1,181 Matching Annotations
  1. Last 7 days
    1. Reviewer #4 (Public Review):

      The manuscript reports an experiment testing how the distribution of rewards and costs influences perceived reward value in ants. Using a bundling manipulation where rewards and costs were presented either in small separated amounts (segregated) or together in a larger amount (bundled), the results show that ants deposited a greater quantity of pheromones (which was used as an index of "liking") when rewards were segregated and costs bundled compared to when both rewards and costs were bundled (although that difference was statistically significant only in ants experiencing the segregated reward condition first during training) and when both rewards and costs were segregated. By contrast, no evidence was found for a bundling effect in terms of choice behaviour (which was used as an index of "wanting"). The authors suggest that these findings demonstrate a bundling effect and a dissociation between "wanting" and "liking" in ants.

      Overall, the experiment provides a worthy contribution to the study of the biases that affect the perceived value of rewards in a translational perspective from humans to invertebrate animals. The experimental manipulation is clever, and the results clearly indicate that manipulating bundling affected pheromone deposition in ants. However, the data reported do not appear to fully support the conclusions of an increased "liking" of the segregated rewards and bundled costs compared to bundled rewards and costs. In addition, more evidence (along with stronger justifications) would be needed to establish that choice behaviour and pheromone deposition are appropriate and sensitive measures of "wanting" and "liking", respectively. This aspect renders any claim of a dissociation between "wanting" and "liking" in ants somewhat premature and speculative at this stage. I describe these concerns in more detail below.

      1) The main hypothesis tested is that segregated rewards with bundled costs should be the most "liked" option relative to bundled rewards and costs and segregated rewards and costs. The results are interpreted as fully in line with this hypothesis. However, the data reported do not suggest this is the case: The difference between the 'segregated rewards' condition and the 'bundled' condition is not statistically significant when all ants are considered (that difference being statistically significant only for ants that first experienced the 'segregated rewards' condition during training). Although this point is briefly acknowledged in the discussion, more nuance and extra caution are needed in the overall interpretation of the findings, so that this statistically nonsignificant result does not appear as being treated as if it were statistically significant.

      2) An important requirement to adequately evaluate the findings from the choice behaviour test is to ensure that ants did learn the associations between the reward conditions and the runway scents. Ruling out potential learning confounds is in fact essential to interpret the results as reflecting the operation of motivational processes such as "wanting". Whereas the results from the pilot experiment suggest that ants learned the contingencies between the runway length and its associated scent, the pilot experiment and the main experiment differ in significant ways. Therefore, it is unclear whether the ants learned the contingencies in the main experiment, which could be advanced as an alternative explanation for the lack of preferences between the two scented arms of the Y-maze during the choice test. Another important aspect to consider is that the reward still has to be valued by the organism to appropriately assess "wanting" processes. Indeed, "wanting" is generally conceptualised as conjointly determined by the associative history between the cue or context (scent) and the reward (sucrose solution) on one hand, and the organism's homeostatic or physiological needs such as hunger on the other hand (e.g., Zhang et al., 2009. https://doi.org/10.1371/journal.pcbi.1000437). In the main experiment, the question arises as to whether reward devaluation could have occurred-resulting in the reward having a diminished value as the ants were able to consume the sucrose solution to satiation multiple times across the experiment. For these reasons, it would be important to provide information showing that (a) the ants learned with which condition the scent was associated and (b) that the reward was still valued during the choice test. These points are key preconditions that need to be fulfilled for ruling out potential confounds that could explain the findings of the choice test as well as for suggesting a dissociation between "wanting" and "liking".

      3) Relatedly, a strong justification needs to be formulated to substantiate that the choice test provides a reliable indicator of "wanting". This is critical to conclude that the results can be interpreted as reflecting a dissociation between "wanting" and "liking". In rodents and humans, "wanting" is typically measured as an increased effort mobilisation during the presentation of a cue associated with a reward (e.g., Pool et al., 2016. https://doi.org/10.1016/j.neubiorev.2016.01.006). It remains however unclear how choice can capture such effects. This questions the extent to which choice represents an adequate operationalisation and measure of "wanting" as described in the incentive salience hypothesis (Berridge & Robinson, 2016. https://doi.org/10.1037/amp0000059). Moreover, it should be clearly explained and motivated whether, and if so how, choice purely measures "wanting" without being contaminated or influenced by liking-based processes, such as preferences or expected pleasantness for instance.

      4) Little information is provided on how pheromone deposition was measured and on the specificities of this measure, such as its physiological bases, timing properties, and granularity. However, detailed information about this measure is of high relevance to be able to assess if pheromone deposition represents a sensitive measure of "liking". "Liking" is typically measured as hedonic reactions during reward consumption across the rodent and human literature (e.g., Pool et al., 2016. https://doi.org/10.1016/j.neubiorev.2016.01.006). Accordingly, a good index of "liking" should be specifically responsive to reward consumption. By extension, an increased pheromone deposition should be particularly evident after the ants consumed the sucrose drop. As it stands, it is unclear whether this is the case as the pilot experiment showed no statistically significant difference in pheromone deposition between the way towards the sucrose drop or back. If the measure of pheromone deposition allows for distinguishing between pheromones deposited on the way towards the drop and pheromones deposited on the way back in the main experiment, a further test that could be run would be to compare the pheromone deposition on the way towards the drop in the 'segregated all' condition versus the 'segregated rewards' and 'bundled' conditions. A higher pheromone deposition on the way towards the sucrose drop in the 'segregated all' condition could provide converging evidence that pheromone deposition is a sensitive indicator of "liking".

  2. Sep 2022
    1. Reviewer #4 (Public Review):

      Overall the paper is clear and well-written. The experimental design is elegant and powerful, and it's a stimulating read. Most QTL mapping has focused on directly measurable phenotypes such as expression or drug response; I really like this paper's distinctive approach of placing bespoke functional assays for a specific molecular mechanism into the classical QTL framework.

    1. GWAS genetic association

      A genome-wide association study (abbreviated GWAS) is a research approach used to identify genomic variants that are statistically associated with a risk for a disease or a particular trait. The method involves surveying the genomes of many people, looking for genomic variants that occur more frequently in those with a specific disease or trait compared to those without the disease or trait. Once such genomic variants are identified, they are typically used to search for nearby variants that contribute directly to the disease or trait.

      source: https://www.genome.gov/genetics-glossary/Genome-Wide-Association-Studies

      this is more like a medical definition... what about plants?

    1. Above all, a fresh and original intellectual approach is needed, avoid-ing all standard solutions.

      This relates to the increasing difficulty of being originial with the rapid advances in productivity today.

    2. A striving for order can, and must, also be expressed inasymmetrical form.

      This relates to sticking to past foundations that are somewhat indispensable.

    3. Thetypographer must take the greatest care to study how his work is read andought to be read.

      Today, this is foundational since there are constantly advances in works of typography making documentation and research important to giving future credit.

    4. Evenin good central-axis composition the contents are subordinated to “beautifulline arrangement.”

      Clarity becomes less important due the focus on the composition being centralized as it relates to improving the visual appeal of the artistic, "arrangement."

    5. the rigidity of central-axis setting hardly allows work tobe carried out with the degree of logic we now demand.

      The central axis in art relates to a somewhat balanced distribution of space on an art piece.

      “ARTTALK Chapter 10 Balance - Ppt Google Img.” SlidePlayer, https://slideplayer.com/slide/10709291/.

    6. This utmost clarity is necessarytoday because of the manifold claims for our attention made by the extraor-dinary amount of print, which demands the greatest economy of expression.

      This emphasizes that having clear communication is made crucially important due to the difficulty of communicating to those who are surrounded by countless other "prints."

