Coser's psychoanalysis is so funny

fw Christians but wasn't one

work hard play hard

oh he was a frat boy

religious background who low key go insane.

NAAUURRRRR

he's HIM

"It's complicated"

i enjoy his appreciate for things outside the modern paradigm of "knowledge"

Rationalization of Protestant Ethic crushed charismatic appeal of previous prophets

For Weber, alienation from means of production was consequence of rationalization more than capitalism as it stands on its own.

Marx and Weber agreed on modern society being alienated from a sort of protection of humanity or freedom despite the modern world being efficient. However, MArx had a vision for future and Weber didn't

Bureaucracy , power and systems based on rational action, gave humans ability to do a lot but also made it hard to handle individual cases.

Marx and Weber on the same page about class dynamic aligning with vast power inequalities, but Weber things the power could have derived from other things.

life-styles bring people together

Class distinguished by actions within market not place in production like Marx

capitalist system founded on rational action in a rational system. Rationalization of economic system realized when everyone believes it moral to act in their own self-interest. An idea posed by Protestant Ethic.

believed that types could mix

3 types of authority - rational-legal - traditional - charismatic

not always abiding by his own doctrine- used structure a lot as a unit of analysis.

in analyzing both historical and social causes requires sort of mental experiments asking of something would occur without a certain action or event- trying to isolate causes.

this highlights a moral complexity where negative actions overshadow positive legacies. This suggests a need to confront uncomfortable truths about historical figures.

this highlights the complicity of the government and its citizens in perpetuating the institution of slavery. it illustrates how laws can compel individuals to participate in morally reprehensible actions, thus raising questions about civic duty and moral responsibility within a republic. this is thought provoking because it forces the reader to confront the responsibilities of citizens to resist immoral legislations and potential consequences of blind obedience to the state.

Douglass calls for unwavering adherence to the principles of the declaration of independence, which signifies the foundational ideals of american democracy. this insistence on commitment to these principles can be linked to the values needed during industrialization, where workers and activists fought for rights and social justice. it suggests that, just as the founders held fast to their beliefs despite opposition, contemporary movements must. also be steadfast in pursuing justice and equality.

This quote suggests that oppression can drive even the wisest and most rational people to the brink of anger or rebellion.

In this quote you can sense a calm, majestic, and rising flood to symbolize something powerful yet beneficial, though mysterious in its nature. "They" likely refers to natural forces or metaphorical forces such as ideas, social movements, or emotions that, though quiet and dignified, can have profound effects. In this interpretation, the quote can be seen as a reflection on how subtle, often unnoticed powers whether in nature, human society, or personal life can bring about renewal, growth, and positive change, even if their workings remain mysterious or complex.

This quote highlights the speaker's amazement and gratitude for having overcome significant obstacles to reach their current position. The speaker acknowledges the many challenges they faced in their journey from slavery to freedom. Their current situation is both astonishing and something they are deeply thankful for, suggesting they never imagined they'd be able to achieve such a feat.

This quote shows a sense of imagery. "Dark clouds" suggests a gloomy or challenging situation, perhaps one filled with fear, doubt, or trouble. However, the "hope in the thought" implies that positive thinking, optimism, or a glimmer of possibility offers a sense of encouragement or solace in the face of adversity.

The underlying fear for his condition adds depth, reflecting the emotional complexity as the woman navigates her role as a supporter.

Surreal. Maybe its because she is too focused on her missing son.

This children has brought so much pain to the whole family that they even wished that he had never been in this world.

Why is this sentence supposed to be here? Maybe it's kind of a manifestation of emotional collapse? I am not sure...

