This should be written in past tense.

The methods section should be in the past tense. This section is in the present tense.

This section is in the present tense and should be in the past tense.

Nothing should "need" to be found out, the methods section should state that it was found and how,

these equations should be formatted rather than just written in regular text.

These sentences are not all complete sentences and not in passive tense.

the x value should be % sucrose

The graph should go in the R+D Section.

This is an equation disguised as a method, and thus should have gone into the introduction section.

You shouldn't be less specific. You should say something like, "The graduated cylinder was filled half way."

This should have gone in the introduction section, with the rest of the equations used in the lab.

Does not explain the measurement the "m" value is using

Still not passive voice

Not in passive voice.

don't have to enter in the amount of water.

Don't include the equation in the methods section, only in the introduction.

The New Deal did little to exercise rights to African Americans

This should have gone into the introduction section.

This is incorrect, as the students should have used the difference between the final volume and the initial volume, to get the volume of the rod.

Does not specify what kind of rod

The graph needs a title in the caption: "Figure 1".

Specify what data was included in the graph, and refer to it as "Figure 1."

The mass was found, not the weight.

AI drawbacks and issues

AI use described

Problem proposed and AI as the solution.

This is a predominate view of language even in anglophone Africa. I can confidently speak at least to my experience as a Ghanaian. Up until university, I was taught to aspire to a native-like (standard English) proficiency in speaking and writing which also equates to white-English. As an English major and a sociolinguist, I learned to deconstruct that notion. My class room experiences helped me challenge that supposed ideal of reaching 'native English' = 'Standard English'.

Doesn't UW have something like this? What do such policies mean? Are they in contrast to the translingual approach to pedagogy that we have been preaching?

This brings me to ask, 'Does UW have an explicit language policy? As instructors, how do we acknowledge the linguistic diversity in our classes and teaching materials?

I see the comparison here, and think that there is merit to it. The "outsourcing" point is particularly strong--i.e. it is tempting to outsource moral actions to simplified optimization functions, which entice us to jump to conclusions about what is good. The question, though, is whether or not Singer encourages this. That is a tougher case. My sense is that Singer would NOT explicitly endorse that kind of behavior, even if he DOES implicitly endorse it, as a way to nudge people to become "more moral than they might otherwise be" according to his tastes.

Important point. People, especially those who are not philosophers, outsource their moral decision-making and opinion-forming to their "cave" of opinion, and moral habits formed therein.

Calling this out as the thrust of the piece. Is Rudy able to defend this point? (FWIW seems like it's still an interesting argument, even if the neolib/lib distinction is not make perfectly clear.)

It'll be a heavy lift to differentiate neolib from lib on the basis of individualism, i.e., to say that liberalism does NOT focus on the individual.

This doesn't strike me as a conflict. In Second Treatise Ch 5, doesn't Locke more or less explicitly call for the conquering of nature/wilderness for the sake of improving the world? Improving in the sense of "making more productive."

I really appreciate this kind of objection. I recently heard this called the tyranny of the easily measureable. There's a serious problem here though. Things that cannot be measured are very hard to reason about. And I think much (maybe not all) of ethics is about reasoning through what is right and wrong. So, not every good should be measurable, but that doesn't mean there isn't a place for measurability.

I think at his strongest, this is true. There's so much to be said here though. Related to the last comment, his argument almost forces us to come to some version of this conclusion ourselves, by relying on our intuitions. "Oh, you think it's immoral to let this kid that you don't really know but is proximate to you drown? Why is that different from a kid on the other side of the world that you don't know? That seems like a legitimate question. The assertion that distance matters is not much more than an assertion. If this thought experiment doesn't cause you to completely flatten your concern curve, should cause you to question its derivative...

This may be a minor point, but I sometimes think Singer is more sublte than this. I think he is saying that we have a strong intuition that saving the kid is the moral thing to do, and that intuition is also relevant to saving other kids. I think that's slightly different than saying it's "clearly immoral" not to save the kid. I think if you want to bite that bullet, he doesn't have much more to say (at least the old PS; I hear he's changing his views a bit).

I think I agree with this claim. But doesn't it make sense of what you state as being odd above. Specifically, here, you are claiming that there has always been a component of progress in classical liberalism. I think that is exactly what Gray is claiming with meiorism. But above, you say, "But perhaps the most interesting claim of Gray’s list is that liberalism is 'meliorism.' If you think about it, it is quite odd that a political philosophy founded on freedoms could evolve to the point where its defenders believe its purpose is to make the world better."

I can see how one might go in this direction, and how it leads to neoliberalism. But I think that is part of Fuk's point: liberalism exists on a knfe edge; there are excesses in both directions (left/right). In a liberal society, neither the Catholic church nor racial, ethinc, or gender groups have a claim on the individual.

I don't come to this conclusion at all. For example, the fact that all people are of equal moral status does not imply that all people will have the same outcomes. The fact that everyone has the right to, idk, a k12 education, does not imply that everyone do the same thing with that opportunity--some will rise to the occasion, some just won't have what it takes to achieve, and others will squander the opportunity. I don't think anything Gray is saying here is blocking these different outcomes. .

My view is that there is a relatively clear mapping from Locke to Gray. The list that is given here for Locke is clearly lacking details. For example, who are the bearers of these rights? Locke had an asnwer, but it's not here. Gray gives us an answer: Individuals, not collectives; it's not the case that some get more rights than others; all humans, not just some.

Three sentences on what I just read,

I believe that BAP is aware of his place in history just like I assume Yuval does. Both authors are not writing as bots recording facts but provide a specialized idological prism to see our current civilization through. Each prisim has its own take, Yuval trying to articulate what the Silicon Valley "Open Conspiracy" types dream of. BAP trying to remind us what it was like to actually be part of history.

The "Why don't CEO's have Harrem's" is the one thing here that is going to stick with me. The women of today are so different from the past. In fact maybe the "Brave New World" reality of nameless sex with strangers and nude play as children is a more desireable world to the Incel, video game, monster can drinking of today.

It seems like the Puritan/Christian sexual practices have really shaped the west into becoming what it is today. I believe most men get their sense of identity from the type of sex they have access to. What's weird about modernity is that we are talking about sex rahter than women with the inherent consideration of children.

This population collapse, as articulated on the Georga Guide Stones, is going to be interesting.

