writing your notes on index cards with page references is quick and simple. These also make good temporary bookmarks. Other related ideas here: https://hypothes.is/users/chrisaldrich?q=tag:%22interleaved%20books%22

Have I just coined "margin shopping"?

"The pop splashes out of the cup and all over my shirt, leaving me drenched."

"... looks at my shirt, tells me how sorry he is, and then I just shake my head and keep walking. 'It’s all just part of the experience,' I tell myself."

This is another "may" argument—reality might be shaped in a way which averts doom; we don't know. It's modestly more persuasive than the others, but I still have plenty of probability mass on recursive self-improvement being possible. RLAIF is certainly very "promising" in that direction.

Bostrom's specific claim is that "more or less any level of intelligence could in principle be combined with more or less any final goal". It's not a claim about the complexity of the motivations—just that their goals may be very different from ours.

Yes, it's possible that the maximizer would want to write poetry. It's also possible that it would want to make a number in its memory be as large as possible. You don't know, and you don't have a good way to reason a priori about which is more likely, so you should treat both as live possibilities.

It's true. It's possible that intelligence can't be maximized, or that it has some low fundamental limit. We don't know. Say you view this "maybe" as a 50-50. That's certainly not a persuasive argument to stop worrying about a potential catastrophe.

I wonder if there's a good book to pair with this one, then

CONNECT:

Diane Nguyen, Bojack Horseman. "Because if I don't [write about my trauma], that means that all the damage I got isn't good damage, it's just damage. I have gotten nothing out of it, and all those years I was miserable was for nothing.

When I was thinking the other day, I was thinking about how we always think of our childhood as disconnected from our adult selves. Yet, it truly was the same person; much of what I liked back then I like now. Just some of it has been repressed or altered, but it's still me.

This idea is something that has caused me to devalue my own accomplishments in a way. I never really saw myself as being very smart as it always just seemed like something that was expected of me. For my close Asian friends who were not doing as well in my classes, I've heard of how even marginally lower scores or grades can affect them tremendously, and it's overall a harmful idea to perpetuate.

The racist and offensive imagery in in-game emblems was something that I saw quite a lot on Call of Duty lobbies when I was younger, and it was quite a common occurrence. There seems to have been a toxic subculture in gaming revolving around edgy and dark humor that often is just an excuse to spew racist statements. Even if people believe that they are doing it "just for a bit" or "as a joke" that does not mean that it is nullified of its impact on others. While not as prevalent today, at least from my experience, I know it still exists and it's honestly sad.

It's a very true statement that the one way to maintain a healthy and appropriate online community is to enforce and police people's social pattern. But more importantly, everyone should study how to manage their negative emotions and be responsible to their speaking online.

In many cases on the internet, you will see people pull the "It's just a joke" card as a getaway from being held accountable from something that may be very offensive or vulgar. Especially ones with no punchline. In my opinion, the word "Joke" has lost it's meaning, for the reason being that people only use for something to undermine.

This quote shocked me only because hearing this being said by the county judge. I do not personally know this person or his beliefs but from what I have experienced those in Texas, especially higher officials, tend to lean more towards voting Republican and having those viewpoints.

This is an interesting point. Is the english language getting worse? When I read something written a long time ago I find it hard to understand, because it's less familiar to me. So is it getting worse or is it just changing? The problem is that anyone would say their language is just fine because it's what they're most comfortable with, so it's hard to compare.

It's notable that none of the people of Rwanda or Burundi identified socially as Hutus despite the fact that Hutu and Tutsi coexisted there, not just as neighbors but also personally and via intermarriage. There were no mixed races; everyone was either Hutu or Tutsi.

Friends is a very nostalgic sitcom and it's legacy that lives on forever. It jumpstarted a lot of the casts' careers, but was also brilliantly centered around friendship. Each episode had a storyline to follow and we slowly learned about each individual character. Nothing felt forced and everything was organically done. It just demonstrated how Jennifer Aniston, Courtney Cox, David Schwimmer, and Matthew Perry were naturally talented.

Full House is iconic not just because it's one of the greatest sitcoms from the 90s. Kids were able to learn about life and how to navigate it when tragedy strikes. It also touched on a lot of issues that kids in different households face like abuse and domestic violence. Aside from the phenomenal acting and music, this show emphasized the importance of family. Why family sticks. by each other through thick and thin. How everyone deserves to be loved and treated with respect. Another thing I loved about this show was how it focused on conflict resolution. It will always be a classic and very dear to my heart.

Language itself the technology that was meant for humans to talk to humans. People complain about social media sites' bot populaces. If sex spam bots can degrade the Tumblr experience and crypto spam bots can degrade the Twitter experience will these new bots degrade the language experience?