We can observe the sarcasm in the sentence which comes from the contrast between Isabel's concern for Kaden and the seemingly trivial nature of the situation she describes—accidentally locking him inside with the keys. On the surface, she reflects on her responsibility as a mother and the anxiety of leaving a child alone, which is a serious concern. However, the way she phrases "unless you count the time she accidentally locked him inside with all the keys" implies a level of absurdity and a flippant attitude towards a situation that could be viewed as neglectful or careless.

the conversation encapsulates a turning point in the narrative, where hope begins to wane and the reality of their situation settles in. It serves to heighten the emotional stakes, portraying the mixed feelings of fear, grief, and a desperate hope for rescue, while also emphasizing their individual struggles as they navigate a terrifying situation.

Bookend the emotional turmoil and urgency that Isabel experiences regarding her child, while also framing the impending threat of danger.

Transition from the turmoil he has just fled-symbolized by the argument and the chaos of the household-into the enveloping tranquility of the forest

captures a vivid and dynamic image of movement, just like describing an animal in motion

It's interesting how this was how people would tell time. I can't imagine not having a clock to tell me what time it is.

I thought that was pretty interesting because we have been using something that was made in 8000 BC.

this was due to undeveloped technology like the loom, etc and it wasn't til they discovered plant material could also be produced into fabric.

that is why technology/strategies are made to make something easier for the people to access or know like for example the early inventions of sundials and now we have clocks.

I also agree with this statement I mean without this knowledge we underapreciate what it takes to progress already existing technology into something more modern/better.

I think the difficuility that they had were the seasons changing, the weather, or some of the work had to be done physically.

intersting to show how other technologies are based from older developments from other regions.

invasion of privacy, lack of trust,

Author response:

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

Public Reviews: 

Reviewer #1 (Public Review):

Aging is associated with a number of physiologic changes including perturbed circadian rhythms. However, mechanisms by which rhythms are altered remain unknown. Here authors tested the hypothesis that age-dependent factors in the sera affect the core clock or outputs of the core clock in cultured fibroblasts. They find that both sera from young and old donors are equally potent at driving robust ~24h oscillations in gene expression, and report the surprising finding that the cyclic transcriptome after stimulation by young or old sera differs markedly. In particular, genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions, while genes associated with oxidative phosphorylation and Alzheimer's Disease lose rhythmicity in the aged condition. Also, the expression of cycling genes associated with cholesterol biosynthesis increases in the cells entrained with old serum. Together, the findings suggest that age-dependent blood-borne factors, yet to be identified, affect circadian rhythms in the periphery. The most interesting aspect of the paper is that the data suggest that the same system (BJ-5TA), may significantly change its rhythmic transcriptome depending on how the cells are synchronized. While there is a succinct discussion point on this, it should be expanded and described whether there are parallels with previous works, as well as what would be possible mechanisms for such an effect.

We’ve expanded our discussion in the manuscript to discuss possible mechanisms and also how the genes/pathways implicated in our study relate to other aging literature.  

Major points: 

Fig 1 and Table S1. Serum composition and levels of relevant blood-borne factors probably change in function of time. At what time of the day were the serum samples from the old and young groups collected? This important information should be provided in the text and added to Table S1. 

We made sure to highlight the collection time in the abstract of the manuscript “We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals at 14:001 and used the serum to synchronize cultured fibroblasts.” The time of blood draw is also in sections of the paper (Intro and Methods). Since Table S1 is demographic information, we did not think that the blood draw time fit best there, but hopefully it is now clear in the text.

Fig 2A. Luminescence traces: the manuscript would greatly benefit from inclusion of raw luminescence traces.

Raw luminescence traces have been added to Figure S3 (S3A).

Fig 2. Of the many genes that change their rhythms after stimulation with young and old sera, what are the typical fold changes? For example, it would be useful to show histograms for the two groups. Does one group tend to have transcript rhythms of higher or lower fold changes? 

We’ve presented these data in Figure S5. There are a few significant differences, but largely the groups are similar in terms of fold change.

Fig. 2 Gene expression. Also here, the presentation would benefit from showing a few key examples for different types of responses. 

Sample traces of genes that gain rhythmicity, lose rhythmicity, phase shift, and change MESOR are now illustrated in Figure S6.

