1. Oct 2025
  2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape
    14
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    pmc.ncbi.nlm.nih.gov/articles/PMC12548782/
  3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Small-Molecule Control of Super-Mendelian Inheritance in Gene Drives
    2
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    pmc.ncbi.nlm.nih.gov/articles/PMC7587219/
  4. www.sciencedirect.com www.sciencedirect.com
    Cancer cells co-opt an inter-organ neuroimmune circuit to escape immune surveillance
    70
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    sciencedirect.com/science/article/pii/S0092867425011298
  5. www.sciencedirect.com www.sciencedirect.com
    SARM1 senses dsDNA to promote NAD+ degradation and cell death
    4
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    sciencedirect.com/science/article/pii/S0092867425011262
  6. www.sciencedirect.com www.sciencedirect.com
    Adrenergic signaling coordinates distant and local responses to amputation in axolotl
    8
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    sciencedirect.com/science/article/pii/S0092867425011250
  7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)
    1
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    pmc.ncbi.nlm.nih.gov/articles/PMC12546807/
  8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Sequestration of plant defenses by spotted lanternfly (Lycorma delicatula) and effects on avian predators
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    pmc.ncbi.nlm.nih.gov/articles/PMC12546476/
  9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Interferon alpha-induced uPAR expression on monocytes as a potential source of increased soluble uPAR in patients with SLE at high risk of developing organ damage
    5
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    pmc.ncbi.nlm.nih.gov/articles/PMC12540527/
  10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    A circular RNA derived from the ryanodine receptor 2 locus controls cardiac hypertrophy and calcium handling
    3
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    pmc.ncbi.nlm.nih.gov/articles/PMC12540953/
  11. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Porphyromonas gingivalis Type 9 Secretion System Promotes Dysregulation of Vascular Smooth Muscle Cell Plasticity With Perturbed TGF‐β/Smad Signaling
    8
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    pmc.ncbi.nlm.nih.gov/articles/PMC12541887/
  12. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Progressive Changes Between Thalamic Nuclei and Cortical Networks Across Stimulus–Response Learning
    9
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    pmc.ncbi.nlm.nih.gov/articles/PMC12547845/
  13. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Propylene–Ethylene Copolymer Covalent Adaptable Networks Synthesized by Resonance‐Stabilized, Radical‐Based Reactive Processing with Excellent Elevated‐Temperature Creep Resistance
    2
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    pmc.ncbi.nlm.nih.gov/articles/PMC12548940/
  14. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Revealing the Effect of Pendant Identity on the Electrochemistry of Non‐Conjugated Redox Active Polymers
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    pmc.ncbi.nlm.nih.gov/articles/PMC12548945/
  15. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Wrap it up: myelination of transplanted neurons for repair
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    pmc.ncbi.nlm.nih.gov/articles/PMC12540482/
  16. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Multimodal reprogramming of the tumor microenvironment by MMR and dual checkpoint blockade in hepatocellular carcinoma models
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    pmc.ncbi.nlm.nih.gov/articles/PMC12546120/
  17. Local file Local file
    Untitled document
    7
    2. b0a04gl 25 Oct 2025
      partitioning

      quick takeaway

      Partitioning = performance tuning (single node)

      Sharding = scaling out (multiple nodes)

      Replication = redundancy or read scaling (same data copied)

      so, 3 separate ideas:

      partition = split table

      shard = split dataset across DBs

      replica = copy dataset across DBs

    3. b0a04gl 25 Oct 2025
      consistency

      before vs after transaction, db is in valid state.. and still all external parts linking to db data is valid ( lilke triggers, indexes, foreign keys )

    4. b0a04gl 25 Oct 2025
      read uncommitted: can read dirty data• read committed: only committed data, no dirty reads• repeatable read: same reads during txn, may allow phantom rows• serializable: strictest, prevents all anomalies, lowest concurrency

      1. read uncommitted

        dirty reads, non repeatable reads, phantom reads

      2. read committed

        non repeatable reads, phantom reads and no dirty reads

      3. repeatable reads

        phantom reads and not nonrepeatable reads, no dirty reads

      4. serializable :

        no phantom, nonrepeatable, dirty reads

    6. b0a04gl 25 Oct 2025
      indexing

      1. primary - data stored in index order - 1step lookup - main access key

      2. secondary - points to primary index fields - 2 step lookup - extra filters / sorts

      3. covered - stores full needed cols - 1 step lookup - readheavy endpoints

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  18. web.archive.org web.archive.org
    Animal Bytes: Aldabra tortoise
    1
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    web.archive.org/web/20000301100126/http://www.seaworld.org/animal_bytes/aldabra_tortoiseab.html
  19. journal.iistr.org journal.iistr.org
    2290
    1
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    journal.iistr.org/index.php/BIKK/article/download/418/323/2290
  20. www.youtube.com www.youtube.com
    The Trump model is failing BADLY
    1
    1. stopresetgo 25 Oct 2025

      for - US Republican governance failure - blue states provide welfare to red states - youtube - Dave Pakman - blue states vs red states - The US survives Trump's mismanagement because the US is a welfare state in which the blue states, with far better social policies is forced to bail out the tax-friendly red states - The red states keep choosing the same dysfunctional policies, and keep having to get bailed out by the blue states - In this sense, the federal government is being exploited to keep red states doing the same thing

      youtube - Dave Pakman - blue states vs red states US Republican governance failure - blue states provide welfare to red states
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    youtube.com/watch
  21. socialsci.libretexts.org socialsci.libretexts.org
    7.2: Communication and Friends
    3
    1. Miriamb 25 Oct 2025
      Failure to perform or respond to friendship-maintenance tasks can lead to the deterioration and eventual dissolution of friendships. Causes of dissolution may be voluntary (termination due to conflict), involuntary (death of friendship partner), external (increased family or work commitments), or internal (decreased liking due to perceived lack of support) (Bleiszner & Adams, 1992).

      Sometimes friendships can also deteriorate due to internal conflict on one side, or personal issues, I've had reasons to end relationships, while I also have been the one who has been theoretically "dumped" in a relationship.

    2. Miriamb 25 Oct 2025
      The number of friends we have at any given point is a situational factor that also affects whether or not we are actually looking to add new friends.

      I think this also is affected by the situation you're in as well, I currently feel incredibly lonely because I struggle to get to the point where I feel comfortable or ready to hang out with someone or be 'real' friends as I say, instead of just acquaintances.

    3. Miriamb 25 Oct 2025
      friendship may develop between two people who work out at the same gym. They may spend time with each other in this setting a few days a week for months or years, but their friendship might end if the gym closes or one person’s schedule changes.

      I feel like this is a situational friend, like if you go to class with someone and you go to study group for that class, but after the class ends we part ways.

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    socialsci.libretexts.org/Bookshelves/Communication/Introduction_to_Communication/Communication_in_the_Real_World_-_An_Introduction_to_Communication_Studies/07:_Communication_in_Relationships/7.02:_Communication_and_Friends
  22. 5a2cca12.jissen-recipe2.pages.dev 5a2cca12.jissen-recipe2.pages.dev
    5.3. 一歩進んだ型ヒントの活用 - Python実践レシピ 第2版 ドキュメント
    5
    5. takanory 25 Oct 2025
      *kwargs引数にTypedDictの型を付

      その手前で、そもそもTypedDictで必須とかオプションとか指定できるようになったので、この話をする必要があるかなと

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    5a2cca12.jissen-recipe2.pages.dev/05_type_hint/2_using_type_hints
  23. socialsci.libretexts.org socialsci.libretexts.org
    7.1: Foundations of Relationships
    2
    1. Miriamb 25 Oct 2025
      Circumscribing

      creating a boundary is good, but not always, it can mean that someone has recognized something they are uncomfortable with about their situation, and want to create space but aren't sure how, which could also relate to avoiding.

    2. Miriamb 25 Oct 2025
      Intensifying

      A lot of the time, or maybe just with me, I can see myself rushing into this stage to get to the integrating stage, but usually it's because i'm so excited to be around the person and to have a 'someone.' which reminds me of how a happy dog is so excited for you to be homme they run up to you and jump on you at the door, and you're so overwhelmed you push them away.

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    socialsci.libretexts.org/Bookshelves/Communication/Introduction_to_Communication/Communication_in_the_Real_World_-_An_Introduction_to_Communication_Studies/07:_Communication_in_Relationships/7.01:_Foundations_of_Relationships
  24. publish.obsidian.md publish.obsidian.md
    Welcome to World History 1! - World History 1 - The Ancient and Medieval World - Obsidian Publish
    4
    1. JosieTalaro2008 25 Oct 2025
      The Ka'ba in the Masjid Al-Haram in Mecca, during the 2018 Hajj season.Muhammad's revelations continued and were written down in what became the Qur'an. The focus on social justice, submission (islam) to god, and monotheism echoed elements of Judaism and Christianity, and Muhammad's followers described their new faith as a continuation of a tradition that began with Abraham and accepted the Hebrew prophets, including Jesus.

      I just learned about The Ba'ba. It is called "The Holiest of Holies." It was built during the Old Testament times when God told them exactly how to build it. They have had to rebuild it, but it has real gold, and the doors (covered in the cloth) are pure gold.

    3. JosieTalaro2008 25 Oct 2025
      The lack of imperial endorsement weakened Theodoric's daughter and her son, and in 535, Justinian invaded Italy

      This is so soon after Theodoric died. Many times, in history when there is a new ruler(s) they get weakened down and invaded.

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    publish.obsidian.md/worldhistory1/Chapter+10/10.2+-+Abbasids
  25. publish.obsidian.md publish.obsidian.md
    9.7 - Sui Dynasty - World History 1 - The Ancient and Medieval World - Obsidian Publish
    1
    1. JosieTalaro2008 25 Oct 2025
      Emperor Wen and his son, Emperor Yang, ruled until 618 and set the stage for the Tang Dynasty

      Random thought but I feel like there are many emperors in China that rule for very long periods of time.

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    publish.obsidian.md/worldhistory1/Chapter+9/9.7+-+Sui+Dynasty
  26. www.amazon.co.jp www.amazon.co.jp
    Amazon.co.jp: 創価学会教学要綱 : 「創価学会教学要綱」刊行委員会: Japanese Books
    1
    1. Kyukancho 25 Oct 2025

      On the Similarities Between the SGI Doctrinal Text and Professor Miyata’s Paper

      Issue 1.

      Lately, on social media, there have been discussions suggesting that The Book on the Doctrinal Foundation of the SGI, published immediately after President Daisaku Ikeda’s passing, closely resembles several papers written by Professor Koichi Miyata. I also share this impression.

      Mr. Suda, former Vice Leader of the SGI Study Department, makes the following claim in his Letter to President Harada regarding the “Teaching Outline”: “I have heard that the main individuals behind the creation of the Teaching Outline were Mr. Miyata and Mr. Kanno, both professors emeritus at Soka University. From their standpoint as researchers, however, they have shown a marked tendency to defer to the Minobu sect of Nichiren Buddhism, which represents the mainstream of academic Nichiren studies, seemingly out of fear of criticism from that sect. As a result, the entire Teaching Outline can be seen as having been assimilated to the doctrines of the Minobu sect.” On the other hand, the SGI Men’s Division Doctrinal Office officially denied any involvement of Professors Miyata and Kanno, stating on the Seikyo Shimbun website that “this claim is factually incorrect, and neither Professor Miyata nor Professor Kanno were members of the publication committee.” (Reference: Seikyo Online) In response, I conducted a careful comparative analysis of The Book on the Doctrinal Foundation of the SGI and Professor Miyata’s papers, employing not only a close textual reading but also the analytical functions of a natural language processing AI (ChatGPT) to ensure objectivity. The results revealed a level of similarity far beyond my expectations—one that can hardly be overlooked.

