we know nothing, lets ban it

are they professionals? what was the time period that they waited?

1-2 minutes at least

not sure how they know this?

I had to rewrite the entire essay so that it could it could become a story with a beginning, a pivotal moment, and an end.

I had to rewrite the entire essay so that it could it could become a story with a beginning, a pivotal moment, and an end.

True story! I came across this course to find inspiration on how to improve a control of a human animation neural network model for a game development domain: 3 control variables, 150 DOF state and a neural network with ~2 millions of weights.

曾濒临死亡的游戏，摇身变成价值270亿美元的应用，如何做到的？

Might also be worth adding indirect spillover to wild game species including nonhuman primates or ungulates and domestic animals such as horses and pigs which can then serve as amplifying reservoirs.

scratching an itch - interessant - die partizipative Architektur der Netze, wie lässt sie sich beschreiben und was macht diese Architektur mit den Nutzer*innen?

key features/techniques: audience: cyclists, fans of g s title: play on words = game of two halves, extraphoric ref "day one" short summary at begining = context, minor dependent clause "trouble is", northern classics: assumed cultural knowledge, we = inclusive pronoun, juxtaposition throughout w cycling, working out is fun and a holiday, lexical choice: ventured, dynamic verb, connotes adventure, risk, location gives him credibility, death march = hypberbolic, repetition of wind, modest language despite being very talented, alliteration: "lumpier route" = harder route lots of descriptions, repetition = "de-tour off our de-tour", jargon of ride guy = modern and hip, informal conversational tone, simile = "heaven" abt dangerous route, polysyndecton "and" "but" "best" = superlative

同样是上班时发现了豆瓣的PSP条目

Now an "artist" is just a creator with no business sense.

另一种选择（这次是与公司相对比）可以在《罗奇代尔原则》中找到。这是一套建立于 19 世纪英国的合作社运作理念。这些原则至今仍被世界各地的合作社积极采用。概括起来是：

1. 建立自愿与开放的会员制；
2. 建立参与式的决策过程；
3. 确保人人都可参与；
4. 在所有协定中允许成员自主；
5. 开展教育和宣传活动，以确保成员平等；
6. 与其他合作社建立网络；
7. 为社区创造正外部性。

I see a footnote for "scandals" but not for lack of fundamentals or illegal activities. Remember, we're talking about bitcoin. You wouldn't think it was right to talk about pink sheet stocks as the same thing as Dow Jones companies. Or a loan from friends and family like a government security. It's bitcoin and everything else.

Packy McCormick 在本文中讨论了区块链上的游戏. Crypto 是一个很好玩的游戏, 一个数十亿人在线玩的游戏. 社交媒体是这个游戏的清晰体现.

成功的电子游戏的设计需要有频繁反馈循环, 可变结果, 控制感, 与和元游戏的连接 (最重要). 互联网就是一个无限的游戏, 在推特, YouTube, Discord, 工作中扮演自己, 积累身份. 比如马斯克就是一个很好的玩家.

Crypto 是互联网游戏内的资金. 越是关心自己的身份, 就越可能打开新的可能性, 越是会受到 NFT 的吸引.

对这个游戏, 不用太认真, 不用等到完美时机再跳进来, 而是慢慢学习, 慢慢积累.

The Contestant Who Outsmarted ‘The Price Is Right’

I was doing some research on counting cards and memory and came across this story from 2010 in Esquire relating to several who were using (unnamed) memory methods to perform better on The Price is Right game show. If nothing else, it’s a fascinating example of applied memory methods in modern culture.

https://www.esquire.com/news-politics/a7922/price-is-right-perfect-bid-0810/

2019-10-26 20:00

indylab

• for - intent - game plan

⨑

• for - intent : game plan

⨒

跟前面Remenber11 互相比较？

一个关于物品、游戏、亲情的小故事

uuuuuuuuuuuuuuuuu

PSP游戏

bidirectional data flow ?! That's a game changer.

analogue in Rails: content_for

https://github.com/sveltejs/kit/pull/3252/files

1. I'm sorry, as opposed to eating live animals?? Stop trying to make this something it isn't dude
2. what is this Game of Thrones? are these animals white walkers or something? calm down
3. ah...it's because they're "useful" animals...and thus capitalism rears its ugly head once again

Yes, and that's just one of the reasons why scanning from the front is invalid. There's nothing special about the signature in file records—it's just a four-byte sequence that might make its way into the resulting ZIP without any intent to denote a file record. If you scan from the front and assume that encountering the signature means a file exists there without cross-referencing the central directory, it means your implementation treats junk bytes as meaningful to the structure of the file, which is not a good idea.

Sure, but that doesn't mean that it's valid to treat the existence of those bytes as if that file is still "in" the ZIP. They should be treated exactly as any other blob that just happens to have some bytes that match the shape of the what a file record would look like if there were actually supposed to be a file there.

"there"

This is, I think, the only legitimate criticism here so far. All the others that amount to questions of "back-to-front or front-to-back?" can be answered: back-to-front.

This particular issue, however, can be worked around by padding the central directory one byte (or four) so that its not at offset 1,247,093,766. Even then, the flexibility in the format and this easy solution means that even this criticism is mostly defanged.

spin:

Or, perhaps the reason for releasing them in smaller packs is... to make more money?!

Twitter Engineer Regrets Retweet Feature

Companies and services are made up of people making decisions. Often decisions that we can't see the impact of...or are unwilling to listen to the wisdom of those that are predicting the impact.

I like this quote, it is really humanizing. No person has all of the experiences of the world or of both sides of a struggle that would allow them to act perfectly just or strategically. The comparison of people to players in the extended metaphor of chess reminds me of the segment of the French Dispatch we watched in class.

This suggests there is enough transparency in social media algorithms to game them.

Are there interventions that can be made with these actors rather than at the level of the algorithms?

if this is true, then banning this activity will make it harder to identify the circumstances surrounding the activity

missing education on the subject

exhaustion is quite common and possible while not doing breath holding activities

an indication there is a vacuum of information about the activity - missing education on the subject

was being supervised by mother

particularly:

but rather the game in and of itself, the constant shifting around of pawns, the circulation of cards, everything that contributes to the fact that the game--as opposed to a work of art--never stands still.

This reminds me of some of the mnemonic devices (cowrie shells) that Lynne Kelly describes in combinatorial mnemonic practice. These are like games or stories that change through time. And these are fairly similar to the statistical thermodynamics of life and our multitude of paths through it. Or stories which change over time.

Is life just a game?

there's a kernel of something interesting here, we'll just need to tie it all together.

Think also of combining various notes together in a zettelkasten.

Were these indigenous tribes doing combinatorial work in a more rigorous mathematical fashion?

TLDR; want to make some reproducible chemistry? Then make something easy for an average chemist to follow in an average laboratory with accessible equipment

SciScore for 10.1101/2022.04.14.22273886: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Table 2: Resources

No key resources detected.

Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

The limitations of such attempts can be particularly serious when the scientific reasoning is based on incomplete information or knowledge. It is for this reason, we caution that the results of ABD modeling such as the equilibriums should only be used as explanatory/exploratory purposes at strategic level, rather than used for advising public at tactic levels. We argue that the methodology we used to model masking behaviors with the ABD game should also be inspirational for exploring other public health policies (measures) such as social distance, lockdown/reopen and quarantines (abbreviated as DLQ hereafter). These measures are designed to physically contain the spreading of pathogens by isolation (distancing or containment) and can be characterized as either “open vs. closed”, i.e., without vs. with enforcing isolation (containment) measures such as DLQ. Obviously, masking also belongs to isolation. According to the metapopulation (i.e., population of local populations) theory (Citron et al. 2021, Ma 2020), infectious diseases such as COVID-19 can be modeled as a metapopulation of infectious pathogens, i.e., consisting of many local (regional) populations of pathogens (carried by human hosts) such as the local or regional outbreaks of COVID-19 (e.g., outbreaks in different countries). Also according to classic ecological theories (Hilker et al. 2009, Friedman et al. 2012, Ma 2020), the extinctions of local populations can be common events, although the global metapopulation...

Results from TrialIdentifier: No clinical trial numbers were referenced.

Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

Results from JetFighter: We did not find any issues relating to colormaps.

Results from rtransparent:

• Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
• Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
• No protocol registration statement was detected.

Results from scite Reference Check: We found no unreliable references.

About SciScore

SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

A little too harsh :)

Too harsh. What, so nothing from the Asset Store -- not even, let's see, assets! -- are ever allowed to be used in a finished game??

Louis-Jean Calvet explains that in writing Michelet, Barthes used his notes on index cards to try out various combinations of cards to both organize them as well as "to find correspondences between them."

i agree this is the main reason that i got into bowling. it can be frustrating at times but you can easily see improvement.

role of institutional devices in protecting cash transfers between state and local governments

build thesis之后，建立早期investor list => 保持关注这些人的链上活动 => 总结来verify你的thesis => 决定exit liq时机

never feel sorry with tp

lmao cult community

观察早期参与者 和 团队的链上行为，总是会为你的决策提供有用信息

always have a plan ab buying and selling

I like this! I think you can make the metaphor a bit clearer for what chess means. Does it mean taking risks to get closer with someone? Is the moral of the story that you just have to play with the right person? Is the chess game between Jane and Charlie a challenge to Charlie's strategization of trying to get a girl? Or his decision to attempt playing at all? It seems at the end Charlie becomes opened up to the possibility that he doesn't have to be nervous and people will want to play with him. Is the story Charlie triumphing over his lack of self confidence, or his understanding that sometimes he'll lose a game no matter what?

Continuing this thought to the title - En Passant is a tricky move. One that seems illegal, but isn't, and catches people off guard at the first moves of their pawn and captures them. Is there any symbolic connection to these ideas with the en passant? Is Jane the one who employs en passant? Or Charlie?

I think making what the challenge is clearer will help viewers be able to align with the stuggle and story for Charlie and root for him - unless it is that we aren't supposed to be, and have a critical outlook on his approach to relationships. The way you set up the character in the beginning - he seems nervous, anxious to make friends, not self confident, and overwhelmed. This makes us want him to succeed, seeing him struggle. But he doesn't seem to want a relationship until Thompson brings it up. We haven't even met Jane yet when Charlie begins his journey to getting her. Perhaps by introducing her at the scene in the coffee shop, maybe ignoring Sadie to look at her, or somehow he goes to the coffee shop just to see Jane, will provide a similar extension of alignment.

By maybe also refining the chess analogy for example will clear up for the audience where they are in alignment to Charlie's story and wants.

But overall I think you've got a great start, and would love to see you experiment a little more with how you tell this story! You don't have to of course, I think my filmmaking style personally is a bit whacky, but this is your short film, have the courage to think of the ways you find personally will powerfully communicate these essences!

From a story stand point - it seems too soon for Charlie to win at chess. He's taken a risk, but has he learned how to win the game, synoynmous with the girl, at this point? The parallel seems disjointed. Perhaps you can show Charlie taking risks at chess mid game for this scene.

