better prepaed framse the hospitals in a postive light when in reality it shows how they knew the conditions were getting bad again so much so that they aere able to predict another strike

The author stating their opinion on the walkot before giving all the facts in making the reaers alreay view the situatioon for a biased persepecitve.

By highlighting the internal conflicts within the union it takes away from the larger picture which the unions conflict with the hospital organization.

Makes the labor union seem like they are going on strikes all willy-nilly

The power of colation and community building is ione of the main ingredients to bring about actual and lasting change. As seen in this entire study; when the evniromentalists joined with labor unions and governemtn offices (however minor or major), it resulted in amuch more balanced and nuanced approach to ensuring both envirmoental protection of the environment and minorities as well as protections and insurance for the laborers that work in the field.

This point must be highlighted to note that the social movements of the 60's was a multi-front and multifacted movement. Too often do historical narratives become condensed and re-written from a reductionist point of view; in order to create a larger dissonance between these events. Another example is that the Civil Rights Movement of the 60's interescted wiht the Vietnam War; Dr. Martin Luther King was an outpsoken and avid anti-war dissenter.

Guilt tripping women seems to be a massive issue, whether it be abortion, their clothing and appearance, their choice to have/not have children, or even their parenting choices once they do have children. I would argue that even women are adept at criticizing and guilting one another rather than providing support. Mothers in particular tend to be the target of scrutiny and I have heard many express frustration that they "cannot do anything right". Anything from breastfeeding to toys to education can create discourse and lead to women being shamed. If you homeschool your child, you are not adequately preparing them. If you do not homeschool them and work full time, you are not an involved mother. If you send them to a public school, you are not setting them up as well as they might be at a private school. Rarely do men seem to be held to these same standards. In fact, so long as men are merely present, people will often behave as though they are inherently wonderful fathers. This overarching narrative of women being solely responsible for their children's success and being forced into traditional roles in the name of upholding the household is detrimental to women's autonomy and overall, to their own wellbeing.

The idea that children are constantly under threat due to incorporating gender and sexuality into the classroom is a topic I have heard about a lot. it is interesting to me because I have seen how the phrase 'protecting children' can be used to shut down conversations before they even begin. Once something is framed as being about children safety, disagreeing with it can make someone appear as dangerous and unreasonable. Teaching students about gender, sexuality, sex education, etc, should not be portrayed as 'exposing children to 'inappropriate ideas' the goal is to give students accurate information to help them make informed decisions and to also be inclusive.

Women’s reproductive health is so important and it needs to be taken more seriously rather than access to it being taken away. It feels selfish to me for others to ignore the necessity of contraception and abortion for many women. It's very common for women and girl to be prescribed birth control purely for health reasons such as hormonal imbalances or other reproductive issues, taking that away would cause a lot of women and girls to struggle. The same can be said about abortion, while I think everyone should have the choice, for some women it isn't just a choice but necessary, lifesaving medical care.

I find it shocking how men feel empowered to say things like this publicly. It's really telling in regards to how our society seems to be going backwards in terms of politics. Women’s rights were fought for and won before my time and yet they're still being debated and even taken away now.

I am held in suspense to a film currently in production called Yesteryear. The movie which is based off a book by the same name seeks to create commentary around the problematic tradwife movement and I am curious on what the reaction is going to be from the named community. It has been weird to watch the tradwife community grow, especially since it is so easy to point out the hypocrisies of the movement by just considering the potential of financial gain of these "stay-at-home wives" doing the full time job of an influencer. Obviously not everyone in the movement is an influencer but it seems like the popular thought of * lets get on back to the "good times"* was pushed by such individuals, which in turn made susceptible people who where lost or questioning the status quo fall in line.

I've also noticed a lot more men complain about this on social media, in my personal life and (oddly) immediately after matching on dating apps. I wholeheartedly believe algorithms are to blame for the rise in men adopting this mindset. I've seen it firsthand through a family member. He'll watch one right-wing-leaning reel, and suddenly his feed is full of them. Then, he'll send me a random Star Wars reel, and suddenly my For You page is filled with "Red Pill" reels. It does make me wonder: What content are they using to train the algorithms? And does anyone approve it before using it to train these algorithms?

I cannot fathom why anyone would think that making adoption for queer couples illegal is a good or beneficial thing. They (the far right) would rather leave children in situations without adequate support systems than place them with people who want a child, but can't have one biologically, solely because they are same-sex couple. This does nothing except negatively impact both parties. Furthermore, there have been multiple studies that support the notion that children raised by same-sex couples, excel and outperform their hetero-parent peers.

I love this idea, because I find it directly opposes the concept of patriarchy being correct because it is natural and traditional. The ideas we discussed in class about how bible stories and other texts are used to point to "how things should be" are challenged simply by the existence of women who hold power, authority, or resist that idea of tradition itself. Furthermore, even in situations where an authoritarian power has already restricted the autonomy of women (Taliban banning the education of young girls), it is still met with resistance, primarily by the women in question (Underground schools run by women). And this has occurred throughout history, with women's rights movements existing now as they did a hundred years ago. Why resist what is right and traditional... unless, maybe, because it is not right or traditional?

We were talking today in my History teachable class about how curriculum documents are inherently political, and it reminded me of this. We work within an education system that is constantly a topic of political discussion and debate, so the curriculum we teach is never completely separate from the political and social context around us. What gets included, what gets left out, and how history is presented can all reflect particular values, perspectives, and ideas about what students should know and understand. It really made me think about how teachers are not just delivering a neutral curriculum and we’re also navigating a system shaped by ongoing political conversations and decisions. We need to think critically about how our lessons carry political weight but also craft emotional burdens on our students. We must attempt everyday to be good ambassadors for our students and strive to understand that agenda of others and see where you lie.

I think the concept of “innocence” brings many complex questions into play. At what point is a child considered innocent, and when does that perception begin to change? What causes this change, and who determines when a child has “lost” their innocence? These questions are particularly complicated in the context of education, where educators are often responsible for understanding and supporting children as they develop. The boundary between childhood innocence and the expectations placed upon children as they mature can be difficult to define, making the concept of innocence especially complex for educators to navigate. I wonder how you would navigate that realm especially when it comes to parents who have differing beliefs to you.

In North America, the mainstream conservative movement frequently claims to support fundamental freedoms, specifically highlighting that of "free speech," while on the other hand banning books. This hypocrisy reveals what I would point to as a fascist tendency to weaponize democracy against its citizens, claiming both that it is under attack and needs to be fixed by them, while simultaneously working to undermine its foundations. This is much easier to do with a poorly-educated population, and therefore goes hand-in-hand with longstanding conservative efforts to defund and destroy public education.

To me, this is such a poorly veiled attempt to disenfranchise groups that already bare the brunt of both patriarchal and racist structures. The article mentions that the falling birth rate is not a crisis, and I would extend this to suggest that it's only a crisis for late stage capitalist overlords who rely on the system of taxpayers for government funding, as if society's most wealthy aren't capable of paying more taxes. It's particularly insidious to me that far right movements push the responsibility for the declining birth rate onto women, non white immigrants, and LGBTQ+ groups when all we want is equal rights.

In one of my English classes, we engaged in extensive discussions about who held agency in the context of the "Fall of Humankind." Our professor suggested that the most straightforward answer was Eve, as she was traditionally believed to have bitten the apple and initiated the fall. However, he encouraged us to think critically and consider alternative perspectives. Notably, these conversations centered on John Milton's "Paradise Lost," rather than the biblical account itself. This distinction prompted me to reflect on whether the Bible, or its interpretations over time, may have been employed as a political tool to suppress women. If this is the case, it raises important questions about the motivations and historical contexts that led to such uses of religious narratives. Furthermore, it invites a broader examination of how literature and religious texts have been interpreted to reinforce or challenge societal power structures, particularly regarding gender roles.