      SGI is a large religious organization with approximately twelve million members in Japan and around the world, and The Book on the Doctrinal Foundation of the SGI appears to have become the organization’s core doctrinal text following President Ikeda’s passing. In this regard, Suda, in his Letter to President Harada regarding the “Teaching Outline”, points out that “Even now, it seems that the ‘Teaching Outline’ is being followed in articles in the Soka Shimpo and Seikyo Shimbun newspapers, as well as in the commentary on The Object of Devotion for Observing the Mind, and I think that this is a dangerous situation.” Therefore, this issue is of considerable importance for the future of the SGI’s doctrinal study.

      At the same time, it should be emphasized that the purpose of this paper is not to criticize any individual personally, but rather to ensure the accuracy and scholarly transparency of doctrinal materials.To maintain the credibility of SGI’s doctrinal studies, it is increasingly necessary to clarify bibliographical sources and secure philosophical consistency in future publications.

      Professor Koichi Miyata, “The Structure and Issues of Udana Nichiko’s Honzon Ryakuben” (2017–2018, pp. 38–39)

      “The passage ‘The doctrine of three thousand realms in a single moment of life is found in only one place, hidden in the depths of the “Life Span” chapter of the essential teaching of the Lotus Sutra’ (WND I: 30) can be interpreted, from the overall context, to mean that the doctrine of the true “three thousand realms in a single moment of life” is hidden in the text of the “Life Span” chapter—that is, in the passage revealing enlightenment countless kalpas ago.” The Book on the Doctrinal Foundation of the SGI (Kyōgaku Yōkō, 2023, p. 70) “The great sage Nichiren states in The Opening of the Eyes, ‘The doctrine of three thousand realms in a single moment of life is found in only one place, hidden in the depths of the “Life Span” chapter of the essential teaching of the Lotus Sutra’ (WND I: 30). He perceived that, at the very depths of the chapter The Life Span of the Thus Come One, which expounds enlightenment countless kalpas ago, the essential doctrine of three thousand realms in a single moment of life in the Lotus Sutra is revealed.” Commentary The Book on the Doctrinal Foundation of the SGI makes no reference to Miyata’s paper. Yet both the book and Miyata’s interpretation share a distinctive view: that the passage describing “enlightenment countless kalpas ago” conceals the doctrine of three thousand realms in a single moment of life. In the Book on the Doctrinal Foundation of the SGI, this interpretation is presented as if it were Nichiren’s own insight, raising serious concerns regarding the proper attribution of scholarly authority. In this respect, the book may be seen as raising a significant issue of academic integrity. Incidentally, the traditional SGI interpretation—found in the third President Daisaku Ikeda’s works such as The Lecture on the Orally Transmitted Teachings II (pp. 32–33)—is that this doctrine is concealed in the passage “Originally I practiced the bodhisattva way” (Burton Watson, The Lotus Sutra, p. 268) in the Life Span chapter. From this perspective, The Book on the Doctrinal Foundation represents a problematic departure from that established tradition.

      In this respect, Suda, former Vice Leader of the SGI Study Department (2024, p. 53), criticizes this book, stating that “Although The Book on the Doctrinal Foundation was published immediately after Ikeda’s passing and claims to have been supervised by him, its content significantly deviates from Ikeda’s ideological framework during his lifetime. Thus, the assertion that the book was under Ikeda’s supervision can be seen as an attempt to misuse his name rather than a genuine reflection of his doctrinal stance.”

      Furthermore, in his paper, Professor Miyata rejects the traditional interpretation that locates the doctrine in the passage “Originally I practiced the bodhisattva way” (Burton Watson, The Lotus Sutra, p. 268) and offers his own alternative view. The following section examines the possibility that this reinterpretation found its way into The Book on the Doctrinal Foundation of the SGI.

      Reference

      Ikeda, D. (1968) Gogikuden Kōgi [Lecture on the Oral Transmission of the Teachings, vol. 2]. Tokyo: Soka Gakkai.

      Miyata, K. (2017–2018). The Structure and Issues of Udana Nichiko’s Honzon Ryakuben. Available at: http://hw001.spaaqs.ne.jp/miya33x/honzonryakuben.pdf [Accessed 24 October 2025].

      Nakamura, M. (2025) Kyôgaku Yōkō to Moto Sōka Daigaku Kyōju no Ronbun no Hikaku Kensō [A Comparative Examination of the Book on the Doctrinal Foundation of SGI and Papers by Former Soka University Professors]. Available at: https://jikatsu.net/wp-content/uploads/2025/10/4f92b9e0e1e7f83a456ee2c6d262748b.pdf [Accessed 24 October 2025].

      Soka Gakkai. (1999). The Writing of Nichiren Daishonin. Tokyo: Soka Gakkai.

      Soka Gakkai (2023) Kyōgaku Yōkō [The Book on the Doctrinal Foundation of SGI]. Tokyo: Soka Gakkai. Available at: https://www.amazon.co.jp/dp/4412017028 (Accessed: 24 October 2025).

      SGI Study Department (2024). “The Teaching Outline” is the Culmination of the Soka Renaissance. Available at: https://www.seikyoonline.com/article/603E8EF7E9B96D20AF2920005F5C1C6B [Accessed 10 October 2025].

      Suda, H. (2024). Letter to President Harada regarding the “Teaching Outline”, 12 September 2024. file_20240930-185744.pdf [Accessed 24 October 2025].

      Suda, H. (2024). A Critique of the Book on Doctrinal Foundation of Soka Gakkai from the Perspective of Buddhist History: In Light of Nichiren Buddhism as the Global Religion Taught by SGI President Daisaku Ikeda. Available at: https://jikatsu.net/download/1st-english-edition-a-critique-of-the-book-on-doctrinal-foundation-of-soka-gakkai-from-the-perspective-of-buddhist-history/

      Watson, B. (1993). The Lotus Sutra. New York: Columbia University Press.

      #SGI #Soka Gakkai #Daisaku Ikeda
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  27. wordpress.org wordpress.org
    Print My Blog – Print, PDF, & eBook Converter WordPress Plugin
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  28. socialsci.libretexts.org socialsci.libretexts.org
    1.2: Basic Principles of Human Communication
    1
    1. vemcafee 25 Oct 2025
      In this image, the “dog” is on the left side, and the “cat” is on the right side.

      Figure 1.2.3 does not have the "dog" on the left side, and the "cat" on the right side. Which feels like an ironic typo given the subject matter of the text.

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    socialsci.libretexts.org/Bookshelves/Communication/Interpersonal_Communication/Interpersonal_Communication_-_A_Mindful_Approach_to_Relationships_(Wrench_et_al.)/01:_Introduction_to_Human_Communication/1.02:_Basic_Principles_of_Human_Communication
  29. www.mrtvarevolucia.net www.mrtvarevolucia.net
    Manifest Mŕtvej Revolúcie
    4
    1. filip.bartek 24 Oct 2025
      V duchu postmoderného myslenia je jeho strata väčším hriechom, než jeho korekcia.

      Proč si autorstvo myslí, že postmoderní myšlení implikuje toto relativní hodnocení ztráty a korekce názoru?

    2. filip.bartek 24 Oct 2025
      špecializovaných povolaní

      Napadá mě jen "logoterapeut" a "filosofický poradce". Odhadl jsem správně, jaká povolání mělo na mysli autorstvo? Jaká povolání napadla nebo napadají vás?

    3. filip.bartek 24 Oct 2025
      dôstojnosť jednotlivca netkvie v plnom bruchu, ale v jeho integrite

      Autorstvo zde, zdá se, předpokládá, že filosofování vede ke kladnému hodnocení integrity; k určité "křesťanské" (pro momentální neschopnost najít vhodnější označení) etice. Rád bych souhlasil a zároveň doufám, že směr etického snažení navržený tímto manifestem by měl smysl i v případě, že by filosofování mohlo vést i k méně obvyklým etickým závěrům. Jinými slovy, nepovažuji filosofování za samospásné. Podobně riskantní, mimochodem, mi připadá spoléhat se na evoluční výhody "křesťanské" etiky.

      philosophy
    4. filip.bartek 24 Oct 2025
      S výnimkou akademickej pôdy (kde debatné súboje aj tak často označujeme za neužitočnú zábavku neužitočných ľudí) a úzko špecializovaných povolaní (ktoré sú napádané podobným spôsobom)

      Praktická filosofie (sokratovské rozhovory atp.) je další takovou výjimkou.

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  30. www.pap.pl www.pap.pl
    Bieganie częściowo naprawia to, co psują fast foody | Polska Agencja Prasowa SA
    1
    1. pyxelr 24 Oct 2025
      Bieganie częściowo naprawia to, co psują fast foody
      • Running can counteract some negative effects of an unhealthy, Western-style diet, according to researchers from University College Cork.
      • The study found that exercise restores key metabolites linked to mental well-being and balances crucial hormones disrupted by a diet high in sugar, fat, and processed foods.
      • Rats fed high-calorie “cafeteria diet” foods showed major disturbances in gut metabolism, with 100 out of 175 metabolites significantly altered; running partially restored balance, especially for anserine, indole-3-carboxylate, and deoxyinosine.
      • Physically active rats on the same poor diet had normalized levels of insulin and leptin compared to sedentary ones, showing exercise helps regulate hormonal balance.
      • The body activated compensatory hormonal mechanisms, such as changes in GLP-1 and PYY levels, to stabilize metabolism under poor dietary conditions.
      • The study also linked exercise to improved neurogenesis (formation of new neurons) in the hippocampus, but only when paired with a healthy diet—junk food appeared to suppress this regenerative effect.
      • Despite running’s benefits, researchers emphasized that good nutrition remains essential for full brain health and mental performance.
      • The findings offer insight into how exercise may protect mental well-being even amid widespread consumption of processed foods.
      health running
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    pap.pl/aktualnosci/bieganie-czesciowo-naprawia-co-psuja-fast-foody
  31. onedrive.live.com onedrive.live.com
    Mestrado Economia da Escola Austríaca - OneDrive
    1
    1. Gandrada 24 Oct 2025

      Duzentos anos atrás, antes do advento do capitalismo, o status social de um homem permanecia inalterado do princípio ao fim de sua existência: era herdado dos seus ancestrais e nunca mudava. Se nascesse pobre, pobre seria para sempre; se rico – lorde ou duque –, manteria seu ducado, e a propriedade que o acompanhava, pelo resto dos seus dias

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    onedrive.live.com/
  32. nmoer.pressbooks.pub nmoer.pressbooks.pub
    Chapter 41: Gathering Reliable Information
    1
    1. Israel_Carrasco 24 Oct 2025
      If you are writing a research paper about reality television shows, you will need to use some reality shows as a primary source, but secondary sources, such as a reviewer’s critique, are also important.

      What kinds of sources, from which perspective, you need.

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    nmoer.pressbooks.pub/english1101/chapter/chapter-31-gathering-reliable-information-mytext-cnm/
  33. bookshelf.vitalsource.com bookshelf.vitalsource.com
    Language and Cultural Practices in Communities and Schools
    2
    1. Melanie.Hartman29 24 Oct 2025
      Leaving aside the question of whether exercises and worksheets are satisfying for children, it is the case that these are solitary activities, and much of the time in schools children are expected to engage in these activities on their own, neither receiving nor providing help that is similar to how children often engage in chores in middle-class families.

      I see my own students more engaged when they are in groups and we are working together. I have put two big tables together in my classroom and started getting away from the solitary exercises because my special education students are already behind in social skills and understanding roles in group activities. I do this because their peers are so far ahead of them academically that they can not engage or contribute to their group the same and then the groups accuse the students of cheating when really they just cannot comprehend what the class is doing. I am trying to help the students learn social cues and academics with the activities that are centered around group work.