What was the rationale to use these cells over the more common U2OS cells? Are there similarities between the rhythmic transcriptomes of the BJ-5TA cells and that of U2OS cells or other human cells? This could easily be assessed using published datasets. 

The original rationale to use BJ-5TA fibroblast cells was that we were aiming to build upon an observation found in a previous study2 which showed that circadian period changes with age in human fibroblasts. While our findings did not match theirs, we think an added benefit of using the BJ-5TA line is that unlike U2OS cells, it is not a carcinoma derived cell line. We’ve added this point in lines 98-101.

Our study finds many more rhythmic transcripts compared to the previous studies examining U2OS cells. This can be attributed to several factors including differences in methods, including the use of human serum in our study, cell type differences, or decoupling of rhythms in some cancer cells. While a comparison of BJ-5TA cells and U2OS cells could be interesting, a proper comparison requires investigation of many data sets, since any pair of BJ-5TA and U2OS data sets will most likely differ in some detail of experimental design or data processing pipeline, which could contribute to observed differences in rhythmic transcripts.

That being said, we compared clock reference genes (see Author response image 1) between BJ-5TA and U2OS cells, comparing circadian profiles obtained from our data with those available on CircaDB. These circadian profiles exhibit many similarities and a few differences. The peak to trough ratios (amplitudes) are quite similar for ARNTL, NR1D1, NR1D2, PER2, PER3, and are about 25% lower for CRY1 and somewhat higher for TEF (about 15%) in our data. We find that the MESORS are generally similar with the exception of NR1D1 which is much lower and NR1D2 which is much higher in our data.

Author response image 1.

BJ-5TA and U2OS Cells Exhibit Similar Profiles of Circadian Gene Transcription. We compared the transcriptomic profiles of the BJ-5TA cells in young and old serum (left) to the U2OS transcriptomic data (right) available on CircaDB, a database containing profiles of several circadian reference genes in U2OS cells. This figure suggests that circadian profiles of these genes exhibit many similarities. We find that the peak to trough ratios (amplitudes) are similar for ARNTL, NR1D1, NR1D2, Per2, PER3, and that the MESORS are similar (with the exception of NR1D1 which is much lower and NR1D2 which is much higher in the BJ-5TA cells). We find that the amplitudes of CRY1 is ~25% lower and TEF is ~15% higher for the BJ5TA cells. The axis for plots on the left show counts divided by 3.5 in order to made MESORs of ARNTL similar to ease comparison.

For the rhythmic cell cycle genes, could this be the consequence of the serum which synchronizes also the cell cycle, or is it rather an effect of the circadian oscillator driving rhythms of cell cycle genes? 

This is an interesting point. Given our previous data showing that the cell cycle gene cyclin D1 is regulated by clock transcription factors3, we believe the circadian oscillator drives, or at least contributes, to rhythms of cell cycle genes. However, the serum clearly makes a difference as we find that MESORs of cell cycle genes decrease with aged serum. This is consistent with the decreased proliferation previously observed in aged human tissue4.

While the reduction of rhythmicity in the old serum for oxidative phosphorylation transcripts is very interesting and fits with the general theme that metabolic function decreases with age, it is puzzling that the recipient cells are the same, but it is only the synchronization by the old and young serum that changes. Are the authors thus suggesting that decrease of metabolic rhythms is primarily a non cell-autonomous and systemic phenomenon? What would be a potential mechanism? 

We are indeed suggesting this, although it is also possible that it is not cycling per se, but rather an overall inefficiency of oxidative phosphorylation that is conveyed by the serum. Relating other work in the field to our findings, we’ve added the following to our discussion: “Previous work in the field demonstrates that synchronization of the circadian clock in culture results in cycling of mitochondrial respiratory activity5,6 further underscoring the different effects of old serum, which does not support oscillations of oxidative phosphorylation associated transcripts. Age-dependent decrease in oxidative phosphorylation and increase in mitochondrial dysfunction7 has been seen in aged fibroblasts8 and contributes to age-related diseases9. We suggest that the age-related inefficiency of oxidative phosphorylation is conferred by serum signals to the cells such that oxidative phosphorylation cycles are mitigated. On the other hand, loss of cycling could contribute to impairments in mitochondrial function with age.”