General comments:

This study carefully delineates the role of magnesium in cell division versus cell elongation. The results are really important specifically for rod-shaped bacteria and also an important contribution to the broader field of understanding cell shape. Specifically, I love that they are distinguishing between labile and non-labile intracellular magnesium pools, as well as extracellular magnesium! These three pools are really challenging to separate but I commend them on engaging with this topic and using it to provide alternative explanations for their observations!

A major contribution to prior findings on the effects of magnesium is the author’s ability to visualize the number of septa in the elongating cells in the absence of magnesium. This is novel information and I think the field will benefit from the microscopy data shown here.

I completely agree with the authors that we need to be more careful when using rich media such as LB. It is particularly sad that we may be missing really interesting biology because of that! It’s worth moving away from such media or at least being more careful about batch to batch variability. Batch to batch variability is not as well appreciated in microbiology as it is for growing other cell types (for example, mammalian cells and insect cells).

For me, the most exciting finding was that a large part of the cell length changes within the first 10min after adding magnesium. The authors do speculate in the discussion that this is likely happening because of biophysical or enzymatic effects, and I hope they explore this further in the future!

I love how the paper reads like a novel! Congratulations on a very well-written paper!

Kudos to the authors for providing many alternative explanations for their results. It demonstrates critical thinking and an open-mind to finding the truth.

Specific comments:

Figure 2C → please include indication of statistical significance

Figure 3C → please include indication of statistical significance

Figure 6A → please include indication of statistical significance

Figure 8B → please include indication of statistical significance

Figure S1B → please include indication of statistical significance

Figure S3B → please include indication of statistical significance

For your overexpression experiments, do the overexpressed proteins have a tag? It would be helpful to have Western blot data showing that the particular proteins are actually being overexpressed. I think the phenotypes that you observe are very compelling so I don’t doubt the conclusions. Western blot data would just provide some additional confirmation that you are actually achieving overexpression of UppS, MraY, and BcrC.

Questions:

Based on your data, there are definitely differences in gene expression when you compare cells grown in media with and without magnesium. Because the majority in cell length increase occurs in such a short time though (the first 10min), I was wondering if you think that some or most of it is not due to gene expression? Do you have any hypotheses what is most likely to be affected by magnesium? Do you think if the membrane may be affected?

Why do you think less magnesium activates this program of less division and more elongation? Additionally why is abundant magnesium activating a program of increased cell division and less elongation? Do you think there is some evolutionary advantage, especially considering how important magnesium is for ATP production?

Related to this previous question, I also wonder if this magnesium-dependent phenotype would extend to other unicellular organisms, may be protists or algae? That would be a really exciting direction to explore!

Regarding the zinc and manganese experiments, why do you think they lead to additional phenotypes compared to magnesium? Do you have any hypotheses?

Regarding your results that Lipid I availability may be a major a problem for the cell division in the absence of magnesium, do you think that is due to effects magnesium has on the enzymes directly, or do you think magnesium affects the substrate availability/conformation by coordinating the phosphate groups? Or something else, may be membrane conformation?

General comments: 1-This is a really important work because in this day and age, transforming DNA into an organism or a cell is an essential tool for any molecular biologist

2-And we still don’t understand how to transform the vast majority of organisms on Earth!

3-I applaud this effort for developing robust and accessible transformation tools for the amoeba Acanthamoeba castellanii. I believe this is an important organism to study but equally important are the general trends/approaches about what works to transform an organism

4-accumulating more and more of this knowledge on transformation across different organisms is essential if we want to access the biology of many more organisms

5-Also kudos for the detailed and meticulous transfection optimization! I really enjoyed your use of the N/P ratio and the combinatorial approach over a range of DNA and PEI concentrations. This is solid science!

Specific comments: 1-Figure 2 → Is it possible to include cell counts, in addition to the RFU signal? This is not a major comment. It’s just that there are cell counts in your other figures so it might be good to include for this figure as well. No need to repeat this experiment if you don’t have cell counts though!

2-Figure 4 → Would it be possible to include arrows or something to indicate which parts of the figure you would like the reader to focus on? It’s great having all of the data included but it may help your narrative if you point in the figure itself to certain key differences or features of the data. Or you might consider including a table to summarize all the data from the figure? May be the table could contain standard deviation around the average for each treatment (or something to show the distribution of the signal but with a single number)?

3-Figure 6 → Would it be possible to include indication of statistical significance?

Questions: 1-How long are plasmids maintained in the transformed cells?

2-Is there a robust selection that could enable you to produce stably transformed lines?

3-And related to Q2, is it possible to produce stable mutant lines (gene deletions or gene introductions), perhaps by transiently transforming CRISPR genes?

4-Does Acanthamoeba castellanii easily undergo transfection in nature? Is there any evidence for that based on its genome?