What is the Opposite of "The Open Conspiracy"

I think this is why Curtis Yarvin's first instruction in Gray Mirror is to detach

• (9) #1: a general theory of collaboration - by Curtis Yarvin

I think we could use more "Bronce Age Mindset" right now. But if every other philsopher was promoting that and not just Bap and his little cult +Andrew Tate I agree we might have a problem.

Philosphers are a type of Tyrant?

They create memetic prisons that design people's behaviors.

They stop people from acting instread requiring people to think and think and think

Ah philosophers are the origional beurocrats

I wonder what Greek Philosophers would think of Ayn Rand Objectivism

A defensive use for cybersecurity from ChatGPT

A method of bypassing ChatGPT

Jailbreaking method

Jailbreaking ChatGPT to gain greater control

Defense

Important

Important

This is the bias of the authors for this particular subject

Techniques used to bypass GenAI safeguards put in to prevent these attacks

Ways GenAI could use to incite a cyberattack

Threats of GenAI need to be taken seriously

Tools that can be used to understand vulnerabilities,attack patterns to prevent cyber attacks

Perspective of the defense side of GenAI

Perspective of the attacking side of GenAI

Two perspectives of this research subject

It’s the first study with enough data to do this kind of comparison, and it offers strong evidence about the factors that influence people’s chances of moving beyond the economic status they were born into. Some of the key factors include education, family structure, and the economic setup of the cities people live in.

This is a case where while being a certain race can make the journey up hard, being born in a "bad area" can make it difficult to, regardless of who you are. People born in these circumstances have no choice but to fight harder to enjoy the same life others can achieve with far less effort, a fact that, while unfair, is true.

This rings true to many people around the world, not just America. Whereas some people in the US have to "climb their way out" where they are from, people from the Philippines for example, have to work their way to places like the US for better life prospects. And still, they want to be near an urban area where jobs pay more, not in the middle of nowhere where some Americans are born into.

This seems absurd to me. Why are there no good jobs near her? Why is she stuck spending a sixth of her day traveling to and from work? There needs to be more accessible jobs, or at least, more efficient transportation.

This makes me think about our discussion about what schools are here for. In this case, it would be social mobility. Also, escaping poverty reminds me of a class I took that focused on this topic. One discussion that stuck with me was the idea that most people with high SES support escaping poverty because it still maintains poverty as an unavoidable thing. In the end, there will still be impoverished people to uphold the 1 percent.

This is a simile because there is a comparison God and him.

This is pathos and personification.

This piece shows the themes of equality and the value of every individual.

These words foreshadow Brutus's good intentions and the tragic consequences of his actions.

Connect Cephalus’s discussion of the value of wealth (329e ff. (Greek)) with Aristotle’s comments about the connection between wealth and happiness (eudaimonia) (NE I.4 1095a18-26 (Greek), I.5 1096a5-7 (Greek), I.8 1099a31-1099b9 (Greek), I.9 1099b26-29 (Greek)). (Christiana Olfert)

Sounds like we should be teaching people to skip the middleman (middle bot?) and just go to the “reliable sources,” then, huh?

It's also interesting to know that the first ever version of the internet was just a connection of multiple computers at first and then evolved into this network where users could only read, to now doing so many stuff with it.

As a Chinese student, I was shocked to read this text, I did not think that in the 1960s and 1970s, there were already E-mail boxes in the world. In my opinion, the 1960s and 1970s seemed to be the period when China vigorously developed industry and agriculture, and such things as E-mail and computers seemed very remote to China at that time.

In the seven consecutive unrhymed four-line stanzas, Whitman provides the song's lyrics. An apostrophe directly addresses the celebration of death in these stanzas. Whitman wishes for death to arrive since he believes it will eventually come to everyone, day or night, and he sees it as a peaceful incident. He praises the universe and love in the second of these stanzas, but he also hails death, as if it were an equal partner in love. He addresses death as a mother and welcomes her in the song's third verse. The fifth verse claims that Whitman will sing with the dead when their time comes since death is an ocean of love and happiness, using the bird's song as a metaphor. This subject is carried over into the last three stanzas of the bird's song. Death, for body and soul alike, is welcome wherever it occurs. The song in favor of death is spread throughout the nation, over cities, fields, and prairies, as the final verse makes clear. It is a song of joy even if it is a song of death.

Whitman leaves behind his vision of the battlefield, the lilac plant blooming in the dooryard, the sight of the evening star, and the song of the bird and the song it inspired in him. But for the sake of the deceased guy he loved, he will always remember them all.

Leaves all of these memories behind with joy

Though he sees countless skeletons and bodies, he understands that these troops are now at peace and are no longer in pain. The living are the ones who suffer—the surviving soldiers, the surviving loved ones of the deceased, and the legions of survivors.

Whitman expands this mental image to involve Manhattan in New York City as well as the entire country, extending from north to south and east to west. He praises the sun in the morning, midday, and evening, as well as the stars and the night sky. He calls the whole thing a miracle.

Whitman questions himself how he can show the man he loved the most that he has lost. What melodies can he perform, what scent can he leave behind after he dies? He chooses to use a metaphor to describe the winds as the breath of his song, which originate in the east and meet in the prairies. He's going to cover the grave with that perfume.

The star, which represents a person's loss, seeks to distract the bird while it sings, holding and imprisoning him.

Whitman listens, understands, and encourages the singing bird to keep singing.

Whitman embraces "death" with his fresh-picked lilacs and other flowers. He wishes to share the beauty he sees in these flowers with the other coffins in addition to this one.

Whitman's description of a corpse being carried across the country, through towns and countryside to its final resting place, makes it less depressing by the vivid images he provides.

grief

In the loneliness of the swamp, the thrush sings a song that hurts its throat; if the bird hadn't given it the ability to sing, he would have preferred to die.

Whitman gives the lilac bush a heart and a strong scent which he loves. With its delicate color, heart shaped leaves with miracle, to which he proceeds to breaks off a twig of the bush, with its flower.

Whitman gives the lilac bush a heart and a strong scent which he loves. With its delicate color, heart shaped leaves with miracles, to which he proceeds to breaks off a twig of the bush, with its flower.

Associating the darkness with grief

Every Spring Whitman mourns when the lilacs were blooming and the evening star (Venus), was visible in the sky at night, as it reminds him of a man he loved.

death? Decomposing in the earth? Reminds me of Wendell Berry's poems about dying and nature

he lives a busy life I guess

not sure what's going on here...