    1. Posted byu/jackbaty4 hours agoCard sizes .t3_xib133._2FCtq-QzlfuN-SwVMUZMM3 { --postTitle-VisitedLinkColor: #9b9b9b; --postTitleLink-VisitedLinkColor: #9b9b9b; --postBodyLink-VisitedLinkColor: #989898; } I've been on-again/off-again with paper for PKM, but one thing remains consistent each time: I don't enjoy using 4x6 index cards. I much prefer 3x5-inch cards. I realize that it's irrational, but there it is.My question is if I dive into building an antinet, will I regret using 3x5 cards? I already have hundreds of them. I have dividers, holders, and storage boxes for them. I just prefer how they _feel_, as weird as that sounds.I'd like to hear if people are using 3x5 cards successfully or if you've come to regret it.

      While it may be slightly more difficult to find larger metal/wood cases for the 4x6 or 5x8 cards, it's a minor nuisance and anyone who wants them will eventually find the right thing for them. Beyond this, choose the card size that feels right to you.

      If you don't have an idea of what you need or like, try things out for 10-20 cards and see how it works for you, your handwriting size, and general needs. People have been using 3x5, 4x6, and even larger for hundreds of years without complaining about any major issues. If Carl Linnaeus managed to be okay with 3x5, which he hand cut by the way, I suspect you'll manage too.

      Of course I won't mention to the Americans the cleverness of the A6, A5, A4 paper standards which allows you to fold the larger sizes in half to get the exact next smaller size down. Then you might get the benefit of the smaller size as well as the larger which could be folded into your collection of smaller cards, you just have to watch out for accidentally wrapping ("taco-ing") a smaller card inside of a larger one and losing it. I suppose you could hand cut your own 5" x 6" larger cards to do this if you found that you occasionally needed them.

      For the pocketbook conscious, 3x5 does have the benefit of lower cost as well as many more options and flexibility than larger sizes.

      At least commercial card sizes are now largely standardized, so you don't have deal with changing sizes the way Roland Barthes did over his lifetime.

      My personal experience and a long history of so many manuals on the topic saying "cards of the same size" indicates that you assuredly won't have fun mixing different sized slips together. I personally use 3x5" cards in a waste book sense, but my main/permanent collection is in 4x6" format. Sometimes I think I should have done 3 x 5, but it's more like jealousy than regret, particularly when it comes to the potential of a restored fine furniture card catalog. But then again...

    1. The drawers are jammed with jokes typed on 4-by-6-inch cards — 52 drawers, stacked waist-high, like a card catalog of a certain comedian’s life’s work, a library of laughs.

      Joan Rivers had an index card catalog with 52 drawers of 4-by-6-inch index cards containing jokes she'd accumulated over her lifetime of work. She had 13 2 drawer stackable steel files that were common during the mid-1900s. Rather than using paper inserts with the label frames on the card catalogs, she used a tape-based label maker to designate her drawers.

      Scott Currie, who worked with Melissa Rivers on a book about her mother, Joan Rivers, at the comedian’s former Manhattan office. Many of her papers are stored there.Credit...Hiroko Masuike/The New York Times

  3. Aug 2022
    1. day-length profoundly affects growth responses with stronger impact on root elongation under SD conditions

      SD has a stronger impact on root elongation...

    1. Forcertainlyagreatervarietyofcards,clippings,andsuchlikecan befiledbehind 4x6slipsthan behind3x5's.

      A benefit of 4 x 6" cards is that clippings and other items can often be more easily filed along with them as opposed to the smaller 3 x 5" cards.

    2. shall I adopt the 3x5 slip or the 4x61

      Dow indicates in 1924 that 3 x 5" and 4 x 6" are both commonly had in a range of materials the US as well as boxes or cases to keep them in. He does mention that one can also cut their own paper, indicating that this is a possibility.

    1. How do publishers design and organize content for their audience and purpose?

      I will just say this: there are both tried and true and normed audiences and purposes as well as dynamic and non-evergreen contents. This is vague I understand but the kinds of content in social media is always changing. When the algorithm changes so, too, does the shape and style of content. I don't know if the larger values, audience and purpose, change, but I suspect the even larger ones like empathy are super evergreen. Sorry. I wish I had more time to make this shorter.

  4. Jul 2022
    1. Reviewer #4 (Public Review):

      Yao and Ochoa conducted a systematic examination of the association study using PCA and LMM with both simulated and empirical datasets. The overall finding is that LMM should be used and generally there is no need to include a few PCs in LMM. While similar studies have been conducted earlier with the comparison goal, the authors made additional effort to conduct this extensive study. Many scenarios were considered, and the results were clearly presented. This paper is interesting to researchers in statistical genetics.

    1. 1. Focus on items that occur with high frequency in the language as awhole (see Table 3.1 for examples). Such items will occur often inmany different texts.2. Focus on strategies that can be used with most texts (see Table 3.1for examples).


    1. there's a crucial distinction between what barney called three and four that's what uh captured me so 01:08:55 if you take the mind as fundamental as existing the only existing thing where where the the movie of the world is reflected into i am not happy 01:09:08 my my culture uh rejects then as a useless point of view to do science that's what but there is an alternative much more interesting and i find much more 01:09:21 deep in which which i read in a garage you know which is what uh barry seems to be is calling the fourth alternative in which the mind is not the fundamental thing in which everything is it's 01:09:32 reflected it's just one part of this uh uh uh interdependence now namely it's not the things that not intrinsic existence but mind has intrinsic existence that's not the 01:09:45 the the there's a more interesting answer namely that mind itself has no intrinsic uh uh existence uh and so it's just uh uh 01:09:57 it has an existence but is is it of course it's an existence my mind exists and i exist but uh and and and and if i think in terms of groups to say i mean all sentience being or all 01:10:10 human beings whatever um together uh which is an ideal also some some some some western philosophy that you know um it's collectively that through language and 01:10:22 that would create a vision of the world but i want to think of this as one aspect of the ensemble of things which is existence where uh uh nothing of that has um 01:10:36 uh has intrinsic existence so i want to think about my mind it's my brain my sensation my all my my my love people loving me the the image that people have of me my instead of the set 01:10:48 of processes uh uh which part of the world and it seems to me that the belgian allows me to think at me as part of the world at the same sense of the same ground as the world being 01:11:01 reflected in my consciousness without having to choose one of the two perspective to be the true one the intrinsic existence um 01:11:12 all all perspectives are uh uh empty they're all good but they are um they are not the the one on which the rest is ground they 01:11:24 each of one i can understand dependently on something else so marios you read a a verse or two from the third chapter of nagarjuna and uh let me comment on that

      Carlo points out the view he now holds, influenced by Nagarjuna's philosophy, that the mind exists, but does not intrinsically exist.

      So he argues on one (conventional) level, his mind and all other minds exist.

      Agreeing with Barry's fourth suggested alternative. The mind is not the fundamental thing, but is just ONE PART of this interdependency. Each view, whether of any human or even non-human is empty but conventional exists in interdependence of many causes and conditions.

      From Stop Reset Go perspective and the Indyweb, a web3 technology that can embody each indivdiual's perspectival knowing through the establishment of their the individuals unique and privately owned data repository can enhance the discovery of the process of emptiness. How? By theoretically having all one's (digital) interactions of the world, one can begin to see in granular detail how one learns about the world and begin to sense the flow of the mind. Through repeated use of the Indyweb and witnessing how one forms new ideas or reforms old ones, the indyvidual becomes increasingly aware of oneself as a process, not a thing. Furthermore, one begins to see self knowledge as hopelessly entangled with cultural and social learning. One begins to sense the 4Ps of propositional, perspectival, participatory and procedural learning, also entangled with each other and with individual/social learning.

      https://docdrop.org/video/Gyx5tyFttfA/#annotations:vkOUgv8rEeypE39kg2ckCw https://hyp.is/go?

      Quick John Varvaeke interview on 4P: url=http%3A%2F%2Fdocdrop.org%2Fvideo%2FERdJDVdbkcY%2F&group=world

      One especially begins to sense perspectival knowing and situatedness and that causes and conditions unique to one's own worldview constructs one's relative reality.