5-Related to Q4, are there known viruses that infect Acanthamoeba castellanii? Knowledge about these viruses may inform alternative methods of gene delivery and also serve as evidence for the transfection rate in nature.

6-I was wondering if you have tried transfecting Acanthamoeba castellanii with one big plasmid containing two fluorescent genes? Does that work? If yes, is the gene expression worse or better compared to having the genes on two plasmids and transfecting the plasmids together?

I am still trying perfect my official teacher look to re-direct my students to what they should be doing.

In my experience of seeing online trolls on different social media platforms. Trolling can stir up online arguments among the online community, however just like the Banana Slicer Reviews on Amazon, I think the trolling like the that parody reviews lead to more internet traffic on Amazon.

I think that this should be a big part of teacher preparation, and that AI in the classroom and students' privacy when using technology should be a required subject for every schools' professional development sessions. In another class, I learned about the school to prison pipeline, and how it's suspected that the government uses children of colors test scores to predict how many jail cells they need to build. While this is based off of written test scores and not technology, if they began to use tracking of students data from technology used in the classroom, this is just one example of how students data can be used. What if a platform like iMovie where many students use voice bites has an ambiguous statement in their privacy policy about their use of voice bites?

I think this also effects the way many people view the ban as it's not simply a website that people can access where you can purchase goods, services. It's also not a website or service that is dedicated to one thing or a problematic subject. It is a platform in which people upload their own content and are able to have that freedom of expression. With it being a social media platform, there is still that policy of users being able to report problematic content and have accounts be banned for violating terms of service rules. I think that just because the company is owned by another country doesn't necessarily deem it a hazard or be enough for there to be removal. At the end of the day, it is a social media platform, which we have a right to access just like any other platform with the freedom of speech and expression.

I can see how this argument can be both hypocritical but also justified. On one hand, it seems a bit hypocritical that the U.S. government is concerned with the Chinese government data mining on user info. However, the government doesn't seem to have a problem with data mining when the company that is doing it is domestic, or U.S. based. It's almost surprising that they won't lay down the ban hammer on social media platforms like Facebook, Instagram, or Twitter when they have been found guilty of similar practices. Ultimately, I think it becomes an argument of "you're not allowed to do that, only we can do that".

Plus, what does that say about people in other countries who also use these platforms? Are they victims of the U.S. accessing their data too? If so, do those respective countries have just as much of a right to ban those social media platforms as well?

On the other hand, I can see how it could become a potential threat, as U.S. relations with China haven't exactly been the best as of late.

This is all really interesting information, but is it serving your article? A quick document search shows that you only ever touch on a lot of these terms in this section. So, is it necessary for people to know this information to understand your article? Why not "get into the fun stuff" right away? If there is information that's necessary for the reader to understand, you could always sum it up and provide a link before explaining why it's necessary to understand.

NOTE: You could always link the articles you've posted about these topics at the end, increasing readership to your other work and keeping this article focused on solar powered quantum computers.

reminiscent of a situation that Anderson Cooper recounted during his visit of seeing a family of corpses on the roadside in the aftermath of the Rwandan genocide. He noticed that the skin had peeled off one of their hands, and he started photographing that - but unbeknownst to him, a fellow photographer was taking images of him photographing that family. And he kept that picture taken by the other photographer as a reminder of what it looks like to go too far.

It's scary how the people in power can control individuals just through a label. This shows just how ingrained a power dynamic is in modern society.

Is this just redundant w/ Fig 2 BC? I see that the values are a lot higher in Fig 2 BC and those were 6-day old, instead of the 5-day old plants shown here. Sorry if it's an ignorant question.

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

Learn more at Review Commons

Reply to the reviewers

We thank the reviewers for their constructive feedback on our manuscript. They did a very comprehensive and helpful job of laying out some key areas that could be improved. We were heartened by the fact that there was a fair amount of overlap between the two reviewers, and that comments were largely addressable without further experimentation.

Below, we provide a summary of how we have attempted to address the comments and concerns from both reviewers. We also provide the rationale and action items for our responses. Overlapping comments from both reviewers have been consolidated and responded to together.

Comment 1 (Reviewer #1, Minor Comment 1 & Reviewer #2, Significance)

Both reviewers raised concerns about our choice to focus on essential genes in our CRISPRi screen, which could potentially underestimate the role of non-essential factors contributing to Tae1 sensitivity or resistance.

Rationale: We agree with the reviewers that including non-essential genes could provide additional insights into the roles of non-essential factors in Tae1 sensitivity and resistance. We believe our focus on essential genes contributes a unique perspective to the field, as there already exists a body of work that interrogates non-essential genes in this space. Here are some citations that represent this body. We will highlight these better in the manuscript.