I feel like he's a little more than a citizen at this point

again the theme of him being a god-like figure

using savage in a supposedly positive way?

wait what is the context for this? I'm confused

toxic amounts of empathy that disrespect the other person and yourself, no way to look after the wounded

this is going to far

I can never tell if he is infatuated with something because it reminds him of himself or if he legitimately loves the nature/people/etc that he is relating

surprising metaphor though it works

so loving/connecting with all these random people is part of how he connects with/loves himself? Either way I keep coming back to Emerson's idea of "Man Thinking" in The American Scholar

enamored is a good word. He does seem extremely enamored by all the people and nature described in the poem

a strange kind of voyeurism here, not sure what he's trying to get across

heheh

he's trying to differentiate between his true Self and the person he has become as a byproduct of his culture etc

perfume as a metaphor for conforming/toxic things that everyone around him is buying in to?

I found it really interesting how updates and information was shared before the rise of the internet. Particularly the grafiti updates. I think that it was a creative way to share information to a large amount of people.

I never thought of the idea of social media prior to internet. I always made the connections that social media was created after internet. But after reading this i can understand how graffti as well as books can be considered social media.

This reminds me of a joke popular in WWI, where soldiers found graffiti stating "Kilroy was here" with a long-nosed bald man peeking over something. It was a simple doodle to recreate, so the graffiti spread with multiple actors contributing.

I find this to be very interesting because history classes don't really mention or bring up this topic too often when it comes to making connections between the past and present when it comes to social media and the development of communication mediums.

The centralization of media is an interesting to note because before the fragmentation of culture due to social media, everyone would consume the same shows, news, and media. Nowadays, with the prevalence of an individualized content diet, we are able to consume more niche content with the caveat of no longer being guaranteed to share a cultural foundation

An interesting point to note is the centralization of media before social media. Back before social media had fragmented culture into niche subgroups, it would be more common for everyone to consume the same shows, watch the same movies, and to recognize the same stars. Nowadays, our notably fragmented media diet has allowed for more individualized taste with the cost of having less in common consumption wise with others.

This is an interesting example of how social media doesn't have to depend on technology, in fact some notes; Graffiti walls; Bulletin boards and other things that can be used as carriers of information transmission can also be called "social media". From this perspective, technology only increases its functions and improves the efficiency of information transmission for social media, and its basic form has been finalized before the emergence of software and smart phones.

It's interesting how we are back in the age of rumors and theories. Back then, people didn't have the tools to easily fact check. In modern times, people don't have the attention span to fact check what they see on the internet. Those short, half truth rumors spread like wildfire now.

This part of the reaiding racial disparities in housing opportunities in the mid-20th century. White Americans had the privilege of choosing where to live. At the same time, Black Americans were restricted by racial covenants—legal agreements that prevented the sale of property to non-white buyers—and racist realtors, limiting their housing options to industrial suburbs like Ferguson, located on the north side of the city.

This text talked about the issues of housing, education, and municipal financing are interconnected and that the systemic failures that led to Michael Brown’s death began long before his interaction with the police, including the inequities in his schooling and environment.

The phrase “not where smog and uglies lurk” suggests that other suburban areas, such as Ferguson, might be associated with factories, blue-collar work, and environmental degradation, further implying that Irvine represents a more desirable, elite alternative. The language reflects the socio-economic and racial divides that often separated white-collar, planned communities from more industrialized, working-class ones.

I found it interesting that as the popularity of social media grew the urge to create a version of social media that had no restrictions grew as-well. I think this led tot he creation of 4Chan and Something Awful. This goes to show how Social Media can turn morally unethical really quickly.

I watched a documentary specifically on the QAnon conspiracy, and the documentary shifts focus early on to focusing on 8chan. It's very unnerving watching how these people use their own platform and QAnon to make the most profit, regardless of the societal harm they are causing. It is partially for this reason the documentary accuses the founders/admins of 8chan to, if not QAnon themselves, be working in collaboration with them.

Its funny how even on a site named "Something awful" a person still felt restricted. But I cant say im mad about it because i feel like i heard a couple useful stories from 4chan due to the lack of restrictions.

Whenever I think of the dark web, I see 8Chan to be a platform amongst the most accessible. The concept of it is absolutely unhinged and it is wild how they were able to manage to keep the site up and running. It is quite alarming to think that if a community of problematic incels could create such a toxic website, imagine what they could do next.

The anonymity aspect of such platform breeds a toxic culture due to groupthink. The lack of accountability allows people to display the worst parts of themselves in a space that encourages such behavior. The shock culture of these communities shifts what is considered normal, and this community has bled out and impacted other online spaces such as during raids.

I feel like the user interface is a super important part of social media as if we talked about in class for making connections and meeting new people. I forgot what that circle you made in class was but it goes over what social media does to you as a person and what you can gain from it as well. But overall the user interface I would say connects a lot to the circle you showed us.

Yes, that is important when navigating the need to create a program that is 'user-friendly." Users can navigate more efficiently when an interface clearly communicates how it should be interacted with could reduce errors and frustrations significantly. Strong feature support promotes product success by facilitating ease of use and increasing user satisfaction, which is key in today’s competitive digital environment.⁤

Yes, infinite scrolling really makes people more addicted to social media. For example, TikTok, I think it's also a kind of infinite scrolling, you can never finish watching short videos, and at the same time, when you finish watching the previous short video, you will look forward to the next content, so it makes you addicted.

Dopamine is the brain's "reward" chemical, and it gets released when we expect something good, like food or positive social interaction. When someone experiences social deprivation, such as a lack of maternal care, the brain compensates by releasing more dopamine to motivate the person to seek rewards or comfort elsewhere. This increased dopamine release drives people to find other rewarding activities, sometimes leading to risky behaviors like gambling, where they continue seeking that dopamine-fueled reward, even when the outcomes are uncertain

In nature, animals can’t always predict when they’ll find food or other important things. First, resources like food are spread out randomly, so animals have to keep trying until they find what they need. Second, cues that signal rewards, like fruit trees, aren't always reliable because the trees don’t have fruit all year. When animals face this uncertainty, their motivation kicks in to keep them going, even when they keep failing. This explains why unpredictability, like in gambling, can keep people engaged even when they’re losing.

damn

OMG like my rumikub lmaoo

!!!!!!!!!!