It's interesting that tradwife influencers are able to tap into peoples frustrations with capitalism and instead of create a push back towards capitalism, they retreat to a reliance on the patriarchy. Where does capitalism come from? Who formed these institutions? Where is the recognition that capitalism works in tandem with the patriarchy? That capitalist ideals, and patriarchal ideals are the same? I can understand as a woman it can sometimes feel like the only option to escape the rat race is to submit to someone who can provide for you, but there needs to be a deeper dissection of how marriage is also an institution and are these women aware of the contract they are signing?

I find this point interesting because the nuclear family is often treated as if it has always been the universal way people have lived. from studying history, I know that family structures have actually varied significantly across different cultures and time periods. additionally, the idea of the nuclear family has particular roles for men and women, such as men as providers and women as caregivers, and treats moving away from those roles as a threat rather than simply a different way. there is not one exact way to live, just because you live one way, does not mean that how someone else chooses to live is 'wrong' it is simply just different and can also be right.

While the resignation of woman from politics is largely concerning and scary, I think it's important to note that women remove themselves from all spaces because of concern for their safety. I personally resigned a co-op at a guitar store in high school that I was initially so excited to work at because the men running the business made the space feel very unwelcome and unsafe. Not only can woman not safely be apart of the political systems that affect their rights, but even job opportunities, clubs and extracurriculars, and participating in culture are not always safe spaces too.

In the last couple of years especially, there has been a rise in protests for families to want their children only to learn things that fall in their own personal belief systems. I have seen influencers online who have chosen to homeschool their children because their religion doesn't believe in ideas like evolution and they don't want their children exposed to information that threatens that belief system. However, what researchers are finding is that a lot of times the people who choose to homeschool their kids for the purpose of limiting their exposure to "corruption" often do not have any experience in teaching or education. And because of this these children are often working at a lower level that they should be for their age. There needs to be a push to educate people that exposing children to conflicting views/ideas/information is essential for developing their critical thinking skills, and that if they learn or hear views that don't match their families views it will not "corrupt" them.

I think its important that groups in opposition to the far right adopt further policy like this. Not simply taking time off when a more left leaning political party is in power but to keep on working to take preventative measures to ensure rights and freedoms are further protected in case a far right government were to come into power. This is something I will largely criticize the Democratic Party in the US for failing to accomplish with 8 years in office but with no effort to codify Roe vs Wade, something that would later be revoked causing woman in many states to lose their reproductive rights

Something that I hear all too often, even from "progressive" individuals, is that feminism has basically done its job, and that gender inequality is an issue of the past. As much as great progress has undoubtedly been made (though I wouldn't go so far as to say it's been solved), people tend to forget that feminism is a global issue, extending beyond the western world. The quality of life, if you can even call it that, for women in Afghanistan is truly the most appalling thing I have encountered in recent years. It is an evolving situation that I revisit from time to time but which I have had to distance myself from at times because it upsets me/angers me so deeply. What few rights remain for these women erode every day. The dehumanization and oppression is such that Meryl Streep aptly described their freedom as being less than even stray cats, because at least the latter have the ability to go unchaperoned to sit on a porch and feel the sun on their face. One of the most horrific recent rulings is the repealing of girls' rights to attend school past grade 8, meaning that they are pulled from classes before ever reaching high school. Additionally, because of the strict rules prohibiting women from seeing any male doctors, and the fact that of course, women are not permitted to reach the level of education required to enter the medical field, there is massive barrier to accessing medical care. The result of this is that the women who are already forbidden from so much as exiting their homes or frequenting public spaces unless they are being accompanied by men, are also being subjected to a healthcare crisis and a rapidly increasing rate of deaths related to childbirth.

The phrase "family first" carries a complex duality, as it often relies on the traditional image of a married man and woman with two children. This narrow definition is problematic because real family units are diverse and take many forms. For example, I come from a divorced family with two separate households and blended siblings. This reality does not fit the "nuclear family" ideal and would historically have been viewed unfavorably, despite sharing the same commitment to prioritizing family. Thus, stating that you are “family first” while striving for the “idealized” family is increasingly problematic, which is why we must view key concepts through a critical lens.

This connects directly to our discussions about tech facilitated gender based violence. What stood out to me is that the purpose of this kind of tech is not necessarily just to embarrass someone but can also discourage them from speaking or participating publicly. It shows tech can become a tool of power, especially when it can become sexualized content or used to intimidate someone.

I find that fear can be used to make unfamiliar groups or ideas appear threatening, especially when people do not understand them. I think some people can weaponize their own lack of knowledge by refusing to learn about an issue and instead relying on fear-based assumptions, which makes a complex topic seem like an immediate threat to their families, values, or way of life. By simplifying an issue and presenting it as something dangerous, fearmongering can make people more willing to accept restrictions or hostility toward groups they may not fully understand.

Abortion is a very real and necessary part of women's reproductive healthcare. They exist for more than just wanting to terminate a viable pregnancy; still a valid reason. However, with regulations like the heart beat ban, you don't only limit access to people wanting abortions, you limit access to people who NEED abortions. examples of this can include a non-viable pregnancy (ectopic, etc.).

This was a very discouraging statistic. Having gone to the website itself (Equal Measures 2030), I have many more questions about this statistic. The last update on this website was 2022 and I can't help but think how much the world has changed in the last 4 years. I question what the base standard was that the team was working from as to sort these countries. I wonder if the USA would be considered in regression since the overturn of Roe vs Wade (June 24, 2022) or still stagnant, as the website does not mention what month these findings were published. I as well ponder what is going on in Switzerland that things in regards to gender equality are considered "very good" in both levels and pace of change.

This is an issue I see a lot with discourse surrounding the teaching of sexual education and gender in school. Many are unironically under the assumption that pornographic material is used to teach about these subjects. On top of being entirely wrong, this reveals how narrow most peoples view is on the subject of sexual education, and discussions around homosexuality. Many automatically think of sexual aspects of LGBTQ experience, dehumanizing them to a sexual action instead of humans with complicated feelings of love.

This makes me consider the intersection of capitalism and patriarchy, since most (if not all) popular social media platforms are owned by billionaires. It seems unlikely that the function of these platforms to create addicting and extremist echo-chambers that tear at the fabric of social cohesion specifically among the working class is accidental. The fact that the owners of these platforms are happy to continue to run them against the public interest in order to increase their ever expanding profits is not surprising and I think frightening.

Far right-wing people owning multi-billion dollar AI and tech companies have coincided with huge bot problems on social media. Twitter, facebook, instagram, etc are complicit in propaganda bot accounts taking over and engaging in targeted harassment of women, 2SLGBTQ+ people, racialized people, etc. There are now bots programmed just to argue with people on specific hashtags. I saw a video recently where someone just said random words, and put hashtags #LindsayClancy #feminist and even though she didn't actually say anything about that, swarms of bots came in with comments arguing about the case and insulting her, because they are programmed to have certain reactions to certain content. Now, whenever I am online, I try not to allow comments to affect my mood, since they're not real people and don't actually represent how the majority of people feel.

I can't believe this is happening! It took a very long time for the 1940s Declaration of Human Rights to really make its way into international policy, and to see elements being overtly repealed makes me sad and angry. Rights are fragile things, as we seem to be learning in so many aspects of society.

This point can be seen through influencers such as Andrew Tate, whose content has gained significant attention among young male audiences. Tate frequently promotes a form of masculinity centred on dominance, control, wealth, and traditional gender roles, while making controversial statements about women and relationships. Repeated exposure to this type of content can influence impressionable young men by presenting these attitudes as normal or desirable characteristics of masculinity. Social media algorithms can further reinforce this exposure by repeatedly recommending similar content, creating an environment where young men may increasingly encounter and internalize these messages about how men and women are expected to behave.