    1. it's a how we know it in some way so it's different forms of how yes it's not based on the content of it so there's different ways you can do taxonomies and people often want to monkey with the taxonomy they said no no like you can make a 00:00:50 taxonomy however you want like if you make the taxonomy on the basis of content you're going to have like you're going to have like you know knowledge about australia knowledge about the solar system and right right now that you're right this is much more about the 00:01:03 manner and the mechanisms of knowing than it is about the content

      The 4 P's is concerned with the "how" of knowing rather than content of knowledge.

    1. Dogen can be very difficult to read or understand. That’s why we often need a commentary or teacher to introduce his way of writing and the underlying teaching. I often say he’s a thirteenth century cubist. Just like Picasso or in the writing world, Gertrude Stein, he tries to show all sides of the story in one paragraph or even one sentence. That is why he repeats himself and contradicts himself all in the same paragraph. If you are looking for the “right” understanding, you become confused and lost in his prism of various interpretations or views. Dogen’s “right” understanding is that there is none.   No one point of view is “right”. According to conditions, any view can be the right view in the right circumstance. Dogen really wants to take away our solid idea of a fixed ground of reality. It is not form or emptiness. It is not both or neither. There is no one right, fixed view. That is our “clinging”.

      Dogen contradicts himself because he tries to show "all sides of the story". His teaching is a "pointing out" instruction that ANY viewpoint is simply that, perspectival knowing.

      An important question then, is this, if Dogen (and Nagarjuna) are claiming that there is no objective reality in our constructed world of concepts and language, is science being denied? Is fake news ok? Is this a position that basically accepts post modernism? No, I would say no to all of these. It's pointing out the LIMITATIONS of concepts and language. They are incomplete and always leave with a sense of wanting more. And since Post Modernism is also one point of view, it is also thrown out by Dogen and Nagarjuna. Remember, ALL points of views are points of view. Fake news is also a point of view so those who practice it can also not justify it.

      What Dogen and Nagarjuna are saying is that as soon as one enters the world of concepts and language, any concept and anything side is inherently one sided. It is inherently perspectival and situated in an inherently incomplete conceptual space.

      As Tibetan doctor/monk Barry Kerzin points out in this conversation with physicist Carlo Rovelli, there is a critical difference between "existence" and "intrinsic existence". The first is not being denied by Nagarjuna, but the second, intrinsic existence, the existence of concepts and the words that represent them, is. If these two are confused, it can lead straight to nihilism.


      This also aligns with John Vervaeke's perspectival and propositional knowing in his 4 P ways of knowing about reality: Propositional, Perspectival, Participatory and Procedural. A good explanation of Vervaeke's 4Ps is here: https://hyp.is/go?url=http%3A%2F%2Fdocdrop.org%2Fvideo%2FGyx5tyFttfA%2F&group=world

    1. we often have too narrow an appreciation of   knowing focusing too much on one or two kinds  of knowing but to live well in a complex world   we need to effectively engage with four kinds  of knowing and perfectly they all begin with a P

      Title: Four Kinds of Knowing Author: Rich Watkins Date


  5. Apr 2022
    1. Siemens (2002) notes that learner-learner interactions in an e-learning course can be viewed as a four stage continuum:

      Communication People ‘talking,’ discussing Collaboration People sharing ideas and working together (occasionally sharing resources) in a loose environment Cooperation People doing things together, but each with his or her own purpose Community People striving for a common purpose

  6. Mar 2022
  7. Feb 2022
    1. When you read widely, your brain is exposed to different ways in which a sentence or paragraph is written. There are patterns in the use of nouns, pronouns, verbs and other parts of speech; there are patterns in syntax and in sentence variation; and there are patterns in sound devices, such as alliteration and assonance. You can annotate these with different symbols or colors, and develop understanding as patterns emerge, and style emerges from patterns. To read like a writer, you need to annotate like one, too.

      I haven't seen very much in the area of annotating directly as a means of learning to write. This is related to the idea of note taking for creating content for a zettelkasten, but the focus of such a different collection is for creating a writing style.

      Similar to boxing the boring words (see Draft #4; http://jsomers.net/blog/dictionary), one should edit with an eye toward the overall style of a particular piece.

      Annotating structures and patterns in books is an interesting exercise to evaluate an author's style as a means of potentially subsuming, modifying, or learning other styles.

    1. We need to getour thoughts on paper first and improve them there, where we canlook at them. Especially complex ideas are difficult to turn into alinear text in the head alone. If we try to please the critical readerinstantly, our workflow would come to a standstill. We tend to callextremely slow writers, who always try to write as if for print,perfectionists. Even though it sounds like praise for extremeprofessionalism, it is not: A real professional would wait until it wastime for proofreading, so he or she can focus on one thing at a time.While proofreading requires more focused attention, finding the rightwords during writing requires much more floating attention.

      Proofreading while rewriting, structuring, or doing the thinking or creative parts of writing is a form of bikeshedding. It is easy to focus on the small and picayune fixes when writing, but this distracts from the more important parts of the work which really need one's attention to be successful.

      Get your ideas down on paper and only afterwards work on proofreading at the end. Switching contexts from thinking and creativity to spelling, small bits of grammar, and typography can be taxing from the perspective of trying to multi-task.

      Link: Draft #4 and using Webster's 1913 dictionary for choosing better words/verbiage as a discrete step within the rewrite.

      Linked to above: Are there other dictionaries, thesauruses, books of quotations, or individual commonplace books, waste books that can serve as resources for finding better words, phrases, or phrasing when writing? Imagine searching through Thoreau's commonplace book for finding interesting turns of phrase. Naturally searching through one's own commonplace book is a great place to start, if you're saving those sorts of things, especially from fiction.

      Link this to Robin Sloan's AI talk and using artificial intelligence and corpuses of literature to generate writing.

    1.  Meaningful discussions may be replaced with comments about the weather or other topics of light conversation. Doctors may spend less time with patients after their prognosis becomes poor. Why do others begin to withdraw?

      I chose this line and it peaked my interest because I bet there is a way to solve most cases of social death. First of all, spreading awareness to the subject will hopefully cause people to think more about their actions, such as withdrawing less from a dying family member.


  8. Jan 2022
    1. https://vimeo.com/232545219

      from: Eyeo Conference 2017


      Robin Sloan at Eyeo 2017 | Writing with the Machine | Language models built with recurrent neural networks are advancing the state of the art on what feels like a weekly basis; off-the-shelf code is capable of astonishing mimicry and composition. What happens, though, when we take those models off the command line and put them into an interactive writing environment? In this talk Robin presents demos of several tools, including one presented here for the first time. He discusses motivations and process, shares some technical tips, proposes a course for the future — and along the way, write at least one short story together with the audience: all of us, and the machine.


      Robin created a corpus using If Magazine and Galaxy Magazine from the Internet Archive and used it as a writing tool. He talks about using a few other models for generating text.

      Some of the idea here is reminiscent of the way John McPhee used the 1913 Webster Dictionary for finding words (or le mot juste) for his work, as tangentially suggested in Draft #4 in The New Yorker (2013-04-22)

      Cross reference: https://hypothes.is/a/t2a9_pTQEeuNSDf16lq3qw and https://hypothes.is/a/vUG82pTOEeu6Z99lBsrRrg from https://jsomers.net/blog/dictionary

      Croatian acapella singing: klapa https://www.youtube.com/watch?v=sciwtWcfdH4

      Writing using the adjacent possible.

      Corpus building as an art [~37:00]

      Forgetting what one trained their model on and then seeing the unexpected come out of it. This is similar to Luhmann's use of the zettelkasten as a serendipitous writing partner.

      Open questions

      How might we use information theory to do this more easily?

      What does a person or machine's "hand" look like in the long term with these tools?

      Can we use corpus linguistics in reverse for this?

      What sources would you use to train your model?