OMG USE THIS

!!!!!!!!!!!

people are less concerned with their REAL losses than they are with their POTENTIAL gains

OMG WTF

!!!!!!!!!!!

!!!!!!!!

!!!!

. In people with PG, the more severe their gambling symptoms, the larger the dopamine release. This suggests that heightened dopamine responses in reward situations may be linked to the severity of gambling problems.

page 11 she ends with who would want to live... I think this really is pushing her own Narrative on to the reader I'm asking them to think about the future in terms of her predictions.

Author: Scientist and activist- Quoted multiple studies and calls for awareness Audience: I think the author is trying to reach a large number of individuals and provide awareness. Most likely to read is probably students and other scientists as well as government Dealing with agriculture. Purpose: To inform those of the danger that pesticides can impose.

This is key evidence of why Biard is so determined to properly Catechize any converts to the Christian religion before they are baptized. This anecdotal evidence supports his point that simply baptizing people is not enough to produce practicing, faithful Christians.

This further emphasizes how important Biard finds proper Catechization. He exemplifies this point later on in the document by referencing converted Christian's who were really only Christian in theory but not in practice.

This demonstrates Biard's observations and awareness that Mi'kmaq communities operated differently from French ones (both in France itself as well as Nouvelle France). He notes that the Mi'kmaq or Canadians are nomadic and thus their lifestyle is not conducive to traditional Christian practices (mass, sermons, sacraments, etc.), this highlights how important it is for missionaries to acclimate to Mi'kmaq culture and communities by living and traveling with them, learning their language, etc. By building these relationships and trust with the Mi'kmaq it becomes easier to facilitate their conversion to the the Catholic faith.

There are so many interesting references to Greek mythology here as well as inconsistencies and rewritten narratives around the mythology. I am wondering if Sol and Luna here is a reference to Apollo and Artemis who are sister and brother and god of the sun and goddess of the moon respectively. It is also very interesting how there is linguistic adaptation of "Sol and Luna" especially since Maier was German.

I would like users to access extra contents of a post(picture, comments, number of likes) immediately. Users can immediately do some positive interaction with the post(writing comment, leaving likes, Subscribe). However, I will set posting and deleting post one or two steps away, to prevent some users accidentally post their privacy or delete their posts.

I compared Twitter (now X) and Instagram post views. Both immediately allow likes, comments, and sharing. One step away, Twitter offers retweets and quoting, while Instagram allows saving posts. Two steps away, Twitter gives options like adding to lists, and Instagram provides reporting. Both focus on easy engagement but differ in extra features like lists vs. post saving.

For a social media site focused on collaborative learning (like a mix of Reddit and Khan Academy), I'd design a profile page showing posts, achievements, and study interests. Immediate actions: create posts, comment, upvote. One or two steps away: start discussions, follow users. Not allowed: deleting others' posts, editing achievements.

2.2.3

An additional ethical framework specific to AI ethics would be "AI4People - An Ethical Framework for a Good AI Society: Opportunities, Risks, Principles, and Recommendations" used in governance regarding AI in the European Union.

The core tenants are to view AI as a tool to enhance to human experience, such as enabling self-realization, agency, and social cohesion while avoiding devaluing human skills.

Diagram used from page 4 of the ethical framework: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3284141

1.2.1

Kumail Nanjiani’s point regarding the lack of incentives for large corporations to consider ethics was something extremely interesting. Their lack of preparation when being asked ethical issues demonstrates the fault of the prevailing incentive and economic structures valuing growth, especially in big tech spaces, in favor of ethical questions.

From a utilitarian perspective, using data driven analytics to drive actions to maximize the happiness of the whole would depend largely on the quality of said collected data. Specifically regarding the unknown factors not collected in data analysis. This would be a general flaw since we as humans do not know what we don't know, and what may be a blind spot to us could have significant real world consequences depending on the situation.

I found that social media users have high stickiness. When I saw that Facebook caused many social media platforms to close down, I thought about why Facebook still has a lot of users since its inception. I think the high stickiness of social media users is because they have posted a lot of posts on this software. When they change the social media they use, the new social media does not have the posts they posted before, so they are reluctant to change.

The concept of nuance being lost in translation from reality to data is notable because this may have larger ethical and moral implications. The person in control of how the data is collected and formatted will embed their implicit biases within the collected data source, a data source that would be taken as "fact".

New York has opted for policies that criminalize poverty, such as militarized policing, mass incarceration, and punitive measures against houselessness. These tactics often fail to address the underlying causes of poverty and instead exacerbate the suffering by destabilizing communities and furthering injustices. This critique is directly connected to the historical practice of redlining and other discriminatory policies that systematically disadvantage already marginalized communities.

I also chose this quote because i feel like it has alot of weight when talking about the current impact redlining has and the impact it has silently had in our society for decades. It also helps us dive into what "The new Deal is" and how the creators had ill intentions with it. It also helps describe the impact this bill had on the citizens of the united states.

!!!! phasic dopaminergic firing= bursts of activity in dopaminergic neurons that occur after activation

the ventral tegmental area, the nucleus accumbens, the cerebellum, and the insula,

notes highlights and reply

!!!!!

!

conscious resistance to assimilation, which is played out stylistically, stresses Rhys's challenging the possibility that "colonies can be assimilated into or foreclosed ..."

consumption linked to sexual activity

body of the economy (national body) considereds alongside Anna's body -- the cacao is designed to enter both and subsequently transform it (by creolization or bodily transformation, respectively)

some specific work with the image to connect it to the idea summarized above

I'm not quite clear how confusion relates to the idea above. Are you focusing on the feelings of being outside the home and having to find a hidden key?

To some extent you miss Ruberg's critique of empathy games that led her to this conclusion. Can you rework the summary to show how Ruberg is suggesting alternatives?

Step Back In Time At The Mesa Typewriter Exchange by [[Phil Latzman]]

In David Gerrold's The Trouble with Tribbles: The Story Behind Star Trek's Most Popular Episode, he describes how he used a 12-pitch Selectric to type the 1967 episode. When the studio retyped it in pica (10-pitch) it came out to 90 pages and had to be cut down significantly to fit the show's running time.

The difference amounts to approximately 3 words per page and about 50 words per page.