Lin, H.-H.; Yu, M.; Sriramoju, M. K.; Hsu, S.-T. D.; Liu, C.-T.; Lai, E.-M. A High-Throughput Interbacterial Competition Screen Identifies ClpAP in Enhancing Recipient Susceptibility to Type VI Secretion System-Mediated Attack by Agrobacterium Tumefaciens. Front Microbiol 2020, 10, 3077. https://doi.org/10.3389/fmicb.2019.03077.

Hersch, S. J.; Sejuty, R. T.; Manera, K.; Dong, T. G. High Throughput Identification of Genes Conferring Resistance or Sensitivity to Toxic Effectors Delivered by the Type VI Secretion System; preprint; Microbiology, 2021. https://doi.org/10.1101/2021.10.06.463450.

Additionally, our screen was experimentally optimized for essential genes using our approach. The knockdown strategy is useful specifically for essential genes because E.coli is phenotypically very sensitive to essential gene perturbations (see more here: https://doi.org/10.1128/mBio.02561-21). While it would have been ideal to include non-essential genes too, doing so would require a different additional optimization that we believe would have diluted our bandwidth for this study. We do thank the reviewers for recognizing how much effort went into this!

We do acknowledge this is a limitation and want to make sure the readership is aware of that. Ideally, one could do more rigorous side-by-side comparisons between studies if the approaches, set-up, and assays are the same. Unfortunately, due to differences in experimental set-up, we could not directly compare with the non-essential screens. We hope others will pick up where we left off. Here are some action items we can take to increase the odds of that:

In the Introduction, we will mention other studies and highlight the need to investigate essential genes side-by-side with non-essential. (Lines 64-7) In the Discussion, we will add a sentence that acknowledges the importance of exploring non-essential genes for a more comprehensive understanding of Tae1 sensitivity and resistance. (Lines 484-5)

Comment 2 (Reviewer #1, Minor Comment 5 & Reviewer #2, Major Comment)

Both reviewers mentioned that the dormancy state in msbA-KD cells is not well characterized and its relationship with Tae1 resistance is not convincingly shown.

Rationale: We agree that our manuscript does not clearly pin down whether Tae1 resistance is linked to a true dormancy state. There are some intriguing similarities between what we observe and what is classically known as “dormancy” or “persistence”, which have specific definitions. Although we don’t yet have a concrete reason to think it’s NOT those states, we also don’t have sufficient data to point to it clearly being the same at a mechanistic or cellular level. This is merely a hypothesis that our work suggests. We would love to see others follow up on this, as we suspect there are overlaps and potentially additional cellular states that have yet to be clearly defined in this field of bacterial physiology.

Here is how we propose to address this concern:

We simplified our language to be more descriptive and less loaded in terms of nomenclature around dormancy or persistence. Namely, we are referring to the cells in a more descriptive way with “slowed growth.” This allows us to clearly describe what we observe without attempting to ascribe mechanism or anything beyond that. It doesn’t fundamentally change the overarching interpretation of our study. (Lines 444, 490,497-9) In the Discussion, we will add text emphasizing the need for follow-up studies to fully address whether there is indeed a connection between Tae1 resistance and slowed growth. (Lines 491-3)

Comment 3 (Reviewer #2, Major Comment)

The reviewer asks if the degradation of the sugar backbone is also required for lysis or if it is just the crosslinking step that is important.

Rationale: This is an astute point. We acknowledge that the degradation of the sugar backbone may play a role in lysis, and it’s predicted that this may be why the Pae H1-T6SS delivers a second PG-degrading toxin (Tge1), a muramidase that targets the sugar backbone. The most parsimonious conclusion from past studies by us and others is that Tae1 is critical for lysis, but not sufficient in the absence of any backbone-targeting enzyme. Indeed, many T6SS-encoding bacterial species also encode >1 type of PG-degrading enzyme, which may speak precisely to the reviewer’s point. However, it should also be noted that there may be endogenous enzymes with activities that can be leveraged alongside these toxins for the same effect.

Action items:

In the Discussion, we will add a sentence addressing the potential role of sugar backbone degradation in the lysis process and the need for future research on this topic. (Lines 524-6)

Comment 4 (Reviewer #1, Minor Comment 2)

The reviewer asks why lptC-KD leads to sensitivity to Tae1, while msbA-KD leads to resistance, considering both genes are implicated in LPS export.

Rationale: We appreciate the reviewer's careful attention to the underlying biology. They are absolutely correct in pointing this difference out. Our interpretation is that the different phenotypes may indicate that although the LPS biosynthesis superpathway intersects with PG synthesis, lptC and msbA may intersect with PG synthesis in distinct ways. We can address this concern through the following:

We will add a sentence in the Discussion section providing our interpretation of the different phenotypes observed for lptC-KD and msbA-KD. (Lines 508-13)

Comment 5 (Reviewer #1, Minor Comment 4)

The reviewer notes that the contribution of msbA to Tae1 resistance appears minor based on the results in Figure 3d.