    2. Melanie.Hartman29 24 Oct 2025
      . There are therefore parallels between the solitary chores children were often asked to do at home and the solitary exercises they engaged in at school.

      This really hit home for me because at home during my childhood everything was done in solitary, from getting ready for the day to chores and even meals. We as a family never ate together except on special occasions. If I got all of my chores, homework or whatever it might need to be taken care of done as soon as possible so I could go to my friends’ homes where we had dinner together and family engagement. I did not mind if I needed to help the family with more work.

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    bookshelf.vitalsource.com/reader/books/9780429943768
  34. www-taylorfrancis-com.ezp2.lib.umn.edu www-taylorfrancis-com.ezp2.lib.umn.edu
    e-Reader | AI and the Music Industry | Transforming Production, Platfo
    19
    1. Grahamh26 24 Oct 2025
      The case demonstrates the significance ofcontinuously seeking new tools and techniques to enhance musicpublishing. Practitioners can benefit from Diana’s approach of experi-menting with different AI tools and incorporating them selectively tomaintain a unique sound and efficient business operations.

      Artists can decide how many tools and which tools they wish to use, depending on their skills, priorities, and amount of time available.

    2. Grahamh26 24 Oct 2025
      connection in music, even when integrating advanced technologieslike AI. Students should understand that while AI can enhance effi-ciency, the authenticity and originality of content are crucial for audi-ence engagement (Wei et al., 2022).2. Strategic Use of AI: Diana’s selective use of AI tools for specific tasks,such as data management and analytics, illustrates the importance ofstrategically adopting technology to enhance workflow without com-promising creative integrity. This teaches students to critically evaluatethe tools they use and ensure they align with their creative goals(Hampe & Schwabe 2001).3. Adaptability and Continuous Learning: Diana’s approach high-lights the need for continuous learning and adaptability in therapidly evolving field of music publishing. Students should beprepared to stay updated with the latest technological advancementsand be willing to experiment and learn from their experiences

      While AI tools are being widely integrated in industries such as music, it is very important not to overuse them, otherwise the human element and critical thinking skills required for these complex tasks are completely lost.

    3. Grahamh26 24 Oct 2025
      The evolving capabilities of AI in natural language pro-cessing and automated content generation might open new avenues forinnovative music marketing and fan engagement strategies. Diana plans tointegrate AI more deeply into her operations through advanced tools forpredictive analytics and automated content management systems, increasingefficiency and scaling her operations to reach a global audience effectively.

      AI makes promotion of music through analytics and social media easier than ever.

    4. Grahamh26 24 Oct 2025
      Ensuring that AI does not compromise the emotional authenticity of musicremains a critical challenge, and Diana emphasizes the importance of usingAI to support rather than overshadow human creativity.

      The age of balanced AI use like Diana's is already coming to an end, as AI tools continually get implemented everywhere.

    5. Grahamh26 24 Oct 2025
      Diana faced challenges in aligning AI toolswith existing workflows and ensuring compatibility. However, throughtargeted training and continuous learning, these challenges were addressed.The initial investment in AI systems was a hurdle, but the long-term benefitsof increased efficiency and reduced errors justified the expenditure.

      These AI tools are difficult to learn with a steep learning curve, but the efficiency boost outweighs this.

    6. Grahamh26 24 Oct 2025
      Diana’s success with AI tools under-scores the importance of balancing technological advancements with main-taining the emotional and artistic integrity of music. Her work serves as anexample of how AI can be used to support rather than replace humancreativity in the music industry

      Diana's use of AI does not undermine the human aspect of it; rather, it makes the process more efficient and keeps the balance between technological assistance and human input.

    7. Grahamh26 24 Oct 2025
      providing adequate trainingand resources is essential for fostering intrinsic motivation and ensuring thatusers feel competent and capable of using new tools. This approach notonly enhances proficiency but also builds confidence in using AI technolo-gies (Ezinwa et al. 2024). The continuous upgrading of IT infrastructure tosupport the latest AI technologies is another crucial aspect of developingthe ability to use AI tools effectively.

      This chapter does not mention energy use or environmental impact at all.

    8. Grahamh26 24 Oct 2025
      AI’s capacity to provide real-time analytics aligns with the findings ofWatson and Leyshon (2022), who emphasize the importance of timely andaccurate data in the music industry. Real-time analytics allow for agiledecision- making, enabling music publishers like Diana to adjust their strate-gies based on current market performance and trends. This capability isparticularly valuable in a fast-paced industry where timing can significantlyimpact the success of promotional campaigns.

      The music industry is very fast-paced, so AI tools are able to help artists like Diana adapt fast to new market trends.

    9. Grahamh26 24 Oct 2025
      AI tools have opened up significant opportunities for Diana, particularly indata management and analytics. These tools enable her to access real-timeanalytics on how songs are performing globally, allowing her to make quickdecisions on promotional strategies. AI also provides the capability tomanage artists’ portfolios and rights across different countries and legalenvironments seamlessly

      AI tools also have access to global analytics that weren't previously easily accessible or centralized in one place.

    10. Grahamh26 24 Oct 2025
      Diana highlighted her motivation by saying:My primary driver is the desire to streamline the complex pro-cesses of music publishing and rights management to ensure thatartists receive their fair share of earnings. AI tools enable us toautomate many of the labour-intensive tasks involved, from track-ing song plays across digital platforms to managing royalties andrights distributions efficiently.

      The way that Diana uses AI for music production is very ethical, simply making complex processes more efficient, and ensuring fair royalty splits.

    11. Grahamh26 24 Oct 2025
      AI-driven financial tools provide significant benefits in terms of optimiz-ing revenue streams and ensuring timely royalty payments (Barata &Coelho, 2021). The ability to analyze market trends and consumer prefer-ences using AI aligns with Diana’s strategies for maximizing revenue andenhancing the commercial success of her music projects

      AI financial tools also ensure maximum revenue by analyzing market trends.

    12. Grahamh26 24 Oct 2025
      Boomplay’s analytics features have providedinsights into popular songs, influencing the release strategy for albums andsingles. By leveraging AI tools for data analysis, Diana ensures that hermarketing efforts are targeted and effective, resulting in higher streamingnumbers and increased revenue.

      An AI tool called Boomplay reveals analytics of popular songs, with the ability to provide a playbook of what release strategies made it successful, so that it can be used for releasing your own music.

    13. Grahamh26 24 Oct 2025
      On the publishing front, AI tools help track music plays acrossdifferent platforms, ensuring accurate royalty collection and distribution.AI- driven analytics have also provided predictive insights that guide produc-tion decisions, enhancing the commercial success of her projects

      Additionally, AI tools track music plays across all platforms, helping to distribute royalties fairly. AI analytics also help guide decisions and help musicians like Dians remain successful in today's industry.

    14. Grahamh26 24 Oct 2025
      AI tools have significantly impacted Diana’s music production and publish-ing processes. A pivotal moment was the training session conducted byVladimir Philippov, CEO of Heaven 11, which enhanced her team’s capabili-ties in using AI tailored for the music industry. The Heaven 11 platformoffers features for music distribution and rights management, crucial forartists aiming to earn from their creativity and have their music distributedglobally

      Heaven 11 is an AI platform that includes tools for music distribution and copyright management, a pivotal part to solving the problem of copyright management with music generated by AI.

    15. Grahamh26 24 Oct 2025
      The adoption of AI tools in Diana’s operations reflects broader trends inthe music industry, where AI is used to enhance various business processes.AI technologies like those used by Diana streamline administrative tasksand financial management, which are crucial for maintaining operationalefficiency. This trend is consistent with findings in Chapter 2, where theimpact of AI on the music industry is discussed extensively in a literaturereview.

      Adoption of AI tools is becoming widespread in all industries, for people like Diana, these tools free up time and allow her to focus on her music more.

    16. Grahamh26 24 Oct 2025
      Diana Hopeson integrates AI tools extensively in her operations as both anartist and a music publisher. She utilizes Google’s business tools for manag-ing interactions and tracking engagements, which streamlines administrativetasks and enhances efficiency. The Oze app is pivotal for her accountingprocesses, simplifying financial transactions and client interactions.

      AI has allowed Diana to work more efficiently and better understand the business metrics of her music.

    17. Grahamh26 24 Oct 2025
      She also attended a needs assess-ment class at the Ghana Institute of Management and Public Administrationand graduated with a master’s degree in philosophy from the University ofEducation, Winneba, in 2019. Diana’s dedication to her craft and continuouslearning have been pivotal in her journey, allowing her to adapt to theevolving music industry and maintain her relevance over the decades.

      She continued her education, getting a master's degree decades later into her career. Her dedication has allowed her to grow and adapt through the decades.

    18. Grahamh26 24 Oct 2025
      In March 2021, she was named among the Top30 Most Influential Women in Music by the 3Music Awards Women’sBrunch.In addition to her music career, Diana has played an instrumental role inshaping the music industry in Ghana. She served as the president of theMusicians Union of Ghana (MUSIGA

      She is a very influential figure in the music industry.

    19. Grahamh26 24 Oct 2025
      Diana Hopeson, also known as Diana Akiwumi, has been a significantfigure in the Ghanaian music industry since 1991. With 11 albums and 15singles released, she has made a name for herself as a gospel artist and apioneering music publisher.

      She is a well-established artist who has been in the industry for several decades.

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    www-taylorfrancis-com.ezp2.lib.umn.edu/reader/read-online/50ab2d6d-4830-4681-b319-33841bbb5cd6/book/pdf
  35. legrandcontinent.eu legrandcontinent.eu
    Mario Draghi : le Fédéralisme pragmatique
    1
    1. FrancoisCarmignola 24 Oct 2025

      C'est dit ! Il n'y a plus que la fédération et les pays n'ont plus rien à dire. Ni l'Italie, ni la France, ni l'Allemagne. L'ex de Goldman Sachs a parlé.

      Cette Europe là doit mourir et le plus tôt sera le mieux. Vae victis.

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    legrandcontinent.eu/fr/2025/10/24/mario-draghi-federalisme-pragmatique/
  36. pubs.aeaweb.org pubs.aeaweb.org
    The Impact of High School Financial Education:Evidence from a Large-Scale Evaluation in Brazil
    2
    2. parisaashoka 24 Oct 2025
      Brazil is divided into 26 states and a Federal District. The Federal District andfive states were part of the study, including three of the most populous and devel-oped states (São Paulo, Minas Gerais, and Rio de Janeiro), and two states (Cearáand Tocantins) that represent less developed areas of Brazil.

      most developed states, so maybe it is a certain type of students. maybe they have more opp to experiment w monetary investments and decisions, maybe they have seen recently started earning good amounts so they are curious and have the means to try out things. maybe students in poorer areas would be more cautious and disciplined due to diff financial goals?

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    pubs.aeaweb.org/doi/pdfplus/10.1257/app.20150149
  37. jeppestricker.substack.com jeppestricker.substack.com
    The Synthetic Knowledge Crisis
    1
    1. anrood 24 Oct 2025
      This is how the synthetic knowledge crisis unfolds. Not through outright falsehoods, but through a gradual weakening of the criteria that distinguish knowing from appearing to know.

      How do we identify the folks who are just faking it until the make it with synthetic knowledge.

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    jeppestricker.substack.com/p/the-synthetic-knowledge-crisis
  38. www.henrikkarlsson.xyz www.henrikkarlsson.xyz
    When is better to think without words?
    1
    1. mrcolbyrussell 24 Oct 2025
      my personal experience, which is that whenever I write what I think about a subject, it always turns out that my thoughts do not hold up on paper? No matter how confident I am in my thoughts, they reveal themselves on the page as little but logical holes, contradictions, and non sequiturs.

      Pre-emptive note: it seems logical that the very next paragraph references Paul Graham directly; my very next move was going to be to connect the writer's self-reported experiences here with Graham on writing, had it not been the case that that job was already done.