The November 1952 issue of Boys Life had an advertisement for contest for a gold-plated Royal Quiet De Luxe typewriter.

timestamp

https://oldbobsoldtypewriters.com/

Scott Drudge is the proprietor<br /> Second generation typewriter repair as his dad Bob was the original namesake of Old Bob's Old Typewriters.

Taking a sabbatical in 2024 and expected back in late 2024.

more detail needed to explain how the example works

awesome point and it works to help clear up the paraphrase--some backwards work witll help.

how does the example follow from the last claim?

a stronger connection to the ideas of the summary is needed. One could perhaps note that GH questions ideas of empathy in the spirit of Ruberg

The 2024 Phoenix Type-In by [[Joe Van Cleave]]

Platen shrinkage

• most typewriters are 6 lines per inch
• 6.5 lines per inch based on actual measurement per JVC on one of his machines
• 2mm shrinkage??
• Per Bob/Typewriter Muse 1.1

Bob had a machine that was supposed to be 1.27 but was measured at 1.259 when pulled off. So shrinkage of platens can be roughly fifteen hundredths of an inch (0.015" or about 0.4mm)

Bob at Typewriter Muse custom tunes platens to the typewriter. Only place doing platens outside of JJ Short.

JVC's partner took him to the Phoenix Type-in for her birthday.

Bill Wahl of Mesa Typewriter Exchange

grandfather started in the 40s<br /> bill started in 73<br /> part time help to 92 and now by himself<br /> does his benchwork after hours and chats during the day

Ted Munk

adding machine database consideration

looking for service manuals for: - royal portables 50-59<br /> - skyriter 40s / 50s<br /> - sm9 service manual

Royal Mercury manual is a clear, well-written manual. The Smith-Corona series 5 typewriter manuals are great too, though a bit more dense.

Brian Goode and Christy organized this year's Phoenix Type-In.

strong point --is this kind of blending of experience what you see gone home as doing?

I wonder if the summary gets at this important claim or idea in Ruberg's passage?

!!!

inescapability of the desire taht any kind of storytelling that will by narrative turn them into something useful/instructive

what danger/risk are there associated w turning these inventoried people from the past into characters form which we extract meaning

"even if I tell stories, is that still doing the same thing history is doing? is there a way out of that? -- trying to make meaning out of the past that respects an ethics of responsibility toward the subjects of the past"

this section may be important for the writing

Observation: Two options of protecting shipping interests from the barbary States which was buila navy to rival from barbary states or pay them protection money.

Interpretation It's only two ways to give exchange to Barbary States which was build a navy to rival that of the Barbary States or pay them protection money which our country decided to pay protection money

Observation: The Government of the United States is not founded on the Christian Religion

Interpretation The Government is not founded on specific religion.

Observation: There a firm and perpetual peace and friendship between the united states of America and the bey.

Interpretation There is a peaceful agreement with the united states of america and the bey.

Insert Stuff >> Video Note

Kwalitatief: informatie verzamelen over cultuur waarmee voor het eerst te maken is, om theoretische modellen op te bouwen en hypotheses te genereren. Kwantitatief: voor hypothesetoetsing; wat?

Minder bias=betere data. Betere data vergelijking wereldwijd=hogere equivalentie.

Author response:

The following is the authors’ response to the original reviews.

Reviewer 1

Overall, this work is quite comprehensive and is logically and rigorously designed. The phenotypic and functional data on 2C are strong.

Thank you for your positive feedback on our findings!

(1) Comment from Reviewer 1 suggesting the mechanistic insights of 2C are primarily derived from transcriptomic and genomic datasets without experimental verification. 

Thank you for emphasizing the importance of experimental validation to support our transcriptomic and genomic findings. We acknowledge the gap in direct experimental evidence for the mechanistic insights of section 2C and recognize the value of such validation in strengthening our conclusions. While we recognize the importance of such validation, our current dataset lacks the comprehensive preliminary results necessary for inclusion in the supplemental material. We believe that the mechanistic insights presented offer a substantial foundation for the future research, where we aim to explore these aspects in depth with targeted experimental approaches.

Reviewer 2

Together their data may suggest a regenerative effect of 2C both in vitro and in vivo settings. If confirmed, this study might unlock therapeutic strategy for cardiac regeneration.

Thank you for your positive comment on the significance of our findings and the valuable therapeutic potential of 2C in cardiac regeneration!

(1) Comment from Reviewer 2 pointing out the the main hypothesis (line 50) that Isl1 cells have regenerative properties is not extremely novel. 

We agree with the reviewer that Isl1-positive cells possess regenerative properties. Following the reviewer’s suggestion, we have revised the original wording (line 46 in the revised manuscript).

(2) Comment from Reviewer 2 asking for providing a rationale for this 20x reduction of A-485 concentration? It would be useful to get a titration of this compound for the effects tested. 

As suggested by the reviewer, we have added the titration results of A-485 in Figure 1—figure supplement 1F-G.

(3) Comment from Reviewer 2 confusing to clearly understand what proportion of CMs dedifferentiate to become RCCs. The lineage tracing data suggests only 0.6%-1.5% of cells undergo this transition. It is difficult to understand how such a small fraction can have wide effects in their different experimental settings. This is specifically true when the author quantified nuclear and cytosolic area on brightfield pictures - would the same effect on nuclear/cytosolic area be observed in Isl1 KO cells. 

We appreciate the reviewer's insightful observation on the proportion of CMs undergoing dedifferentiation into RCCs and the potential impact of this subset on our experimental outcomes. The lineage tracing data indicating that only 0.6%-1.5% of CMs transition to RCCs indeed reflects a modest proportion. This observation raises valid questions regarding the broader implications of such a limited fraction in the context of cardiac regeneration and the experimental effects reported. It's important to note that while the proportion of CMs dedifferentiating into RCCs is small, the biological significance and potential impact of these RCCs could be disproportionately large. Emerging evidence suggests that even a minimal number of stem or progenitor cells can exert significant effects on tissue repair and regeneration, possibly through paracrine mechanisms or by acting as key signaling centers within the tissue microenvironment (Fernandes et al., 2015). Regarding the specific question about 2C’s effects on nuclear/cytosolic area in Isl1 knockout (KO) cells, we appreciate the suggestion and consider that such comparative studies would provide valuable insights for future comprehensively understanding the significant impact of 2C-induced RCCs in future search. In addition, ISL1 KO cells are also described in detail in the article published in eLife in 2018 by Quaranta et al.