Rationale: There are actually two aspects to this concern, which we note below. We found it difficult to fully capture it in the manuscript, but our thoughts are as follows.

(1) Technical viewpoint:

Bacterial competition experiments are inherently noisy. The quantitative read-out is easily impacted by a number of parameters, including cellular density, input ratio between competitor cell types, growth stage, and possibly other environmental factors that are difficult to predict. In general, our view is that we should avoid over-indexing on the degree of the phenotype, focusing more on the direction of the phenotype (loss of statistically-significant Tae1 sensitivity) and the fact that it is reproducible in our hands. Furthermore, our argument is bolstered by clear validation of the loss of Tae1 sensitivity through orthogonal lysis assays (Fig. 4a-c).

(2) Biological viewpoint

It is challenging to isolate the specific interaction between Tae1 and individual genetic determinants, as we think it’s a complex system with multiple factors simultaneously at play. It is crucial to acknowledge that the unique contribution of Tae1 is only a part of the T6SS. There may be other compensatory actions that influence the outcomes observed, such as upregulation of non-Tae1 toxins, regulation of system activation/firing, timing and location of T6S injections, etc. We think these are exciting possibilities and that more groups should delve into the context-dependent dynamics of the system. Although outside the scope of our manuscript, we would be open to suggestions for how we can further emphasize this point.

Comment 6 (Reviewer #2, Minor Comment)

The reviewer recommends that we discuss whether our findings are specific to Tae1 or if they can be extrapolated to other toxins.

Rationale: We understand the reviewer's interest in understanding the broader implications of our findings. Although our study focuses specifically on Tae1, we believe that our findings may provide insights into the mechanisms of sensitivity and resistance to other toxins that target the cell wall. However, experimentally investigating this would fall outside the scope of our current manuscript.

Additional Minor Revisions

Table 1: I would label MsbA and LptC as "LPS transport" and not "LPS synthesis" (Reviewer 1) Rationale: We agree that using “LPS transport” to describe the gene functions for lptC and msbA is more specific to their functions.

Table 1 was updated to change the “pathway/process” categorizations for lptC and msbA from “LPS synthesis” to “LPS transport”. In line with this comment, we also changed the pathway/process categorization for murJ (Lipid II flippase) to “PG transport”. Figure 3 legend: "...deformed membranes .........are demarcated in (g) and (h)" (Reviewer 1) We thank the reviewer for pointing out the missing text in this figure legend.

We corrected the error by adding the missing text back in Figure 3. Line 339-341: Supp. Fig. 9 should be Supp. Fig. 8 (Reviewer 1) Referenced Supp. Fig. was corrected. * Second, (L422-425) the authors conclude that their data demonstrate a "reactive crosstalk between LPS and PG synthesis". I disagree. There is no information in the paper that this is the case. The authors can only suggest that cross talk may occur. (Reviewer 2) We agree. Line 421-2: replaced “demonstrate” with “suggest” to soften the argument. *

I think the diagram could be a little clearer and maybe it would help the students understand better. For example, making the DNA and RNA strands different colors would make them easier to quickly distinguish. Same for the Cas9 protein vs. the DNA-modifying enzyme. You could also put a box around the target base location just to make it very clear where that empty label box is pointing.

I would make sure that however you depict the system in the worksheet, it's identical to how it's shown in the slides.

In my port of judell's slideshow tool, I made these built-ins. (They're bindings that are created in the ContentStereotype implementation.)

In that app, the stereotype body is just a return statement. Perhaps the ContentStereotype implementation should introspect on the source parameter and check if it's an expression or a statement sequence. The rule should be that iff the first character is an open param, then it's an expression—so there is no need for an explicit return, nor the escaped backtick...

This still gives the flexibility of introducing other bindings—like the ones for _CSSH_ and _CSSI_ here—but doesn't doesn't penalize people who don't need it.

I'm not a vanguard for the FSF per se, but when I think about the community norms and attitudes that are most exclusionary and turn people away, it's the sort of stuff that Drew and his fans are most often associated with. Stallman at least e.g. views Emacs as something that "secretaries" can be taught. Drew's circle tends to come across as having superiority complexes and holding strong opinions about computing that stops them just short of calling you a little bitch for not being as hardcore as they are...

Reviewer #1 (Public Review):

The authors evaluate a number of stochastic algorithms for the generation of wiring diagrams between neurons by comparing their results to tentative connectivity measured in cell cultures derived from embryonic rodent cortices. They find the best match for algorithms that include a term of homophily, i.e. preference for connections between pairs that connect to an overlapping set of neurons. The trend becomes stronger, the older the culture is (more days in vitro).