This stood out to me since social media can make certain gender roles seem much more normal and desirable than they are people are constantly being exposed to content about what men and women are supposedly to look like or act like. I think this is espesically important for young people because algorithms can repeatedly show them the same ideas until they start to feel like commmon sense rather than one particular perspective.

I see this often in my own life, as with every current issue I bring up to my parents (often from a liberal perspective), there seems to be another side of the issue that they have already bought into (often from a conservative perspective). They've sent me anti-LGBTQ+ posts showing footage of queer protesters that are A.I. generated, which I had to explain to them. It really creates a divide between us because it leaves little room to discuss the issue ourselves, like how we see it as individuals, without it becoming an argument about "brainwashing" or where we are getting our information from.

I think this paragraph as well as the paragraph above talks heavily about what we touched onto today in class as well as otherclass. The idea of these gender role ideologies of the "role of women" to be to stay home and raise the kids and the "mans role" is to go out into the world and work to provide to his family. This also touches a lot on what is currently happening united states wher people in power are trying to take away rights of people who are not male, or conform to the ideology of those making the rules and are in power.

I found this point interesting because it shows how frustration about larger social and economic issues can be redirected toward groups that are easier to blame. By portraying women, LGBTQ+ people, and their supporters as responsible for social problems, these movements create a clear 'enemy' and shift attention away from the underlying causes of public dissatisfaction and make it more difficult to make any positive change.

In my history and English classes, we often discuss how personal experiences are inherently political, and how religion can have a deep impact on each individual. These discussions usually focus on the idea of improving one's soul. I believe religion is often a tricky slope to go down but that is why you must look at traditional beliefs in a way to better the society as a whole but also to include those citizens who often got left out or ostracized by these communities.

We can see very clearly in North American culture of the assault on women's rights. Right-wing politicians have passed laws/dismantled existing laws to try and control women (ex. abortions rights in the US). While this was one of the first things that Trump's government put in motion to try and control individuals, but we have seen this trickle down effect to laws being passed about transgender individuals (like having the gender stated on their passport match their sex assigned at birth). As disappointing as it is, I expect we'll probably see laws/legislation being passed to continue to attack and control the American people (and these ideals can and will impact us in Canada too as other Canadian right-wing politicians take a page out of the US's book).

I found this particularly interesting because it points out the how the language of protecting children or protecting families can be used to justify restrictions on other peoples rights. It makes me think about how difficult it can be to challenge an argument when its presented as being about safety. I also think this connects to education because school;s constantly have to balance parental concerns with students rights and inclusion.

I find it interesting to note these periods where far-right conservative organizations became most active, since they both followed popular left-wing movements. First in the 1960s, where the "hippie" movement and labour/vietnam protests resulted in massive cultural backlash in the 70s and 80s. And in the late oughts, where the occupy wall street movement/Obama elections and the short era of liberal optimism were also met with the backlash we are still living in today. It's as though every short bubble of left-wing activity gets crushed afterward by waves of massively conservative-funded operations.

I think it's incredibly interesting and also shocking how social media influencers have shifted to promote this ideology more recently. When I started getting into activism and politics in high school the mindset of people seemed much different. To me, things seemed accepting and more hopeful then. I find it scary how quickly politics and common beliefs have shifted away from being accepting to being very exclusionary, and hostile.

This is something I have noticed as well. The same people who call feminists feminazis, and think a woman's place is in the kitchen will say their issue with trans women or immigrants is that they are attacking women. However, when women speak out on actual assaults, they are told they're lying and delegitimized. These people only "care" about women when it is convenient for their agenda. As mentioned below, it's similar to how people want to force women to give birth under the guise of "caring about children" but then when children are born into poverty, there is no support or care for that child from those people.

This point shows how language about “protection” can sometimes be used to make restrictive or oppressive ideas appear reasonable or justified. I think this is especially important when religion is used as a tool to support a particular political or social position, rather than recognizing that religious beliefs can be interpreted in different ways. It raises the question of how we can distinguish genuine expressions of faith from the use of religion to justify control over one another.

I find this sentiment to be so cruelly ironic. Manufacturing a panic surrounding inclusivity prevents children from learning and knowing about their own bodies, rendering them more susceptible to abuse. To me, this recalls Reagan-era sex education policies enforced during the early AIDS epidemic, which encouraged people to practice abstinence opposed to teaching students methods of keeping themselves safe.

Once it becomes possible...

I found this really interesting because it shows how the language of protecting children or protecting families can be used to justify restrictions on other people's right. It also makes me think about how difficult it can be to challenge an argument when it is presented as being about safety. I also believe that it connects to education because schools constantly have to balance parental concerns with students rights and inclusion.

I think this point is very important to reflect on. Much of modern culture war discourse is being funded by organizations such as these conservative think tanks especially in the US. In my undergraduate, i conducted a study looking into "moms for liberty", a Florida based parental rights group who attacked teachers who practise inclusive teaching practises. The organization was tied to and directly funded by conservative think thanks such as the aforementioned Heritage and Koch foundation. These foundations dictate much of the public conscious without them being hardly known and ties into our class discussion on the intersection between patriarchy, racism, and capitalism all as dominant restricting forces.

I think it's incredibly interesting to see the drastic shift social media had taken towards the idea of women's domestic life. In my early life you would hear of influencers or celebrities fighting for womens equal rights or for equal pay in work setting. But now, even as we progress through the years we have seen a shift to women perpetuating the idea that women should be stay at home moms, and they should home-school their kids (especially when looking at the rise of Mormon influencers in popular media and their religious ideals directing individuals views). I think this could also have a really detrimental effect on young women and girls in schools who are very active on social media and are being fed this idea that their place isn't in the work force but to stay home and care for their family.

This is an important concept to highlight because it happens often throughout history. When many people don't understand certain identities or stories, they can respond out of fear, which often turns into hate. This helps explain why a hierarchical structure emerges from this dynamic: people seek a hierarchy so they can control what they otherwise lack control over.

This point highlights how social media can reinforce traditional gender roles by presenting women’s domestic submission as desirable while promoting misogynistic beliefs among young men. Influencers such as Nara Smith and online figures associated with red-pill ideology demonstrate how different forms of gender messaging can shape expectations about masculinity and femininity. Together, these trends show how digital platforms can normalize unequal gender roles and deepen divisions between men and women.

It's quite an obvious way to pull power towards an authoritarian government, and away from the people. However, in practice it's much less easy to spot, especially when there is so much fear mongering and social media spreading ideas faster than ever. It's also difficult to understand that a lack of trust between groups also means a lack of empathy and care for one another.

I think this is particularly relevant to highschool educators like us, since this kind of "manosphere" content is particularly popular among teenage boys. I think it's important to address this kind of content with our students, explaining where the funding and promotion comes from, and what agendas it serves. I have also found that the ideologies promoted have seeped into the ways in which male students interact with their peers and even their teachers.

This sentence specifically reminds me of the continuous topic of debate surrounding transgender males using the womens washroom. Statistically, there is no evidence that suggests that allowing transgender individuals to use the bathroom of their choice leads to violence against cisgendered woman. But right-wing conservatives use the language of womens safety to deny the right for trans people to exist and be in public spaces.

This is also a very white Western/Eurocentric view on family. So many different cultures have different ideas on family (polygamy, multi-generation homes, children being raised by whole village, etc). How can one family structure be defined as natural, when it is not universal, and takes an enormous amount of propaganda to get people to participate in it?