(4) Comment from Reviewer 2 asking for the effect of CHIR + I-BET-762 alone. 

As suggested by the reviewer, we have added the results of CHIR + T-BET-762 in Figure 1—figure supplement 1H.

(5) Comment from Reviewer 2 suggesting a transparent explaination about the effects of A-485 on acetylation status.

We thank the reviewer for highlighting the confusion regarding the effects of A-485 on the acetylation status of H3K27Ac and H3K9Ac. Upon re-examination of our data and statements, we recognize the need for clarity in our explanation and the inconsistency it may have caused (lines 223-231 on page 8).

Initially, our observations suggested a selective effect of A-485 on H3K27Ac based on early experimental results (Figure 7—figure supplement 1). This conclusion was drawn from preliminary analyses that focused predominantly on this specific histone mark. However, upon further comprehensive examination of our data, including additional replicates and more sensitive detection methods, we observed that A-485 also impacts H3K9Ac levels (Figure 7—figure supplement 1F). This latter finding emerged from expanded datasets that were not initially considered in our preliminary conclusions.

The "further analyses" mentioned referred to these subsequent experimental investigations, which included chromatin immunoprecipitation (ChIP) assays and extended sample sizes, providing a more robust dataset for evaluating the effects of A-485. We understand the importance of transparency and rigor in scientific communication. To address this, we have revised the manuscript to clearly delineate the progression of our analyses and the evidential basis for our revised understanding of A-485's effects. This includes a detailed description of the methodologies employed in our follow-up experiments (line 537 on page 27), the statistical approaches for data analysis (lines 226-227 in supporting information), and how these led to the updated interpretation regarding A-485's impact on histone acetylation (lines232-269).

(6) Comment from Reviewer 2 asking for the difference in the ChIP peaks representation of the y-axis on the ChIP traces.

Thank you for raising this quest. Actually, we did not normalise the sequencing depth and the y-axis represents the number of counts (line 537 on page 27 and lines 226-227 in supporting information).

(7) Comment from Reviewer 2 suggesting the possibility of testing this 2C protocol on mESCs to see if similar changes are subject to and how these mouse RCCs differ transcriptionally from Isl1+ progenitor cells isolated from neonatal mice (P1-P5)?

Thank you for your insightful questions. Testing the 2C protocol on mouse embryonic stem cells (mESCs) to observe if similar changes occur presents an excellent opportunity to further validate the versatility and applicability of our findings across different stem cell models. We agree that such experiments would not only strengthen the current study but also provide valuable insights into the conservation of mechanisms across species. We are currently in the process of setting up experiments to address this very question and anticipate that the results will significantly contribute to our understanding of cardiomyocyte differentiation processes. Regarding the transcriptional comparison between mouse regenerative cardiac cells (RCCs) induced by our 2C protocol and Isl1+ progenitors isolated from neonatal mice (P1-P5), this comparison is indeed crucial for delineating the specific identity and developmental potential of the RCCs generated. However, a comprehensive side-by-side transcriptomic analysis is required to systematically identify these differences and understand their biological implications. We plan to undertake this analysis as part of our future studies, which will include detailed RNA sequencing and comparative gene expression profiling to elucidate the transcriptional similarities and differences between these cell populations. These future directions will enhance our current findings, provide a deeper mechanistic understanding, and confirm the potential of the 2C protocol in regenerative medicine applications. We appreciate the reviewer's suggestions and acknowledge the importance of these experiments in advancing the field.

(8) Comment from Reviewer 2 with a suggestion to have a precise clarification of statistics & data acquisition.

As suggested by the reviewer, we have revised clarifications to make them clearer (lines 228-233 in supporting information and a precise description of each paragraph involving statistical analyses).

Reviewer 3

The findings may have a translation potential. The idea of promoting the regenerative capacity of the heart by reprogramming CMs into RCCs is interesting.

Thank you for your appreciation of the significance and translational potential of our findings!

(1) Comment from Reviewer 3 suggesting the mechanism involved in the 2C-mediated generation of RCCs is unclear and the lead found in the RAN-seq and ChIP-seq are not experimatally validated.

We acknowledge the reviewer's concern regarding the lack of experimental validation for the mechanisms identified through RNA-seq and ChIP-seq analyses in the generation of RCCs from the 2C state. We understand the importance of substantiating these molecular leads with empirical data to strengthen our conclusions. Currently, our findings are based on in-depth bioinformatic analyses, which have provided us with valuable insights and a strong basis for hypothesis generation. Moving forward, we plan to prioritize experimental validation of key pathways and targets identified in our study. This will include designing targeted experiments to elucidate the functional roles of these mechanisms in the 2C-mediated generation of RCCs. We appreciate the opportunity to clarify our approach and future directions, and we are committed to addressing this gap in subsequent work.

(2) Comment from Reviewer 3 considering the very low number of RCCs (0.6%-1.5% of cells) generated cannot protect the heart from MI, and whether 2C affects the the survival or metabolism of existing CM under hypoxia conditions, and what percentage of cells are regenerated by 2C treatment post-MI?

We appreciate the reviewer's insightful queries regarding the protective effects of 2C treatment against myocardial infarction (MI) given the low percentage of RCCs generated. It is our hypothesis that the benefits of 2C treatment extend beyond mere cell numbers. We propose that 2C may enhance the survival and metabolic resilience of existing CMs under hypoxic conditions, thereby contributing to cardiac protection post-MI. Our future investigations will aim to quantify the precise percentage of cells regenerated by 2C treatment post-MI and explore its broader impacts on cardiac tissue survival and repair mechanisms.

(3) Comment from Reviewer 3 suggesting the administration of 2C in mice, as well as whether 2C affects cardiac function under basal conditions and any physiology in mice, and the need to examine cardiac structural and functional parameters after administration of 2C.

We appreciate the reviewer's interest in the potential effects of 2C administration on cardiac function and overall physiology in mice. While we observed a decrease in body weight at P5 compared to controls, our immunofluorescence staining did not indicate any changes in cardiac structure (Figure 4— figure supplement 1E). This suggests that while 2C administration impacts neonatal rat physiology, it does not adversely affect cardiac structure under basal conditions. Further investigations are planned to assess the functional parameters of the heart post-2C administration to comprehensively understand its effects.