      • Andrej Karpathy. 2015. "The Unreasonable Effectiveness of Recurrent Neural Networks"
      • Samuel R. Bowman, Luke Vilnis, Oriol Vinyals, et al. "Generating sentences from a continuous space." 2015. arXiv: 1511.06349
      • Stanislau Semeniuta, Aliaksei Severyn, and Erhardt Barth. 2017. "A Hybrid Convolutional Variational Autoencoder for Text generation." arXiv:1702.02390
      • Soroush Mehri, et al. 2017. "SampleRNN: An Unconditional End-to-End Neural Audio Generation Model." arXiv:1612.07837 applies neural networks to sound and sound production
    1. Les ressources minérales

      Arg4: Les ressources minérales sont également très convoitées

      • les utilisations technologiques minerais: Cobalt, cuivre, nickel, or, diamant terres rares: cérium, scandium Nodules polymétalliques = hautes technologies (tel, odrinateurs)

      • jeu géopolitique dps 2010's fouilles Etat // monopole chinois Chine = 90% terres rares M

    2. Argument 4 : Les espaces maritimes et les points de passage stratégiques : des zones sensibles menacées

      Arg 4: Les choke points et les EM sont menacés Pirtarie maritime 2018: 201 attaques // navires marchands 4000 attaques depuis 20 ans selon l'IRIS 330M $ de rançons en 7 ans = financement activités criminelles Golfe de Guinée Golfe d'Aden Asie du Sud (Bangladesh) Asie du Sud Est (Détroit de Malacca) Amérique du Sud (Bolivie et Venezuela) = 2 régions les + touchés => next to routes maritimes

  9. Dec 2021
    1. Dissent by Justince Kennedy

      Opinions are partially correct they are actually: Opinion of the court: Brennan Concurring: Kenny Dissenting: Rehnquist, Stevens

    1. 7–2

      Decision was not 7-2... it was 5-4, ruling that that the Ohio school-voucher program did not violate the establishment clause of the First Amendment

  10. Nov 2021
    1. district

      incorrect - it was the state that set up the program (according to text book), not the district

  11. Oct 2021
    1. students could choose from among five options

      parents were the one's who got to choose among the options

    1. The argument on the part of the State of Maryland is not that the States may directly resist a law of Congress, but that they may exercise their acknowledged powers upon it,

      Wouldn't that be unconstitutional? To not abide to the laws enacting by congress? Isn't it up to the Judiciary to interpret the acknowledged powers?

    1. Can Congress take over an industry in order to prevent a union from striking?

      incorrect: not necessarily union but "Can the President constitutionally authorize the Secretary of Commerce to take possession and operate steel mills?"

    1. During the transatlantic slave trade, Europeans essentially enlisted the “help” of Africans to assist enslavement of their own peoples. They did this by giving small rewards of weapons, luxury goods, and winning wars against neighboring tribes. During initial explorations, “free” slaves guided the colonizers through the land and water. For any of this to occur, it was a plotted strategy using persuasion and even coercion. With the births of “mulattos” (children of Europeans and Africans), were bought back to Africa and infiltrated to continue the enslavement of African people. This was the beginning of the mental programming and trauma that has been engrained in the beings of POC and passed down for generations.



  12. Sep 2021
    1. Merino Vermont

      Não existem mais animais assim, apesar de com essas dobras produzir mais lã a tosquia desses animais é muito mais complicada o que gastava mais tempo, animais mais susceptíveis a parasitas, produziam mais suardas (sujeira) o que dava mais prejuízo, lã mais irregular.

    1. leader of a community project, sponsored by a voluntary society, on a c

      Community-based research



    1. The world opened up, and it was with great joy that I responded, "I know the thing what you speak exact now.Talk me more, plus, please, plus."

      i think he realizes that to speak a language doesnt only mean you have to know basic words. you have to undersatnd the flow of it the reasoning behind it. just becasue it sounds insulting doesnt mean that it is.

    2. You exhaust me with your foolishness and reward my efforts with nothing but pain, do you understand me?"

      does she mean im sick of you not understanding what i mean but understand what i say ?

    3. Over time, it became impossible to believe that any of us would ever improve. Fall arrived, and it rained everyday. It was mid-October when the teacher singled me out, saying, "Every day spent with you is like having acesarean section." And it struck me that, for the rst time since arriving in France, I could understand every wordthat someone was saying

      he is starting to realize maybe her words that are insulting dont mean what they sound like. in order to speak a language you have to know not everything means what is sounds like .

    4. My only comfort was the knowledge that I was not alone. Huddled in the smoky hallways and making the mostof our pathetic French, my fellow students and I engaged in the sort of conversation commonly overheard inrefugee camps

      atleast he isnt alone . seems like there is noone competing against eachother the teacher basically has it out for everyone

    5. Refusing to stand convicted on the teacher's charges of laziness, I'd spend four hours a night on my homework,working even longer whenever we were assigned an essay. I suppose I could have gotten by with less, but I wasdetermined to create some sort of an identity for myself. We'd have one of those "complete the sentence"exercises, and I'd fool with the thing for hours, invariably settling on something like, "A quick run around thelake? I'd love to. Just give me a minute to strap on my wooden leg." The teacher, through word and action,conveyed the message that, if this was my idea of an identity, she wanted nothing to do with it.

      trying really hard to make himself stand out. spending alot of time on his work maybe going above and beyond. its all for nothing though teacher doesn't seem amused

    1. L’article L. 111-4 du code de l’éducation dispose que les parents d’élèves participent, par leurs représentants, aux conseils d’école et aux conseils d’administration des établissements scolaires et aux conseils de classe.
  13. Aug 2021
    1. ZDB-ALT-160815-4

      DOI: 10.1016/j.devcel.2021.07.021

      Resource: (ZFIN Cat# ZDB-ALT-160815-4,RRID:ZFIN_ZDB-ALT-160815-4)

      Curator: @Naa003

      SciCrunch record: RRID:ZFIN_ZDB-ALT-160815-4

      What is this?

    2. ZDB-ALT-061204-4

      DOI: 10.1016/j.devcel.2021.07.021

      Resource: (ZFIN Cat# ZDB-ALT-061204-4,RRID:ZFIN_ZDB-ALT-061204-4)

      Curator: @Naa003

      SciCrunch record: RRID:ZFIN_ZDB-ALT-061204-4

      What is this?

    3. ZDB-ALT-060623-4

      DOI: 10.1016/j.devcel.2021.07.021

      Resource: (ZFIN Cat# ZDB-ALT-060623-4,RRID:ZFIN_ZDB-ALT-060623-4)

      Curator: @Naa003

      SciCrunch record: RRID:ZFIN_ZDB-ALT-060623-4

      What is this?

    1. Reviewer #4 (Public Review):

      This research fills a valuable gap in our understanding of neural cell populations. There is immense complexity in the neuron subtype landscape of the dorsal root gangion (DRG). Profiling had been previously conducted in mouse, but not within human. Providing the data and analysis of the human DRG is a valuable resource because substantial differences in cell populations and expression programs can exist between mouse and human. Any research that is focussed on the translational potential of a gene or pathway should verity its conservation across species.

      However, additional evidence is required to support a major claim of the manuscript: that there are mouse-specific and human-specific neuron subtypes. This claim is based on two major pieces of evidence. First, cluster comparison and co-clustering identify some cell populations that are species specific. Although this approach is suggestive, it is not definitive. Clustering separates populations of cells based major axes of variability, but those axes may not perfectly align across conditions or species. For example, excitatory cortical neurons may vary based upon cortical layer or whether they originate from the primary or secondary visual cortex. It is possible that one source of variation is stronger in one species and another source of variation is stronger in another species, leading to differences in clustering. The co-clustering may overcome of those limitations, but if the differences across species and experimental parameters are large enough, then even cells that come from the same population may not align. The in situ hybridization experiments also provide some support for species specificity, but it the overlap of specific markers could be confounded when the expression of individual marker genes evolve while the overall cell population remains consistent.

  14. Jul 2021

      I forget that data and visualization show up in entertainment as well. It is like this section says, you have to look outside of spreadsheets and text files to see that photos and status updates could also qualify. This just reminds me that data can be used in so many different ways and not just the more common ones you may think of off the top of your head. People like their entertainment so Facebook and OkCupid were most likely successful in using their data in that way.