"Sometimes we need to dive deep to reach the bottom and think slow to arrive at an insight". Gavin Haus Sep 21 2026 Module 1 I enjoy this sentence and image of a deep sea diver because it really helped me understand what what it takes to reach the bottom of an argument or issue. Like mentioned earlier, many people think too fast and come to conclusions and judgments quickly and based on emotion even for complex issues that may be better treated with logic, objective reasoning, and deep thinking. This image of a deep sea diver reminded me that to dive deep you have to first relax and let go of tension in your body. To me it's the same with thinking about a big issue, relax and let go of previous judgments or quick decisions/bias about the issue, slow down and process objectively to come to a conclusion.

Europe has had equally violent time periods, if not more violent, than the Middle Eastern governments.

This page highlights the pigeonholing of Muslim communities into violent and incapable leaders of democracy.

During peaceful protest, Americans, despite the heavily anti-Arab sentiment at the time, felt themselves aligned with the Arab citizens -- violent protests once again outcasted Arab people.

The spread of information is never fully stifled by the government and is more powerful than any other method of recruiting protestors. This is similar to the Haitians learning from the French Revolution.

cretin

I couldnt agree anymore i mean i was in school like 10 years ago and going back to school now its like nobody wants to ask questions anymore. Nobody wants to discuss what we learned or even as for an explanation from anyone. We rely on a computer to speak to us then we lose that connection from each other the wisdom experiance growth that a computer can never compute. Yes AI is exceptionally beneficial to society and making us expand on the information we know. But if we are not taking the time to think reflect or understand then we are more likely to follow blindly to what is being said to us. I really believe it has some potential but just like everything there is if we dont take the proactive steps to work along side it it will work against us very quick

I noticed that people dont deep depper than the surface level anymore. We have made learning way before AI surface level. Yes, AI has accelerated that process but there wouldnt have been a need for AI if we havent lost the true development of learning. We made education this institution of learning to gain something. When you stripped what is is to learn to what you can by learning then more and more people will come out from the end of this road having degrees and lacking any degree of discernment,

This shows that both approaches have a purpose.

This makes the intellectual game sound exclusive by making a comparison.

analogy

The idea is applied to an actual disagreement here.

It is easy to understand through a relatable example.

science example

credibilty

this helps to show what having another viewpoint actually means

direct command

This shows that personal opinions can interfere with doubting.

comparison

Our own beliefs make it harder to be objective.

As Lucas’ ‘25 annotation notes, Eliot contrasts Milton’s “Native perfumes” in the garden of Eden that are naturally dispersed by “gentle gales” with the woman's “strange synthetic perfumes,” emphasizing a shift from natural purity to artificiality. Building on this contrast, Eliot’s description suggests not just artificial vs natural but sensory corruption. Whereas Milton’s perfumes “dispense” themselves gently throughout Eden, Eliot’s perfumes “lurk,” a verb that gives them a hidden, almost predatory quality. The scents aren’t pleasureable, instead, they “troubled, confused / And drowned the sense in odours.” The woman is surrounded with glittering jewels, candlelight, and expensive cosmetics in an attempt to recreate the luxury of Paradise through material value. However, the room produces disorientation rather than fulfillment because its luxury is entirely artificial, relying on manufactured objects and excess consumption. By replacing Milton’s natural fragrances with manufactured scents that overwhelm the senses, Eliot turns Eden's harmony into an atmosphere of discomfort and unease.

In the archives, H.D. kept an extensive record of multiple literary figures' horoscopes, including T.S. Eliot, Ezra Pound, and Sigmund Freud.

The cytoskeleton helps: * Hold the GABA\(_A\) receptor in the correct place on the cell membrane * Keep it near the synapse, where GABA is released * Prevent the receptor from freely drifting around the membrane * Organize and stabilize the receptor

means healthy study participants who do not have panic disorder or another relevant psychiatric condition.

Yohimbine typically triggers or worsens anxiety rather than treating it, acting as a pharmacological stressor that increases noradrenergic (norepinephrine) activity.

I completely agree with this statement. Its like the tool was designed to help us expand our minds but it ultimately became fast food for our thoughts. If we continue on this path to technological advancement we will lose the bright minds in the process. It will be a great loss to humanity and more so a entrophy for future generations to come. I already knew the decline was at the cusp when we used social media to create a herd mentality.

This is so true i had times when i did use ai related apps it felt like i knew the information they were giving me wasnt so accurate and i really had to double check on every answer was said. It was really frustrating because i thought it was suppose to be more reliable than google.

Note that P(A)P(B) > P(A,B) can be true for some A and B. if x and y are independent, then P(x,y) = 0. if not, there can be some negative terms, but the sum is always positive.

Useful line

It’s interesting to see how much high school is similar across the decades and cultures, Even though there’s quite a few differences like their style and exchanging music on CDs, there’s so many similarities That makes it easy to appeal to a wide audience and Give the reader an opportunity to relate to their own experiences.

Wish we got some more characterization of Tom other than his ability to persuade people and hustle.

How much of that is because of the country’s pride and culture vs gaps or Emphasis on Certain history in schools

Okay I understand that a bmw would be impressive but why didn’t he cut his loses? A cool car showing up an hour late is still an hour late He should have taken no as no and just driven the Masada and been there on time.

The correct order is: Ambre Lesurtel; Vanessa Matos Gonçalves; Sebastian Warma, Jascha Drew Jäger, Alexandra Eckhardt; Mirdita Useni; Bola Grace; Jörg Goldhahn; Noé Brasier. This will be changed in the next revision and the final manuscript.

What role should content moderators play in preventing the spread of health misinformation? Do companies have a role in mitigating the spread of these false narratives, and should they be penalized if individuals are hurt as a result?

This altered sense of objectivity can truly be detrimental to science and patient care. Who ultimately decides what is true vs. untrue? And how does confirmation bias play into this?

This paragraph assumes that politicizing health concerns creates bias towards a specific partisan issue. Healthcare is often politicized in the United States and creates significant disparities across socioeconomic groups. If politics were taken out of healthcare, how would this impact patient outcomes?

I imagine this heated discussion surrounded bodily autonomy and religious ideologies. This reminds me of what occurred during mandated COVID vaccines. I wonder if there was an increase in discussion based on gender and age?

"El open source (o código abierto) es un modelo de desarrollo de software donde el código fuente es público y accesible para que cualquier persona pueda verlo, modificarlo y distribuirlo libremente."

Fuente: https://www.redhat.com/es/topics/open-source/what-is-open-source

"El Big Data (o macrodatos) se refiere a conjuntos de datos tan grandes y complejos que las herramientas de software tradicionales no pueden almacenarlos ni procesarlos de forma eficiente."

Fuente: https://www.ibm.com/think/topics/big-data

https://www.jetpens.com/blog/The-Best-Lead-Holders/pt/740

The 5 leadership skills are good to follow because when wanting to be a leader those are certain steps we can to step up. I thin they are good for when you don't know how to be a good leader but these steps are to help you so you can learn to be a leader.

How do people know when its the right time to step up and be a leader and when its not?

the get a demo button is a different style then the two above

the button below and at the top of the page are different color oranges

update to:

High-Definition Ultrasound Made Easy

Just because you say you're an ally doesn't mean you really are. Some people will pretend to be supportive to your face but really don't support you at all.

It's okay to get things wrong and not always being right. Most people are scared to answer things out loud because they don't want to be wrong infront of everyone but really its a good was to break out of your comfort zone.

Did you consider/is there a reason you chose not to train on (in combination with these mammalian data) simulated data under these different models to take advantage of additional supervision during training?

Ethos - established credibility Pathos - use of humor logos - use of evidence

Avoid allowing your body or clothing to come into contact with soiled items while handling them.

it's stories turned into music?

this is popular all over the wolrd

a man named tim drinks too much and falls off a ladder. everyone thinks he is dead so they have a wake for him. when everyone is drinking and fighting whiskey spills on tim and he wakes up. the story is funny because everyone thought he was dead but he was actually alive.