      As I've said before: I'm not in the same boat with Graham on the writing-is-thinking stance. The difficulty with seeing my own thoughts fixed in words after an initial pass is not in their inadequacy or their being a source of illusory and fleeting comfort with said illusion now made stark for everyone to see, but a mixture of (a) a lack of "punch", and/or (b) the places where a dishonest broker could exploit the yet-to-be shored up wording to suggest/assert the presence of some weakness in thought regarding the thing being argued for, where such purported weakness would be the real illusion.

      The lack of satisfaction I feel when trying to capture my thoughts in English (my first language) isn't too far off from the lack of satisfaction at being able to comprehensively express a simple declarative in another language only because of the fact that don't know, say, the right word for the noun in that language. It doesn't lead me to agonize about how well-supported my observations about a backhoe are just because I've never been introduced to the word for backhoe in that language.

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    henrikkarlsson.xyz/p/wordless-thought
  39. www.biorxiv.org www.biorxiv.org
    How serially homologous neuroblasts produce different temporal cohorts along the Drosophila larval body axis
    4
    1. EMBOpress 24 Oct 2025

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

      Learn more at Review Commons

      Reply to the reviewers

      Manuscript number: RC-2025-03130

      Corresponding author(s): Ellie S. Heckscher

      [The "revision plan" should delineate the revisions that authors intend to carry out in response to the points raised by the referees. It also provides the authors with the opportunity to explain their view of the paper and of the referee reports.

      • *

      The document is important for the editors of affiliate journals when they make a first decision on the transferred manuscript. It will also be useful to readers of the reprint and help them to obtain a balanced view of the paper.

      • *

      If you wish to submit a full revision, please use our "Full Revision" template. It is important to use the appropriate template to clearly inform the editors of your intentions.]

      1. General Statements [optional]

      We thank all three reviewers for their feedback on the paper. Reviewers stated that the paper was of broad interest to developmental biologists and neurobiologists. However, we want to ensure that our two key conceptual contributions are clear. We clarify in the following paragraph and include a revised abstract. We will update the introduction and paper to better reflect these advances. We also attach a supplemental table 1, which was inadvertently omitted from the previous submission due to our error.

      The first advance is that serially homologous neuroblasts follow a multimodal production model: In principle, stem cells can divide any number of times, from once to throughout the entire lifetime of the animal. And, on each division, a stem cell can generate either a proliferative daughter cell or a post-mitotic neuron. Together, therefore, there is a vast potential number of neurons any given stem cell could produce. From the literature on the vertebrate neocortex, we had the following models: (1) "random production" model, in which any number of neurons could be made by a stem cell; or (2) "unitary production" model, in which the same number of neurons (~eight) is produced by a stem cell regardless of context. Our data revealed an entirely new "multi-modal production" model, which could not have been predicted by prior literature. In the context of serially homologous neuroblasts arrayed along the Drosophila larval body axis, sets of five to seven neurons are produced in increments of one, two, or four. These increments correspond to units called temporal cohorts. Temporal cohorts are lineage fragments, or small set of neurons that share synaptic partners, making them lineage-based units of circuit assembly. Thus, in a multimodal production model, serially homologous stem cells produce different numbers of temporal cohorts depending on location. Our data advance the field by showing that stem cells produce circuit-relevant sets of neurons by adding or omitting temporal cohorts from a region, to meet regional needs.

      Key to understanding the second advance is that there are multiple types of temporal cohorts: early-born Notch OFF, early-born Notch ON, late-born Notch OFF, and late-born Notch ON. One temporal cohort type, the early-born Notch OFF, is found in every segment, which we term the "ubiquitous" temporal cohort. The other temporal cohort types can be produced in various combinations depending on the stem cell division pattern and segmental location. In a result that could not have been predicted, we found that the ubiquitous temporal cohorts are refined both in terms of the number of neurons and their connectivity, depending on body region. In contrast, when other temporal cohort types are produced, they are not refined to the same degree.

      The impact of this work is to advance how we think about stem cell-based circuit assembly.

      2. Description of the planned revisions

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

      *Summary: The study by Vasudevan et al intends to address how serially homologous neural progenitors generate different numbers and types of neurons depending on their location along the body axis. *

      Investigation of full repertoire of neurogenesis for these progenitors necessitates a precise ability to track the fates of both progenitors and their neuronal progeny making it extremely difficult in vertebrate paradigm. The authors used NB3-3 in the developing fly embryo as a model to investigate the full extent of the flexibility in neurogenesis from a single type of serially homologous stem cell. Previous work showed NB3-3 generates neurons including lateral interneurons that can be positively labeled by Even-skipped, but detailed characterization of the NB3-3 lineage mainly focused on 3 segments during embryogenesis. The authors defined the number of EL neurons in all segments of the central nervous system in early larvae after the completion of circuit formation and carried out clonal analyses to determine the proliferation pattern of NB3-3. They described the failure to express Eve in Notch OFF/B neurons as a new mechanism for controlling the number of EL neurons and PCD limits EL neurons in terminal segments.

      • *Thank you! In addition to the contributions highlighted by the reviewer, we also showed that all segments have ELs with early-born molecular identities, but only a subset have ELs with late-born identities (Figure 5). And we showed that early-born temporal cohorts can be mapped into different circuits depending on the axial region (Figure 6).

      *Major comments: The authors performed careful analyses of the NB3-3 lineage using EL neurons. My main concerns are limited applicability of their findings and lack of mechanisms as how NB3-3 generate various numbers of EL neurons. Their findings are exclusively relevant to the NB3-3 lineage despite their effort in highlighting that other NB lineages also generate temporal cohorts of EL neurons. *

        Thank you for raising these points. First, to clarify, as Reviewer 4 also mentioned, NB3-3 is the only lineage to produce EL neurons. We will ensure that this is clearly stated in the revised text.

      We agree that our findings might not apply beyond the NB3-3 lineage. However, as this is the first study of its kind, it is impossible to know a priori to what extent the concepts surfaced here are generalizable. In our opinion, this speaks to the novelty and impact of the study. A contribution is to motivate a need for future studies. We will make this explicit in our updated manuscript in the Discussion section.

        Our manuscript provides cell biological mechanisms that explain how stem cells give rise to different numbers of EL neurons in different regions, including stem cell division duration and type, neural cell death, identity gene expression, and differentiation state. If the reviewer is interested in genetic or molecular mechanisms, this is an interesting point. Several prior studies using NB3-3 as a model (e.g., Tsuji et al., 2008, Birkholz et al., 2013, Baumgardt et al., 2014) have elucidated the genetic regulation of specific cell biological processes. However, these studies provided fragmentary insight with regard to serially homologous stem cell development along the body axis. A comprehensive understanding of how the NB3-3 lineage, or any other serially homologous lineage, develops was missing. This is what makes our study both novel and needed. Without an analysis that both examines every segment and assays multiple cell biological processes, we would have missed key insights: that there is a ubiquitous type of temporal cohort, and that neurons within the ubiquitous temporal cohort are selectively refined post-mitotically (See General Statements for more details).

      *I disagreed with their conclusion that failure to express Eve as a mechanism for controlling EL neuron numbers when Eve serves as the marker for these neurons. Are there any other strategy to assess the fates and functions of these cells beside relying solely on Eve expression? I am not familiar with the significance of Eve expression on the functions of these neurons. Is it possible to perform clonal analyses of NB3-3 mutant for Eve and see if these neurons adopt different functionalities/identities? *

      • We agree that if Eve were only a marker, our logic would be circular. The Eve homolog, Evx1/2 is crucial for vertebrate interneuron cell fate (Moran-Rivard et al., 2001). Eve is essential for motor neuron morphology in Drosophila *(Fujioka et al., 2003). Eve is critical in Even-skipped for both the morphology and function of Even-skipped interneurons (Marshall et al., 2022). Hence, ELs cannot fully differentiate or incorporate into circuits without Eve. Thus, we use the failure to express Eve as a mechanism for controlling EL number. Furthermore, our prior study (Wang et al., 2022) showed that NB3-3 Notch OFF neurons in A1 that fail to express Eve have small soma and "stick-like" neurite projections that are typical of undifferentiated neurons. We will be sure to add this context to the revised manuscript.

      *If NB3-3 in the SEZ continually generate GMCs based on the interpretation of clonal analyses and depicted in Fig. 2A, why is the percent of clones that are 1:0 virtually at or near 100% from division 6-11 shown in 2G? *

      Admittedly, the ts-MARCM heat-shock-based lineage tracing experiments are inherently messy. This is part of the reason why we included the G-TRACE lineage tracing experiments in Figure 3. In Figure 3E, one can see that the number of Notch ON/A neurons in SEZ3 is equal to the number of ELs in that segment (Figure 1E). This is a second independent method that supports the assertion that in SEZ, NB3-3 stem cells continually generate GMCs. Given this independent observation, it leads us to believe that this question is most likely explained by technical issues inherent in ts-MARCM. These issues include but are not limited to: cell-type specific accessibility/success of heat-shock induced recombination; variably effective RNAi; and idiosyncrasies of the EL-GAL4 line used to detect recombination events. If the question is why the data is only reported for division 6-11, the answer is that the ts-MARCM dataset, which included SEZ clones only used later heat-shock time points (line from the paper "for the SEZ-containing dataset, inductions started at NB3-3's 5th division"). Along with this revision plan, we will include Supplemental Table 1, which was inadvertently omitted from the previous submission due to our error. This table shows all of the clonal data. We will include a section in the discussion to describe limitations in ts-MARCM.

      The authors also indicate that NB3-3 in the abdomen directly generate Notch OFF/B cells that assume EL neuronal identity. In this scenario, shouldn't the percent of 1:0 clones be 100% in later divisions in Fig. 2G? Based on the number of clones in abdomen shown in Fig. 2E, I cannot seem to understand how the authors come to the percent of 1:0 clones shown in Fig. 2G

        We agree that one might expect the 12th division to be 100% 1:0 clones in the abdomen. Unfortunately, we didn't sample that late in our dataset, and even when we sampled the inferred 11th division, we had a small sample size (Figure 2E). Other studies suggest that NB3-3 in the abdomen directly generates Notch OFF/B neurons (Baumgardt et al., 2014), which served as our starting point. We will revise the text to make this clearer. As you can see from Figure 3E, there is only one NB3-3 Notch ON/ A neuron produced in each abdominal segment in comparison to the number of NB3-3 Notch OFF/B/EL neurons (Figure 1E). According to two independent assessments, Figure 3 and Baumgardt et al., 2014, the data support the conclusion that NB3-3 in the abdomen directly generates Notch OFF/B cells that assume EL identity for all but one of their divisions. Again, we believe technical issues make the ts-MARCM dataset messy. We will include a section in the discussion to describe limitations in ts-MARCM.

      *There are many potentially interesting questions related to this study that can significantly broaden the impact of this study. For example, are other NB lineages that also generate distinct temporal cohorts of EL neurons display similar proliferation patterns (type 1 division in SEZ, early termination of cell division in thoracic segments and type 0 division in abdomen)? *

      • *NB3-3 is the only lineage that makes ELs; Many lineages switch proliferation fates along the body axis. Previous studies have described how this switch in division patterns produces the wedge-shaped CNS: Cobeta et al., 2017. In the revision, we will be sure to clarify both points.

      *Why does NB3-3 in the thoracic segment become quiescence so much sooner than SEZ and abdominal segments? *

      • *NB3-3 in the thorax enters quiescence due to Hox genes and temporal transcription factors (Tsuji et al., 2008). In the revision, we will be sure to clarify this point.