      This is very true that it is easy to spout averages and numbers while lumping another human being in as a statistic. I agree that the numbers do represent individuals so the data should be approached that way too. If we start talking about the people being directly affected by it instead of just going by numbers and data points more people would probably relate to it and learn more about it. This link https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1410028703 shows both the percentage and the actual number of people affected. This way we can see that the percentage does not seem all that big but the actual number of people affected is thousands.


      I like the way that this was worded. I always thought of data as just numbers that you plug in and learn things from but that was all it was to me. The fact that it can be as complex or as simple as you want or as long or as short as you want means that each piece of data is unique to the person who created it. This has reminded me of the class and all of our final projects. We may be using some of the same software or tools to make our projects or we may even have a similar topic to someone else but each one is still going to turn out different. We will use the software and tools in our own way to represent the point we are making. This is something I have found throughout the whole course which is that even though each piece of digital humanities seems like there would only be one way to do it like data sets, there are actually so many interpretations and ways you can go with it.

  15. Jun 2021
  16. May 2021
    1. Prestige Sector 150 Noida

      Prestige Group Sector 150 in Noida is the latest project of a well-known real estate builder i.e Prestige group’s pioneer to yield one of the best residential property in Noida including 2/3/4 BHK luxury & lavish apartments with great amenities. There are lots of residential facilities such as Vaastu compliant design, double-height entrance lobby, Tower heights- G+19 & G+22, and facing green landscape. etc. Apart from that, you can also get state-of-the-art facilities such as a green area, swimming pool, clubhouse, children play area, power backup, etc.

    1. So

      Having identified the cases in which action is not voluntary, Ar. finishes this chapter by telling us what voluntary action is: it is those actions which are initially caused by us (find their origin in us) and in which we are aware of the particulars of the situation. He also argues that even actions caused by non-rational desires are in a sense voluntary.

      1111a22-1111b3 So, given that counter voluntary...to count these things as counter-voluntary.

    1. ZFIN: ZDB-ALT-110408-4

      DOI: 10.1016/j.devcel.2020.07.015

      Resource: (ZFIN Cat# ZDB-ALT-110408-4,RRID:ZFIN_ZDB-ALT-110408-4)

      Curator: @Naa003

      SciCrunch record: RRID:ZFIN_ZDB-ALT-110408-4

      What is this?

    2. ZFIN: ZDB-ALT-051223-4

      DOI: 10.1016/j.devcel.2020.07.015

      Resource: (ZFIN Cat# ZDB-ALT-051223-4,RRID:ZFIN_ZDB-ALT-051223-4)

      Curator: @Naa003

      SciCrunch record: RRID:ZFIN_ZDB-ALT-051223-4

      What is this?

    1. RRID:ZFIN_ZDB-ALT-130110-4

      DOI: 10.1016/j.cub.2020.06.086

      Resource: (ZFIN Cat# ZDB-ALT-130110-4,RRID:ZFIN_ZDB-ALT-130110-4)

      Curator: @scibot

      SciCrunch record: RRID:ZFIN_ZDB-ALT-130110-4

      What is this?

  17. Apr 2021
    1. Résultats ? Il semblerait que l’on ne parle pas de la même chose dans tous les contextes, à tous les types de destinataires.

      confirmation de l'hypothèse selon laquelle la désinformation doit aussi être étudiée sous l'angle de la perception de l'information selon les contextes de vie sociale. Cependant l'échantillon est faible, la généralisation est donc moins évidente.

    2. Ensuite parce que ces traces numériques sont bien laconiques par rapport aux commérages, parlementages ou ergotages que la réception de « fake news » est susceptible d’engendrer dans la vie réelle. Car après tout, est-ce parce qu’une « fake news » a été partagée par des milliers d’internautes que chacun d’entre eux y a cru ? Que ce soit sur Facebook ou dans un groupe WhatsApp, au téléphone ou au comptoir d’un café, les réactions des individus face aux informations qu’ils reçoivent peuvent être multiples et variées. byronv2/Flickr, CC BY-SA Ne se peut-il pas au contraire que certains l’aient diffusée pour signaler sa fausseté comme ce fut par exemple le cas pour l’infox ayant désigné Emmanuel Macron comme étant gay ? Ou encore, pour la détourner et s’en moquer auprès de leurs amis ? Difficiles à appréhender, ces questions nécessitent d’aller à la recherche des significations cachées derrière certaines données numériques. Voilà pourquoi, avant de partir du postulat d’un public naïf et passif, il devient crucial d’étudier davantage les circuits conversationnels de la réception d’informations pour lesquels il existe à ce jour un manque drastique de connaissances.

      second argument en faveur de l'idée selon laquelle la désinformation n'est pas seulement le fruit d'une diffusion massive de la fake news.

    3. Tout d’abord, parce que pris à l’état brut, ces nombres absolus ne veulent pas dire grand-chose. Par exemple, il a été montré que les 20 « fake news » les plus partagées pendant la campagne électorale américaine de 2016 ont suscité 8,7 millions de likes, partages et commentaires sur Facebook. A priori vertigineux, ce chiffre, qui a soulevé beaucoup d’inquiétudes auprès du grand public en raison de son importante couverture médiatique, a bien moins fière allure si on le met perspective avec le nombre total des interactions des utilisateurs américains du réseau social sur la même période car il ne représente alors plus que 0,006 % !

      premier argument démontrant qu'une diffusion qui peut paraitre massive n'est pas nécessairement le signe d'une désinformation effective.

    1. Reviewer #4 (Public Review):

      In this paper, the author uses an impressive comparative dataset of 172 species to investigate the relationship between intraspecific genetic diversity and census (actual) population size. They find that even when they use phylogenetic comparative methods, the relationship between neutral diversity and population size is much weaker than predicted by theory and that selection on linked sites is unlikely to explain this difference. The paper convincingly demonstrates that the paradox of variation first pointed out by Lewinton in the 70s remains paradoxical.

      This paper is exceptionally strong in multiple ways. First, it is statistically rigorous; this is particularly impressive given that the paper uses methods and data from multiple fields (genomics, macroecology, conservation biology, macroevolution). This is the most robust estimate of the relationship between diversity and population size that has been published to date. Second, it is conceptually rigorous: the paper clearly lays out the various hypotheses that have been put forth over the years for this pattern as well as the logic behind these. The author has done a great job at synthesizing some complex debates and different types of data that are potentially relevant to resolving it. Third, it is exceptionally well-written. I sincerely enjoyed reading it. Overall, I think this is a major contribution to this field and though the paper does not resolve the challenge laid down by Lewinton, I think these analyses (and curated data/computational scripts) will inspire other researchers to dig into this question.

      I do however, have some suggestions as to how this paper could be strengthened.

      First, in phylogenetic comparative methods (PCMs) there has been a persistent confusion as to what phylogenetic signal is relevant -- when applying a phylogenetic generalized linear model with a phylogenetically structured residual structure (which the author does here), one is estimating the phylogenetic structure in the errors and not the traits themselves. The comparative analysis are well-done and properly interpreted but at some points in the text, particularly when addressing Lynch's conjecture that PCMs are irrelevant for coalescent times and comments/analysis on the appropriateness of Brownian motion as a model of evolution, that there is some conceptual slippage and I suggest that author take a close look and make sure their language is consistent. Strictly speaking the PGLM approach doesn't assume that the underlying traits are purely BM -- only that the phylogenetic component of the error model is Brownian. As such running the node-height test on the both the predictors and the response variable separately -- while interesting and informative about the phylogenetic patterns in the data (including the shift points you have observed) isn't really a test of the assumptions of the phylogenetic regression model. It is at least theoretically plausible (if not biologically) that both Y and X have phylogenetic structure but that the estimated lambda = 0 (if for instance, Y and X were perfectly correlated because changes in Y were only the result of changes in X). To be clear, I am fine with the PGLM analysis you've done and with the node-height test; I just don't think that the latter justifies the former.