The delayed shifts after aged serum for clock transcripts (but not for Bmal1) are interesting and indicate that there may be a decoupling of Bmal1 transcript levels from the other clock gene phases. How do the authors interpret this? could it be related to altered chronotypes in the elderly? 

One possible explanation is that the delay of NPAS2, BMAL1’s binding partner, results in the delay of the transcription of clock controlled genes/negative arm genes. Since the RORs do not seem to be affected, Bmal is transcribed/translated as usual, but there isn’t enough NPAS2 to bind with BMAL1. In this case downstream genes are slower to transcribe causing the phase delay.

Reviewer #2 (Public Review): 

Schwarz et al. have presented a study aiming to investigate whether circulating factors in sera of subjects are able to synchronize depending on age, circadian rhythms of fibroblast. The authors used human serum taken from either old (age 70-76) or young (age 25-30) individuals to synchronise cultured fibroblasts containing a clock gene promoter driven luciferase reporter, followed by RNA sequencing to investigate whole gene expression. 

This study has the potential to be very interesting, as evidence of circulating factors in sera that mediate peripheral rhythms has long been sought after. Moreover, the possibility that those factors are affected by age which could contribute to the weaken circadian rhythmicity observed with aging. 

Here, the authors concluded that both old and young sera are equally competent at driving robust 24 hour oscillations, in particular for clock genes, although the cycling behaviour and nature of different genes is altered between the two groups, which is attributed to the age of the individuals. This conclusion could however be influenced by individual variabilities within and between the two age groups. The groups are relatively small, only four individual two females and two males, per group. And in addition, factors such as food intake and exercise prior to blood drawn, or/and chronotype, known to affect systemic signals, are not taken into consideration. As seen in figure 4, traces from different individuals vary heavily in terms of their patterns, which is not addressed in the text. Only analysing the summary average curve of the entire group may be masking the true data. More focus should be attributed to investigating the effects of serum from each individual and observing common patterns. Additionally, there are many potential causes of variability, instead or in addition to age, that may be contributing to the variation both, between the groups and between individuals within groups. All of this should be addressed by the authors and commented appropriately in the text. 

We are not aware of any specific feature distinguishing the subjects (other than age) that could account for the differences between old and young. The fact that we see significant differences between the two groups, even with the relatively small size of the groups, suggests strongly that these differences are largely due to age. Nevertheless, we acknowledge that individual variability can be a contributing factor. For instance, the change in phase of clock genes appears to be driven largely by two subjects. We have commented on this and individual differences, in general, in the discussion.  

The authors also note in the introduction that rhythms in different peripheral tissues vary in different ways with age, however the entire study is performed on only fibroblast, classified as peripheral tissue by the authors. It would be very interesting to investigate if the observed changes in fibroblast are extended or not to other cell lines from diverse organ origin. This could provide information about whether circulating circadian synchronising factors could exert their function systemically or on specific tissues. At the very least, this hypothesis should be addressed within the discussion. 

It is likely that factors circulating in serum act on several tissues, and so their effects are relatively broad. However, this would require extensive investigation of other tissues. We now discuss this in the manuscript.

In addition to the limitations indicated above I consider that the data of the study is an insufficiently analysis beyond the rhythmicity analysis. Results from the STRING and IPA analysis were merely descriptive and a more comprehensive bioinformatic analysis would provide additional information about potential molecular mechanism explaining the differential gene expression. For example, enrichment of transcription factors binding sites in those genes with different patters to pinpoint chromatin regulatory pathways.