      The authors' observations suggest that NB3-3 in SEZ and abdomen generate a similar number of EL neurons despite the difference in their division patterns (type 1 vs type 0). Are the mechanisms that promote EL neuron generate in NB3-3 in SEZ and abdomen the same? Anything else is known beside Notch OFF?

      • We agree this is an interesting point. Previous work has detailed NB3-3 division patterns, showing Type 1 divisions in the thorax, and Type 1 to Type 0 switch in the abdomen (Baumgardt et al., 2014). However, the proliferation pattern of NB3-3 in the SEZ had not been addressed until our study. Figures 2 and 3 suggest the following (1) SEZ proliferates for the duration of embryonic neurogenesis; (2) It produces a GMC on each division; (3) the GMC divides to produce one EL Notch OFF neuron and one Notch ON neuron. In our revision, we will manipulate the Notch pathway using two mutants, sanpodo, which produces two Notch OFF cells, and numb*, which produces two Notch ON cells (Skeath et al., 1998), to specifically test how ELs in the SEZ are regulated by Notch signaling. The other difference we know of between the SEZ, and abdomen is Hox gene expression. In Figure S2, we show that a subset of ELs in the SEZ express the anterior Hox genes, Sex combs reduced (Scr). The role of Hox genes in this lineage is an interesting question, as addressed in the discussion. This is an important future direction that merits in-depth study and is beyond the scope of what of this study is trying to accomplish.

      Minor commentsThe authors' writing style is highly unusual especially in the result section. There is an overwhelming large amount of background information in the result section but very thin description on their observations. The background information portion also includes previously published observations. Since the nature of this study is not hypothesis-driven, it is very confusing to read in many places and difficult to distinguish their original observations from previously published results and making. One easily achievable improvement is to insert relevant figure numbers into the text more often.

      Thank you for this comment. It is invaluable. In the revision, we will expand the background into a more comprehensive introduction and present the results more clearly. We will certainly insert relevant figure numbers. In responding to the reviewer's comments above, we can see where our writing lacked clarity and will improve these areas. Thank you again.

      Reviewer #1 (Significance (Required)):

      The study by Vasudevan et al intends to address how serially homologous neural progenitors generate different numbers and types of neurons depending on their location along the body axis. Investigation of full repertoire of neurogenesis for these progenitors necessitates a precise ability to track the fates of both progenitors and their neuronal progeny making it extremely difficult in vertebrate paradigm. The authors used NB3-3 in the developing fly embryo as a model to investigate the full extent of the flexibility in neurogenesis from a single type of serially homologous stem cell. Previous work showed NB3-3 generates neurons including lateral interneurons that can be positively labeled by Even-skipped, but detailed characterization of the NB3-3 lineage mainly focused on 3 segments during embryogenesis. The authors defined the number of EL neurons in all segments of the central nervous system in early larvae after the completion of circuit formation and carried out clonal analyses to determine the proliferation pattern of NB3-3. They described the failure to express Eve in Notch OFF/B neurons as a new mechanism for controlling the number of EL neurons and PCD limits EL neurons in terminal segments.

      Because this text is the same as the summary, please see our response to that section.

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

      In this manuscript, Vasudevan et al provide a detailed characterisation of the different numbers and temporal birthdates of Even-skipped Lateral (EL) neurons produced at in different segments from the same neuroblast, NB3-3. The work highlights the differences in EL neuronal generation across segments is achieved through a combination of different division patterns, failure to upregulate EL marker Eve and segment-specific program cell death. For neurons born within the same window and segment, the authors describe additional heterogeneity in their circuit formation. The work underscores the large diversity that the same neuroblast can generate across segments.

      Thank you!

      Major comments:

      - Based on the ts-MARCM 1:0 clones representing 100% of the SEZ clones at any given inferred cell division, the authors conclude "NB3-3 neuroblasts generate proliferative daughter GMCs in the SEZ and thorax on most divisions". Figure 2G does not have any data for SEZ before inferred division 5, whereas there is data in other regions. The authors also state "In the SEZ and abdomen, ELs were labelled regardless of induction time." In reference to Fig 2F, which seems inaccurate given there are no SEZ clones before inferred division 5. There is no comment on this fact, which is surprising give their focus on temporal cohorts. The authors should explain this discrepancy, if known, or modify their statements to reflect the data.

      • *Thank you for raising this point. The reason is because we produced two ts-MARCM datasets. One had SEZ clones, the other did not. The dataset with SEZ clones used heat shock protocols only for later time points, because those were most informative. The text from the paper is "We combined a published ts-MARCM (Wang et al., 2022) dataset with a new one (Table S1). The differences between the datasets are (1) CNSs were imaged either at low resolution for all regions (SEZ to terminus) or higher resolution for nerve cords (thorax to terminus); (2) for the SEZ-containing dataset, inductions started at NB3-3's 5th division. The combined data includes ~12 different heat shock protocols, 80 CNS, and 234 clones (Table S2)". In response to this comment, however, we will further clarify this point. In addition, we are submitting Supplemental table 1, which contains all the clonal data, as you can see experiments a-h lack SEZ data and experiments i-k contain SEZ data.

      - The temporal cohort (early-born vs late-born) identity is exclusively examined based on markers. Given the absence of SEZ clones from early NB3-3 divisions, a time course showing that the SEZ generate early-born Els or some other complementary method would be desirable.

      Thank you for raising this point. We show early-born versus late-born identity using markers in Figure 5. We conducted the time-course experiment as suggested and can confirm that there are early-born ELs in the SEZ at stage 13. We will include a new Supplemental Figure that includes a time course of EL number at stages 11, 13, 15, and 17 for segments SEZ3 to Te2 in the revision. See figure below.

      - The authors repeatedly refer to their work as showing how a stem cell type can have "flexibility". Flexibility would imply that NB3-3 from one segment could adopt a different behaviour (different division pattern, or cell death or connectivity) if it were placed in a different segment. This is not what is being shown. In my opinion, "heterogeneity" of the same neuroblast across different segments would be more appropriate.

      • *Thank you for this comment. We will change the wording to heterogeneity in the revision.

      Minor comments:

      - Figure 2A depicts a combination of known data and conclusions from their own (mainly SEZ). The authors might consider editing the figure to highlight what is new. A possibility would be for figure A to be a diagram of the experimental design and their summary division pattern to be shown after the new data instead of being panel A.

      Thank you for this suggestion. We will make the suggested change.

      - The authors state that they combined published ts-MARCM with their new one, which differed in a number ways that they list, but they don't specify which limitations are associated with the published vs new dataset. Could the authors please clarify?

        We now include Supplemental Table 1, which shows the complete combined datasets. In the first dataset, experiments a-h, the CNS was imaged at high resolution, but in a smaller region. The limitation is that the SEZ is missing. In the second dataset, i-k, inductions started at NB3-3's 5th division. The limitation is that we fail to sample early time points. This was a strategic decision. There were two possible scenarios: (1) in the SEZ, NB3-3 divided early, made GMCs, but both daughters expressed Eve. (2) in the SEZ, NB3-3 divided for the entirety of the embryonic neurogenesis, making GMCs, with only the Notch OFF daughters expressing Eve-our data support (2). Only late heat shocks were needed to distinguish between these possibilities. As these experiments are labor-intensive, we focused our efforts on the later time points. We will make this clearer in our revised text.

      - The title refers exclusively to "temporal cohorts", which in the manuscript are defined quite narrowly and do not seem to apply to all segments.

      • *Thank you! This, in our opinion, is a central, not a minor point to raise, because the impact of this study involves temporal cohort biology. We outlined the essential concepts in Part 1 "general statements" section of this revision plan. We did not mean to use "temporal cohort" in a limited sense, and we can see how the writing of our results section led to this comment. We will revise to make this clear.

      - Several cited references are missing from the Reference list at the end. Could the authors please double check this? (e.g. Matsushita, 1997; Sweeney et al., 2018)

      • *Thank you, we will remedy this!

      - Legend for figure 2 is a bit confusing, there is a "(A)" within the legend for (D), which indicates that segments A1-A7 are shown (this seems inaccurate, as it only goes to A6).

      Thank you, we will remedy this!

      Reviewer #3 (Significance (Required)):

      This study provides a comprehensive analysis of different cell biological scenarios for a neuroblast to generate distinct progeny across repeating axial units. The strength is the detailed and systematic approach across segments and possible scenarios: different division patterns, cell death, molecular marker expression. While it focuses on one specific neuroblast of the ventral nerve cord of Drosophila, the authors have done extensive work to place their findings and interpretation in the context of other cell types and across model organisms both in the introduction and discussion. This makes the work of interest for developmental biologists in general, neurodevelopment research in particular and those interested in circuit assembly, beyond their specialised community. This point of view comes from someone working in vertebrate CNS development.

      Thank you!

      Reviewer #4 (Evidence, reproducibility and clarity (Required)):

      Summary

      This manuscript addresses the question of how the number of neurons produced by each progenitor in the nervous system is determined. To address this question the authors use the Drosophila embryo model. They focus on a single type of neural stem cell (neuroblast), with homologues in each hemisegment along the anterior-posterior axis.

      Using a combination of clonal labelling, antibody stainings, and blockade of programmed cell death, they provide a detailed description of segment-specific differences in the proliferation patterns of these neuroblasts, as well as in the fate and survival of their neuronal progeny.

      Furthermore, by employing trans-synaptic labelling, they demonstrate that neurons derived from the same progenitor type receive distinct patterns of synaptic input depending on their segmental origin, in part due to their temporal window origin.

      Overall this work shows that different mechanisms contribute to the final number and identity of the neuronal progeny arising from a single progenitor, even within homologous progenitors along the anterior posterior body axis.

      Thank you!

      Major Comments

      I would suggest adding line numbers to the text for future submissions, this massively helps providing comments.

        Thank you for this comment. We will definitely add line numbers to the revised manuscript. We also thank you for providing comments despite this oversight on our part. We appreciate your time, and did not mean to make extra work.

      *The authors propose that all neuroblasts produce the same type of temporal cohort (early born) and that, by changing the pattern of cell division, different temporal cohorts can be added. The way this this presented in the abstract sounds like an obvious thing, what would be the alternative scenario/s? *

        Thank you for raising the point that the abstract should be updated. We have included a revised abstract. The things that are obvious are: (1) changing a neuroblast's division pattern will change the number of neurons produced, and (2) if you have late-born neurons, the stem cell must at some point, have made early-born neurons. However, within those bounds is an extremely large parameter space. Each stem cell can choose to divide or not, and it can also choose to produce a proliferative daughter or not. The stem cell must navigate these choices at every division. The field had two models for what a stem cell might do - a "random production" model and a "unitary production" model. Our data support a third "multimodal production" model, which could not have been predicted based on prior literature or data.

      We had raised these points in the discussion as follows-

      "Under a null model, the durations and types of proliferation would vary stochastically across segments, resulting in a continuous and unstructured distribution of neuron numbers (Llorca et al., 2019). In a unitary production model, based on the vertebrate neocortex, there is a fixed neurogenic output of ~8-9 neurons per progenitor (Gao et al., 2014). However, our data support a third model, a multimodal production model. In a multimodal model, serially homologous neuroblasts generate different numbers of neurons depending on the segment."

      We will now update the text to address this concern.

      Here it's the late born neurons that lack in thoracic segments because of early NB quiescence, but it cannot be excluded that different neuroblast types adopt a different strategy.

      • *True. Neural development is complex. Other lineages could easily employ alternative strategies. Our study presents a new conceptual framework that should inspire future research.

      I found the ts-MARCM results confusing for 2 reasons:

      1- It's not clear to me why there are so many single cell clones in div 3 and 4 in abdominal segments. This is not compatible with the division model depicted for abdominal segments, unless GMCs are produced in those division window and the MARCM hits the GMC, as also mentioned in the legend for G. This aspect is important because, either the previous model by Baumgardt et al. - please correct cit. currently Gunnar et al. 2026 - is wrong, or something strange happens in this experiment, or the relative temporal order is incorrect.