      One note about the ancestral character reconstruction: I think it is a fine visualization and realize you didn't put too much emphasis on it but strictly speaking the ASR's were done under a constant process model and therefore they wouldn't provide evidence for (a probably very real shift) between phyla. I think it was a good idea to run the analyses on the clade specific trees (particularly given how deep and uncertain the branches dividing the phyla are) but I just don't think you could have gotten there from the ASR.

      I am not convinced that the IUCN RedList analysis helps that much here and in my view, you might consider dropping this from the main text. This is for two reasons: 1) species may be of conservation concern both because they have low abundance in general and/or that their abundance is known to have experienced a recent decline -- distinguishing these two scenarios is impossible to do with the data at hand; and 2) there is of course a huge taxonomic bias in which species are considered; I don't think we can infer anything ecologically relevant from whether a species is listed on the RedList or not (as you suggest regarding the lynx, wolverine, and Massasauga rattlesnake) except that people care about it.

      This is not really a weakness but I find it notable that recombination map length is correlated with body size. I realize this is old news but I was left really curious as to a) why such a relationship exists; and b) whether the mechanism that generates this might help explain some of the patterns you've observed. I would be keen to read a bit more discussion on this point.

    1. Entry ID: 370-620d

      The tone wasn't awkward and felt more like someone talking than the other poems. They used repetition well.

    2. Entry ID: 421-caea

      This one was one of the few that had a more dramatic and entertaining telling of what it's like to live in the strange world of the pandemic. I think this one is my favorite.

    1. Reviewer #4 (Public Review):

      The authors analysed flavinylation across different species. They analysed impressive number of 31.910 prokaryotic genomes. They mined flavinylation associated gene clusters using a bioinformatic approach. They define five different protein classes responsible for transmembrane electron transfer. Moreover, they predicted and validated flavinylation of two domains with unknown functions (by ApbE). Unfortunately, the vast majority of predictions made in this study were not experimentally validated. It is therefore very difficult to judge the reliability of predictions, proposals and claims made in the manuscript.

    1. Reviewer #4 (Public Review):

      Higashi et al. provide a new "Brownian ratchet" model for DNA loop extrusion mechanism by cohesin, a member of SMC protein family complexes. Based on previous works on crystal structures, cryo-EM structures, and DNA-protein crosslinking experiments, they shed light on two HEAT-repeat DNA binding modules on cohesin - Scc2-head and Scc3-hinge - and their relationships. They hypothesized that the association between Scc2-head and Scc3-hinge modules were dissociated and Scc2-head released DNA upon ATP hydrolysis, driving DNA slipping. By performing FRET experiments, they found that Scc2 and hinge modules indeed come close only in ATP-bound "Gripping" state, while hinge and Scc3 are always close to each other. Therefore, they suggest that, for DNA loop extrusion model, 1) upon ATP binding to the head domains, both Scc2-head and Scc3-hinge modules grip DNA, 2) when ATPs are hydrolyzed, Scc2-head module releases DNA so that DNA-associating Scc3-hinge module pulls DNA depending on stochastic Brownian motion of Scc3-hinge module, then 3) both Scc2-head and Scc3-hinge modules release DNA and go back to the state 1). This "Brownian ratchet" model also provides an explanation of how cohesin entraps DNA by opening the gate between Smc3 and Scc1, which also nicely explains the known facts regarding Scc1 cleavage-dependent DNA release and in vitro behaviors of single cohesin molecules that topologically bound to DNA. In addition, by performing computational modeling, they showed that the Brownian ratchet model well fits all previously reported in vitro loop extrusion assays by cohesin and condensin, making their model rigid and reliable.

      Their model is mostly well supported by data, but several detailed points need to be explained or clarified.

      1) In Figure 2C FRET experiments, proximity of Scc3-C and Scc2-N does not seem to be drastically increased in Gripping state compared to the case of hinge and Scc2-N. This could be because the FRET pairs (Scc3-C and Scc2-N) are still far. If the authors could label internal part in Scc3, this could solve the problem. In addition, if Scc3-C and Scc2-N are always close to each other irrespective of Gripping state, the authors should consider this fact in their modeling.

      2) Major differences between topological loading and loop extrusion is kleisin-gate opening and head gate passage. Even if kleisin-gate wouldn't be opened, DNA should be released after head opening like in the topological loading. In case it happens, DNA and Scc1 would be tangled and it seems to be difficult to come back to next gripping state again. It would be helpful to add the explanation of why such tangling DNAs do not have to be considered in the model.

      3) In the manuscript line 338, the authors mention "After DNA dissociation from the Scc3-hinge module, there is a time without tight contact between the cohesin ring and the DNA loop." However, both in Figure 3B and 4F, it seems that head-Scc2 always associates with DNA. This could be discrepancy. The authors should clarify the point if certain free time without any contact to DNA is assumed in the modeling.

      4) Generally, initial DNA bending is the most challenging part in loop extrusion models. Especially in Figure 3B-a, such a bent DNA seems to be impossible if we consider the persistence length of DNA is 50 nm. The authors should discuss how DNA loop extrusion could be initiated.

    1. • que cette assistance ne donne lieu à aucune contrepartie directe ou indirecte ;• que l’aide apportée ait un but exclusivement humanitaire
  18. Mar 2021
    1. Reviewer #4 (Public Review):

      This article describes the results of an impressive meta-analysis based on a high number of published effects investigating the relationship between sexual dimorphism in men and their mating and reproductive success.

      The article is very well written and covers a vast amount of literature.

      Most of my comments are not corrections, but rather subjective ideas on how the text could be restructured. In my opinion, the article is clearly written and the rationale behind research questions and methodology is well explained. I appreciate how the authors present the entire analysis, adding multiple robustness tests and presenting their results in an easy to follow manner (which was not easy, due to the complexity of the methodology implemented).

      I cannot criticise any major issues in this manuscript.

      The main outcomes of the article not only present a robust test of previously mixed results, but also provide a strong recommendation of how future studies should be conducted (i.e. how to use mating success proxies, and what samples to include).

    1. Reviewer #4 (Public Review):

      The goal of the manuscript was to add to the research on the rates of success of African American/Black PI in their pursuit of NIH funding. The authors specifically addressed variability in funding levels of NIH Institutes and Centers(ICs). The authors were successful in identifying that there are differentials rates of award rates by IC. The authors describe that topic choice was not associated with funding after accounting for IC assignment which vary in their funding rates.

    1. Reviewer #4 (Public Review):

      Using a transgenic line of Platynereis, in which GFP is expressed under the control of cis-regulatory elements for r-opsin, the study isolates r-opsin expressing cells from the head (eye photoreceptors) and trunk region (a population of segmentally repeated r-opsin expressing cells associated with the parapodia) by FACS. Subsequent RNA-Seq establishes that both populations of cells express genes for all components of the rhabdomeric phototransduction cascade, while the population of trunk sensory cells additionally expresses genes encoding proteins involved in mechanosensation. Using heterologous expression in a mammalian cell line, it is shown that the Platynereis r-opsin responds to blue light via coupling to Gαq suggesting that it mediates photoresponses via a canonical rhabdomeric phototransduction cascade. Transcriptomic analysis of an r-opsin mutant created by TALEN mediated gene editing then reveals that expression levels of the mechanosensory Atp2b channel are modulated by protracted exposure to blue light, a response abolished in the mutant. Behavioral analysis further suggests that undulatory movements of the worms are equally altered under these illumination conditions. Taken together this suggests that the r-opsin expressing trunk sensory cells act as both photo- and mechanoreceptors and that their mechanosensory properties are modulated in response to light. In combining the transcriptomic analysis of cell types with experimental studies of gene function and behavioral analyses, this study provides exciting new insights into the evolution of sensory cells. Several prior studies have found co-expression of photosensory and mechanosensory proteins in sensory cells of various bilaterians, and comparative studies suggested that photo- and mechanosensory cells may share a common evolutionary origin. However, the current study goes far beyond these findings in establishing a direct functional link between photo-and mechanosensation in a population of sensory cells suggesting that these sensory cells function as multimodal cells and that their mechanosensory properties are altered in response to light. Furthermore, the behavioral data (based on a novel machine-learning based tool of analysing the animals' movement) suggest that these cells have a behaviorally relevant function. Because r-opsin was found to be expressed in mechanoreceptors not only in lophotrochozoans (including Platynereis) but also in ecdysozoans and vertebrates (although functional studies are lacking here) and r-opsins belong to a large family of opsins, almost all of which are responsive to light, the present study suggests that r-opsins may have an ancestral bilaterian role in modulating mechanosensory function in response to light (in addition to their purely photosensory role in the photoreceptors of the eyes). Light-independent functions of r-opsin as recently revealed in Drosophila may, thus, be secondarily derived.