From there, they branch off to a set of related results: First, that connectivity states reached by the optimal algorithm along the way are similar to connectivity in younger cultures (fewer days in vitro). Second, that connectivity in a more densely packed network (higher plating density) differs only in terms of shorter-range connectivity and even higher clustering, while other topological parameters are conserved. Third, blocking inhibition results in more unstructured functional connectivity. Fourth, results can be replicated to some degree in cultures of human neurons, but it depends on the type of cell.

The culturing and recording methods are strong and impressive. The connectivity derivation methods use established algorithms but come with one important caveat, in that they are purely based on correlation, which can lead to the addition of non-structurally present edges. While this focus on "functional connectivity" is an established method, it is important to consider how this affects the main results. One main way in which functional connectivity is likely to differ from the structural one is the presence of edges between neurons sharing common innervation, as this is likely to synchronize their spiking. As they share innervation from the same set of neurons, this type of edge is placed in accordance with a homophilic principle. In other words, this is not merely an algorithmic inaccuracy, but a potential bias directly related to the main point of the manuscript. This is not invalidating the main point, which the authors clearly state to be about the correlational, functional connectivity (and using that is established in the field). But it becomes relevant when in conclusion the functional connectivity is implicitly or explicitly equated with the structural one. Specifically, considering a long-range connection to be more costly implies an actual, structural connection to be present. Speculating that the algorithm reveals developmental principles of network formation implies that it is the actual axons and synapses forming and developing. The term "wiring" also implies structural rather than functional connectivity. One should carefully consider what the distinction means for conclusions and interpretation of results.

The main finding is that out of 13 tested algorithms to model the measured functional connectivity, one based on homophilic attachment works best, recreating with a simple principle the distributions of various topological parameters.<br /> First, I want to clear up a potential misunderstanding caused by the naming the authors chose for the four groups of generative algorithms: While the ones labelled "clustering" are based on the clustering coefficient, they do not necessarily lead to a large value of that measure nor are they really based on the idea that connectivity is clustered. Instead, the "homophilic" ones are a form of maximizing the measure (but balanced by the distance term). To be clear, their naming is not wrong, nor needs to be changed, but it can lead to misunderstandings that I wanted to clear up. Also, this means that the principle of "homophilic wiring" is a confirmation of previous findings that neuronal connectivity features increased values of the clustering coefficient. What is novel is the valuable finding that the principle also leads to matching other topological network parameters.

The main finding is based on essentially fitting a network generation algorithm by minimizing an energy function. As such, we must consider the possibility of overfitting. Here the authors provide additional validation by using measures that were not considered in the fitting (Fig 5, to a lesser degree Fig 3e), increasing the strength of the results. Also, for a given generative algorithm, only 2 wiring parameters were optimized. However, with respect to this, I was left with the impression that a different set of them was optimized for every single in-vitro network (e.g. n=6 sets for the sparse PC networks; though this was not precisely explained, I base this on the presence of distributions of wiring parameters in Fig 6c). The results would be stronger if a single set could be found for a given type of cell culture, especially if we are supposed to consider the main finding to be a universal wiring principle. At least report and discuss their variability.

Next, the strength of the finding depends on the strengths of the alternatives considered. Here, the authors selected a reasonably high number of twelve alternatives. The "degree" family places connections between nodes that are already highly connected, implementing a form of rich-club principle, which has been repeatedly found in brain networks. However, I do not understand the motivation for the "clustering" family. As mentioned above, they do not serve to increase the measure of the clustering coefficient, as the pair is likely not part of the same cluster. As inspiration, "Collective dynamics of 'small-world' networks" is cited, but I do not see the relation to the algorithm or results presented in that study. A clearly explained motivation for the alternatives (and maybe for the individual algorithms, not just the larger families) would strengthen the result. 

Related to the interpretation of results, as they are presented in Fig3a, bottom left: What data points exactly go into each colored box? Specifically, into the purple box? What exactly is meant by "top performing networks across the main categories" mean? Compared with Supp Fig S4, it seems as if the authors do not select the best model out of a family and instead pool the various models that are part of the same family, albeit each with their optimized gamma and eta. Otherwise, the purple box at DIV14 in Fig3 would be identical to "degree average" at DIV14 in S4. If true, I find this problematic, as visually, the performance of one family is made to look weaker by including weak-performing models in it. I am sure one could formulate a weak-performing homophily-based rule that drives the red box up. If such pooling is done for the statistical tests in Supp Tables 3-7, this is outright misleading! (for some cases "degree average" seems not significantly worse than the homophily rules).

The next finding is related to the development of connectivity over the days in vitro. Here, the authors compare the connectivity states the network model goes through as the algorithm builds it up, to connectivity in-vitro in younger cultures. They find comparable trajectories for two global topological parameters. <br /> Here, once again it is a strength that the authors considered additional parameters outside the ones used in fitting. However, it should be noted that the values for "global efficiency" at DIV14 (the very network that was optimized!) are clearly below the biological values plotted, weakening the generality of the previous result. This is never discussed in the text.