      Thank you for raising this point. Having multiple single-cell (i.e., 1:0) clones in divisions 3 and 4 is not precisely what would be predicted by the model in Figure 2C. In part because heat-shock-based recombination methods in fly are stochastic and inherently "messy", we also conducted a second set of lineage tracing experiments, as shown in Figure 3, using G-TRACE. Figure 3E shows one Notch ON/A neuron in each abdominal segment, suggesting there is only one GMC present during lineage progression. But Figure 3E's result does not localize the GMC to any particular division. One possibility is that the GMC is generated once, but randomly throughout lineage progression. This possibility is consistent with the idea that the relative temporal order is incorrect and suggests that Baumgardt is erroneous. However, the Baumgardt data are strong, so we do not favor this idea. A second possibility, which we favor, is that something strange happened in this experiment. Here is how we envision the strange occurrence: heterogeneity in the EL driver. Ts-MARCM's recombination timing dictates the upper limit for the number of cells within a clone. However, recombination is detected by GAL4. So, if the GAL4 driver for some reason detects fewer cells than one expects, then one would see unusually small clones as is the case in question. To detect Ts-MARCM recombination in Figure 2, we used the EL-GAL4 driver. The EL-GAL4 driver is an enhancer fragment, ~400KB, meaning that it does not capture the full regulatory context of the eve locus. In our experience (e.g., Manning et al., 2012), drivers using small enhancers tend to give highly-specific, but somewhat variable expression, and this is the case for EL-GAL4 in our experience. We will update the discussion to discuss the ts-MARCM dataset and its limitations. And, we will correct the citation to Baumgardt et al., 2014, not Gunnar. Thank you!

      2- In segments other than abdomen, it is quite rare to hit proper clones, it appears that only GMCs are hit by recombination, with very few exceptions. Could the author please provide an explanation for this or at least mention this aspect?

      • *This is true. We cannot explain it. It could have something to do with the RNAi cassettes that are used in ts-MARCM, because in the original paper they mention that RNAi can be differently regulated in GMCs versus neuroblasts (Yu et al., 2009). We will mention it in the revised discussion about ts-MARCM limitations.

      It is also unclear whether in F the graph includes all types of clones (including 1:0 clones). This is important, because the timing of division for NBs and GMCs is different, and inclusion of 1:0 might lead to a wrong estimate of the NB proliferation window (longer than it actually is because GMCs divide for longer). This is particularly important for the SEZ, where most clones in normalised division 10 and 11 are with ratio 1:0, thus compatible with both terminal division as well as GMC division.

      • *The graph in F does include all types of clones. We provide Supplemental Table 1, which shows the full dataset. Unfortunately, we do not have enough data to analyze only NB clones. We agree that the estimate of the NB proliferation window is coarse using this analysis method and could overrepresent the division time by one cell division. We will mention this in the discussion and make sure that our results text is free from any overreaching claims about the precision of these measurements.

      To obtain an estimate of the timing of division, the authors normalise clone size to the size of the bigger clone in the abdomen. What happened to those samples where no abdominal clones were hit? Were they simply excluded from the analysis?

        From the analysis in Figure 2, we excluded the clones that were SEZ, thorax, or terminus only. They were rare. They are shown in Supplemental Table 1, which will now be added in our revision plan.

      It is proposed that in the thorax late temporal cohort neurons are not produced, yet the ts-MARCM experiment detects some 1:0 clones. What is the fate of these cells? Are they all derived from GMC division and therefore decoupled from the temporal identity window? Or is this a re-activation of division?

      Figure 2F shows at the inferred 11th NB3-3 division, 100% of thoracic clones are of the 1:0 type. This is an n=1 observation (Supplemental Table 1, row f-Jan20-2). When we look at the morphology of this thoracic EL, we can see that it is a fully differentiated neuron that crosses the midline and ascends to the CNS, which is similar to EL morphologies in A1, so we don't think it's a whole new cell type. We have no way of determining whether this neuron was derived from a GMC division. It is also possible that this is an infrequent event or a technical anomaly. To address the question of reactivation of the thoracic NB3-3 division, we plan to include a Supplemental Figure of EL number over developmental time (stages 11, 13, 15, 17) for segments SEZ3 to Te2. This is the same data that we mentioned to Reviewer 3. This will reveal the extent to which the thorax produces late-born ELs.

      *"in A1, a majority of segments had one Notch OFF/B neuron that failed to label with Eve" does "the majority" in this sentence mean that there were cases where all B neurons were labelled with Eve? If yes, where would this stochasticity come from? *

        • Yes, "the majority" in this sentence means that there were cases where all B neurons were labeled by Eve. In Figure 3F, for segment A1, that number is four. In contrast, there are 6 cases where B neurons failed to label with Eve. We can only speculate about the origin of the stochasticity. It could be biological (e.g., low level of Eve expression) or technical (e.g., poor antibody penetration). We plan to mention this in the discussion.

      Additionally, there is no evidence that it's the first born NotchOFF neuron in A1 that does not express Eve. The authors should clarify where this speculation comes from.

      • *The evidence that the first-born Notch OFF neuron in A1 does not express Eve comes from our ts-MARCM data: "So far, our ts-MARCM analyses grouped segments into regions (Figure 2A-C), however, EL number varies on a segment-by-segment basis (Figure 1). Therefore, we looked for segment-by-segment differences in ts-MARCM data (Table S1). The only detectable difference was between A1 and the other abdominal segments: When both A1 and another abdominal segment were labeled in a single CNS, a majority had smaller A1 clones. These data suggest that the production of ELs by NB3-3 neuroblasts lags in A1 compared to A2-A7." We will add a representation of these data to the ts-MARCM figure. As we stated above, we will add a Supplemental Figure of EL number over developmental time (stages 11, 13, 15, 17) for segments SEZ3 to Te2, which could strengthen this point.

      When discussing trends shared with other phyla:

      A- "In the mammalian spinal cord, more neurons are present in regions that control limbs (Francius et al., 2013). Analogously, EL numbers do not smoothly taper from anterior to posterior; instead, the largest number of ELs is found in two non-adjacent regions, SEZ and the abdomen." It's unclear what is the link between the figure in the mammalian spinal cord and the Drosophila embryo. The embryo doesn't even have limbs and the number of neurons measured here refer only to a single lineage, while there could be (and in fact there are) lineage-to-lineage differences that could depict a different scenario.

      Thank you for this comment. We will rewrite this sentence, "in the mammalian spinal cord, more neurons are present in regions that control limbs (Francius et al., 2013)" to more accurately reflect the data in the Francius paper, and make the parallel more explicit. We will say "the size of columns of V3, V1, V2a, V2b, and V0v neurons differ at brachial compared to lumbar levels in the developing spinal cord." This removes the confusion about limbs and somewhat mitigates the concern about lineage-to-lineage differences, at least from the perspective of the spinal cord.

      B- The parallelism between V1 mouse neurons and EL Drosophila neurons is also unclear to me. The similarity in fold change across segments could be a pure coincidence and, from what I understand, the two cell types are not functionally linked.

        Thank you for this comment. We believe this is the sentence in question (sorry about no line numbers). "(3) In the mouse spinal cord, ~10-fold differences in molecular subtypes for V1 neurons (Sweeney et al., 2018). In *Drosophila*, NB3-3 neuroblasts show differences in EL number, depending on region, with similar fold changes, suggesting this trait is shared across phyla."  The emphasis was intended to be on the fold-changes, not cell types. Coincidence or not, it is parallel. We will update the sentence to say "(3) In the mouse spinal cord, ~10-fold differences in molecular subtypes for V1 neurons (Sweeney et al., 2018). Although V1 neurons are not direct homologs of EL neurons, the number also varies ~10-fold depending on the region. One possibility is that this trait is shared across phyla." And, we will remove the final part of the paragraph, which distracts from the point "Thus, for this study and future research, NB3-3 development now offers a uniquely tractable, detailed, and comprehensive model for studying how stem cells flexibly produce neurons."

      Minor comments:

      I found the manuscript somewhat difficult to follow, even though I am familiar with both the model and the topic. For non-specialist readers, I expect it will be even more challenging. The presentation of the results often feels fragmented, at times resembling a sequence of brief statements rather than a continuous narrative. I would encourage the authors to provide more synthesis and interpretation, for example by summarising key findings, rather than listing in detail the number of neurons labelled in each segment for every experiment. This would make the results more accessible and easier to digest.

      • *Thank you for this comment. We will provide more synthesis and interpretation in results by summarizing key findings.

      From the way the MS is written it's not clear from the beginning that the work focuses exclusively on embryonic-born neurons. Since in Drosophila neuronal stem cells undergo two rounds of neurogenesis, one in the embryo and one in the larva, this omission could lead to confusion.

        Thank you for this comment. We will mention this in the abstract, introduction and discussion.

      In the abstract, what would be the other temporal cohorts generated in specific regions? (ref to: "In specific regions, NB3-3 neuroblasts produce additional types of temporal cohorts, including but not limited to the late-born EL temporal cohort.")

        In this manuscript, we use lineage tracing to identify four types of temporal cohorts- early-born Notch ON, early-born Notch OFF, late-born Notch ON, and late-born Notch OFF. This is now reflected in the revised abstract. ELs are early-born Notch OFF and/or late-born Notch OFF.

      This sentence in the introduction is inaccurate: "The Drosophila CNS is

      organized into an anterior hindbrain-like subesophageal zone (SEZ) and a posterior spinal cord-like nerve cord". The anterior hindbrain-like portion of the CNS is in fact the supraesophageal ganglion (or cerebrum), while the SEZ is a posterior-like region.

        Thank you. We will change this sentence to: "The *Drosophila* CNS is

      organized into a hindbrain-like subesophageal zone (SEZ) and a spinal cord-like nerve cord".

      Fig 1E: the encoding of the significance is not immediately clear. In the legend the 4 stars could also be arranged in the same way for clarity.

      • *Thank you. We will change it for clarity.

      Fig 2E legend: it is mentioned that B corresponds to a 1:4 clone, however the MARCM example is shown for C and it's a 1:5.

      Thank you. We will fix this.

      The occurrence of "undifferentiated" neurons in Th segments is in less than 10% of the clones, I wonder if this a stochastic or deterministic event and to what extent small cell bodies could just be the consequence of local differences in tissue architecture.

      • Because we are using a stochastic technique, it is difficult for us to determine whether the occurrence of neurons with small somas is a stochastic or deterministic event. Several papers suggest neurons with small axons are found across insect species (Pearson and Fourtner, 1975; Burrows, 1996). Neurons with a small soma and short axons/ axonless are found in the Drosophila embryonic abdominal nerve cord (Lacin et al., 2009). In our unpublished work from the Drosophila* nerve cord at a first instar larval stage, we found small somas with short axons in segment A1 (see Figure 4.6 below). This leads us to believe it is not a consequence of local tissue architecture.

      Fig 2I: it's unclear what the purple means (I suppose it might be Eve expression) and why in J there should be one purple cell not labelled by the ts-MARCM when this is not present in H and I.

      Purple is Eve. We will add labels for stains used in H and I, and remove the extra purple cell from the illustration in J.

      "When synapses do occur, they are numerically similar from segment to segment". It's unclear where the evidence for this statement comes from, please clarify or remove the sentence.

      We calibrated our trans-Tango data against available connectomic data using segment A1 as a reference. We learned that the trans-tango method only identifies strongly (>15 synapses) connected neurons.

      "First, we calibrated trans-Tango for use in larval Drosophila, focusing on segment A1, where connectome data are available (Wang et al., 2022). In the connectome, of the five early-born ELs in A1, three are strongly connected to CHOs (>15 synapses), two are weakly connected (15 synapses) connected to somatosensory neurons."