We performed LinC similarity analysis (LISA) to study enrichment of transcription factor binding. Results are displayed in Fig 3B and in lines 157-168. 

Recommendations for the authors:

The two reviewers and reviewing editor have agreed on the following recommendations for the authors: 

Major: 

(1) The bioinformatic analysis would benefit from a more thorough focus on variability between individuals. Specifically, the main conclusion of the manuscript could be significantly influenced by individual variabilities within and between the two age groups. This is of particular concern, as the groups are relatively small (four individual two females and two males, per group). In addition, the consideration of factors such as food intake and exercise prior to blood drawn, or/and chronotype, known to affect systemic signals should be more adequately explained. The lab is an experienced chronobiology lab, and thus we are confident that these factors had been thought of, but this needs to be better made clear.

As seen in Figure 4, traces from different individuals vary heavily in terms of their patterns, which is not addressed in the text. Only analysing the summary average curve of the entire group may be masking the relevant data. Furthermore, there are many potential causes of variability, instead or in addition to age, that may be contributing to the variation both, between the groups and between individuals within groups. All of this should be addressed by the authors and commented appropriately in the text. 

We are not aware of any specific feature distinguishing the subjects (other than age) that could account for the differences between old and young. The fact that we see significant differences between the two groups, even with the relatively small size of the groups, suggests strongly that these differences are largely due to age. Nevertheless, we acknowledge that individual variability can be a contributing factor. For instance, the change in phase of clock genes appears to be driven largely by two subjects. We have commented on this and individual differences, in general, in the discussion. 

(2) The study would benefit from a more thorough analysis of the data beyond the rhythmicity analysis. Results from the STRING and IPA analysis were merely descriptive and a more comprehensive bioinformatic analysis would provide additional information about potential molecular mechanism explaining the differential gene expression. For example, enrichment of transcription factors binding sites in those genes with different patters to pinpoint chromatin regulatory pathways. This would provide additional value to the study, especially given the otherwise apparent lack of any mechanistic explanation. 

We performed LinC similarity analysis (LISA) to study enrichment of transcription factor binding. Results are displayed in Fig 3B and in lines 157-168.

(3) There were some questions about the amplitude of the core circadian clock gene rhythms raised, which in other human cell types would be much higher. A comment on this matter and the provision of the raw luminescence traces for Fig 2A would be greatly beneficial.

Addressing the same topic: what are the typical fold changes of the many genes that change their rhythms after stimulation with young and old sera? For example, it would be useful to show histograms for the two groups. Does one group tend to have transcript rhythms of higher or lower fold changes? The presentation of the manuscript would further benefit from showing a few key examples for different types of responses. 

The average luminescence trace for each individual serum sample from Fig 2A has been added to Fig S3A.

We’ve presented the fold change data in Figure S5. There are a few significant differences, but largely the groups are similar in terms of fold change.

(4) There are several points that we recommend to consider to add to the discussion: 

What was the rationale to use these cells over the more common U2OS cells? Are there similarities between the rhythmic transcriptomes of the BJ-5TA cells and that of U2OS cells or other human cells? It should be relatively easy to address this point by assessing published datasets. 

The original rationale to use BJ-5TA fibroblast cells was that we were aiming to build upon an observation found in a previous study2 which showed that circadian period changes with age in human fibroblasts. While our findings did not match theirs, we think an added benefit of using the BJ-5TA line is that unlike U2OS cells, it is not carcinoma derived cell line. We’ve added this point in lines 98-101. 

Our study finds many more rhythmic transcripts compared to the previous studies examining U2OS cells. This can be attributed to several factors including differences in methods, including the use of human serum in our study, cell type differences, or decoupling of rhythms in some cancer cells. While a comparison of BJ-5TA cells and U2OS cells could be interesting, a proper comparison requires investigation of many data sets, since any pair of BJ-5TA and U2OS data sets will most likely differ in some detail of experimental design or data processing pipeline, which could contribute to observed differences in rhythmic transcripts.