Stories can express hardships, but should also lift people up.

The importance of people's strengths gives people another way to look at them, in a better way.

She started realizing the dangers of believing one single story

Growing up, she didn't know much about her own world, and that was expressed through her writing, creating the same characters over and over again.

Impressions are made by what little information a person knows

Only being exposed to certain information about a person or place makes your brain think that that is what it is instead of actually exploring what it truly is.

The author saw how people in America believed one story of people like her, as she did with the family in her country that she saw as just poor.

Learning more about the world around you will broaden your perspective of people.

Being influenced by books doesn't give you the the story of the real world, and can often lead you to believe one single thing instead of seeing the full perspective.

She often started writing about things she didn't have in Nigeria.

the boy only put his finger in his mouth because he burned it on the oil. he didn't think about getting any of the wisdom but he did

Finegas caught the salmon and told someone to fry it but to not eat any of it because he wanted all the wisdom to himself

so anyone who basically caught the old man as a salmon and ate it would have all the wisdom in the world

this old man turned into a salmon?

.

it was a gift and they were told that it represents wisdom but did not know why

that's what they thought a salmon looked like

In other words, writing papers helps you thoroughly go through the whole writing process and have better revision and editing skills.

What are some resources that you highly recommend, especially for someone that struggles to learn online?

What are 'points of departure'?

Benandonner saw a "huge baby" in the crib and thought to himself that if the "baby" was that big then how big was finn? he basically got scared and ran home

Finn returned home so he wasn't there when the giant woke up and his wife "turned him into a baby" so that when the other giant came they could play him

finn realized that he probably could not beat this other giant

finn made the the causeway out of chunks from the coastline

Finn was made out to be the biggest giant in Ireland but is he really? he wanted to fight but didn't know how he'd get over there

Benandonner seems jealous of Finn so Benandonner wants to fight Finn to prove that he is better

Finn wasn't an ordinary giant

brains over brawn? never heard of that so i looked it up. google says "intelligence and clever strategies work better to solve problems than physical strength and raw force"

so use your brain basically?

physical or sensory details trigger the brain to actually feel emotion

abstract concepts like a politcal movement need concrete physical metaphors to be able to be fully digested and grasped by the readers

i think removing filler words is something i need to do instead of just directly putting "he said" "she said"

telling the audience what somethin is NOT leaves their imagination to fill in the gaps and create something unique to every reader

all words mean white but they all set tone differently and its up to the reader to determine it but the writer almost sways the reader in the direction he wants

i like this because writing is both an art and interpretation so there is beauty in it all even when it doesn't make sense to you

using these 8 verbs in succession so shortly keeps the flow of the scene without creating a giant paragraph.

i think its cool that chronological ordering happens naturally when describing a process. the reader doesn't need to try and piece things together.

"freezing the frame" lets the writer essentially stop time for the reader which is also good for setting up scenes before they happen.

O'Keeffe used real objects as "treasures" to fuel her abstract art. this shows that good description starts with physical observation.

California's white paper about their career passport efforts

need to know these to be able to read a graph like this

"since it also issues longer-term bonds, and since the 1970s it has allowed the rates on these to be determined at Treasury auctions, it has created the wrong impression that markets dictate the government’s borrowing costs (and can, by extension, force the government to change policy course)

ㅜ

whenever this is last syllable in a word, becomes wa

ㅣ

oh, bit less rounded than ㅗ

eh, bit more full than ㅐ

name of the vowel

complex syllables are made up of several unit onsets and codas. The vowel shows which consonant is central, with one prefix and two suffixes before the ' here

consonant placeholder

It could be useful/illustrative to indicate on this tree where the Plectocretacicoidea calibration is positioned.

This sentence doesn’t show logic which is the main thing for the argument.

sacaría los ; ya que las preguntas están separadas como una lista

añadiría entre paréntesis que esto representa una sumatoria, para quien quiera profundizar en detalles más técnicos

creo que aquí sería provechoso añadir una imagen del plano cartesiano, así podría ser más fácil de explicar la idea de los promedios de ambas variables y sus signos respectivos

lo mismo que mi comentario de más arriba. Orientaciones de código las dejaría en un call out para que resalten un poco más

reemplazaría esto por Ejercicio Autónomo

positiva / negativa

lo dejaría en una lista solamente para que sea más digerible visualmente

acá enfatizaría que hay distintas formulas (equivalentes) para llegar a Pearson; en clases vimos 2 más y las pondría acá para mantener la coherencia

estos tips/explicaciones de código las dejaría en un call out

en clases utilizamos para esto el término "residuo"

acá se achicó la letra

wa is "person from"?

honourific he

re can also be used to express humility, particularly if you use it over yin when talking about yourself

usually the number is put after, so dangpo = 1?

It's simply how many sig figs after the decimal. 202.88 has 2 sig figs after the decimal. 1.013 has 3 sig figs after the decimal. So the answer is 201.87

Apenas este año estamos cambiando el mapa con el que navegamos el mundo desde hace 500 años, un signo muy obvio, tan a la vista, que no nos dábamos cuenta!

Her beliefs were against every major oppression system, being racism, feminism, and classism.

After living through the first signs of the fall of slavery, she would start her career as an activist when more laws were added to oppress them.

Her first influence leading her to becoming an activist.

Burrough's perspective on social equality is that social equals are not based on any sort of categorization (like race, ethnicity, gender, etc) but rather based on personal qualities like tastes and interests

Callias, son of Hipponicus recommends Evenus of Paros to Socrates as a Sophist teacher whose fee is five minas.

Compare this five minas to the price Socrates mentions at the end of the trial as potential penalty. Socrates says he can afford one mina while his friends could put up 30 minas for him.

1. [Editors:] These were all well-known Sophists. For Gorgias and Hippias see Plato’s dialogues named after them; both Hippias and Prodicus appear in Protagoras.

The editors call out these philosophers/teachers as Sophists. Compare where they appear in Protagoras.

Socrates is accused of impiety. Several times throughout this piece there are various mention of god (singular) and gods (plural). Which is it? Is there a linguistic difference from the Greek to English and what effect, if any, is there on the culture being represented and how does that interact with Socrates' argument and position with respect to impiety?

Those who maliciously [d] and slanderously persuaded you—who also, when persuaded themselves then persuaded others—all those are most difficult to deal with: one cannot bring one of them into court or refute him; one must simply fight with shadows, as it were,

Synopsis: Rumor is a difficult thing to fight

Socrates defense will be broken up into two parts:<br /> - lying accusations by the first accusers<br /> - these are of the nature of rumors which he poses as untrue and which received no defense and fell on the ready ears of young and inexperienced people who presumably were indoctrinated unquestioningly<br /> - later accusations by later acusers (Meletus, et al.)

Othello will eventually be a devoted husband despite is flaws in this moment and that Iago may not actually love Desdemona but more just wants her out of spite for Othello.

"The phrase is a satirical, cynical comment: it suggests that Cassio’s appeal is based on superficial, youthful charm rather than genuine worth, and that such charm is exactly what “folly and green minds” — people without judgment or experience — would chase."

This surprisingly gives a good explanation of what I think an interpretation of these lines should mean.

These are very intense words to just simply mean focus on me. I bet in a play this scene is extremely intense.

I love how the words othello used really show his true deep happiness in this moment. He expresses how he would be happy dying here because of how wonderful this moment truly is for him.

"In short, Shakespeare uses this passage to show Iago’s mocking, ironic style, and to highlight the gap between an idealized image and the practical reality of human behavior."

This answer from copilot helped me understand why he was saying what he was saying.

Note that the causal Markov Assumption implies statistical independence for non-immediate ancestors. It says nothing about the causality itself.

actually, under the causal Markov assumption, if X is not the immediate ancestor, it is not causal.