The conclusion of the authors in this part derives from values of modularity decreasing over time in both model and data, and global efficiency increasing. The main impact of "time" in this context is the addition of more connections, and increasing edge density. And there is a known dependency between edge density and the bounds of global efficiency. I am not convinced the result is meaningful for the conclusion in this state. If one were to work backwards from the DIV14 model, randomly removing connections (with uniform probabilities): Would the resulting trajectory match DIV12, DIV10, and DIV7 equally well? If so, the trajectory resulting from the "matching" algorithm is not meaningful.

Further, the conclusion of the authors implies that connections in the cultures are formed as in the algorithm: one after another over time without pruning. This could be simply tested: How stable are individual connections in vitro over time (between DIV)? 

The next finding is that at higher densities, the connections formed by the neurons still have very comparable structures, only differing in clustering and range; and that the same generative algorithm is optimal for modelling them. I think in its current state, the correlation analysis in Fig. 4a supports this conclusion only partially: Most of these correlations are not surprising. Shortest path lengths feature heavily in the calculation of small worldness and efficiency (in one case admittedly the inverse). Also for example network density has known relations with other measures. The analysis would be stronger if that was taken into account, for example showing how correlations deviate from the ones expected in an Erdos-Renyi-type network of equal sizes.

Yet, overall the results are supported by the depicted data and model fits in Supp. Fig S7. With the caveat that some of the numerical values depicted seem off: <br /> What are the units for efficiency? Why do they take values up to 2000? Should be < 1 as in 4b. Also, what is "strength"? I assume it's supposed to be the value of STTC, but that's not supposed to be >1. Is it the sum over the edges? But at a total degree of around 40, this would imply an average STTC almost three times higher than what's reported in Fig 1i. Also, why is the degree around 40, but between 1000 and 1500 in Fig S2? <br /> Finally, it should be mentioned that "degree average" seems (from the boxplot) to work equally well.

Further, the conclusion of the "matching" algorithm equally fitting both cases would be stronger if we were informed about the wiring parameters (η and γ) resulting in both cases. That way we could understand: Is it the same algorithm fitting both cases or very different variants of the same? It is especially crucial here, because the η and γ parameters determine the interplay between the distance- and topology-dependent terms, and this is the one case where a very different set of pairwise distances (due to higher density) are tested. Does it really generalize to these new conditions?

Conversely, the results relating to GABAa blocking show a case where the distances are comparable, but the topology of functional connectivity is very different. (Here again, the contrast between structural and functional connectivity could be made a bit clearer. How is correlational detection of connections affected by "bursty" activity?) The reduction in tentative inhibition following the application of the block is convincing.

The main finding is that despite of very different connectivities, the "matching" algorithm still holds best. This is adequately supported by applying the previous analyses to this case as well. <br /> The authors then interpret the differences between blocked and control by inspection of the η and γ parameters, finding that the relative impact of the distance-based term is likely reduced, as a lower (less negative) exponent would lead to more equal values for different distances. This is a good example of inspecting the internals of a generative algorithm to understand the modeled system and is confirmed by longer edge lengths in Supp Fig. S12C.

The authors further inspect the wiring probabilities used internally at each step of the algorithm and compare across conditions. They conclude from differences in the distribution of P_ij values that the GABAa-blocked network had a "more random" topology with "less specific" wiring. This is the opposite of the conclusion I would draw, given the depicted data. This may be partially because the authors do not clearly define their concept of "random" vs. "specific". I understand it to be the following: At each time step, one unconnected pair is randomly picked and connected, with probabilities proportional to P_ij, as in Akarca et al., 2021; "randomness" then refers to the entropy of that process. In that case, the "most random" or highest entropy case is given by uniform P_ij values, which would be depicted as a delta peak at 1 / n_pairs in the present plot. A flatter distribution would indicate more randomness if it was the distribution of P_ij over pairs of neurons (x-axis: pairs; y-axis P_ij). The conclusion should be clarified by the use of a mathematical definition and supported by data using that definition.

Next, the methods are repeated for various cultures of human neurons. I have no specific observations there.

In summary, while I think the most important methods are sound, and the main conclusions (reflected in the title of the paper) are supported, the analysis of more specific cases (everything from Fig 3e onwards, except for Fig 5) requires more work as in the current state their conclusions are not adequately supported.

Now with internet, for example; tik tok. If I see someone do a dance I like, I do it. It's crazy how much internet has changed the world.

This CHALLENGES. I don't think that naming dishes after characters is immersive theming--i just think it's corny.