That being said, we compared clock reference genes (see Author response image 1) between BJ-5TA and U2OS cells, comparing circadian profiles obtained from our data with those available on CircaDB. These circadian profiles exhibit many similarities and a few differences. The peak to trough ratios (amplitudes) are quite similar for ARNTL, NR1D1, NR1D2, PER2, PER3, and are about 25% lower for CRY1 and somewhat higher for TEF (about 15%) in our data. We find that the MESORS are generally similar with the exception of NR1D1 which is much lower and NR1D2 which is much higher in our data.

For the rhythmic cell cycle genes, could this be the consequence of the serum which synchronizes also the cell cycle, or is it rather an effect of the circadian oscillator driving rhythms of cell cycle genes? 

This is an interesting point. Given our previous data showing that the cell cycle gene cyclin D1 is regulated by clock transcription factors3, we believe the circadian oscillator drives, or at least contributes to rhythms of cell cycle genes. However, the serum clearly makes a difference as we find that MESORs of cell cycle genes decrease with aged serum. This is consistent with the decreased proliferation previously observed in aged human tissue.

While the reduction of rhythmicity in the old serum for oxidative phosphorylation transcripts is very interesting and fits with the general theme that metabolic function decreases with age, it is puzzling that the recipient cells are the same, but it is only the synchronization by the old and young serum that changes. Are the authors thus suggesting that decrease of metabolic rhythms is primarily a non cell-autonomous and systemic phenomenon? What would be a potential mechanism? 

It may not be the cycling per se, but rather an overall inefficiency of oxidative phosphorylation that is conveyed by the serum. Relating other work in the field to our findings, we’ve added the following to our discussion: “Previous work in the field demonstrates that synchronization of the circadian clock in culture results in cycling of mitochondrial respiratory activity5,6 further underscoring the different effects of old serum, which does not support oscillations of oxidative phosphorylation associated transcripts. Age-dependent decrease in oxidative phosphorylation and increase in mitochondrial dysfunction7 is seen also in aged fibroblasts8 and contributes to age-related diseases9. We suggest that the age-related inefficiency of oxidative phosphorylation is conferred by serum signals to the cells such that oxidative phosphorylation cycles are mitigated. On the other hand, loss of cycling could contribute to impairments in mitochondrial function with age.”

The delayed shifts after aged serum for clock transcripts (but not for Bmal1) are interesting and indicate that there may be a decoupling of Bmal1 transcript levels from the other clock gene phases. How do the authors interpret this? Could it be related to altered chronotypes in the elderly? 

One possible explanation is that the delay of NPAS2, BMAL1’s binding partner, results in the delay of the transcription of clock controlled genes/negative arm genes. Since the RORs do not seem to be affected, Bmal is transcribed/translated as usual, but there isn’t enough NPAS2 to bind with BMAL1. In this case downstream genes are slower to transcribe causing the phase delay.

The discussion would also benefit from mentioning parallels and dissimiliarities with previous works, as well as what would be possible mechanisms for such an effect. 

We’ve expanded our discussion in the manuscript to discuss possible mechanisms and also how the genes/pathways implicated in our study relate to other aging literature.  

Minor: 

While time of serum collection is provided in the methods, it would be very useful to provide this information, along with the accompanying argumentation also at a more prominent position and to also add it to Table S1. 

We made sure to highlight the collection time in the abstract of the manuscript “We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals at 14:001 and used the serum to synchronize cultured fibroblasts.” The time of blood draw is also in sections of the paper (Intro and Methods). Since Table S1 is demographic information, we did not think that the blood draw time fit best there, but hopefully it is now clear in the text.

L73 EKG: define the abbreviation 

We rewrote this paragraph, but defined the term where it is used the paper.  

L77: transfected BJ-5TA fibroblasts. Mention in the text that these are stably transfected cells. 