Is this in like retrospect to the real charlie? Does the real charlie exisit here? If so, maybe explain this transition more and where exactly we end up. Is this imaginary charlie in his room? In a void?

1. </span>00:00<span> Jess and Crabbe – Hell and Back
2. </span>05:00<span> Le Knight Club – Santa Claus (Paul Johnson Remix)
3. </span>07:42<span> For the Floorz – Body Angels
4. </span>11:43<span> Aloud – Sex and Sun III
5. </span>14:26<span> Sedat – Feel Inside
6. </span>19:51<span> We in Music – Grandlife (Time Code Mix By Play Paul)
7. </span>25:19<span> Alex Gopher – Party People
8. </span>27:47<span> Kid Creme – The Game (Kid’s Piano Mix)
9. </span>32:27<span> Royksopp – Remind Me (Ernest Saint Laurent’s Moonfish Mix)
10. </span>34:54<span> Trankilou – Champagne
11. </span>39:44<span> Raw Man – Europa
12. </span>42:41<span> Le Knight Club – Cherie D’Amour
13. </span>47:07<span> Cheek – Venus
14. </span>50:04<span> Sedat – The Turkish Avenger
15. </span>53:42<span> The Eternals – Wrath of Zeus (Acapella)
16. </span>54:20<span> Daddy’s Favourite – Good Times
17. </span>57:32<span> Alan Braxe and Fred Falke – Intro
18. </span>01:00:57<span> Crydajam – Loaded
19. </span>01:05:24<span> Lifelike – Black Chess
20. </span>01:08:28<span> Archigram – Carnaval
21. </span>01:12:34<span> Bel Amour – Promise Me (Extended)
22. </span>01:17:06<span> Billy Lo – Everytime
23. </span>01:19:49<span> Phoenix – If I Ever Feel Better (Buffalo Bunch Remix)
24. </span>01:24:15<span> Le Knight Club – Gator
25. </span>01:28:06<span> Fantom – Faithful (Etienne de Crecy Remix)
26. </span>01:30:04<span> Fantom – Faithful (Original)
27. </span>01:33:32<span> Fantom – Faithful (Prassay Remix)
28. </span>01:36:44<span> The Buffalo Bunch – Music Box
29. </span>01:40:00<span> Thomas Bangalter – Ventura
30. </span>01:43:16<span> Crydajam – Playground
31. </span>01:46:16<span> Archigram – In Flight
32. </span>01:51:05<span> Le Knight Club – Mosquito
33. </span>01:53:48<span> Deelat – Wetness Anthem
34. </span>01:56:26<span> We in Music – Now That Love Has Gone (Ice Creamer Remix By Aloud)
35. </span>01:59:48<span> Modjo – No more tears (Alex Gopher Remix)
36. </span>02:03:07<span> Stardust – Music Sounds Better With You (Bibi & Dimitri Anthem From Paris)
37. </span>02:08:11<span> Cheek – Venus (I:Cube Remix)
38. </span>02:12:15<span> Cassius – La Mouche (Played Live By DJ Falcon)
39. </span>02:16:18<span> Modjo – Music Takes You Back
40. </span>02:19:17<span> Daft Punk – Musique
41. </span>02:22:23<span> Play Paul – Holy Ghostz
42. </span>02:25:56<span> Vinyl Fever – 1h45 A.M on the Floor
43. </span>02:29:30<span> Modjo – On Fire (Archigram’s When What Remix)
44. </span>02:33:48<span> Aloud – Bob O’lean
45. </span>02:36:38<span> Archigram – Mad Joe
46. </span>02:41:04<span> Raw Man – Lovers
47. </span>02:44:15<span> Daft Punk – One More Time
48. </span>02:49:04<span> DJ Falcon – Honeymoon
49. </span>02:52:46<span> Rhythm Masters – Good Times
50. </span>02:56:38<span> Cassius – Nulife
51. </span>02:58:35<span> Jess & Crabbe – Crack Head (Seduction Mix by Deelat)
52. </span>03:03:02<span> Modjo – On Fire
53. </span>03:05:45<span> Together – Together
54. </span>03:11:19<span> Daft Punk – Voyager (Dominique Torti Wild Style Remix)
55. </span>03:15:25<span> Patrick Alavi – How Much That Means To Me</span>

play-to-earn feature

Rephrase: the end clause is misplaced

As in Squid Game, when Gi-hun decides at the end to return to the deadly games in order to dismantle them. This was a metaphor for a union man bent on beating capitalistic society

I get the hunger game reference to support this, but the idea of many dystopians remain a possible portrayal of the future. For example, 1984 depicts life with continuous surveillance. We know right now that our conversations are listened to and cameras are likely watched. This has been proven in many ways and Snowden has described how out of hand this is.

Maybe I'll try this.

This is the third reason (connected to the above two)

酒吧游戏

It'd be interesting to make a list of what is Actually Doable on the internet and what is Not

What is The Trip Report? MoneyStuff is a format Stratechery is a format Both are delivered through the media type known as email

most literature has pictures power centralization as something that involves the state, upper classes, and lower classes (seemingly limited factors)

I personally do not like this method of learning because I feel that it taught me during my education to "make the external stimulus stop". For example, during a Kahoot game, I would quickly scan the room before answering in order to make sure I choose the most popular answer in order to prevent me from a glowing red screen within the classroom.

xD

playful and competitive activity

For a long time, Austen's use of the word baseball in Northanger Abbey was cited as its first appearance in the English language. But as this episode from the podcast The Thing About Austen explains, this was a mistake. Co-hosts Zan Cammack (she/her) and Diane Neu (she/her) address past speculation regarding Austen's role in the invention of this word, while providing illuminating historical context about Regency sports (Did Austen's contemporaries play baseball?), gender (Was it socially acceptable for women to play cricket and baseball?), and the supposed "all-American" game (If it was common in Britain, when did baseball makes its way into American national identity?).!

Das sollte einleitend im Abschnitt stehen

This is so stupid I don't even know where to start. The implication here is that, in an inherently negative world, positive judgement is only reactionary. It ignores the negativity itself is a reaction, and that one can be in what he concludes as a negative situation, not know it, and therefore not see it as negative (unless he thinks people in poverty have never experienced happiness and will never as long as they are in that situation, which is just so wrong). The longevity of life argument can be used here as well: As life expectancy increases, do the shorter lives of people before us become negative in consequence? They probably didn't think so and considered it a positive to live to 40. Is a short, successful life now more negative than a long unfulfilled one? Benatar's argument is reminiscent of a child playing make-believe and deciding the rules of the game on-the-fly with the only consistency being "What I say goes."

It might be cool if the card game they're playing reflects some thematic aspect of the scene

Manwood (1665) notes that foresters took an oath to protect game from poachers (pp. 400-39). However, here the author implies that the prevalence of poaching can be blamed on their inattentiveness and venality.

在推荐别人的文章时，也可以推荐自己写过的类似的文章。

I would say gratuitous complexity;

Best solutions are simple and permanent

https://hyp.is/VJoswqnkEeyxDWs7XaA_Fw/www.linkedin.com/feed/update/urn:li:activity:6911789281980092416/?commentUrn=urn:li:comment:(activity:6911789281980092416,6912027572851593216)

True value attainable is inversely proportional to the amount of money that can be created

The most money can be created by generating actual harm

See Wars

would be much improved if we acknowledge

that Data is but people in disguise

created for the purpose of making money not true value

as a priority.

provincial IT

part I

Favorite quote: It makes the process of figuring out why it spread as it did sound like a game.

n

The biggest adjustment will have to come from employers. How can they replace the trust previously offered by universities? This looks like winner-takes-all game in which digital technologies allow some universities to scale enough to absorb or kill the rest based on brand and performance.

The competitive focus should be on non-digitizable learning experiences

Demosthenes was widely known amongst groups to be a renowned orator. He was even a part of the start of the democratic party. For some he was considered witty which caused many to not like him but he was still able to uphold valid arguments against his peers. As Rabelias used Demosthenes for a key figure of "fighting another day" shows that Demosthenes was usually one to play a manipulation game before any battle of his.

Sagar, Rahul. “Presaging the Moderns: Demosthenes’ Critique of Popular Government.” The Journal of Politics, vol. 71, no. 4, [The University of Chicago Press, Southern Political Science Association], 2009, pp. 1394–405, https://doi.org/10.1017/s002238160999017x.

I believe that Amanda Knox has important things to say about the matter of being a public figure. I don't want to trivialize her situation, but this type of "fame" has run rampant in the age of social media. People are thrust into the public eye; it could be in the form of a meme, a video, a tweet, etc. Once someone goes viral, you can't easily put the cork back on the bottle, so to speak. Their private lives all of a sudden become public, and once you're a public figure, everything about you is fair game to the media. We consider that celebrities chose to be in the public eye, so the dissection of their lives is considered okay. At what point does that distinction happen? Does merely creating something that a mass audience enjoys mean that they must give up their privacy?

随机数生成

Result 使用注意点

Quality needs to be an emergent property of the way we create knowledge graphs. Tain't what you do but the way that u do it, that's what gets result.

The elephant is in the room indeed.

Addressing Quality requires us finding a way to commensurate adjecent conceptualizations

https://www.linkedin.com/feed/update/urn:li:activity:6915553578552070144?commentUrn=urn%3Ali%3Acomment%3A%28activity%3A6915553578552070144%2C6915558471815831552%29

Need to recognise that "Quality is in the eye of the beholder" is linked to intents of involved agencies

Elephant in the Room: Validating Knowledge Graph Quality

Quality needs to be an emergent property of the way we create knowledge graphs. "'Tain't what you do but the way that u do it, that's what gets results"

Quality The elephant is in the room indeed.

Quality is not an extensional measure

It arises from intentional situatedness and requires agency with a skin in the game

Addressing Quality requires us finding a way to commensurate adjecent conceptualizations too

You always have the option of Not playing THAT game!

Web browsers are a mess * design-wise (html, css, js, webworkers - all known to me leaves hoping for a better world) * performance wise (can't compete with a game engine) * cross-browser interoperability-wise (especially in small details, good luck getting it pixel perfect)

E.g., Tonsky's rants and his work on having a better desktop program execution environment.

I say this all the time!

a hypercube house

Open practices are, indeed, continually negotiated. This is another way of looking at openness - that doing things in the open leave them in a contingent state. i.e. openness as the opposite of 'closure'. Perhaps then what we need is to create structures for teaching and learning that enable this kind of contingency - the ability to review and re-negotiate what we are doing and how we are doing it? This is a form of metacognitive learning on a personal and organisational level. Each teacher/learner needs to be able to observe the system they are in and negotiate how to change it as they proceed. In my own OEP, I do this, this way:

"Nonaka’s and Takeuchi’s practical adaptation of ‘Nishida philosophy’ – their SECI model of organisational knowledge creation – proposes everything is implaced within a “ba” (field). Such Ba can be physical or conceptual. We can think of the basho as a shifting context (such as being a student in a University) or set of moving constraints (like the rules of a game). Either way, what we do / what we are is something implaced within a larger field.