        We will modify this sentence to say "when synapses do occur they are of similar strengths from segment to segment"

      "In SEZ2, NB3-3 divides 10 times (Figure 2F)". Figure 2F does not support this statement and Figure 7 shows 12 divisions. Possibly SEZ2 and 3 have been inverted in this statement, please clarify.

      Thank you for pointing this out. We will correct it!

      **Referees cross-commenting**

      I agree with most of the comments/suggestions provided by the other two reviewers.

      In particular:

      I agree with reviewer #1's comment about failure to express Eve being a mechanism for controlling neurons number, as this is a circular argument.

      • *We address this earlier and direct you to that text. Briefly, Eve is not just a marker, but a key differentiation gene for ELs.

      I agree with reviewer #2's concern about the use of the word "flexibility"; "heterogeneity" would be a more appropriate term, as I would associate the word "flexibility" to the ability of a single neuroblast in a single segment to produce neurons with different fates under, for example, unusual growth conditions. Here no genetic/epigenetic manipulations were performed to address flexibility and the observed (stereotypical) differences result from axial patterning.

      • *We will change this, thank you.

      *As a note, Reviewer #1 asks about other temporal cohorts of EL neurons produced by other lineages, but these neurons are specifically generated from NB3-3. *

      • *Thank you for adding this clarification.

      To generalise the observations reported in this study, the authors would need to focus on other molecularly defined temporal cohorts or, more generally, on other lineages, which, however, are likely to adopt different combinations of mecahnisms to tune progeny number across segments.

      • *We agree that further studies are needed to assess the generalizability of our findings.

      Reviewer #4 (Significance (Required)):

      In Drosophila melanogaster, the relationship between neural progenitors and their neuronal progeny has been studied in great detail. This work has provided a comprehensive description of the number of progenitors present in each embryonic segment, their molecular identities, the number of neurons they produce, and the temporal transcriptional cascades that couple progenitor temporal identity to neuronal fate.

      This work adds to the existing knowledge a detailed characterisation of intersegmental differences in the pattern of proliferation of a single type of neuronal progenitor as well as in post-divisional fate depending on anterior-posterior position in the body axis (i.e. programmed cell death and Notch signalling activation). This is a first step towards understanding the cellular and molecular mechanisms underlying such differences, but it's not disclosing them.

      We have disclosed the cellular mechanisms- stem cell division duration and type, neural cell death, identity gene expression, and differentiation state -unless something else is envisaged by this comment. The molecular mechanisms are beyond the scope of this paper.

      That homologous neuroblasts can generate variable numbers of progeny neurons depending on their segmental position has been established previously. What this manuscript adds is the demonstration that these differences arise through a combination of altered division patterns and differential programmed cell death, thereby revealing a more complex and less predictable scenario than could have been anticipated from existing knowledge in other contexts. The advance provided by this study is therefore incremental, refining rather than overturning our understanding of how segmental diversity in neuroblast lineages is achieved.

      The key conceptual advances provided by this study are described in the General Statements section above. We don't overturn, but we advance the field.

      By touching on the general question of how progenitors generate diversity, this work could be of broad interest to developmental neuroscientists beyond the fly field. However, the way it is currently written does not make it very accessible to non-specialists.

      Thank you for this comment. We will endeavor to make it more accessible in the revised manuscript. Reviewer 3, an expert in vertebrate neurobiology, agreed that our work was of broad interest.

      My expertise: Drosophila neurodevelopment, nerve cord, cell types specification

      3. Description of the revisions that have already been incorporated in the transferred manuscript

      Please insert a point-by-point reply describing the revisions that were already carried out and included in the transferred manuscript. If no revisions have been carried out yet, please leave this section empty.

      With this Revision Plan, we submit a revised abstract, and a supplemental table 1. We plan to address every point raised by the reviewers.

      4. Description of analyses that authors prefer not to carry out

      Please include a point-by-point response explaining why some of the requested data or additional analyses might not be necessary or cannot be provided within the scope of a revision. This can be due to time or resource limitations or in case of disagreement about the necessity of such additional data given the scope of the study. Please leave empty if not applicable.

      PeerReviewed
    2. EMBOpress 24 Oct 2025

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

      Learn more at Review Commons

      Referee #3

      Evidence, reproducibility and clarity

      Summary

      This manuscript addresses the question of how the number of neurons produced by each progenitor in the nervous system is determined. To address this question the authors use the Drosophila embryo model. They focus on a single type of neural stem cell (neuroblast), with homologues in each hemisegment along the anterior-posterior axis.

      Using a combination of clonal labelling, antibody stainings, and blockade of programmed cell death, they provide a detailed description of segment-specific differences in the proliferation patterns of these neuroblasts, as well as in the fate and survival of their neuronal progeny. Furthermore, by employing trans-synaptic labelling, they demonstrate that neurons derived from the same progenitor type receive distinct patterns of synaptic input depending on their segmental origin, in part due to their temporal window origin. Overall this work shows that different mechanisms contribute to the final number and identity of the neuronal progeny arising from a single progenitor, even within homologous progenitors along the anterior posterior body axis.

      Major Comments

      I would suggest adding line numbers to the text for future submissions, this massively helps providing comments.

      The authors propose that all neuroblasts produce the same type of temporal cohort (early born) and that, by changing the pattern of cell division, different temporal cohorts can be added. The way this this presented in the abstract sounds like an obvious thing, what would be the alternative scenario/s? Here it's the late born neurons that lack in thoracic segments because of early NB quiescence, but it cannot be excluded that different neuroblast types adopt a different strategy.

      I found the ts-MARCM results confusing for 2 reasons:

      1. It's not clear to me why there are so many single cell clones in div 3 and 4 in abdominal segments. This is not compatible with the division model depicted for abdominal segments, unless GMCs are produced in those division window and the MARCM hits the GMC, as also mentioned in the legend for G. This aspect is important because, either the previous model by Baumgardt et al. - please correct cit. currently Gunnar et al. 2026 - is wrong, or something strange happens in this experiment, or the relative temporal order is incorrect.
      2. In segments other than abdomen, it is quite rare to hit proper clones, it appears that only GMCs are hit by recombination, with very few exceptions. Could the author please provide an explanation for this or at least mention this aspect? It is also unclear whether in F the graph includes all types of clones (including 1:0 clones). This is important, because the timing of division for NBs and GMCs is different, and inclusion of 1:0 might lead to a wrong estimate of the NB proliferation window (longer than it actually is because GMCs divide for longer). This is particularly important for the SEZ, where most clones in normalised division 10 and 11 are with ratio 1:0, thus compatible with both terminal division as well as GMC division.

      To obtain an estimate of the timing of division, the authors normalise clone size to the size of the bigger clone in the abdomen. What happened to those samples where no abdominal clones were hit? Were they simply excluded from the analysis?

      It is proposed that in the thorax late temporal cohort neurons are not produced, yet the ts-MARCM experiment detects some 1:0 clones. What is the fate of these cells? Are they all derived from GMC division and therefore decoupled from the temporal identity window? Or is this a re-activation of division?

      "in A1, a majority of segments had one Notch OFF/B neuron that failed to label with Eve" does "the majority" in this sentence mean that there were cases where all B neurons were labelled with Eve? If yes, where would this stochasticity come from? Additionally, there is no evidence that it's the first born NotchOFF neuron in A1 that does not express Eve. The authors should clarify where this speculation comes from. When discussing trends shared with other phyla:

      A- "In the mammalian spinal cord, more neurons are present in regions that control limbs (Francius et al., 2013). Analogously, EL numbers do not smoothly taper from anterior to posterior; instead, the largest number of ELs is found in two non-adjacent regions, SEZ and the abdomen." It's unclear what is the link between the figure in the mammalian spinal cord and the Drosophila embryo. The embryo doesn't even have limbs and the number of neurons measured here refer only to a single lineage, while there could be (and in fact there are) lineage-to-lineage differences that could depict a different scenario.

      B- The parallelism between V1 mouse neurons and EL Drosophila neurons is also unclear to me. The similarity in fold change across segments could be a pure coincidence and, from what I understand, the two cell types are not functionally linked.

      Minor comments:

      I found the manuscript somewhat difficult to follow, even though I am familiar with both the model and the topic. For non-specialist readers, I expect it will be even more challenging. The presentation of the results often feels fragmented, at times resembling a sequence of brief statements rather than a continuous narrative. I would encourage the authors to provide more synthesis and interpretation, for example by summarising key findings, rather than listing in detail the number of neurons labelled in each segment for every experiment. This would make the results more accessible and easier to digest.

      From the way the MS is written it's not clear from the beginning that the work focuses exclusively on embryonic-born neurons. Since in Drosophila neuronal stem cells undergo two rounds of neurogenesis, one in the embryo and one in the larva, this omission could lead to confusion.

      In the abstract, what would be the other temporal cohorts generated in specific regions? (ref to: "In specific regions, NB3-3 neuroblasts produce additional types of temporal cohorts, including but not limited to the late-born EL temporal cohort.")

      This sentence in the introduction is inaccurate: "The Drosophila CNS is organized into an anterior hindbrain-like subesophageal zone (SEZ) and a posterior spinal cord-like nerve cord". The anterior hindbrain-like portion of the CNS is in fact the supraesophageal ganglion (or cerebrum), while the SEZ is a posterior-like region.

      Fig 1E: the encoding of the significance is not immediately clear. In the legend the 4 stars could also be arranged in the same way for clarity.

      Fig 2E legend: it is mentioned that B corresponds to a 1:4 clone, however the MARCM example is shown for C and it's a 1:5.

      The occurrence of "undifferentiated" neurons in Th segments is in less than 10% of the clones, I wonder if this a stochastic or deterministic event and to what extent small cell bodies could just be the consequence of local differences in tissue architecture.

      Fig 2I: it's unclear what the purple means (I suppose it might be Eve expression) and why in J there should be one purple cell not labelled by the ts-MARCM when this is not present in H and I.

      "When synapses do occur, they are numerically similar from segment to segment". It's unclear where the evidence for this statement comes from, please clarify or remove the sentence.

      "In SEZ2, NB3-3 divides 10 times (Figure 2F)". Figure 2F does not support this statement and Figure 7 shows 12 divisions. Possibly SEZ2 and 3 have been inverted in this statement, please clarify.

      Referees cross-commenting

      I agree with most of the comments/suggestions provided by the other two reviewers. In particular: I agree with reviewer #1's comment about failure to express Eve being a mechanism for controlling neurons number, as this is a circular argument. I agree with reviewer #2's concern about the use of the word "flexibility"; "heterogeneity" would be a more appropriate term, as I would associate the word "flexibility" to the ability of a single neuroblast in a single segment to produce neurons with different fates under, for example, unusual growth conditions. Here no genetic/epigenetic manipulations were performed to address flexibility and the observed (stereotypical) differences result from axial patterning. As a note, Reviewer #1 asks about other temporal cohorts of EL neurons produced by other lineages, but these neurons are specifically generated from NB3-3. To generalise the observations reported in this study, the authors would need to focus on other molecularly defined temporal cohorts or, more generally, on other lineages, which, however, are likely to adopt different combinations of mecahnisms to tune progeny number across segments.

      Significance

      In Drosophila melanogaster, the relationship between neural progenitors and their neuronal progeny has been studied in great detail. This work has provided a comprehensive description of the number of progenitors present in each embryonic segment, their molecular identities, the number of neurons they produce, and the temporal transcriptional cascades that couple progenitor temporal identity to neuronal fate. This work adds to the existing knowledge a detailed characterisation of intersegmental differences in the pattern of proliferation of a single type of neuronal progenitor as well as in post-divisional fate depending on anterior-posterior position in the body axis (i.e. programmed cell death and Notch signalling activation). This is a first step towards understanding the cellular and molecular mechanisms underlying such differences, but it's not disclosing them.