(4) Comment from Reviewer 3 suggesting the potential effects of 2C on other cell types of the heart, including fibroblasts and endothelial cells, in vitro and in vivo.

We value the reviewer's suggestion to explore the effects of 2C on various cardiac cell types, including fibroblasts and endothelial cells, both in vitro and in vivo. We acknowledge the importance of understanding the broader impact of 2C treatment across different cell populations within the heart, given its potential protective effects. To address this, we are designing a series of experiments to assess 2C's influence on these cell types, aiming to elucidate any changes in their behavior, proliferation, and function following treatment. This comprehensive approach will allow us to better understand the mechanistic basis of 2C's cardioprotective effects.

(5) Comment from Reviewer 3 suggesting validation the effect of 2C in a dose-dependent manner.

As suggested by the reviewer, we have supplemented the effect of 2C in dose-dependent (Figure 1— figure supplement 1F-G).

(6) Comment from Reviewer 3 suggesting an explanation of how A-485 affects H3K27Ac and H3K9Ac.

We appreciate the reviewer pointing out the discrepancy regarding the effects of A-485 on H3K27Ac and H3K9Ac. Upon re-examination of our data, we realize that our initial interpretation may have overlooked the broader impact of A-485 on histone acetylation patterns. It appears that A-485 does indeed influence both H3K27Ac and H3K9Ac, contrary to our initial statement. This oversight will be corrected in our revised manuscript, where we will provide a more detailed analysis and discussion of A-485's impact on these histone marks, alongside an explanation for the observed effects (lines 223-269 across page 8-9).

(7) Comment from Reviewer 3 with a correction to use "regeneration" at the screeing stage.

As suggested by the reviewer, we have amended the wording in the text (line 66 on page 3).

Reviewer 4

Comment from Reviewer 4 suggesting more information that clarifies and justifies the hypothesis.

As suggested by the reviewer, we added more information to clarify and justify the hypothesis (lines 39-47 on page 3).

(1) Comment from Reviewer 4 pointing out the story line is not well developed.

To address the reviewer’s question, we revised the manuscript to ensure a smooth and coherent logical flow.

(2) Comment from Reviewer 4 pointing out the purpose in choosing to study ISL1-CMs.

As raised by the reviewer, we have clarified the rationale for using ISL1 as a marker to define RCCs in revised manuscript (lines 39-47 on page 3).

(3) Comment from Reviewer 4 pointing out the missing references in row 57-58.

Thank you for pointing this out, we fixed it.

(4) Comment from Reviewer 4 suggesting more explains and show the results of the screening compounds.

As suggested by the reviewer, we added additional explanations in lines 65-73 and showed the screening results in Figure 1—figure supplement 1F-H.

(5) Comment from Reviewer 4 suggesting an in-depth discussion of the findings.

Thank you for the suggestion, we included additional discussion at the end of the article.

(6) Comment from Reviewer 4 suggesting a conclusion should be inculded in the main text.

Thank you for the suggestion, we made a revision.

(7) Comment from Reviewer 4 pointing out the cell viability under different concentrations of 2C.

As mentioned by the reviewer, have supplemented the cell numbers during different doses of 2C treatment (Figure 2F).

(8) Comment from Reviewer 4 pointing out the missing information in the methods.

Thank you for the suggestion, we made additions.

(9) Comment from Reviewer 4 suggesting more explanations in Figure S3A.

As mentioned by the reviewer, we made a revision in original Fig.S3A (now is Figure 2—figure supplement 1).

(10) Comment from Reviewer 4 pointing out the high variability of mCherry cells (%) in Figure 3J.

Thank you. We made a revision.

(11) Comment from Reviewer 4 suggesting more explanations on the DNA-binding motif of ISL1 in the cells treated with A-485 or 2C.

Thank you for the suggestion, we added additional explanations (lines 270-274 on page 9).

(12) Comment from Reviewer 4 pointing out the unclear labeling in Figure S1B and D.

Thank you for the suggestion, made a revision (lines 240-245 in supporting information).

(13) Comment from Reviewer 4 suggesting a relative quantification of the proteins in Figure 1H.

Thank you for the suggestion. We have quantified the relative expression levels of proteins in original Fig. 1H. As shown in Figure 1F.

(14) Comment from Reviewer 4 suggesting to provide detailed information in the methodology part about the compounds.

Thank you for the suggestion, we made a revision.

(15) Comment from Reviewer 4 pointing out the insufficient explanations on figure legends.

Thank you for the suggestion, we made a revision.

(16) Comment from Reviewer 4 suggesting more independent experiments to reduce the high variations in “ns” between NC and 2C at 60h+3d shown in Figure 2E and F.

Thank you for the suggestion, we made a revision in Figure 2F.

(17) Comment from Reviewer 4 suggesting a limitations should be provided in the text.

Thank you for the suggestion, we have made provide a limitation statement in the revised manuscript (lines 300-311 on page 10).

eLife Assessment

This manuscript offers valuable information on the combinatory effect of small molecules, CHIR99021 and A-485 (2C), during the reprogramming of mature cardiomyocytes into regenerative cardiac cells on stimulating cardiac cell regeneration. Although the study used several hESC lines and an in vivo model of myocardial injury to demonstrate the regenerative potential of cardiac cells, the manuscript is still incomplete as several concerns remain unanswered, including the lack of validation of the conclusions from scRNA-seq. It is still unclear how a small fraction of dedifferentiating cardiac cells can offer such broad effects on regeneration both in vitro and in vivo. If validated, this study might unlock potential therapeutic strategies for cardiac regeneration.

Reviewer #1 (Public review):

The present manuscript by Zhou and colleagues investigates the impact of a new combination of compounds termed CHIR99021 and A-485 on stimulating cardiac cell regeneration. This manuscript fits the journal and addresses an important contribution to scientific knowledge.

Comments on latest version:

The authors have addressed all of our comments.