When it comes to learning, a key thing here is to think less not only about how and where we implace ourselves, but equally about what sort of field we are generating. Ba/sho is akin to a habitat; habits develop in relation to specific habitats. If we want to change our habits, we need to also change our habitat. In ‘Nishida philosophy’ subject and object are one, people and environment correlate." Source: Neil Mulholland Build-A-Basho | Thursday 23rd September 2021

Value test. Can you live up to the value you state? Commitment to value is questioned. Basis for challenge is uncertainty.

Risking material value and moral value. Consequence tied to value. Not only would you be incongruent to the value for losing but you also lose money. Skin in the game.

While it is important to pay attention in school, and I don't think the kids should have been allowed to play the game, there is a certain hostility to this kind of disciplinary action that feels depressingly counter productive. The previous school had the right idea in a number of ways - people use things like games as a means of self expression and of practicing cognitive skills. Being very engaged with something, even if it's not part of the curriculum, is healthy and good. Plus, it it's a kind of engagement which the school can't provide but that the developing brain craves, then it forms a hostile relationship between the school and the student.

Perhaps, to some degree, due to inability of having it in the first place with non-ECS systems?

It may be useful to have nodes as an optional interface as some may find it more easy. It is not core to processing, as pointed, I'd like to have my hands on the core - data+logic.

Complexity is not taken away this way, it's hidden, It's still there, but behind a more 'easy' interface perhaps.

'event' is an easy interface.

However, it adds complexity.

The need to describe/"decide" is still there.

"event" captures data needed for a decision. "event handler" decides.

We can't escape the need of data+logic.

What I like in ECS is how data and logic is separated and how it results in a generic processing system.

Whereas with events it's.. yet another system to process data.

Why should they be? Why is it not the one system to crunch data?

And ECS just has Entities.

Also, Systems can be Entities as well, however we'd need a piece of logic to bootstrap.

And Entities are IDs, we don't need that either. Or, if we do, content-based id can be used.

.c1

This was new to me so I looked it up. It is essentially a set of activities and practices for facilitating innovation and generate new ideas. A facilitator leads a group towards some goal by way of a game, a structured activity that provides scope for thinking freely. More like improv or extended ice-breaker activities.

As someone who has spent their entire life playing some for of roleplaying game or another, I immediately thought of the character creation process when the concept of persona construction was first presented to me. I have literally created hundreds of characters over time and strive to steer away from cliché or overused archetypes. I believe this will give me an edge when developing personas for my learning designs.

This sounds simple and straightforward, but in reality it might be a challenge to understand and be mindful of 'all' cultures especially within the diverse population we are in today. I had run into this issue myself when I adopted a hangman game in my training. I received a comment that it is highly offensive to the African American group. As a result I adjusted my training accordingly.<br> Image source: Wikimedia Commons

.

Other interesting applications of Game Theory in today's digital business environment:

https://www.itproportal.com/2015/05/27/canary-box-is-a-trap-for-hackers/

https://analyticssteps.com/news/we-forge-canary-trap-confuse-hackers

https://www.businessinsider.com/nba-canary-trap-media-2014-12

I mean, Ultimate is supposed to be the great hurrah for Smash. Isn't it the last game too? I'm going to give a hard disagree on this one.

i forgot he was even in smash lmao

(For context, this post was made in 2020) It's put a bit dramatically, but I do see what they're saying. When a lot of shit is happening in one's life, the little things tend to get to you a lot more.

I love this metaphor, because it truly defines how present we need to be with our students. We have to be able to pay attention and respond, not just in a complimentary or excited way, but with intention.

Yes! This supports what was mentioned earlier about how a teacher has many roles to play, sometimes the observer, the researcher, or the friend… but it is absolute true that one of our main jobs is to give space and attention to their joy because it is the spark of their learning.

I mean, probably.

What was their target?

annotating for the first time... sorry for being late to the annotation game!

• oversiloing
• repeat QA
• silo by silo

perpetual annuity income stream

gift keeps giving

part II

Data managment , the very idea is flawed. Data is created always in some intentional context. Narrow focusing on it renders the task of Management ultimately awry.

Taking the narrow view was instrumental at the point of bootstrapping, getting IT off the ground. It is time we pay attention to Ted

https://www.youtube.com/watch?v=hZ3gmh-d9oI

https://www.youtube.com/watch?v=gWDPhEvKuRY

http://www.thetednelson.com/videos.php

I was more wanting to speak on the graph above, being that a small confusion I was having on my end was that, with a plan with as this, could misinformation come into account in a bigger way?

annotation as well as computation

intelligent systems

I have mixed feelings about the physicality of the story being introduced so late in the game. I DO like the spare details, don't need to beautifully illustrate the parking lot, but I think one, MAYBE two more lil pull back/intro scenes could fix this abruptness. Also unsure how I feel about Larry himself being described physically so late. Mental image was kinda the same though -> largely because of title I think lol.

Die Inhalte mögen trivial wirken - aber bedeutet das, dass die Methode per se oder gänzlich dem Trivialen verschrieben ist? Ich denke nicht - ich denke auch nicht, dass es zufällig ist, dass diese neue Lernform ihre ersten Schritte in seichtem Gewässer geht

Fact

Chaos game için filogenetiğe ekle

Chaos game representation için filogenetiğe ekle

Unity 2D Phát Triển game

i love kahoot! i have learned about behaviorism before, but never noticed the connection between the two. I think another similar tool would be the games within Quizlet

Another tool that would fit into the category of behaviorism is Quizlet. Its games and flashcard tools are a great example of stimulus-response learning through immediate feedback. There is one right or wrong answer and the user receives immediate praise or help after answering the questions.

I didn't know Kahoot could fit into the category as a behaviorist app. Kahoot is often used in the language classroom as a tool to make a class. I've used it and my students have had lots of fun especially when there's room for competition. On the flip side, the person from the comment above is right since it doesn't address accessibility nor promotes universal design for learning leaving disabled students out. It's interesting to see that Kahoot claims to follow global and commonly accepted standards for accessibility which state that their products are perceivable, operable, and understandable. https://trust.kahoot.com/inclusion-and-accessibility-policy/ On the other hand, Paramjit Kaur on his study among 50 secondary students in an international school about their language learning experiences with Kahoot! says that almost all the students found Kahoot! to be an effective tool in their language classrooms and they feel happy and competitive when they are engaged in Kahoot! based activities. https://www.researchgate.net/publication/338035766_KAHOOT_IN_THE_ENGLISH_LANGUAGE_CLASSROOM

I take issue with recommending Kahoot as a tool. Although it is an accurate use of behaviorist learning and can be successful in classroom settings, it is incredibly ableist and does not do enough to address its accessibility issues and implement universal design for learning. I am going to do some research to see if there is a tool that we can recommend instead of Kahoot that still implements behaviorist theory and is quiz based with immediate feedback, but more accessible to the disabled community.

Discussion, revision and decision

Decision - Verified with reservations

Charles A. Schumpert: Verified manuscript

Max Shokhirev: Verified with reservations

Author response and revisions

Author response to reviewer Max Shokhirev

Dear Dr Shokhirev,

Thank you so very much for having reviewed my paper; your comments have been very helpful for me to improve it. Please find attached two identical copies of my revision of the paper (changes are highlighted in one of the copies) and a supplementary file that relates to one of your comments. Please see below my response to your comments when applicable.

Does the work cite relevant and sufficient literature? Some, but seems to be very limited in terms of biological literature.

I recognize and acknowledge this issue. It will be addressed in some of the specific responses below.

Are the conclusions adequately supported by the results? No

I understand this question and its answer as the theory presented in the paper (the conclusions) not providing new, proof-of-principle evidence (the results). That is correct, the theory is based only on existing evidence (most importantly, the already described age-dependent "transcriptional noise"), it is consistent with it and, importantly, it provides (in the new revision) three additional, experimentally testable predictions.

The author has laid out a theoretical argument for senescence as a tradeoff between information capacity between epigenetic and non-epigenetic content.“A constraints-based theory of senescence: imbalance of epigenetic and non-epigenetic information in histone crosstalk.” This work is interesting, but is based on a superficial understanding of the biology underlying senescence/aging, makes several dangerous oversimplifications and assumptions, and does not provide any data or analysis to support the theory.

I would argue the theory is not based on a superficial understanding of the biology of senescence as it is currently established—in fact it is not based on the current biology of senescence at all. The theory is actually based on my previous theoretical work where I show (supported by real data analysis) how the constraints on transcription start site-adjacent histone crosstalk that are explicitly uncorrelated with transcriptional levels associate strongly with cell differentiation states—even more strongly than those constraints correlated with transcriptional levels (an association which is expected and already described in previous work). This in turn suggests the existence of an additional, higher-order type of biologically meaningful information conveyed by histone crosstalk, with this information is by definition uncorrelated with the information for precise epigenetic control of transcriptional levels. I called this information "hologenic" because it associates to cell differentiation trajectories necessary for the development of the multicellular individual as as a whole while being explicitly uncorrelated with the transcriptional levels. My previous work showed that the capacity for hologenic information in histone crosstalk grows at the expense of that for epigenetic information (this is necessary for the development of the multicellular individual). I emphasize that the theory proposed here relies on only two assumptions: (i) the overall histone crosstalk remains statistically constant in magnitude throughout adulthood and (ii) the hologenic component of the overall histone crosstalk increases at the expense of the epigenetic component throughout adulthood (with the exceptions depicted in Fig. 1b). These assumptions are of course not to be taken for granted, so in the new revision of the paper they are presented as predictions that can falsify the theory. I will further elaborate on these assumptions in my specific responses below.

All the above being said, the version of the paper you reviewed apparently gives the wrong impression that the theory is a comprehensive description of the senescence process with all its complexity. It is not. It is not surprising then that the theory appears to oversimplify the explanatory power of mechanisms known to be part of the senescence process when in reality they are claimed—this is a big theoretical claim I am making—to be the consequence of the primary cause of senescence. It is only this primary cause what the proposed theory is all about. For these reasons and thanks to your observation, I stated this distinction explicitly in the new subsection 1.2 "Scope" and also modified the title of the paper accordingly.

I recognize and acknowledge that the paper does not present new data or experimental results in direct support of the theory—something that arguably makes it less compelling to be considered let alone to be tested experimentally. But I do wish to point out that a scientific theory, must "only" (i) effectively explain the phenomena it is aimed to explain (in this case, the primary cause of senescence), (ii) be consistent with existing observations/results (most importantly, with the well described age-dependent "transcriptional noise" in this case), and (iii) provide non-trivial, experimentally testable predictions that can falsify it. I have tried to make up for the lack of preliminary supporting evidence by adding three new straightforward, experimentally testable predictions that can falsify it. Importantly, two of said predictions (C and D in subsection 2.6) relate to precisely how senescence can be slowed down, even stopped, or accelerated—and with associated effects in terms of resistance/propensity to carcinogenesis—in any non-human species, because the direct testing requires genome editing. In this context, I have no problem granting that the prior probability of predictions C and D being verified experimentally is exceedingly small. On the other hand, the experimental verification of predictions C and D would arguably be a game-changing result in terms of the fundamental understanding of the senescence process, however unlikely this scenario is a priori. In this context, I submit to you that the extraordinary nature of predictions C and D in both theoretical and practical terms (I reiterate, this is not to say predictions C and D will be verified) more than makes up for the lack of preliminary evidence for the theory. The prospect of slowing down or even stopping the senescence process may catch the attention of at least some research groups with genome-editing capabilities, given that the gene edits described in predictions C and D are very specific. (You can find more about predictions C and D in my response to your comments related to the subsection 2.4 of the paper you reviewed).