Author response:

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

Public Reviews:

Reviewer #1 (Public review):

The authors conducted a comprehensive benchmarking and evaluation of co-folding platforms, including AlphaFold3, Boltz-2, Chai-1, and the docking algorithm Dock3.7, which employs a physics-based scoring function that incorporates van der Waals interactions, electrostatics, and ligand desolvation energies. The system of interest was the SARS-CoV-2 NSP3 macrodomain (Mac1), an increasingly popular antiviral target, and the ligand sets comprised 557 unseen ligand poses (keeping the training for these co-folding platforms in mind). Additionally, the authors investigated whether the co-folding models could distinguish true ligands from non-binding small molecules. The study is thorough, with extensive statistical support and consensus across multiple metrics (chemoinformatics for quantifying ligand similarity and efficacy). The questions that the authors aim to address are whether the co-folding models struggle with memorization, whether they can distinguish between a true and a false binder, whether they replicate experimental binding affinities and efficacy, and how they compare to the physics-based docking algorithm (Dock3.7).

We thank Reviewer 1 for this thoughtful summary of our work.

Strengths:

Overall, this is a scientifically solid paper. The work is highly detailed and well executed, featuring thorough data analysis and statistical assessment.

Weaknesses:

My main concern is that the study's aim is a bit unclear. Modern benchmarking studies comparing physics-based docking with deep learning-based co-folding approaches (e.g., AF3, Boltz-2, Chai-1, and others) are increasingly expected to go beyond aggregate performance metrics.

Indeed, we have gone into several examples of failures and successes for each of these methods. As we are not developing these methods ourselves, we also think this dataset will be a valuable contribution for improving them further.

In addition to rigorous dataset construction, transparent methodology, and appropriate statistical evaluation, high-impact benchmarks typically provide actionable guidance on when each method class is most appropriate, reflecting their distinct inductive biases and practical constraints. Failure-mode analyses that link performance differences to protein flexibility, ligand chemistry, or binding-site characteristics are particularly valuable, as they move comparisons beyond "scoreboard" assessments toward mechanistic understanding.

Right now, we do not observe meaningful trends that separate the failure modes for any individual method. This is covered in Supplementary Figures 6 and 7.

While full biological validation is not expected, qualitative interpretation grounded in physical and biological principles strengthens conclusions. Providing reproducible workflows or reference pipelines is not mandatory, but it is increasingly viewed as a best practice because it facilitates adoption and helps contextualize results for practitioners.

We note that our code is available (https://github.com/jongbin99/Cofolding/) and all structural data will be publicly accessible in the PDB alongside publication (we only held it back only for “blinding” during peer review to avoid contamination with any new deep learning methods).

Reviewer #2 (Public review):

Summary:

The manuscript by Kim et al. evaluates the performance of three modern AI-based methods in predicting complex structures and binding affinities between proteins and chemical compounds. An honest 'prospective' evaluation is achieved by studying benchmark structures and chemical compounds that did not exist in the PDB at the time the AI structure prediction models (AlphaFold3, Chai-1, Boltz-2) were trained.

Strengths:

(1) The study addresses an important question in modern computational biology and drug discovery, and establishes the strengths and limitations of the three tools in solving various computational chemistry tasks, including compound pose prediction, active-inactive discrimination, and potency ranking.

(2) The conclusions are based on examination of four separate targets and respective compound datasets, where for one of the targets, the authors also obtained numerous X-ray structures to serve as experimental answers for the binding pose prediction task.

(3) The study reports relationships between structure prediction confidence, predicted energies (DOCK3.7), and affinity predictions (Boltz-2) with the geometric accuracy of compound pose prediction as well as the experimentally measured potency.

(4) One of the key findings is the limited ability of co-folding methods to predict conformational rearrangements, which does not correlate with their ability to predict binding poses of the compounds inducing these rearrangements.

(5) The findings could serve as useful guidelines for computational chemists in selecting appropriate software and scoring schemes for each task.

We appreciate Reviewer 2’s summary of the novelty of the dataset and analysis.

Weaknesses:

While I consider this a solid study, several aspects would need to be addressed to make it really strong:

(1) DOCK3.7 docking and scoring experiments were performed using one experimental structure of Mac1, selected from dozens of structures based on a criterion that is not sufficiently well justified. For sigma2 receptor, dopamine D4 receptor, and AmpC β-lactamase, it is not clear which structures or models were selected for docking at all. It is well known that geometry predictions, scoring, and active-inactive ROC AUCs are all strongly influenced by the selected structure. It would be important to attempt Mac1 docking using all available experimental Mac1 structures, or at least against representative structures in various conformations; it would also be quite insightful to compare results to docking of the same compound sets to AF3, Boltz-2 and Chai-1 predicted structures of Mac1. Same goes for the docking studies of sigma2, D4, and AmpC β-lactamase.

In any program, a decision has to be made as to which template will be used for docking, we justified the choice in the methods:

“We used this structure because the inhibitor (Z5014193706) was the most potent molecule with a structure determined around the same time as the ligands in this dataset were tested.”

We stand by this as a reasonable assumption. Similarly, for sigma2, D4, and AmpC β-lactamase, the template was chosen in the respective papers:

a) The σ2 receptor bound to cholesterol (PDB ID: 7MFI) was used in the docking calculations.

- This structure was determined in the paper, the first structure of sigma2 and therefore a worthy template

b) The D4 receptor campaign used PDB 5WIU

- This was one of two D4 structures available and chosen because it was not bound to sodium

c) For AmpC, the campaign used the structure in the Protein Data Bank (PDB) 1L2S

- This maximizes comparisons to other docking studies that used the same receptor template.

The major goal of this study is to compare different methods under reasonable (but perhaps as the reviewer points out, not optimal) conditions, not to optimize docking score.

(2) For binding affinity predictions, as a control, authors should consider compound co-folding with an unrelated protein, or even with a pseudo-peptide that consists of a few random single amino acids - this would provide an honest baseline for such predictions.

This suggestion would be valuable for understanding the performance for these methods from the perspective of ligand specificity (a valuable, but separate, goal). Surely this will generate some number or some prediction - but what would this baseline mean and how would it be relevant for drug discovery? Therefore, we do not think this suggestion is relevant for the issues being investigated in this manuscript.

(3) ROC curves Figure 3 and elsewhere should be shown, and AUCs quantified/reported on a log or square-root scaled x-axis, to emphasize early enrichment, which is the area of practical significance for these predictions. For example, Figure 3A currently suggests that the pose prediction performance of AF3 exceeds that of Boltz-2 whereas the early enrichment is clearly better for Boltz-2.

We agree with this, and added a semi-logAUC plot for Figure 3A. For Figure 5, we also generated a semi-logAUC plot to see early ligand enrichment clearly, added as Supplementary Figure 11. We added the text:

“Considering its early enrichment performance, Boltz-2 Ligand ipTM was the strongest predictor of pose accuracy based on normalized logAUC (20.5% above random, Fig. 3a). In contrast, although Boltz-2 pIC50 showed poor overall discrimination, it overestimated its ability to enrich true positive poses at low false positive rates, despite having a weak early enrichment behavior”

(4) 'Trained set' in figures and text should probably be 'training set'? Or otherwise explain this new term the first time it is introduced.

Thank you for pointing out this for clarification. ‘Training set’ is the correct word, and we made changes appropriately across all figures and texts.

(5) Figure 1 illustrates a projection onto the first two principal components of a space that apparently had only one (scalar) metric for each compound pair (% maximum common substructure or Tanimoto coefficient); the authors need to better explain the principle behind this analysis and visualization.