      The study is very carefully conducted and well presented. The only minor flaw is that in its present form, the discussion of the evolutionary implications of the finding lacks in clarity and specificity. The authors here often refer ambiguously to an "ancient" or "ancestral" role of r-opsins without specifying the lineage referred to (ancestral for lophotrochozoans? bilaterians? eumetazoans? metazoans?). The discussion should, therefore be revised with an explicit phylogenetic framework in mind.

    1. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 100; 0.1 µM: 65; 0.8 µM: 18; 1 µM: 15

      AssayResultAssertion: Abnormal

      Approximation: Exact cisplatin concentrations and assay result values not reported; values estimated from Figures 4b and 4d.

    2. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 80; 0.1 µM: 52; 0.8 µM: 18; 1 µM: 5

      AssayResultAssertion: Abnormal

      Approximation: Exact cisplatin concentrations and assay result values not reported; values estimated from Figures 4b and 4d.

    3. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 102; 0.1 µM: 65; 0.8 µM: 18; 1 µM: 10

      AssayResultAssertion: Abnormal

      Approximation: Exact cisplatin concentrations and assay result values not reported; values estimated from Figures 4b and 4d.

    4. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 85; 0.1 µM: 40; 0.8 µM: 20; 1 µM: 13

      AssayResultAssertion: Abnormal

      Approximation: Exact cisplatin concentrations and assay result values not reported; values estimated from Figures 4b and 4d.

    5. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 90; 0.1 µM: 60; 0.8 µM: 15; 1 µM: 15

      AssayResultAssertion: Abnormal

      Approximation: Exact cisplatin concentrations and assay result values not reported; values estimated from Figures 4b and 4d.

    6. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 65; 0.08 µM: 50; 0.8 µM: 30; 8 µM: 20

      AssayResultAssertion: Abnormal

      Approximation: Exact Olaparib concentrations and assay result values not reported; values estimated from Figures 4a and 4c.

    7. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 102; 0.1 µM: 85; 0.8 µM: 55; 1 µM: 25

      AssayResultAssertion: Normal

      ControlType: Normal; wild type PALB2 cDNA

      Approximation: Exact cisplatin concentrations and assay result values not reported; values estimated from Figures 4b and 4d.

    8. Viability assayPALB2 variants were introduced into B400 cells using mCherry-pOZC expression vector and flow cytometry for Cherry-red was performed to select for cells expressing PALB2. Sorted cells were plated in 96-well plates and exposed to increasing amounts of Olaparib or cisplatin and incubated for a period of 5 days. Presto Blue (Invitrogen) was added and incubated for 1–2 hours before measuring fluorescence intensity on a Cytation 3 microplate reader (BioTek).

      AssayGeneralClass: BAO:0003009 cell viability assay

      AssayMaterialUsed: CLO:0036938 tumor-derived cell line

      AssayDescription: Transient expression of wild type and variant mCherry-tagged PALB2 cDNA constructs in Trp53 and Palb2-null mouse cell line; exposure to increasing concentrations of cisplatin for 5 days induces interstrand-crosslink DNA damage; cell survival is determined by measuring fluorescence intensity after staining with a cell viability reagent.

      AssayReadOutDescription: Percent cell survival after treatment with cisplatin

      AssayRange: %

      AssayNormalRange: Cisplatin resistance levels comparable to that of cells expressing wild type PALB2; no numeric threshold given

      AssayAbnormalRange: Not reported

      AssayIndeterminateRange: Not reported

      ValidationControlPathogenic: 0

      ValidationControlBenign: 0

      Replication: Not reported

      StatisticalAnalysisDescription: Not reported

    9. WT-PALB2 was associated with robust formation of damage-induced RAD51 foci, whereas the four variants were associated with defective foci formation (Fig. 3d, e).

      AssayResult: 1

      AssayResultAssertion: Abnormal

      Approximation: Exact assay result value not reported; value estimated from Figure 3e.

    10. Results for individual PALB2 variants were normalized relative to WT-PALB2 and the p.Tyr551ter (p.Y551X) truncating variant on a 1:5 scale with the fold change in GFP-positive cells for WT set at 5.0 and fold change GFP-positive cells for p.Y551X set at 1.0. The p.L24S (c.71T>C), p.L35P (c.104T>C), p.I944N (c.2831T>A), and p.L1070P (c.3209T>C) variants and all protein-truncating frame-shift and deletion variants tested were deficient in HDR activity, with normalized fold change <2.0 (approximately 40% activity) (Fig. 1a).

      AssayResult: 0.8

      AssayResultAssertion: Abnormal

      StandardErrorMean: 0.14

    11. A total of 84 PALB2 patient-derived missense variants reported in ClinVar, COSMIC, and the PALB2 LOVD database were selected

      HGVS: NM_024675.3:c.104T>C p.(Leu35Pro)


      AssayResult: 81

      AssayResultAssertion: Not reported

      PValue: Not reported

      Approximation: Exact assay result value not reported; value estimated from Figure 6C.


      AssayResult: 8

      AssayResultAssertion: Indeterminate

      PValue: Not reported


      AssayResult: 76.21

      AssayResultAssertion: Indeterminate

      PValue: 0.0001

      Comment: Exact values reported in Table S3.

    4. To this end, 44 missense variants found in breast cancer patients were identified in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar) and/or selected by literature curation based on their frequency of description or amino acid substitution position in the protein (Supplemental Table S1).

      HGVS: NM_024675.3:c.136C>T p.(His46Tyr)

    1. While 3 VUS (p.W912G, p.L961P, and p.G1043D) had a dramatic impact on the percentage of cells showing RAD51 foci, 2 VUS (p.G937R and p.L947S) displayed a more minor effect.

      AssayResult: 19.52 foci/cell

      AssayResultAssertion: Indeterminate (described as "minor effect")

      Range: 0 - 70

      Comment: Exact values reported in "Source Data" file

    2. While 3 VUS (p.W912G, p.L961P, and p.G1043D) had a dramatic impact on the percentage of cells showing RAD51 foci, 2 VUS (p.G937R and p.L947S) displayed a more minor effect.

      AssayResult: 15.80 foci/cell

      AssayResultAssertion: Indeterminate (described as "minor effect")

      Range: 0 - 74

      Comment: Exact values reported in "Source Data" file

    3. While 3 VUS (p.W912G, p.L961P, and p.G1043D) had a dramatic impact on the percentage of cells showing RAD51 foci, 2 VUS (p.G937R and p.L947S) displayed a more minor effect.

      AssayResult: 13.96 foci/cell

      AssayResultAssertion: Abnormal

      Range: 0 - 69

      Comment: Exact values reported in "Source Data" file

    4. While 3 VUS (p.W912G, p.L961P, and p.G1043D) had a dramatic impact on the percentage of cells showing RAD51 foci, 2 VUS (p.G937R and p.L947S) displayed a more minor effect.

      AssayResult: 3.19 foci/cell

      AssayResultAssertion: abnormal

      Range: 0 - 32

      Comment: Exact values reported in "Source Data" file

    5. While 3 VUS (p.W912G, p.L961P, and p.G1043D) had a dramatic impact on the percentage of cells showing RAD51 foci, 2 VUS (p.G937R and p.L947S) displayed a more minor effect.