Sections 1.1-1.3 The author only mentions the Hayflick limit as a biological reference for senescence. There is a very rich body of literature on senescence and aging that is completely overlooked here. The author should include additional references to reviews for senescence and aging to orient the reader to the complexity of these biological processes (e.g. PMC8658264, PMC7846274).

Thank you for pointing this out. I have included the suggested review articles as references and, most importantly, I tried now to clarify the scope of the theory in a new subsection (1.2 Scope). The scope of the theory is in a sense, very limited: it is indented to explain only the beginning of the causal chain of age-related changes we identify as aging at the multicellular-individual level. In other words, it is about what fundamentally triggers the process. On the other hand, such a scope (i.e., describing the first cause) is quite ambitious in the sense that it should allow, at least in principle, for the manipulation of the process (either slowing it down or accelerating it). I will come back to this point later in my response.

Please clarify what you mean by senescence vs aging for both cells and individuals. Senescence is a natural biological process that cells/organisms use to turn off cell replication due to damage (e.g. telomere shortening, double-stranded breaks, etc.). Other cells can also facilitate this process through signaling (e.g. immune cells or contact inhibition).

I am not a native English speaker, and one the first things I did when addressing this problem was to study the associated terminology in the literature. Unfortunately, this terminology is not particularly monolithic. In some articles, the age-dependent, progressive dysfunction undergone by multicellular individuals once they reach their mature form is referred to as "senescence" (PMID 1677205, 6776406, 12940353, 22884974, among others), "biological aging" (PMID 31833194, 33982659, 34700008, among others), or even simply as "aging" (PMID 24862019, 34990845, 31173843, among others). In this context, I decided to stick to "senescence" mainly because (i) it is only one word and (ii) unlike "aging", "senescence" directly and unambiguously implies time-dependent dysfunction or decay. At any rate, to distinguish the term from cellular senescence/cellular aging I created a Glossary in the paper where these terms and others are clarified to avoid confusion.

Aging is typically thought of as an organismal phenomenon, which is still poorly understood but is theorized to include tradeoffs (as you describe in section 1.2). It is also accepted that aging is cell, tissue, and organism specific. Since you talk about senescence and aging across both biological scales, it is important to define exactly what your theory pertains to.

I am glad we agree that senescence is poorly understood (especially in comparison to cellular senescence). Unfortunately, some colleagues in the community interpret this as saying the research been done on the topic is worthless—it is not—when it is really pointing out the phenomenon largely lacks falsifiable theories, let alone an already tested falsifiable theory (with experiments failing to falsify it).

Section 1.4

The author posits that senescence is an imbalance in information contents of histone post-translational modifications around transcription start sites. This is just one level of regulation, albeit an important one. The author seems to completely overlook many other types of regulation (e.g. microRNA, lincRNAs, metabolic/energetic constraints, non-proximal regulation at enhancers, higher ordered structure of the chromatin, post-translational regulation of proteins, and etc.). How can all of these other important levels of regulation fit into this theory? All have been implicated in senescence/aging in some form or another.

What you point out here is very important, thank you. In a remarkable piece of research, Kumar and colleagues showed that core nucleosomal histone post-translational modification (hPTM) profiles are able to predict transcript abundance levels with very high accuracy (R~0.9, ref. 33). The constraints on hPTMs underpinning this predictive power (in turn underpinned by DNA-histone octamer interactions)—as well as those constraints on hPTMs that are explicitly uncorrelated to transcriptional levels—are central to the theory proposed. As stated in the new section 1.2, the complex cascade of changes/interactions characterizing senescence escapes the scope of the theory. In this context, most of the types of regulation you mention are under this theory not actually regulation in a "teleological" (the quotes are meant to avoid alienating the reader) sense but rather types of propagation/amplification of truly regulated/dysregulated changes. One of my goals when developing this theory was to try shift attention from "molecule A-collides with molecule-B, which collides to..." into higher-order constraints and trying to explain phenomena such as the well-known, age-dependent "transcriptional noise", which under the theory presented should be understood as senescence itself. Furthermore, I maintain the relative slow progress we have made in understanding phenomena such as cancer and senescence (in spite of the abundance of high-throughput data) comes from

The author further suggests that histone crosstalk information content can be decomposed into two unrelated components: epigenetic and non-epigenetic. The non-epigenetic component is described as “hologenic information content,” which stems from a previously published work by the author. Non-epigenetic is confusing in this context since really this is information content that stems from the synergies of individual cells to form a whole, e.g. the emergent information content that comes from many cells working together (or at least this is how I understand the underlying theory). This information content is important for the general maintenance and survival of the organism. The author should clarify this point further, since this seems to be one of the fundamental assertions being made in the paper. For example, bringing in the descriptions used in section 2, can further clarify these central points.

In my previous work, "hologenic" information content is defined as being uncorrelated with (i.e., orthogonal to) changes in transcriptional levels, in the same way "epigenetic" information has been defined (traditionally and for good reason) as being uncorrelated with changes in the DNA reason. Hologenic information content emerges when proliferation-generated extracellular gradients of secreted molecules start to being used to perform regulatory work (after being transduced) on the histone crosstalk of each cell's nucleus.

In addition, the author states: “ Moreover, the sum decomposition in Eq. 1 implies that the growth in magnitude (bits) of the hologenic (i.e., non-epigenetic) component must be accompanied by a decrease in magnitude of the epigenetic component.” This is not necessarily true, since signaling is a separate biological process from the regulation of gene expression. In other words, both can increase or decrease simultaneously. For example, a healthy non-senescent immune cell can upregulate very specific transcriptional programs that lead to very complex signaling and extra-cellular interactions. You can argue that both represent an increase in information content for both the epigenetic and non-epigenetic “hologenic” components. In addition, as cells naturally senesce they are programmed to turn off cell-cycling while upregulating autophagy and repair processes. They may not upregulate extracellular signaling at this time, which would seem to contradict the author’s theory/statement. In this case, the simplification that all cells are the same is dangerous because it overlooks the tradeoff of information contents between cells. It also ignores important repair pathways (senescence being one of them), to deal with cells that have dysregulated their natural processes over time. It also overlooks the important action of immune cells that work to get rid of cancer and poorly-functioning cells.

This comment of yours (referring to complex yet specific signaling pathways and interactions) clearly shows I did a poor job (if not utterly failed) in conveying that the epigenetic and hologenic components must be understood in chromatin-wide terms. Yes, the random variables used to define both components in the sum decomposition of Eq.1 are defined with respect to a single, generic transcription start site, but these random variables take their respective values from data for all transcription start sites in the nucleus. This is why the terms Eq. 1 and the log-ratio in Eq. 2 must be understood as chromatin-wide terms. Again, this approach intends to shift attention from specific (however important) molecular mechanism to higher-order, information conveying hologenic/epigenetic constraints (whose imbalance are proposed to trigger senescence as proposed in this theory). The chromatin-wide nature of the hologenic and epigenetic components is not an obvious consideration but it is a very important one, so it is now explicit (twice) in the revised text and I thank you for bringing this to my attention.

For a statistically invariant level of overall histone crosstalk C(X1,...,Xn) in Eq. 1, a growth in magnitude of the hologenic (i.e., non-epigenetic) component must be accompanied by a decrease in magnitude of the epigenetic component and vice versa. This chromatin-wide trade-off might not hold, as you suggest, only if the overall histone crosstalk C(X1,...,Xn) varies significantly (in particular, if it varies significantly throughout adulthood). If, in fact, the overall histone crosstalk C(X1,...,Xn) varied significantly throughout adulthood the proposed theory would make no sense whatsoever. Mathematically, C(X1,...,Xn) is finite and upper bounded by ΣH(Xi) - max H(Xi) (where H(Xi) is the marginal Shannon uncertainty of Xi), and one can further expect that the overall histone crosstalk represented nu C(X1,...,Xn) remains statistically invariant for a number of reason, chief among them the massive chromatin instability that would ensue if it indeed C(X1,...,Xn) varied. For this reason, I included the C(X1,...,Xn) time-invariance as an additional prediction for the falsifiability of the theory.

Also, it seems crosstalk, correlation, capacity, and content, are used interchangeably. Please clarify that these are all the same, or use one of these terms to avoid confusion.

I went through the use of these terms in the paper and, unfortunately, I cannot reduce them to just one term or dispense with them altogether without losing rigor for the theory. Because of this I decided to include them in the Glossary, hoping that it will make any reader recognize that their respective uses in the text are actually not interchangeable.

Section 1.5 The author provides a general approach for measuring the log of the ratio of epigenetic and non-epigenetic capacities for a particular histone modification at three positions (i,j,k), and for some measured abundance of mRNA Y. Since we typically measure abundance of a particular modification genome-wide, and the mRNA level for tens of thousands of genes, how would a realistic equation look like (i.e. one that has 10k mRNA levels, and 10k histone positions)? In addition, the author does not explain how to combine correlations across multiple histone modifications. Please expand this section to make it relevant for real-world genome-wide measurements since this will be important for falsifying the theory.

Since public datasets are available (e.g. the aging atlas https://doi.org/10.1093/nar/gkaa894), the author should show an example of how a dataset might be used to falsify or demonstrate the theory in more detail.

This response to this observation can be found in the new Fig. 2 and with greater detail in Supplementary File 1. In summary, the data analysis approach is basically the same used by Kumar et al. (ref. 33). That is, with tandem RNA-seq/ChIP-seq data obtained from the same cell sample a table can be constructed with the rows representing the transcription start sites (TSSs) in the genome and the columns displaying the normalized ChIP-seq signal for each hPTM in different positions relative to the respective TSS (variables X1,...,Xn in the paper) plus a column with the respective measured transcript abundance for each TSS (variable Y).

Section 2.1 The author uses correlation of the log ratio of the epigenetic and non-epigenetic content with age as a readout of “reassignment” of crosstalk/contents, arguing that for cancer cells this correlation should be essentially zero. This seems like an oversimplification of the “reassignment” process since senescence may occur in phases across the age of a cell/organism, and since there might be both increases and decreases in the log ratio of contents due to natural biological processes and variability. Would it not be better to measure the sum of changes in the log ratio or the difference between the log ratios at different ages?

In addition, the biological age of a cell/tissue/organism can vary. For example, stem cells may have negligent aging, while other cells might age relatively quickly. Again, the author should clarify the context of age: are we measuring strictly chronological age correlation? Should we consider different correlations for each cell/tissue in the organism? What about tradeoffs in information content between cell types and tissues? In other words, it is unclear how the theory should be applied to biological systems.