This suggestion is valuable, since we often use PCA to reduce dimensionality for more complex features. For clarification, we actually have a full pairwise similarity matrix for all tested Mac1 compounds based on each of Tc and MCS%. PCA for each MCS% and Tc is a representation of each pairwise similarity matrix. We also made a change in Figure 1 caption to make this point clearer:

“projection of compounds represented by their full pairwise similarity vectors (by ECFP-4 Tc and MCS%)”

Reviewer #3 (Public review):

Summary:

This study's core conclusions are well-supported by data. It is shown that co-folding outperforms docking in known ligand pose/affinity prediction (validated by RMSD and IC₅₀ correlation), struggles with false-positive discrimination in virtual screens (lower AUC values), and is complementary to docking (non-correlated errors, distinct strengths in drug discovery stages).

Strengths:

(1) Unprecedented prospective design with 557 novel Mac1-ligand complexes ensures rigorous, independent evaluation of co-folding methods.

(2) Comprehensive comparison of 3 co-folding tools (AlphaFold3, Chai-1, Boltz-2) with DOCK3.7 across diverse targets and metrics enables nuanced performance assessment.

(3) The study clearly demonstrates complementary roles of co-folding (superior pose/affinity prediction for known ligands) and docking (better hit prioritization), and addresses deep learning memorization concerns via ligand similarity analysis.

We thank Reviewer 3 for pointing out the unprecedented and comprehensive nature of our study

Weaknesses:

(1) Limited generalization to diverse protein families (e.g., no ion channels/transporters).

We agree - we have not explored the entire proteome and these are important target classes that will surely be investigated by future studies. We focused on targets here where we had large number of X-ray crystal structures (Mac1) and affinity/inhibition measurements from docking (the other three targets).

(2) Ambiguity in the mechanism underlying co-folding's failure to predict rare conformational changes.

Again, we agree. We are not the developers of these methods. We observe that these methods do not predict conformational changes with high fidelity and this weakness is an area that co-folding methods will surely prioritize in the future.

(3) Virtual screen comparison is unbalanced (docking-prioritized hit lists bias results).

We acknowledge this in the results: “An important caveat is that the hit-lists were composed of molecules prioritized by docking in the first place, giving it an advantage on these particular sets.” and discussion: “Finally, comparing co-folding to docking based on hit-lists themselves selected by docking is arguably unfair to co-folding. Counter-balancing this is the inclusion, in each of the three hit lists, of molecules that had mediocre and poor docking scores intentionally selected to test the correlation between docking score and hit-rate. Here too, the correlation between co-folding score and likelihood to bind, what we sometimes call a “dock-response-curve” was no better than docking’s, often worse (SFig.11).”

Recommendations for the authors:

Reviewer #1 (Recommendations for the authors):

Here are suggestions for revisions:

(1) The writing is at times obtuse and hard to follow.

This happens sometimes when multiple authors are writing together. We apologize and are happy to respond to specific areas that can be streamlined to be easier to follow.

(2) In the Results section, "A set of 557 previously unreported Mac1 ligand complexes", the authors have compared the ligand poses across different metrics such as Tc - a standard, highly effective method in chemo-informatics and MCS (maximum common substructures); these are standard metrics for quantifying the structural similarity between pairs of small molecules. This part of the analysis checks whether this is memorization; it is critical to compare the two metrics, but it is not sufficient to draw a conclusion.

Thank you for pointing out about the structural similarity of molecules co-folded to those present in the training set (resolved as Mac1 complexes and deposited in PDB before training dates). We have conducted an analysis where we do a pairwise similarity comparison for all ligands present in the PDB (regardless of the target), by both Tc and MCS, and overlay the cluster of ligands we tested (Mac1, AmpC, sigma2, D4). This should show where our tested benchmark datasets lie in the chemical space covered in the entire PDB. Each cluster (around 500 to 1300 compounds per target system) is overlaid on the cluster of all ligands deposited in PDB (over 50,000 compounds), and each cluster was relatively diverse by both Tc and MCS.

(3) In the "Co folding can accurately reproduce poses of ligands dissimilar to those trained." Subsection under Results, the authors' conclusions are hard to follow; they state that the co-folding models often mispredict or miss the alternative conformation, but they also predict poses that are distinct from the training set. What does that imply?

Our interpretation is actually a somewhat unsettling one: co-folding gets the ligand pose right even when it gets the protein wrong, and even when the ligand is novel. This suggests the models may be anchoring on conserved pharmacophoric interactions (like the adenosine-mimicking purine scaffold) rather than truly modeling the physics of the full complex. We added to the results section:

This result suggests that co-folding reliably recapitulates dominant ligand-binding interactions even in the absence of accurate protein conformational modeling, providing further support to the idea that they are learning specific interaction patterns rather than a deeper physics-based representation (Masters et al. 2025).

(4) The Discussion section connects the results and conclusions, but it can be challenging to grasp the study's overall message.

We think the final paragraph hits on three major points:

- Co-folding accurately predicts ligand poses for known binders, but fails to capture conformational changes

- Co-folding does not reliably distinguish true binders from false positives in virtual screening hit lists

- Docking and co-folding are complementary rather than competing tools

(5) The work is highly detailed and well executed, featuring thorough data analysis and statistical assessment. The value of the paper would be further enhanced by explaining how it differs from seemingly similar results reported in other studies, including the one cited in this manuscript (see https://www.biorxiv.org/content/10.64898/2025.12.04.692352v1).

The Mac1 results are completely unique. However, the docking datasets are exactly the same as those analyzed in the Menon et al manuscript. We don’t think our results differs from conclusions of the Menon et al manuscript as we wrote: These observations are supported by a fascinating study on some of the same ligand sets as investigated here, using AlphaFold3, reaching similar conclusions (Menon et al. 2025).

Reviewer #3 (Recommendations for the authors):

(1) Expand target diversity to include ion channels, transporters, etc., beyond enzymes and GPCRs.

(2) Investigate the cause of co-folding's failure in predicting rare conformational changes (e.g., adjust sampling, MSA inputs, or add experimental constraints).

(3) Mitigate docking bias in virtual screens (e.g., re-analyze unbiased compound libraries).

We addressed these three points in the public review above

(4) Test Boltz-2's affinity predictions without linear calibration and compare with FEP.

The data without linear calibration are included in the manuscript. Comparing such a large number of compounds with FEP is currently beyond our capabilities.

(5) Conduct proof-of-concept to test co-folding-docking integration for better hit rates.

We think this is well beyond the scope of this manuscript - but look forward to testing this idea in the future.

We also got one community review that we respond to below:

Summary

This manuscript evaluates the performance of co-folding models when tasked with 1) the recapitulation of a large number of experimentally determined co-crystal structures of Mac1 with a series of Mac1 ligands and 2) the rescoring of hits to identify false positives originally derived from a set of large docking-based virtual screens. The evaluation leverages a dataset of crystal structures and affinity data from high-throughput crystallographic and biophysical screens, respectively. These data uniquely enable this report to focus on the ability of co-folding models to handle ligands, resulting in an analysis that is particularly timely given the wide adoption of co-folding models and the relative scarcity of such ligand-focused benchmarks among existing evaluations, which have primarily focused on protein structure prediction or binder design.