I think this answers question 2 being "how does the writer establish their credibility" because in the begenining the author explains that the writer and artists borrow knowledge and at the end of the paragraph, it relays a link towards another source for credibility!

I never knew that this was a thing. I feel like it can be really useful if the tweet is from a source that is reputable. Let's say you are trying to retweet that this is a scam site or a site that steals IP addresses, adding friction here just makes the person trying to help others go through a bit more work. Even though it's very minimal, I still think that just these small things can make someone not want to retweet aymore.

Credit is an excellent example also because it's so pointy

What is this sentence meant to do? If all it's doing is listing "protective codes of conduct" and "clear lines of accountability" as ways that feminists establish intentionally bounded gathering spaces, you can just say "for example, by X and Y". Phrasing it this way is confusing and also spends your word count unnecessarily (you could use those words elsewhere, to provide much-needed elaboration for your many interesting references)

Okay, wrapping up this deep reading of the paragraph. I think there are a few things going on here.

First, this paragraph is trying to do way too many things at once. It is trying to introduce "listening at scale", constraint vs enabling, and "tools for conviviality", but because you're trying to fit that all in one paragraph there isn't space to even explain what each thing means, let alone how they relate to each other. Each of these concepts should be at least a paragraph, if not more.

I think this is symptomatic of a broader issue with the book, which is that it tries to talk about everything and as such doesn't have much time to either teach the reader, or try to persuade the reader. (You do make arguments but you spend so little time on each one, and there are so many, that I find it hard to remember what they even are.)

In the fiction-writing world we have a concept called "kill your darlings". That doesn't mean "kill off your favorite characters", it means: be willing to cut your favorite characters, scenes, plotlines, descriptions, dialogues, etc, if it is not serving the story. Every single sentence has to justify its existence. If I was your editor I would ask you to look at the book as a whole, determine the half of your arguments/references/quotes/concepts that feel the most crucial to what you're trying to convey, and cut the rest. Then you could use the freed up space to actually explain these concepts and how they relate to your larger arguments.

I know you're pretty far along in the process, so "cut out half the book" is not helpful advice, but perhaps an approach to consider next time. You clearly have a ton to say and a lot of amazing references/projects/sources to mention, but the way it's done here just feels like it's not making the most of either your talent as a writer nor the material you're trying to present.

Thoughts: So far it appears there is no law about who can diagnose. What there is is: - description of a rubric to grade a expert witness - general description that states cannot operate outside area if training and competence (but how to define that area is absent) - core services / FFPSA law mandating evidence based, trauma Informed, Clearinghouse designated, best available science, meet particular needs of family - law (or in draft) defining trauma Informed - licensing and professional associations standards and code of ethics regarding non black and white values and efforts mandates - there are laws that say if you can call yourself a doctor, therapist, etc, but non if them limit what they can or cannot do - therefore, legally, anyone can diagnose anyone with anything, including DSM codes, and you can take money for it...you just can't call yourself any of the protected titles

So, when it comes to who is "legally qualified" or a "legally allowed expert", (which is just the expert, and not ultimately the credibility of the "evaluation/recommendation" it comes down to just who can provide a stronger argument that the expert in question is "more expert" than the other "expert". It's the exact same concept as scientific theory. You can't "prove" a scientific theory. You can only provide increasingly stronger (ultimately just means, whether for good reasons or bad, the emotion that something feels stronger or better) arguments that it is true. As in you can't prove "expertise" or that an eval is correct. However, you can "disprove" expertise or scientific theory.

In psychotherapy there is an enormous gap of a system that gives a credible prediction of what a "provider" is likely to soundly be able to evaluate (and further a system for them to soundly know when and how to refer out). Perhaps some kind of "certifications needed" section for each DSM code.

So what you can do is: - used the defined law and prof orgs law and ethics as rubrics (like a grading table), the table in this paper is a good one to incorporate, to make an argument of strongest expert. - you can also get more than one expert or experts from different areas which have all of them agreeing - strategy: also send evaluation off to credible authority to get their endorsement - strategy: do that memorandum thing (ABA guide how to influence judges) to advance submit law and argument to judge - all of this is the exact same issue, concept, and strategy to battle "reasonable efforts"

Contra [1], the ZIP format was brilliantly designed and natively supports a solution to this; ZIP was conceived with the goal of operating under the constraint that an archive might need to span multiple volumes. So just use that.

1. https://games.greggman.com/game/zip-rant/

I see this a lot—and it seems like it's a lot more prevalent than it used to be—reasoning from a proxy. Like trying to suss out how competent someone is in your shared field by looking at their GitHub profile, instead just asking them questions about it (e.g. the JVM). If X is the thing you want to know about, then don't look at Y and draw conclusions that way. (See also: the X/Y problem.) There's no need to approach things in a roundabout, inefficient, error-prone manner, so don't bother trying unless you have to.