This is a great observation, thank you. Yes, the correlation in Eq.3 relates strictly to chronological age (in other words, to time). The correlation must hold for somatic cells of the same type according to the theory; now this condition is explicit in the text. In this context, some cell types and tissue may senesce (see new Fig 1c, center) faster than others as you point out; in this case the associated slope is predicted to be steeper, whereas cell types that senesce relatively slower the slope should be gentler. Only in species displaying negligible senescence the hologenic/epigenetic log-ratio should remain constant (i.e., zero slope, as depicted in Fig. 1b, blue curve), or fluctuate significantly in species displaying "reversible" development (Fig. 1b, magenta curve).

Section 2.2 The author argues that senescence is an emergent property of the loss of information content for epigenetic histone crosstalk and an increase in information content of “hologenic” information content (e.g. cell signaling and anti-tumor signaling). I believe this premise does not stem from the reality of biological systems (see my comments for section 1.4).

The trade-off between capacity for hologenic and epigenetic information within a constant overall histone crosstalk magnitude—in particular, the growth of the former at the expense of the latter throughout adulthood generating a dysfunctional imbalance—is arguably the cornerstone of the theory in fundamental terms. Whatever my response was to your comments about subsection 1.4, this crucial trade-off cannot be taken for granted, however compelling the arguments are. In this context, there is no better solution than putting the hologenic/epigenetic trade-off to the test (see prediction B for falsifiability of the theory, also further detailed in the new revision of the paper). Realistically, however, I expect prediction B to be tested (and the hologenic/epigenetic log-ratio quite thoroughly examined) only if predictions C and D are verified. In that scenario, it will be interesting to see whether the hologenic/epigenetic log-ratio increase may be steeper in some tissues (which should then explain why those tissues senesce faster than others).

Also, this section seems to be contradicting the author’s conclusions and is very confusing. The author seems to argue that there is both more AND less constraint at the multi-cellular level (organismal)? Please clarify or remove this section.

I can see now how it seems contradictory because I was saying the capacity for hologenic information (which is about transcriptional levels being accurate for the multicellular individual as a whole) increases up to the point of being dysfunctional at the multicellular-individual level. Here I failed to convey that said dysfunctional outcome derives from the concurrent decrease of capacity for epigenetic information, not from the increase of capacity for hologenic content per se). Thank you for bringing this to my attention. I decided to remove this subsection altogether because the hologenic/epigenetic trade-off is covered in greater detail in the next subsection.

Section 2.3

Senescence as transcriptional overregulation is vague. Here the author is arguing that as epigenetic constraint decreases, you have a decrease in precision (e.g. loss of regulation), but then you have a competing global or hologenic increase in constraints, which constrains the expression of genes for the overall benefit of the organism. A shift toward global constraint.

My intention here is to establish a fundamental contrast between the group of diseases we call cancer and senescence using the difference between the concepts of accuracy (average closses of the actual values to a target value) and precision (variance of the actual values, also added to the Glossary). In this context, since cancer is an almost canonical example of gene dysregulation (transcriptional accuracy is lost because capacity for hologenic information is lost), we can understand senescence as transcriptional overregulation in the sense of too much capacity for hologenic information gained over time at the expense of capacity for epigenetic information, thereby losing transcriptional precision). I added a third panel "c" to Fig. 1 to clarify the proposed contrast between cancer and senescence, in terms of impaired transcriptional regulation (i.e., inaccurate up to dysfunction in cancer and imprecise up to dysfunction in senescence).

Section 2.4 This seems to be describing an illustrative real-world example? This section is incredibly specific and again only focuses on one possible mechanism and does not include any measured data or analysis. Please preface this section to explain that this is just one of many possible examples. Again, it will be good to provide other examples looking at other aspects of aging biology (not just histone modifications).

I am not including examples of mechanisms propagating dysfunctional changes in the senescence process because this theory is not about adding one more possible mechanism to the collection of well-described mechanisms associated to senescence. The theoretical claim I am making here is that the sequence of steps described in subsection 2.4 constitute the primary cause that triggers senescence throughout the multicellular individual's adulthood. This is of course an extraordinary theoretical claim and, as the great Carl Sagan pointed out, as such requires extraordinary evidence (or, in this theoretical paper, an extraordinary prediction aimed to obtain said evidence).

This is why I also added two predictions, C and D, to the now completely rewritten subsection 2.6 "Falsifiability". These predictions are extraordinary in that they provide extremely specific sufficient conditions for either slowing down or accelerating the senescence process in any non-human species. For this reason (i.e., adding predictions C and D) I have duly updated the "Competing interests" section of the paper. [Note: in a separate paper I explore in greater depth the theoretical underpinnings of predictions C and D.]

Section 2.5-2.9,3

This seems to be a general discussion. It would be easier to organize these sections into one discussion section for added clarity. Again, I would recommend not talking about sweeping statements like “Senesensce’s ultimate cause” and “Can senescence be stopped?” since this theory only addresses one small aspect of the biology underlying aging and senescence and does not address the heterogeneity of aging. These topics are controversial and should be addressed very carefully to avoid alienating the biological community.

Thank you for your suggestion, I organized a Discussion section accordingly, placing the predictions for falsifiability in it. Additionally, I changed “Senescence’s ultimate cause” for “Senescence’s proposed ultimate cause”, clarifying also in the Scope subsection 1.2 that ultimate/proximate is used only in terms of the concepts of causality as introduced and named by Ernst Mayr.

Following your advice, I removed the subsection “Can senescence be stopped?” Now, I believe this theory is bound to alienate at least some colleagues in the biological community (among those who read the paper, that is). As you point out, the theory addresses only one small aspect of the senescence process, but it is not any small aspect. It is about what triggers the process or, equivalently, what is the initial link of the causal chain leading to senescence with all its mechanistic complexity. This implies all other proposed primary causes would, simply by logical exclusion, be incorrect.

One of the reasons I developed this theory in the first place is that I failed to find even a single falsifiable description proposing a primary cause of senescence that integrates Mayr's proximate and ultimate concepts of causality. To be clear, this is not a shortage of explanatory accounts for the senescence process; it is a shortage of experimentally falsifiable ones. There are scientific fields where falsifiability is inherently difficult or probably impossible to meet, such as paleoclimatology. But that is not the case in biology—certainly not in developmental biology. This is why I agree with you in that the senescence process is still poorly understood in fundamental terms (which by no means implies all work in the field is worthless).

Forgive me for the following related digression/personal note: Since I started writing this paper I faced the dilemma of how many research works on this topic should I cite, given there is plenty (even considering this is not a review-type article). We scientists are only human and as such we very much like our work being cited in terms of current knowledge. That changes, however, when the explanatory account we like the most (or even worse, the explanatory account we ourselves proposed) is being cited to acknowledge its existence but the lack of predictions to falsify the "theory" is also pointed out (our reaction changes probably because unfalsifiable explanatory accounts can be always dismissed as just storytelling, however compelling the story might be). These rather petty emotional responses of ours have of course nothing to do with the advancement of science. Yet, many scientific journals—however prestigious, and particularly in the life sciences—routinely publish articles the word "theory" describing the work in the title and/or body when there is no prediction to be found for falsifiability. As a student, this is when I learned the interests of the scientific publishing industry (as we know it) and those of science are completely uncorrelated—not really surprising since their respective goals are so different. In this context, I found the PeerRef initiative/model very interesting since it aims to focus purely on the scientific content as opposed to essentially non-scientific considerations.] In the previous revision of the paper I offered only one prediction to falsify the theory, which is arguably cumbersome—and therefore arguably not too appealing—for experimentalist colleagues to test. For that reason I added three predictions (A, C, and D) which are straightforward to test in the laboratory. In this context, I am hoping the scientific community will be open to consider and to test falsifiable theories, however alienating they might be. Especially when we are dealing with a phenomenon for which paradigmatically accepted explanatory accounts is, at least to the best of my knowledge" all we currently have. Last but certainly not least, I wish to express again my gratitude for all the time you devoted to review my paper. Whether or not the theory it presents resists falsification attempts, I firmly believe the paper itself is now better than it was before thanks to your feedback.

Reviewer response

In general, it seems the paper is improved and includes quite a bit of additional clarification and qualifying statements.

The scope is also much more constrained and it is clear that the author is sticking only to proposing a possible theory, which is fine with me, albeit not as exciting as it might have been if the author had gone through and provided real-world examples or evidence. It still bothers me that the work is trying to implicate a very specific mechanism for senescence (chromatic cross-talk and regulation), since now it is clear that the work is mostly a theoretical exercise without much basis in established biology. In other words, chromatin cross talk might be an example of one way that this could happen among others (e.g. other epigenetic regulation or lack thereof). As a theoretical work it is fine as long as you agree that it is sufficient for the scope of the journal

Decision changed - Verified with reservations: The content is scientifically sound, but has shortcomings that could be improved by further studies and/or minor revisions.

Author response to reviewer Charles A. Schumpert

Dear Dr Schumpert,

I wish to thank you for having reviewed my paper; your comments have been very encouraging for the effort of moving my theory forward. Please find attached two identical copies of my revision of the paper (changes are highlighted in one of the copies) and a supplementary file that relates to one of your comments. Please see below my response to your comments when applicable.

Overall the manuscript is written brilliantly and provides excellent context to the audience about a complex theoretical biological concept. No flaws can be found, although one could argue against a few of the points in the assumptions used to construct the theory, there’s nothing illogical or irrational.

Thank you for kind words, but I have to admit any and all brilliance that may be found in the write-up must be credited to my wonderful editor Angelika Hofmann. Regarding the assumptions, this theory relies on two critical ones, which of course cannot be taken at face value. This is why these assumptions inform prediction B (in the new revision). There are now four experimentally testable predictions to falsify the theory; hopefully some will be appealing to experimentalist colleagues.

In your opinion how could the author improve the study? The writing of the paper makes it easy to read, which can sometimes be a challenge with theoretical biology manuscripts. Potentially adding a bit more context on the various theories of aging may help demonstrate the marriage of the ideas into the theory he constructed.

One of the problems I faced when writing this paper was how many different explanatory accounts (there is plenty) I was going to cite provided I would have to underscore their lack of testable predictions for falsifying them—which in time becomes dangerously close of being downright unfalsifiable. As Wolfgang Pauli famously said, unfalsifiable theories are not even wrong. In other words, the problem was how many readers I was going to alienate while having no intention to do so. Navigating academia's social ocean is not an easy task, at least not to me, so I decided to compromise. To be clear, I am by no means claiming my theory is correct but underscoring that (i) it can be tested experimentally and (ii) explains the known age-dependent, cell-to-cell transcriptional noise that I argue should be regarded as senescence itself in fundamental terms.