Thank you for this thoughtful summary of our work

Feedback

The experiments and analyses in the manuscript are well thought-out and do not have any significant issues. There are a few high-level points that may improve the clarity and completeness of the results. Importantly, none of the suggested additional experiments will affect the conclusions of the paper, but rather help provide additional context for the results:

The first section presents an exciting opportunity to frame the Mac1 ligands against ligands in the PDB more broadly. It would be informative to assess whether chemotypes that are easier or harder to predict accurately and confidently are over- or under-represented in the PDB as a whole. Note that this is not a recommendation that new scaffold similarity metrics be incorporated into the analysis, but rather that analyses similar to those already performed in the manuscript are performed using all ligands in the PDB. For example, PCA-based analyses similar to those in Fig. 1c could be used to examine Mac1 ligands in the context of all PDB ligands enabling questions such as whether similarity to a nearest PDB neighbor, cluster size in a Tc/MCS PCA space, or other frequency-based measures show any relationship with prediction vs. crystal structure RMSD. Such analyses could provide additional insight into how effectively models leverage ligand information present in the PDB overall, as opposed to biases arising specifically from scaffolds represented in Mac1 structures in the PDB, which are already well covered in the manuscript. The conclusion that Tc/MCS do not correlate with the ligand RMSDs for the ligands already associated with the Mac1 is well supported, and presumably suggests that a correlation would not exist against the backdrop of the PDB, but it would be interesting to see the data using analyses similar to those already done in the manuscript nonetheless.

We are adding new figures in SFig.1 that consider how different clusters of ligands tested for our co-folding analysis are distributed across the chemical space in PDB. This is done by making a similarity comparison between every ligand in PDB and those tested in our analysis by Tc and MCS%, then plotting in PCA space for each metric. We are excited to see that each dataset covers a wide scope in PCA space, but at the same time, there are unexplored areas in the chemical space of PDB by co-folding.

Similarly, even though the four proteins used in this manuscript are not themselves the primary focus of the analysis, it would be valuable to perform a high-level assessment of the precedent for each protein in the PDB (beyond the count of liganded structures in Table S6), either in protein sequence space (e.g., MSAs) or structural space (e.g., FoldSeek). An analysis like this would provide important context about whether any of the proteins in the study have close homologs with liganded structures in the PDB, or are generally overrepresented in the PDB. The fact that the AUC for L-pLDDT for AmpC is higher than σ2 and D4, for example, is notable given the relative abundance of liganded AmpC structures in the PDB (this raises potentially interesting questions related to where DOCK3.7 and AF3 actually place the ligands, given the orthosteric β-lactam binding pocket in AmpC, although this is outside of the scope of this manuscript).

High-level assessment of the precedent for each protein in the PDB will definitely help to understand if proteins we used have close homologs with liganded structures in the PDB. Our Supplementary Table 6 covers the extent to which these liganded structures were available by cutoff dates for AF3, Chai-1 and Boltz-2. AmpC had more homologs than sigma2 and D4, and this may explain a better AUC for AF3 L-pLDDT specifically for this target.

A discussion of the affinity probability results (`affinity_probability_binary`) from Boltz-2 is likely warranted in the second section in addition to the pIC50s that are already reported (`affinity_pred_value`). The former seems like it would be more applicable for section 2 of the manuscript, but both warrant inclusion—they should both be calculated by default when the affinity pipeline in Boltz-2 is turned on, so it wouldn't involve any more inference.

As boltz-2 affinity module outputs both affinity probability binary output and affinity predicted value, we kept track of both metrics. So we tried re-ranking hit lists using both metrics. Where boltz-2 performed better (Sigma2, D4), binary probability values were more representative as a metric to differentiate true actives from non-binders. This was more clear in semi-logarithmic ROC plots. However, in AmpC, both Boltz-2 scoring metrics performed similarly. Such inconsistency in trend made it difficult to draw conclusions.

Minor points

A more detailed description of the experimental methods used to generate the ground-truth data in the introduction (even though these have been explained in prior works) would help orient the reader early on, and ground the benchmarking aspect of the story. In general, the abstract and introduction would benefit from a more cohesive through-line to tie the two complementary but orthogonal sections of the paper together.

We will include a more thorough description alongside the PDB depositions. As for the two sections, we have tried to tie them together from the perspective of drug discovery workflows…

The cutoffs in the "Co-folding can accurately reproduce..." section shift between 2.5 Å (from the ligand center of mass) and 2.0 Å. Is there a reason for this? Along similar lines, mentioning cutoffs for true positives/negatives when introducing the ROC analyses later on in the Mac1 section seems unnecessary since no cutoff should be necessary here.

We used 2.5A distance to COM to just get at “broadly the correct binding site” for fast filtering and 2.0A RMSD because that is the broadly accepted standard in the field for “relatively correct binding pose”.

Reviewer #3 (Public review):

Summary:

Core conclusions are well-supported by data: co-folding outperforms docking in known ligand pose/affinity prediction (validated by RMSD and IC₅₀ correlation), struggles with false positive discrimination in virtual screens (lower AUC values), and is complementary to docking (non-correlated errors, distinct strengths in drug discovery stages).

Strengths:

Unprecedented prospective design with 557 novel Mac1-ligand complexes ensures rigorous, independent evaluation of co-folding methods, provides an unbiased and rigorous benchmark dataset, which contains structures and compounds absent from the co-folding models training sets. Comprehensive comparison of 3 co-folding tools (AlphaFold3, Chai-1, Boltz-2) with DOCK3.7 across diverse targets and metrics enables nuanced performance assessment. The revised results clarify an intriguing finding: co-folding can predict correct ligand poses even when protein formations are mispredicted. The study clearly demonstrates complementary roles of co-folding (superior pose/affinity prediction for known ligands) and docking (better hit prioritization), and addresses deep learning memorization concerns via ligand similarity analysis.

Weaknesses:

The study identifies a major limitation of co-folding-failure to capture rare protein conformational changes, which deserve future investigation. The authors include uncalibrated Boltz-2 affinity data (addressing a prior comment) but note that large-scale free energy perturbation (FEP) comparisons are beyond their capabilities.

Appraisal of Aims Achieved:

The authors successfully achieved their primary aims and the results provide strong, well-supported evidence for their core conclusions. Key conclusions are grounded in the study's unbiased, training-set independent data, ensures the conclusions are not confounded by model memorization and are broadly applicable to the field's use of these co-folding models.

Field Impact:

This study provides a critical reality check for the field: co-folding models are powerful tools for pose prediction but are not yet standalone solutions for virtual screening, a key distinction that will prevent over-reliance on these models and guide more rational tool selection.

Reviewer #1 (Public review):

The authors conducted a comprehensive benchmarking and evaluation of co-folding platforms, including AlphaFold3, Boltz-2, Chai-1, and the docking algorithm Dock3.7, which employs a physics-based scoring function that incorporates van der Waals interactions, electrostatics, and ligand desolvation energies. The system of interest was the SARS-CoV-2 NSP3 macrodomain (Mac1), an increasingly popular antiviral target, and the ligand sets comprised 557 unseen ligand poses (keeping the training for these co-folding platforms in mind). Additionally, the authors investigated whether the co-folding models could distinguish true ligands from non-binding small molecules. The study is thorough, with extensive statistical support and consensus across multiple metrics (chemoinformatics for quantifying ligand similarity and efficacy). The questions that the authors aim to address are whether the co-folding models struggle with memorization, whether they can distinguish between a true and a false binder, whether they replicate experimental binding affinities and efficacy, and how they compare to the physics-based docking algorithm (Dock3.7).

Strengths:

Overall, this is a scientifically solid paper.

The work is highly detailed and well executed, featuring thorough data analysis and statistical assessment.

Comments on revised version:

The authors have adequately addressed my concerns.

eLife Assessment

This study addresses an important gap in drug discovery by delivering a rigorous, large-scale evaluation of widely used co-folding methods for predicting ligand-bound protein complexes and virtual screening. A key strength is the comprehensive benchmarking framework, which leverages structures and chemical compounds that were absent from the AI models training set, thereby providing particularly compelling and unbiased evidence of co-folding performance. The findings clearly delineate the complementary roles of deep learning-based co-folding and physics-based docking, offering practical guidance for their rational integration into drug discovery workflows. Overall, the conclusions are well supported by thorough analyses across a representative set of cases.