      That homologous neuroblasts can generate variable numbers of progeny neurons depending on their segmental position has been established previously. What this manuscript adds is the demonstration that these differences arise through a combination of altered division patterns and differential programmed cell death, thereby revealing a more complex and less predictable scenario than could have been anticipated from existing knowledge in other contexts. The advance provided by this study is therefore incremental, refining rather than overturning our understanding of how segmental diversity in neuroblast lineages is achieved. By touching on the general question of how progenitors generate diversity, this work could be of broad interest to developmental neuroscientists beyond the fly field. However, the way it is currently written does not make it very accessible to non-specialists.

      My expertise: Drosophila neurodevelopment, nerve cord, cell types specification

      PeerReviewed
    3. EMBOpress 24 Oct 2025

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

      Learn more at Review Commons

      Referee #2

      Evidence, reproducibility and clarity

      In this manuscript, Vasudevan et al provide a detailed characterisation of the different numbers and temporal birthdates of Even-skipped Lateral (EL) neurons produced at in different segments from the same neuroblast, NB3-3. The work highlights the differences in EL neuronal generation across segments is achieved through a combination of different division patterns, failure to upregulate EL marker Eve and segment-specific program cell death. For neurons born within the same window and segment, the authors describe additional heterogeneity in their circuit formation. The work underscores the large diversity that the same neuroblast can generate across segments.

      Major comments:

      • Based on the ts-MARCM 1:0 clones representing 100% of the SEZ clones at any given inferred cell division, the authors conclude "NB3-3 neuroblasts generate proliferative daughter GMCs in the SEZ and thorax on most divisions". Figure 2G does not have any data for SEZ before inferred division 5, whereas there is data in other regions. The authors also state "In the SEZ and abdomen, ELs were labelled regardless of induction time." In reference to Fig 2F, which seems inaccurate given there are no SEZ clones before inferred division 5. There is no comment on this fact, which is surprising give their focus on temporal cohorts. The authors should explain this discrepancy, if known, or modify their statements to reflect the data.
      • The temporal cohort (early-born vs late-born) identity is exclusively examined based on markers. Given the absence of SEZ clones from early NB3-3 divisions, a time course showing that the SEZ generate early-born Els or some other complementary method would be desirable.
      • The authors repeatedly refer to their work as showing how a stem cell type can have "flexibility". Flexibility would imply that NB3-3 from one segment could adopt a different behaviour (different division pattern, or cell death or connectivity) if it were placed in a different segment. This is not what is being shown. In my opinion, "heterogeneity" of the same neuroblast across different segments would be more appropriate.

      Minor comments:

      • Figure 2A depicts a combination of known data and conclusions from their own (mainly SEZ). The authors might consider editing the figure to highlight what is new. A possibility would be for figure A to be a diagram of the experimental design and their summary division pattern to be shown after the new data instead of being panel A.
      • The authors state that they combined published ts-MARCM with their new one, which differed in a number ways that they list, but they don't specify which limitations are associated with the published vs new dataset. Could the authors please clarify?
      • The title refers exclusively to "temporal cohorts", which in the manuscript are defined quite narrowly and do not seem to apply to all segments.
      • Several cited references are missing from the Reference list at the end. Could the authors please double check this? (e.g. Matsushita, 1997; Sweeney et al., 2018)
      • Legend for figure 2 is a bit confusing, there is a "(A)" within the legend for (D), which indicates that segments A1-A7 are shown (this seems inaccurate, as it only goes to A6).

      Significance

      This study provides a comprehensive analysis of different cell biological scenarios for a neuroblast to generate distinct progeny across repeating axial units. The strength is the detailed and systematic approach across segments and possible scenarios: different division patterns, cell death, molecular marker expression. While it focuses on one specific neuroblast of the ventral nerve cord of Drosophila, the authors have done extensive work to place their findings and interpretation in the context of other cell types and across model organisms both in the introduction and discussion. This makes the work of interest for developmental biologists in general, neurodevelopment research in particular and those interested in circuit assembly, beyond their specialised community. This point of view comes from someone working in vertebrate CNS development.

      PeerReviewed
    4. EMBOpress 24 Oct 2025

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

      Learn more at Review Commons

      Referee #1

      Evidence, reproducibility and clarity

      Summary: The study by Vasudevan et al intends to address how serially homologous neural progenitors generate different numbers and types of neurons depending on their location along the body axis. Investigation of full repertoire of neurogenesis for these progenitors necessitates a precise ability to track the fates of both progenitors and their neuronal progeny making it extremely difficult in vertebrate paradigm. The authors used NB3-3 in the developing fly embryo as a model to investigate the full extent of the flexibility in neurogenesis from a single type of serially homologous stem cell. Previous work showed NB3-3 generates neurons including lateral interneurons that can be positively labeled by Even-skipped, but detailed characterization of the NB3-3 lineage mainly focused on 3 segments during embryogenesis. The authors defined the number of EL neurons in all segments of the central nervous system in early larvae after the completion of circuit formation and carried out clonal analyses to determine the proliferation pattern of NB3-3. They described the failure to express Eve in Notch OFF/B neurons as a new mechanism for controlling the number of EL neurons and PCD limits EL neurons in terminal segments.

      Major comments: The authors performed careful analyses of the NB3-3 lineage using EL neurons. My main concerns are limited applicability of their findings and lack of mechanisms as how NB3-3 generate various numbers of EL neurons. Their findings are exclusively relevant to the NB3-3 lineage despite their effort in highlighting that other NB lineages also generate temporal cohorts of EL neurons. I disagreed with their conclusion that failure to express Eve as a mechanism for controlling EL neuron numbers when Eve serves as the marker for these neurons. Are there any other strategy to assess the fates and functions of these cells beside relying solely on Eve expression? I am not familiar with the significance of Eve expression on the functions of these neurons. Is it possible to perform clonal analyses of NB3-3 mutant for Eve and see if these neurons adopt different functionalities/identities? If NB3-3 in the SEZ continually generate GMCs based on the interpretation of clonal analyses and depicted in Fig. 2A, why is the percent of clones that are 1:0 virtually at or near 100% from division 6-11 shown in 2G? The authors also indicate that NB3-3 in the abdomen directly generate Notch OFF/B cells that assume EL neuronal identity. In this scenario, shouldn't the percent of 1:0 clones be 100% in later divisions in Fig. 2G? Based on the number of clones in abdomen shown in Fig. 2E, I cannot seem to understand how the authors come to the percent of 1:0 clones shown in Fig. 2G

      There are many potentially interesting questions related to this study that can significantly broaden the impact of this study. For example, are other NB lineages that also generate distinct temporal cohorts of EL neurons display similar proliferation patterns (type 1 division in SEZ, early termination of cell division in thoracic segments and type 0 division in abdomen)? Why does NB3-3 in the thoracic segment become quiescence so much sooner than SEZ and abdominal segments? The authors' observations suggest that NB3-3 in SEZ and abdomen generate a similar number of EL neurons despite the difference in their division patterns (type 1 vs type 0). Are the mechanisms that promote EL neuron generate in NB3-3 in SEZ and abdomen the same? Anything else is known beside Notch OFF?

      Minor comments:

      The authors' writing style is highly unusual especially in the result section. There is an overwhelming large amount of background information in the result section but very thin description on their observations. The background information portion also includes previously published observations. Since the nature of this study is not hypothesis-driven, it is very confusing to read in many places and difficult to distinguish their original observations from previously published results and making. One easily achievable improvement is to insert relevant figure numbers into the text more often.

      Significance

      The study by Vasudevan et al intends to address how serially homologous neural progenitors generate different numbers and types of neurons depending on their location along the body axis. Investigation of full repertoire of neurogenesis for these progenitors necessitates a precise ability to track the fates of both progenitors and their neuronal progeny making it extremely difficult in vertebrate paradigm. The authors used NB3-3 in the developing fly embryo as a model to investigate the full extent of the flexibility in neurogenesis from a single type of serially homologous stem cell. Previous work showed NB3-3 generates neurons including lateral interneurons that can be positively labeled by Even-skipped, but detailed characterization of the NB3-3 lineage mainly focused on 3 segments during embryogenesis. The authors defined the number of EL neurons in all segments of the central nervous system in early larvae after the completion of circuit formation and carried out clonal analyses to determine the proliferation pattern of NB3-3. They described the failure to express Eve in Notch OFF/B neurons as a new mechanism for controlling the number of EL neurons and PCD limits EL neurons in terminal segments.

      PeerReviewed
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    biorxiv.org/lookup/doi/10.1101/2024.11.09.622783
  40. www.preceptaustin.org www.preceptaustin.org
    John 14 Commentary | Precept Austin
    2
    1. mattmaldre 24 Oct 2025
      The word “way” is the Greek word hodos. It forms, for example, the word “exodus” which means “the way out.” The word hodos means “a path, road, or journey from one place to another, a course at sea.”

      What is the source for this? The word "way" forms the word "exodus"?

      Oh, I found it. Exodus is from the Greek word ἔξοδος (éxodos), which means "a going out" or "departure". It is a compound word from ἐξ (ex), meaning "out of," and ὁδός (hodos)

    2. mattmaldre 24 Oct 2025
      Notice the three uses of "the" (Greek definite article "he"), which is crucial to comprehend. Jesus is saying with each use of "the" that He is the definitive way, the definitive truth and the definitive life. The clear implication is that there is absolutely NO OTHER way, truth or life! Jesus Christ not only states the truth; he is the truth.

      Interesting point about paying attention to the "the". Normally we skip over "the". But here, "the" has sigficiant meaning.

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  41. Local file Local file
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  42. www.rifesautobody.com www.rifesautobody.com
    Home - Rife's Autobody
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    1. Bleak_Morn 24 Oct 2025
      Email

      Emailed them at this address in 9/2025 and got no response. Emailed again with no response in 10/2025. Called and was given yet another email address. Not sure why businesses don't update their emails on their websites anymore. Phone meetings are dumb.

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  43. www.newadvent.org www.newadvent.org
    SUMMA THEOLOGIAE: Modesty as consisting in the outward movements of the body (Secunda Secundae Partis, Q. 168)
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    1. jsmith25 24 Oct 2025
      "playful actions are not directed to something else." But it is a requisite of virtue that the agent in choosing should "direct his action to something else,"

      I am a bit confused on how to interpret this. From looking at the link, the "Philosopher" he refers to is Plato, and the quote I am guessing, from the citations, is from Plato's ethics. Plato lists several virtues: courage, moderation, piety, and justice (Scavone 2023). I'd like to read the original by Plato before making real conclusions, but I believe the author's argument is appealing to both the virtues of moderation and piety. We've established already that among the differing medieval attitudes around games, one of the conclusions was moderation was key, such as this passage selected from the textbook, which was originally by John Salisbury, "'There are, however, times when, viewed from a certain aspect, games of chance are permissible. For example, if without evil consequences they alleviate the strain of heavy responsibilities and if without harming character they introduce an agreeable period of relaxation. Liberty to do as one pleases is justified if moderation controls the act'" (Milliman, 587), and so it's easy to see how, say, dice games would contradict Plato's virtue of moderation from a more severe perspective, since they can become addictive and make a gambler of a person. There is also a contradiction to the virtue of piety that the author may be appealing to, that since a person should "direct his action to something else" he means, potentially, that games distract a person from both their other responsibilities (both religion and justice if you were to look at it under the lens of Plato's virtues) and from the worship of God, not because a person should be spending every second of their time on these things, but because they have the capacity to steer a person the wrong way and tempt them away from keeping to the virtues.

      I've left a link to the article I looked at here, it is by Daniel C. Scavone.

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    newadvent.org/summa/3168.htm