Discussion, revision and decision

Decision - Verified with reservations

Charles A. Schumpert: Verified manuscript

Max Shokhirev: Verified with reservations

Author response and revisions

Author response to reviewer Max Shokhirev

Dear Dr Shokhirev,

Thank you so very much for having reviewed my paper; your comments have been very helpful for me to improve it. Please find attached two identical copies of my revision of the paper (changes are highlighted in one of the copies) and a supplementary file that relates to one of your comments. Please see below my response to your comments when applicable.

Does the work cite relevant and sufficient literature? Some, but seems to be very limited in terms of biological literature.

I recognize and acknowledge this issue. It will be addressed in some of the specific responses below.

Are the conclusions adequately supported by the results? No

I understand this question and its answer as the theory presented in the paper (the conclusions) not providing new, proof-of-principle evidence (the results). That is correct, the theory is based only on existing evidence (most importantly, the already described age-dependent "transcriptional noise"), it is consistent with it and, importantly, it provides (in the new revision) three additional, experimentally testable predictions.

The author has laid out a theoretical argument for senescence as a tradeoff between information capacity between epigenetic and non-epigenetic content.“A constraints-based theory of senescence: imbalance of epigenetic and non-epigenetic information in histone crosstalk.” This work is interesting, but is based on a superficial understanding of the biology underlying senescence/aging, makes several dangerous oversimplifications and assumptions, and does not provide any data or analysis to support the theory.

I would argue the theory is not based on a superficial understanding of the biology of senescence as it is currently established—in fact it is not based on the current biology of senescence at all. The theory is actually based on my previous theoretical work where I show (supported by real data analysis) how the constraints on transcription start site-adjacent histone crosstalk that are explicitly uncorrelated with transcriptional levels associate strongly with cell differentiation states—even more strongly than those constraints correlated with transcriptional levels (an association which is expected and already described in previous work). This in turn suggests the existence of an additional, higher-order type of biologically meaningful information conveyed by histone crosstalk, with this information is by definition uncorrelated with the information for precise epigenetic control of transcriptional levels. I called this information "hologenic" because it associates to cell differentiation trajectories necessary for the development of the multicellular individual as as a whole while being explicitly uncorrelated with the transcriptional levels. My previous work showed that the capacity for hologenic information in histone crosstalk grows at the expense of that for epigenetic information (this is necessary for the development of the multicellular individual). I emphasize that the theory proposed here relies on only two assumptions: (i) the overall histone crosstalk remains statistically constant in magnitude throughout adulthood and (ii) the hologenic component of the overall histone crosstalk increases at the expense of the epigenetic component throughout adulthood (with the exceptions depicted in Fig. 1b). These assumptions are of course not to be taken for granted, so in the new revision of the paper they are presented as predictions that can falsify the theory. I will further elaborate on these assumptions in my specific responses below.

All the above being said, the version of the paper you reviewed apparently gives the wrong impression that the theory is a comprehensive description of the senescence process with all its complexity. It is not. It is not surprising then that the theory appears to oversimplify the explanatory power of mechanisms known to be part of the senescence process when in reality they are claimed—this is a big theoretical claim I am making—to be the consequence of the primary cause of senescence. It is only this primary cause what the proposed theory is all about. For these reasons and thanks to your observation, I stated this distinction explicitly in the new subsection 1.2 "Scope" and also modified the title of the paper accordingly.

I recognize and acknowledge that the paper does not present new data or experimental results in direct support of the theory—something that arguably makes it less compelling to be considered let alone to be tested experimentally. But I do wish to point out that a scientific theory, must "only" (i) effectively explain the phenomena it is aimed to explain (in this case, the primary cause of senescence), (ii) be consistent with existing observations/results (most importantly, with the well described age-dependent "transcriptional noise" in this case), and (iii) provide non-trivial, experimentally testable predictions that can falsify it. I have tried to make up for the lack of preliminary supporting evidence by adding three new straightforward, experimentally testable predictions that can falsify it. Importantly, two of said predictions (C and D in subsection 2.6) relate to precisely how senescence can be slowed down, even stopped, or accelerated—and with associated effects in terms of resistance/propensity to carcinogenesis—in any non-human species, because the direct testing requires genome editing. In this context, I have no problem granting that the prior probability of predictions C and D being verified experimentally is exceedingly small. On the other hand, the experimental verification of predictions C and D would arguably be a game-changing result in terms of the fundamental understanding of the senescence process, however unlikely this scenario is a priori. In this context, I submit to you that the extraordinary nature of predictions C and D in both theoretical and practical terms (I reiterate, this is not to say predictions C and D will be verified) more than makes up for the lack of preliminary evidence for the theory. The prospect of slowing down or even stopping the senescence process may catch the attention of at least some research groups with genome-editing capabilities, given that the gene edits described in predictions C and D are very specific. (You can find more about predictions C and D in my response to your comments related to the subsection 2.4 of the paper you reviewed).

Sections 1.1-1.3 The author only mentions the Hayflick limit as a biological reference for senescence. There is a very rich body of literature on senescence and aging that is completely overlooked here. The author should include additional references to reviews for senescence and aging to orient the reader to the complexity of these biological processes (e.g. PMC8658264, PMC7846274).

Thank you for pointing this out. I have included the suggested review articles as references and, most importantly, I tried now to clarify the scope of the theory in a new subsection (1.2 Scope). The scope of the theory is in a sense, very limited: it is indented to explain only the beginning of the causal chain of age-related changes we identify as aging at the multicellular-individual level. In other words, it is about what fundamentally triggers the process. On the other hand, such a scope (i.e., describing the first cause) is quite ambitious in the sense that it should allow, at least in principle, for the manipulation of the process (either slowing it down or accelerating it). I will come back to this point later in my response.

Please clarify what you mean by senescence vs aging for both cells and individuals. Senescence is a natural biological process that cells/organisms use to turn off cell replication due to damage (e.g. telomere shortening, double-stranded breaks, etc.). Other cells can also facilitate this process through signaling (e.g. immune cells or contact inhibition).

I am not a native English speaker, and one the first things I did when addressing this problem was to study the associated terminology in the literature. Unfortunately, this terminology is not particularly monolithic. In some articles, the age-dependent, progressive dysfunction undergone by multicellular individuals once they reach their mature form is referred to as "senescence" (PMID 1677205, 6776406, 12940353, 22884974, among others), "biological aging" (PMID 31833194, 33982659, 34700008, among others), or even simply as "aging" (PMID 24862019, 34990845, 31173843, among others). In this context, I decided to stick to "senescence" mainly because (i) it is only one word and (ii) unlike "aging", "senescence" directly and unambiguously implies time-dependent dysfunction or decay. At any rate, to distinguish the term from cellular senescence/cellular aging I created a Glossary in the paper where these terms and others are clarified to avoid confusion.

Aging is typically thought of as an organismal phenomenon, which is still poorly understood but is theorized to include tradeoffs (as you describe in section 1.2). It is also accepted that aging is cell, tissue, and organism specific. Since you talk about senescence and aging across both biological scales, it is important to define exactly what your theory pertains to.

I am glad we agree that senescence is poorly understood (especially in comparison to cellular senescence). Unfortunately, some colleagues in the community interpret this as saying the research been done on the topic is worthless—it is not—when it is really pointing out the phenomenon largely lacks falsifiable theories, let alone an already tested falsifiable theory (with experiments failing to falsify it).

Section 1.4

The author posits that senescence is an imbalance in information contents of histone post-translational modifications around transcription start sites. This is just one level of regulation, albeit an important one. The author seems to completely overlook many other types of regulation (e.g. microRNA, lincRNAs, metabolic/energetic constraints, non-proximal regulation at enhancers, higher ordered structure of the chromatin, post-translational regulation of proteins, and etc.). How can all of these other important levels of regulation fit into this theory? All have been implicated in senescence/aging in some form or another.

What you point out here is very important, thank you. In a remarkable piece of research, Kumar and colleagues showed that core nucleosomal histone post-translational modification (hPTM) profiles are able to predict transcript abundance levels with very high accuracy (R~0.9, ref. 33). The constraints on hPTMs underpinning this predictive power (in turn underpinned by DNA-histone octamer interactions)—as well as those constraints on hPTMs that are explicitly uncorrelated to transcriptional levels—are central to the theory proposed. As stated in the new section 1.2, the complex cascade of changes/interactions characterizing senescence escapes the scope of the theory. In this context, most of the types of regulation you mention are under this theory not actually regulation in a "teleological" (the quotes are meant to avoid alienating the reader) sense but rather types of propagation/amplification of truly regulated/dysregulated changes. One of my goals when developing this theory was to try shift attention from "molecule A-collides with molecule-B, which collides to..." into higher-order constraints and trying to explain phenomena such as the well-known, age-dependent "transcriptional noise", which under the theory presented should be understood as senescence itself. Furthermore, I maintain the relative slow progress we have made in understanding phenomena such as cancer and senescence (in spite of the abundance of high-throughput data) comes from

The author further suggests that histone crosstalk information content can be decomposed into two unrelated components: epigenetic and non-epigenetic. The non-epigenetic component is described as “hologenic information content,” which stems from a previously published work by the author. Non-epigenetic is confusing in this context since really this is information content that stems from the synergies of individual cells to form a whole, e.g. the emergent information content that comes from many cells working together (or at least this is how I understand the underlying theory). This information content is important for the general maintenance and survival of the organism. The author should clarify this point further, since this seems to be one of the fundamental assertions being made in the paper. For example, bringing in the descriptions used in section 2, can further clarify these central points.

In my previous work, "hologenic" information content is defined as being uncorrelated with (i.e., orthogonal to) changes in transcriptional levels, in the same way "epigenetic" information has been defined (traditionally and for good reason) as being uncorrelated with changes in the DNA reason. Hologenic information content emerges when proliferation-generated extracellular gradients of secreted molecules start to being used to perform regulatory work (after being transduced) on the histone crosstalk of each cell's nucleus.

In addition, the author states: “ Moreover, the sum decomposition in Eq. 1 implies that the growth in magnitude (bits) of the hologenic (i.e., non-epigenetic) component must be accompanied by a decrease in magnitude of the epigenetic component.” This is not necessarily true, since signaling is a separate biological process from the regulation of gene expression. In other words, both can increase or decrease simultaneously. For example, a healthy non-senescent immune cell can upregulate very specific transcriptional programs that lead to very complex signaling and extra-cellular interactions. You can argue that both represent an increase in information content for both the epigenetic and non-epigenetic “hologenic” components. In addition, as cells naturally senesce they are programmed to turn off cell-cycling while upregulating autophagy and repair processes. They may not upregulate extracellular signaling at this time, which would seem to contradict the author’s theory/statement. In this case, the simplification that all cells are the same is dangerous because it overlooks the tradeoff of information contents between cells. It also ignores important repair pathways (senescence being one of them), to deal with cells that have dysregulated their natural processes over time. It also overlooks the important action of immune cells that work to get rid of cancer and poorly-functioning cells.