Reviewer #2 (Public review):

Summary:

This manuscript reports that a combination of two small molecules, 2C (CHIR99027 and A-485) enabled to induce the dedifferentiation of hESC-derived cardiomyocytes (CMs) into regenerative cardiac cells (RCC). These RCCs had disassembled sarcomeric structures and elevated expression of embryonic cardiogenic genes such as ISL1, which exhibited proliferative potential and were able to differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Lineage tracing further suggested that RCCs originated from TNNT2+ cells, not pre-existing ISL1+ cells. Furthermore, 2C treatment increased the numbers of RCC cells in neonatal rat and adult mouse hearts, and improves cardiac function post-MI in adult mice. Mechanistically, bulk RNA-seq analysis revealed that 2C led to elevated expression of embryonic cardiogenic genes while down-regulation of CM-specific genes. Single-cell RNA-seq data showed that 2C promoted cardiomyocyte transition into an intermediate state that are marked with ACTA2 and COL1A1, which subsequently transform into RCCs. Finally, ChIP-seq analysis demonstrated that CHIR99027 enhanced H3K9Ac and H3K27Ac modifications in embryonic cardiac genes, while A-485 inhibited these modifications in cardiac-specific genes. These combined alterations effectively induced the dedifferentiation of cardiomyocytes into RCCs. Overall, this is an important work, presenting a putative cardiac regenerative cell types that may represent endogenous cardiac regeneration in regenerative animals. With that said, here are suggestions for the authors:

Strengths:

Overall, this work is quite comprehensive and is logically and rigorously designed. The phenotypic and functional data on 2C are strong.

Weaknesses or suggestions:

(1) In Figure 4, the authors should perform additional experiments on analyzing 2C effect on cardiomyocytes, endothelial cells, and fibroblasts in adult mouse hearts after myocardial infarction.<br /> (2) In Figures 5-7, the mechanistic insights of 2C are primarily derived from transcriptomic and genomic datasets without experimental verification.<br /> (3) The authors should compare transcriptomic profiling of the RCCs with other putative cardiac progenitors from public databases.

Reviewer #3 (Public review):

Summary:

The ability of cardiac cells to regenerate has been the object of intense (and sometimes controversial) research in biology. While lower organisms can robustly undergo cardiac regeneration by reactivation of embryonic cardiogenic pathway, this ability is strongly reduced in mice, both temporally and qualitatively. Finding a way to derive precursor cells with regenerative ability from differentiated cells in mammals has been challenging.

Zhou, He and colleagues hypothesized that ISL-1-positive cells would show regenerative capacity and developed a small molecules screen to dedifferentiate cardiomyocytes (CM) to ISL1-positive precursor cells. Using hESC-derived CM, authors found that the combination of both, WNT activation (CHIR99021) and p300 acetyltransferase inhibition (A-485) (named 2C protocol) induces CM dedifferentiation to regenerative cardiac cells (RCCs). RCCs are proliferative and re-express embryonic cardiogenic genes while decreasing expression of more mature cardiac genes, bringing them towards a more precursor-like state. RCCs were able to differentiate to CM, smooth muscle cells and endothelial cells, highlighting their multipotent property. In vivo administration of 2C in rats and mice had protective effects upon myocardial infarction.

Mechanistically, authors report that 2C protocol drives CM-specific transcriptional and epigenetic changes.

Strengths:

The authors made a great effort to validate their data using orthogonal ways, and several hESC lines. The use of lineage tracing convincingly showed a dedifferentiation from CM. They translate their findings into an in vivo model of myocardial injury, and show functional cardiac regeneration post injury. They also showed that 2C could surprisingly be used as preventive treatment. Together their data may suggest a regenerative effect of 2C both in vitro and in vivo settings. If confirmed, this study might unlock therapeutic strategy for cardiac regeneration.

Weaknesses:

Updated General comments:

Experimental design & Interpretation

(1) The titration provided by the author following the first round of revision is puzzling to me. Based on the authors explanation, the initial screen was performed using 10uM of A-485, allowing the authors to choose CHIR + A-485 as a combination of drugs increasing Isl1-positive cells. However, in the titration provided, the combination of CHIR + 10uM of A-485 (used during the screen) shows *no* increase of the percentage of Isl-1-positive cells compared to DMSO control. How is that possible? Can the authors provide a transparent explanation of the experimental design for their screen. How was A-485 isolated from the 4000+ compounds tested if it does not show any effect on the titration? This titration raises significant concerns about the rational of following up with the combination of compounds.

(2) The authors have not really addressed the concern raised earlier. If only ~1% of the cells de-differentiate and become Isl-positive, how can anybody quantify a nuclear/cytosolic ratio at the global population and show statistical significant when only 1% of the cells should be different?

(3) Authors now provide a quantification of the effect of I-BET-762 (Supp 1H). While the authors state " [the combination of CHIR + I-BET-762] was less effective than A-485 in combination with CHIR99021", the figure provided does not test that. A side-by-side comparaison of the effect of A485 and I-BET should have been performed on the same graph. I-BET increases by 4 fold, while A-485 increases by 5-fold, which, based on the variation of their data, will unlikely be statistically different. The rational for disregarding the effect of I-BET-762 is therefore weakened.

(4) Why NR2F2 is statistically significant in one set of experiments (Fig 2 - Fig. supplement 1) and then non-significant in another set (Fig. 1G) using the exact same experiment design (NC vs 2C for 60h) and similar statistical test applied?

Statistics & Data Acquisition

(1) Authors should refrain from deriving statistics from 2 biological repeats (Figure 3G).<br /> (2) Authors still do not state whether the normality of their data was tested.<br /> (3) What is the rational for using a two-way ANOVA for Fig 3G? Authors are only comparing the effect of their treatment for each marker. Same question for most panels from Figure 1, Fig 2C, 2F, and throughout the manuscript. This needs clarification/justification especially because in other experiments, they used multiple unpaired t-test (Fig 2 - Fig. supplement 1).

Others

(1) Authors should try to make their manuscript colorblind-friendly: No modification added following this comment.

The graph shouldn't have any extra space on the X and Y axis. most obvious being the 18% sugar on x axis because there wasn't a 18% standard.

don't mention the lab packet.

The reader doesn't know what this refers to.

should be separated from the text and labeled as, "equation 1"

Not necessary.

This isn't the definition of m in the equation; it is just mass.

There is no mention of the Erlenmeyer flask used to gather the calibration standard.

They didn't mention calculating density or identifying the metal.

Don't mention recording the mass; this is assumed.

I don't think this is necessary to include.

This is supposed to be revenge against Fortunato? Why is the narrator insisting he go back? Did he know it wouldn't change Fortunato's mind? Is he doing this to make his character still seem good?