      AssayResult: 1.24 foci/cell

      AssayResultAssertion: Abnormal

      Range: 0 - 25

      Comment: Exact values reported in "Source Data" file

    6. Following exposure to IR, the average number of RAD51 foci was scored in cyclin-A- and YFP-PALB2-expressing S-phase cells

      AssayResult: 24.90 foci/cell

      AssayResultAssertion: Normal

      Range: 1 - 90

      ControlType: Normal; wild type PALB2 cDNA

      Comment: Exact values reported in "Source Data" file

    7. To further assess the impact of the 5 selected VUS on PALB2, we examined whether they affected the accumulation of RAD51 at IR-induced DSBs by measuring the formation RAD51 foci.

      AssayGeneralClass: BAO:0000450 fluorescence microscopy

      AssayMaterialUsed: CLO:0003684 HeLa cell

      AssayDescription: Transient expression of wild type and variant PALB2 cDNA constructs in HeLa cells following PALB2 siRNA knockdown; exposure ionizing radiation induces DNA damage; RAD51 foci formation is measured by immunofluorescence microscopy 4 h after irradiation

      AssayReadOutDescription: Number of RAD51 foci per S-phase cell (determined by cyclin A detection)

      AssayRange: foci/cell

      AssayNormalRange: RAD51 foci numbers comparable to that of cells expressing wild type PALB2; no numeric threshold given

      AssayAbnormalRange: RAD51 foci numbers comparable to that of cells expressing empty vector; no numeric threshold given

      AssayIndeterminateRange: Not reported

      ValidationControlPathogenic: 0

      ValidationControlBenign: 0

      Replication: 3 independent experiments

      StatisticalAnalysisDescription: Not reported

    8. Source Data

      AssayResult: 83.16

      AssayResultAssertion: Not reported

      ReplicateCount: 2

      StandardErrorMean: 0.2

      Comment: Exact values reported in “Source Data” file.

    9. Source Data

      AssayResult: 67.82

      AssayResultAssertion: Not reported

      ReplicateCount: 2

      StandardErrorMean: 10.97

      Comment: Exact values reported in “Source Data” file.

    10. Source Data

      AssayResult: 44.9

      AssayResultAssertion: Not reported

      ReplicateCount: 2

      StandardDeviation: 9.75

      StandardErrorMean: 6.89

      Comment: Exact values reported in “Source Data” file.

    11. We, therefore, analyzed the effect of 48 PALB2 VUS (Fig. 2a, blue) and one synthetic missense variant (p.A1025R) (Fig. 2a, purple)29 on PALB2 function in HR.

      HGVS: NM_024675.3:c.110G>A p.(R37H)

    1. Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.1

      AssayResultAssertion: Abnormal

      ReplicateCount: 19

      StandardErrorMean: 0.1

      Comment: This variant had loss of function of peak current (<10% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1. (Personal communication: A. Glazer)

    2. we selected 73 previously unstudied variants: 63 suspected Brugada syndrome variants and 10 suspected benign variants

      HGVS: NM_198056.2:c.1058C>T p.(Thr353Ile)

    1. We then applied the p53 functional assay on blood samples sent to our laboratory for TP53 molecular analysis (NGS screening of the 11 exons complemented by QMPSF). Molecular and functional analyses were performed in parallel, in double blind conditions.

      AssayGeneralClass: BAOCL:20:0010044 targeted transcriptional assay

      AssayMaterialUsed: CL:2000001 peripheral blood mononuclear cell from patients

      AssayDescription: Comparative transcriptomic analysis using reverse transcription to compare peripheral blood mononuclear cells of patients with wild type or pathogenic TP53 variants in the context of genotoxic stress induced by doxorubicin treatment. p53 RNA levels were evaluated and expressed as a percentage of the mean levels obtained for the three wild-type TP53 individuals.

      AdditionalDocument: PMID: 23172776

      AssayReadOutDescription: The p53 mRNA levels were expressed as a ratio of the normal values obtained for 3 TP53 wild-type control individuals.

      AssayRange: UO:0000187 the p53 RNA levels were evaluated and expressed as a percentage of the mean levels obtained for three wild-type TP53 individuals.

      AssayNormalRange: >65%

      AssayAbnormalRange: <65%

      AssayIndeterminateRange: N/A

      AssayNormalControl: wild type TP53

      AssayAbnormalControl: LFS patient cells

      ValidationControlPathogenic: 8 individuals had seven distinct TP53 variants which could be considered as likely pathogenic or pathogenic based on their ClinVar classification or their truncating nature.

      ValidationControlBenign: 51 individuals had no detectable germline TP53 variant

      Replication: at least two wells were seeded per patient (treated and untreated) and duplicates or triplicates were performed whenever possible.

      StatisticalAnalysisDescription: Differentially expressed genes between doxorubicin-treated and untreated cells were arbitrarily defined using, as filters, a P<0.01 and fold-change cutoffs >2 or <2, for up and down regulation, respectively. The resultant signal information was analyzed using one-way analysis of variance (ANOVA, P= 0.001), assuming normality but not equal variances with a Benjamani–Hochberg correction for multiple comparisons using three groups: controls, null, and missense mutations.

      SignificanceThreshold: P=0.001

      Comment: statistical analysis and P value from previous publication.

    1. Reviewer #4 (Public Review):

      Coombs et al. aimed to establish a pharmacological tool to distinguish calcium-permeable (CP) AMPA receptors (AMPAR) from calcium impermeable AMPA receptors unambiguously. Towards this end, the authors examined the effects of intracellularly applied NASPM, PhTx-433, PhTx-74, and spermine. The authors showed that NASPM completely blocked outward glutamate-evoked currents with a desensitization blocker, cyclothiazide, from outside-out patch membranes from HEK cells expressing GluA1. In contrast, spermine and PhTx-433/74 partially blocked the outward currents in a voltage-dependent manner (Figure 1). TARPg-2 co-expression reduced potencies of spermine and NASPM, and altered shapes of their conductance-voltage relationship (Figure 2) as well as various kinetics of GluA1, including decay kinetics and recovery kinetics (Figure 3). Further, the authors showed that NASPM blocked GluA1 co-expressed with one of the AMPAR auxiliary subunits, TARPg-2, g-7, CNIH2 GSG1L (Figure 4). Finally, the authors showed that NASPM blocked AMPAR-mediated mEPSC events at +60 mV, but not -70mV, in cultured cerebellar stellate neurons from GluA2 knockout mice. Overall, this manuscript provides high-quality data and critical information about TARPg-2, GluA1, and GluA2 knockout mice.

      This provides a solid analysis of GluA1, TARPg-2, 7, CNIH2, GSG1L, and GluA2 knockout neurons. However, it remains unclear whether intracellular NASPM allows an unambiguous functional measure of CP-AMPAR, especially considering many combinations of AMPARs and auxiliary subunits, e.g., GluA1-4 with splicing isoforms, six TARPs, four CNIHs, GSG1L and CKAMP44, etc.


      The experimental design to evaluate drugs and receptors with outside-out patch membranes and a piezoelectric device provides the highest-resolution analysis and meaningful information.

      Both experiments and analyses are rigorous and of high quality. However, it remains unclear if intracellular NASPM allows an unambiguous functional measure of CP-AMPAR.


      Because the authors tested a limited combination of receptors and auxiliary subunits, it is difficult to conclude whether NASPM blocks all CP-AMPAR unambiguously.

      Slopes of the conductance-voltage relationships are changed upon TARPg-2 co-expression or different concentrations of NASPM.

    1. RRID:ZFINID:ZDB-ALT-190104-4

      DOI: 10.7554/eLife.63595

      Resource: (ZFIN Cat# ZDB-ALT-190104-4,RRID:ZFIN_ZDB-ALT-190104-4)

      Curator: @evieth

      SciCrunch record: RRID:ZFIN_ZDB-ALT-190104-4

      What is this?