This comment of yours (referring to complex yet specific signaling pathways and interactions) clearly shows I did a poor job (if not utterly failed) in conveying that the epigenetic and hologenic components must be understood in chromatin-wide terms. Yes, the random variables used to define both components in the sum decomposition of Eq.1 are defined with respect to a single, generic transcription start site, but these random variables take their respective values from data for all transcription start sites in the nucleus. This is why the terms Eq. 1 and the log-ratio in Eq. 2 must be understood as chromatin-wide terms. Again, this approach intends to shift attention from specific (however important) molecular mechanism to higher-order, information conveying hologenic/epigenetic constraints (whose imbalance are proposed to trigger senescence as proposed in this theory). The chromatin-wide nature of the hologenic and epigenetic components is not an obvious consideration but it is a very important one, so it is now explicit (twice) in the revised text and I thank you for bringing this to my attention.

For a statistically invariant level of overall histone crosstalk C(X1,...,Xn) in Eq. 1, a growth in magnitude of the hologenic (i.e., non-epigenetic) component must be accompanied by a decrease in magnitude of the epigenetic component and vice versa. This chromatin-wide trade-off might not hold, as you suggest, only if the overall histone crosstalk C(X1,...,Xn) varies significantly (in particular, if it varies significantly throughout adulthood). If, in fact, the overall histone crosstalk C(X1,...,Xn) varied significantly throughout adulthood the proposed theory would make no sense whatsoever. Mathematically, C(X1,...,Xn) is finite and upper bounded by ΣH(Xi) - max H(Xi) (where H(Xi) is the marginal Shannon uncertainty of Xi), and one can further expect that the overall histone crosstalk represented nu C(X1,...,Xn) remains statistically invariant for a number of reason, chief among them the massive chromatin instability that would ensue if it indeed C(X1,...,Xn) varied. For this reason, I included the C(X1,...,Xn) time-invariance as an additional prediction for the falsifiability of the theory.

Also, it seems crosstalk, correlation, capacity, and content, are used interchangeably. Please clarify that these are all the same, or use one of these terms to avoid confusion.

I went through the use of these terms in the paper and, unfortunately, I cannot reduce them to just one term or dispense with them altogether without losing rigor for the theory. Because of this I decided to include them in the Glossary, hoping that it will make any reader recognize that their respective uses in the text are actually not interchangeable.

Section 1.5 The author provides a general approach for measuring the log of the ratio of epigenetic and non-epigenetic capacities for a particular histone modification at three positions (i,j,k), and for some measured abundance of mRNA Y. Since we typically measure abundance of a particular modification genome-wide, and the mRNA level for tens of thousands of genes, how would a realistic equation look like (i.e. one that has 10k mRNA levels, and 10k histone positions)? In addition, the author does not explain how to combine correlations across multiple histone modifications. Please expand this section to make it relevant for real-world genome-wide measurements since this will be important for falsifying the theory.

Since public datasets are available (e.g. the aging atlas https://doi.org/10.1093/nar/gkaa894), the author should show an example of how a dataset might be used to falsify or demonstrate the theory in more detail.

This response to this observation can be found in the new Fig. 2 and with greater detail in Supplementary File 1. In summary, the data analysis approach is basically the same used by Kumar et al. (ref. 33). That is, with tandem RNA-seq/ChIP-seq data obtained from the same cell sample a table can be constructed with the rows representing the transcription start sites (TSSs) in the genome and the columns displaying the normalized ChIP-seq signal for each hPTM in different positions relative to the respective TSS (variables X1,...,Xn in the paper) plus a column with the respective measured transcript abundance for each TSS (variable Y).

Section 2.1 The author uses correlation of the log ratio of the epigenetic and non-epigenetic content with age as a readout of “reassignment” of crosstalk/contents, arguing that for cancer cells this correlation should be essentially zero. This seems like an oversimplification of the “reassignment” process since senescence may occur in phases across the age of a cell/organism, and since there might be both increases and decreases in the log ratio of contents due to natural biological processes and variability. Would it not be better to measure the sum of changes in the log ratio or the difference between the log ratios at different ages?

In addition, the biological age of a cell/tissue/organism can vary. For example, stem cells may have negligent aging, while other cells might age relatively quickly. Again, the author should clarify the context of age: are we measuring strictly chronological age correlation? Should we consider different correlations for each cell/tissue in the organism? What about tradeoffs in information content between cell types and tissues? In other words, it is unclear how the theory should be applied to biological systems.

This is a great observation, thank you. Yes, the correlation in Eq.3 relates strictly to chronological age (in other words, to time). The correlation must hold for somatic cells of the same type according to the theory; now this condition is explicit in the text. In this context, some cell types and tissue may senesce (see new Fig 1c, center) faster than others as you point out; in this case the associated slope is predicted to be steeper, whereas cell types that senesce relatively slower the slope should be gentler. Only in species displaying negligible senescence the hologenic/epigenetic log-ratio should remain constant (i.e., zero slope, as depicted in Fig. 1b, blue curve), or fluctuate significantly in species displaying "reversible" development (Fig. 1b, magenta curve).

Section 2.2 The author argues that senescence is an emergent property of the loss of information content for epigenetic histone crosstalk and an increase in information content of “hologenic” information content (e.g. cell signaling and anti-tumor signaling). I believe this premise does not stem from the reality of biological systems (see my comments for section 1.4).

The trade-off between capacity for hologenic and epigenetic information within a constant overall histone crosstalk magnitude—in particular, the growth of the former at the expense of the latter throughout adulthood generating a dysfunctional imbalance—is arguably the cornerstone of the theory in fundamental terms. Whatever my response was to your comments about subsection 1.4, this crucial trade-off cannot be taken for granted, however compelling the arguments are. In this context, there is no better solution than putting the hologenic/epigenetic trade-off to the test (see prediction B for falsifiability of the theory, also further detailed in the new revision of the paper). Realistically, however, I expect prediction B to be tested (and the hologenic/epigenetic log-ratio quite thoroughly examined) only if predictions C and D are verified. In that scenario, it will be interesting to see whether the hologenic/epigenetic log-ratio increase may be steeper in some tissues (which should then explain why those tissues senesce faster than others).

Also, this section seems to be contradicting the author’s conclusions and is very confusing. The author seems to argue that there is both more AND less constraint at the multi-cellular level (organismal)? Please clarify or remove this section.

I can see now how it seems contradictory because I was saying the capacity for hologenic information (which is about transcriptional levels being accurate for the multicellular individual as a whole) increases up to the point of being dysfunctional at the multicellular-individual level. Here I failed to convey that said dysfunctional outcome derives from the concurrent decrease of capacity for epigenetic information, not from the increase of capacity for hologenic content per se). Thank you for bringing this to my attention. I decided to remove this subsection altogether because the hologenic/epigenetic trade-off is covered in greater detail in the next subsection.

Section 2.3

Senescence as transcriptional overregulation is vague. Here the author is arguing that as epigenetic constraint decreases, you have a decrease in precision (e.g. loss of regulation), but then you have a competing global or hologenic increase in constraints, which constrains the expression of genes for the overall benefit of the organism. A shift toward global constraint.

My intention here is to establish a fundamental contrast between the group of diseases we call cancer and senescence using the difference between the concepts of accuracy (average closses of the actual values to a target value) and precision (variance of the actual values, also added to the Glossary). In this context, since cancer is an almost canonical example of gene dysregulation (transcriptional accuracy is lost because capacity for hologenic information is lost), we can understand senescence as transcriptional overregulation in the sense of too much capacity for hologenic information gained over time at the expense of capacity for epigenetic information, thereby losing transcriptional precision). I added a third panel "c" to Fig. 1 to clarify the proposed contrast between cancer and senescence, in terms of impaired transcriptional regulation (i.e., inaccurate up to dysfunction in cancer and imprecise up to dysfunction in senescence).

Section 2.4 This seems to be describing an illustrative real-world example? This section is incredibly specific and again only focuses on one possible mechanism and does not include any measured data or analysis. Please preface this section to explain that this is just one of many possible examples. Again, it will be good to provide other examples looking at other aspects of aging biology (not just histone modifications).

I am not including examples of mechanisms propagating dysfunctional changes in the senescence process because this theory is not about adding one more possible mechanism to the collection of well-described mechanisms associated to senescence. The theoretical claim I am making here is that the sequence of steps described in subsection 2.4 constitute the primary cause that triggers senescence throughout the multicellular individual's adulthood. This is of course an extraordinary theoretical claim and, as the great Carl Sagan pointed out, as such requires extraordinary evidence (or, in this theoretical paper, an extraordinary prediction aimed to obtain said evidence).

This is why I also added two predictions, C and D, to the now completely rewritten subsection 2.6 "Falsifiability". These predictions are extraordinary in that they provide extremely specific sufficient conditions for either slowing down or accelerating the senescence process in any non-human species. For this reason (i.e., adding predictions C and D) I have duly updated the "Competing interests" section of the paper. [Note: in a separate paper I explore in greater depth the theoretical underpinnings of predictions C and D.]

Section 2.5-2.9,3

This seems to be a general discussion. It would be easier to organize these sections into one discussion section for added clarity. Again, I would recommend not talking about sweeping statements like “Senesensce’s ultimate cause” and “Can senescence be stopped?” since this theory only addresses one small aspect of the biology underlying aging and senescence and does not address the heterogeneity of aging. These topics are controversial and should be addressed very carefully to avoid alienating the biological community.

Thank you for your suggestion, I organized a Discussion section accordingly, placing the predictions for falsifiability in it. Additionally, I changed “Senescence’s ultimate cause” for “Senescence’s proposed ultimate cause”, clarifying also in the Scope subsection 1.2 that ultimate/proximate is used only in terms of the concepts of causality as introduced and named by Ernst Mayr.

Following your advice, I removed the subsection “Can senescence be stopped?” Now, I believe this theory is bound to alienate at least some colleagues in the biological community (among those who read the paper, that is). As you point out, the theory addresses only one small aspect of the senescence process, but it is not any small aspect. It is about what triggers the process or, equivalently, what is the initial link of the causal chain leading to senescence with all its mechanistic complexity. This implies all other proposed primary causes would, simply by logical exclusion, be incorrect.

One of the reasons I developed this theory in the first place is that I failed to find even a single falsifiable description proposing a primary cause of senescence that integrates Mayr's proximate and ultimate concepts of causality. To be clear, this is not a shortage of explanatory accounts for the senescence process; it is a shortage of experimentally falsifiable ones. There are scientific fields where falsifiability is inherently difficult or probably impossible to meet, such as paleoclimatology. But that is not the case in biology—certainly not in developmental biology. This is why I agree with you in that the senescence process is still poorly understood in fundamental terms (which by no means implies all work in the field is worthless).

Forgive me for the following related digression/personal note: Since I started writing this paper I faced the dilemma of how many research works on this topic should I cite, given there is plenty (even considering this is not a review-type article). We scientists are only human and as such we very much like our work being cited in terms of current knowledge. That changes, however, when the explanatory account we like the most (or even worse, the explanatory account we ourselves proposed) is being cited to acknowledge its existence but the lack of predictions to falsify the "theory" is also pointed out (our reaction changes probably because unfalsifiable explanatory accounts can be always dismissed as just storytelling, however compelling the story might be). These rather petty emotional responses of ours have of course nothing to do with the advancement of science. Yet, many scientific journals—however prestigious, and particularly in the life sciences—routinely publish articles the word "theory" describing the work in the title and/or body when there is no prediction to be found for falsifiability. As a student, this is when I learned the interests of the scientific publishing industry (as we know it) and those of science are completely uncorrelated—not really surprising since their respective goals are so different. In this context, I found the PeerRef initiative/model very interesting since it aims to focus purely on the scientific content as opposed to essentially non-scientific considerations.] In the previous revision of the paper I offered only one prediction to falsify the theory, which is arguably cumbersome—and therefore arguably not too appealing—for experimentalist colleagues to test. For that reason I added three predictions (A, C, and D) which are straightforward to test in the laboratory. In this context, I am hoping the scientific community will be open to consider and to test falsifiable theories, however alienating they might be. Especially when we are dealing with a phenomenon for which paradigmatically accepted explanatory accounts is, at least to the best of my knowledge" all we currently have. Last but certainly not least, I wish to express again my gratitude for all the time you devoted to review my paper. Whether or not the theory it presents resists falsification attempts, I firmly believe the paper itself is now better than it was before thanks to your feedback.

Reviewer response

In general, it seems the paper is improved and includes quite a bit of additional clarification and qualifying statements.

The scope is also much more constrained and it is clear that the author is sticking only to proposing a possible theory, which is fine with me, albeit not as exciting as it might have been if the author had gone through and provided real-world examples or evidence. It still bothers me that the work is trying to implicate a very specific mechanism for senescence (chromatic cross-talk and regulation), since now it is clear that the work is mostly a theoretical exercise without much basis in established biology. In other words, chromatin cross talk might be an example of one way that this could happen among others (e.g. other epigenetic regulation or lack thereof). As a theoretical work it is fine as long as you agree that it is sufficient for the scope of the journal

Decision changed - Verified with reservations: The content is scientifically sound, but has shortcomings that could be improved by further studies and/or minor revisions.

Author response to reviewer Charles A. Schumpert

Dear Dr Schumpert,

I wish to thank you for having reviewed my paper; your comments have been very encouraging for the effort of moving my theory forward. Please find attached two identical copies of my revision of the paper (changes are highlighted in one of the copies) and a supplementary file that relates to one of your comments. Please see below my response to your comments when applicable.

Overall the manuscript is written brilliantly and provides excellent context to the audience about a complex theoretical biological concept. No flaws can be found, although one could argue against a few of the points in the assumptions used to construct the theory, there’s nothing illogical or irrational.

Thank you for kind words, but I have to admit any and all brilliance that may be found in the write-up must be credited to my wonderful editor Angelika Hofmann. Regarding the assumptions, this theory relies on two critical ones, which of course cannot be taken at face value. This is why these assumptions inform prediction B (in the new revision). There are now four experimentally testable predictions to falsify the theory; hopefully some will be appealing to experimentalist colleagues.

In your opinion how could the author improve the study? The writing of the paper makes it easy to read, which can sometimes be a challenge with theoretical biology manuscripts. Potentially adding a bit more context on the various theories of aging may help demonstrate the marriage of the ideas into the theory he constructed.

One of the problems I faced when writing this paper was how many different explanatory accounts (there is plenty) I was going to cite provided I would have to underscore their lack of testable predictions for falsifying them—which in time becomes dangerously close of being downright unfalsifiable. As Wolfgang Pauli famously said, unfalsifiable theories are not even wrong. In other words, the problem was how many readers I was going to alienate while having no intention to do so. Navigating academia's social ocean is not an easy task, at least not to me, so I decided to compromise. To be clear, I am by no means claiming my theory is correct but underscoring that (i) it can be tested experimentally and (ii) explains the known age-dependent, cell-to-cell transcriptional noise that I argue should be regarded as senescence itself in fundamental terms.

In this strictly Christian times homosexuality is completely regarded as incomprehensible and isn't even suggested as an option for Sir Gawain.

"To complicate the consideration of those kisses: remember that if Gawain had succumbed fully to the lady's seduction and if he had honored the terms of his promise to the lord he would in fact have had to have sex with the lord-to yield his winnings, that is, his sexual conquest, in his own body, just as he has done with the kisses he received. Homosexual sex is thus one hypothetical fulfillment-in fact we might say the logical end of the interlocking plots the lady and Bertilak play out-but it is a forbidden end. Or rather, not forbidden, but unintelligible within the heterosexual world of this poem. It is in this way fully inside the culture of the poem (it is produced by the game the three are playing) however apparently outside it (unreasonable, impossible: Gawain and Bertilak?)"

Dinshaw, Carolyn. "A kiss is just a kiss: Heterosexuality and its consolations in Sir Gawain and the Green Knight." diacritics 24 (1994): 205-205.

This very excerpt from the poem suggests the importance of the Knights Code of Chivalry and how honor played a huge role in the social and moral respect of the time. It states in the article that "A knight was expected to have not only the strength and skills to face combat but to also be able to uphold this aggressive side of a knight with a chivalrous side to his nature". This describes Arthur's unwavering pride at the hands of "death" which is quite inevitable as the game presented by the Green Knight was nothing more than a death sentence. King Arthur in this instance was clearly exhibiting shame for the members of the round table, who did not want to participate in the game. Even so he knew someone needed to represent them and for all the consequences that were to arise from this event he needed to set an example for his kingdom and his people.

https://www.scasd.org/cms/lib/PA01000006/Centricity/Domain/1487/Knights%20Code%20of%20Chivalry.pdf

• This is a tale that contains the Beheading Game. This “game” was not necessarily a game, but rather a challenge. The Green Knight formulates a challenge: kill me now and you will die later, by the same arrow—or whatever the weapon is. To be more specific, “he offers to allow any one of he knights present—not specifically Arthur—to chop off his head now in exchange for a return-blow a year later” (Weiss 361). What’s interesting is how the Green Knight markets this challenge as an oath, not necessarily a game. Perhaps, knights call it a game because its risky like one.

Citations: Weiss, Victoria. L. “Gawain’s First Failure: The Beheading Scene in ‘Sir Gawain and the Green Knight’” The Chaucer Review. vol. 10, no. 4, 1976, pp. 361-366.

A challenge often used in medieval romance , players exchange blows to decapitate the opponent . A stranger or mystical figure appears and propose the challenge . It is one of the most important scenes at the beginning of SGGK as established the plot of the whole story when Gawain accepted the Green Knight challenge taking Arthur's place.

https://www.ancient-origins.net/myths-legends-europe/gawain-0013391

https://en.wikipedia.org/wiki/Beheading_game

In a way, the Green Knight's provocation and taunting of the men of the dais is an attempt to "disturb the social and personal order" not only amongst Lord Arthur's knights, but amongst Lord Arthur himself (Bogar 5). The Green Knight disrupts social order in the name of entertainment and fun- but he also knows that for King Arthur, disrupting the social order means that there is a chance King Arthur may act in a way which defies one or more of the tenets of the Knight's Code of Chivalry, including "Honour, Honesty, Valour and Loyalty" (SCASD 1). Essentially, the Green Knight's taunting of King Arthur's knights and King Arthur's power as a ruler is a surefire way to ensure that King Arthur will accept his request of the beheading game he wishes to play. If Arthur did not react, he may be seen as lacking courage, or 'valour'; if Arthur reacted too brash, he could be seen as disrupting the tenet of "honor". Essentially, the Green Knight holds Arthur right in the palm of his hand, knowing his actions will warrant a certain response from King Arthur.

Bogar, Michael. “The Green Knight as a Trickster.” Academia.edu, Academia, https://www.academia.edu/40706877/THE_GREEN_KNIGHT_AS_TRICKSTER_Acade_ed_version.

Knight’s Code of Chivalry - State College Area School District. SCASD, https://www.scasd.org/cms/lib/PA01000006/Centricity/Domain/1487/Knights%20Code%20of%20Chivalry.pdf.

This was a knight of the round table who was given this title of savage due to his love of hunting wild game. He was considered a valiant knight and one who would Gawain would want by his side. I enjoy how each of these knights were able to search and have back stories provided to them. It enhances the story.

http://nightbringer.se/nightbringer/a_dodinel.html

Sir Gawain is the nephew of Aurthur and a well-respected knight of the round table. He is the main protagonist of the story and has to go up against the green knight in a death game. However, "his greatest foe ultimately turns out to be not the Green Knight, but himself." During his journey he has to look inside himself and face his weak points in order to overcome the challenge that he has accepted. He faces both the good and bad parts of himself and learns from his mistakes to become a better person and a better knight. https://csis.pace.edu/grendel/prjs2d/charactr.htm

The Green Knight's enormous build, wild appearance, and green complexion set him apart from the beardless knights and beautiful ladies of Arthur's Camelot. He is an ambiguous figure: he says that he comes in friendship, not wanting to fight, but the friendly game he proposes is quite deadly. The site states that the Knight is seen as "supernatural being" when he arrives.

Citation:Sparknotes, SparkNotes, https://www.sparknotes.com/lit/gawain/characters/#:~:text=The%20Green%20Knight's%20huge%20stature,he%20proposes%20is%20quite%20deadly.

Here Gawain Isn't acting nobly as he should but instead is acting brashly because of the taunts of the green night. If it weren't for Gawain, King Arthur would have put his kingdom in jeopardy, having to fulfill the second part of the green nights "game". As described in "the Song of Roland" Sir Gawain fulfills many tenets of the code of chivalry because he served his lord king Arthur by defending his court's honor in participating in the game (Knights Code of Chivalry 1). spoiler alert He also goes on to fulfill many more tenets of the code while up holding the second half of the game, though he does break one or two when met with his looming death. The last consideration is that Gawain is protecting Arthur's honor because Arthur has hastily jumped into this competition with no regard for its morality or how it may endanger his court. This is a strong moral justification for Gawain's actions but it does completely let him off the hook for decapitating a man in the middle of the festivities.

https://www.scasd.org/cms/lib/PA01000006/Centricity/Domain/1487/Knights%20Code%20of%20Chivalry.pdf

Unlike my previous annotation, this is definitely the least virtuous thing Gawain does for the entirety of the story. Though we find out later this wont kill the green knight, Gawain doesn't know this and swings the axe with the intent of cutting off heads (killing). Perhaps Gawain's action was acceptable in the context of the Green knight's test but according to the middle evil knight's codes he was "expected to temper this aggressive side of a knight with the chivalrous side to his nature" (Knights Code of Chivalry 1). This would probably be where Gawain asks the strange knight why he wants his head chopped off or tell him a new-years festival might not be the place to hold this competition. to be fair to Gawain, he does ask the Green Knight where he might find him and what he might call him so he may fulfill the second part of the game.

https://www.scasd.org/cms/lib/PA01000006/Centricity/Domain/1487/Knights%20Code%20of%20Chivalry.pdf

this game has a winning strategy

Interesting concept. I wonder if there is digital game of this, that would generate games to play. And each time have new kanji