We added this to the text.

L88: Day 2 also revealed different phases of cyclic expression between young and old "groups" for a larger number of genes. Here it is only two donors, right? 

Yes, we swapped out the word “groups” for “subjects”.

L115. MESORs of steroid biosynthesis genes, particularly those relating to cholesterol biosynthesis, were also increased in the old sera condition. This is quite interesting, can the authors speculate on the significance of this finding? 

We’ve added discussion about this finding in the context of the literature in our discussion.

Fig 3. - FDRs are only listed for certain KEGG pathways, and gene counts for each pathway are also missing, which excludes some valuable context for drawing conclusions. Full tables of KEGG pathway enrichment outputs should be provided in supplementary materials. Input gene lists should also be uploaded as supplementary data files.

Both output and input files are included in this submission as additional files.  

Line 322 - How many replicates were excluded in the end for each group? Providing this information would strengthen the claim that the ability of both old and young serum to drive 24h oscillations in fibroblasts is robust and not only individual. 

Each serum was tested in triplicate in two individual runs of the experiment. Of the 15 serum samples, on one of the runs, a triplicate for each of two serum samples (one old, one young) was excluded. Given that only one technical replicate in one run of the experiment had to be excluded for one old and one young individual out of all the samples assayed, this supports the idea that young and old serum drive robust oscillations.

Line 373 - Should list which active interaction sources were used for analysis. 

In this manuscript we used STRING (search tool for retrieval of interacting genes) analysis to broadly identify relevant pathways defined by different algorithms. From these data, we focused in particular on KEGG pathways.

Reviewer #1 (Recommendations For The Authors): 

These comments are in addition to those provided above: 

Minor: 

L73 EKG: define the abbreviation 

We rewrote this paragraph, but defined the term where it is used the paper.  

L77: transfected BJ-5TA fibroblasts. Mention in the text that these are stably transfected cells. 

We added this to the text.

L88: Day 2 also revealed different phases of cyclic expression between young and old "groups" for a larger number of genes. Here it is only two donor, right? 

Yes, we swapped out the word “groups” for “subjects”.

L115. MESORs of steroid biosynthesis genes, particularly those relating to cholesterol biosynthesis, were also increased in the old sera condition. This is quite interesting, can the authors speculate on the significance of this finding? 

We’ve added discussion about this finding in the context of the literature.

Fig.4 The fold change amplitude of the clock gene seems quite a bit lower than what is usually expected (for Nr1d1 it is usually 10 fold). The authors should provide an explanation and discuss this. 

There are a variety of factors that contribute to the fold change amplitude of clock genes. First, the change in amplitude of clock genes is lower in vitro compared to in vivo samples. For example, in U2OS cell cultures the fold change in the cycling of Nr1d1 is only 2 fold and is not significantly different from the fold change we observe (as shown in the U2OS data from CircaDB plotted in Figure 1R). Second, the method of synchronization contributes to the strength of the rhythms. Serum synchronization is generally less effective at driving strong clock cycling than forskolin or dexamethasone although, as noted in the manuscript, it may promote the cycling of more genes. Lastly, rhythm amplitude is also dependent on the cell type in question so cell to cell variability also contributes to differences. However, overall, we do not find major differences in comparing the U2OS data and ours. Please note that the y-axis has a logarithmic scale.

What is the authors' strategy to identify which serum components that are responsible for the reported changes? This should be discussed. 

In the future, we intend to analyze the serum factors using a combination of fractionation and either proteomics or metabolomics to identify relevant factors. We have added this to the discussion.

Reviewer #2 (Recommendations For The Authors): 

Overall, the article is well-written but lacks some more rigorous data analysis as mentioned in the public review above. In addition to a more thorough analysis approach focusing much more heavily on individual variability, several other changes can be made to strengthen this study:

Fig 3. - FDRs are only listed for certain KEGG pathways, and gene counts for each pathway are also missing, which excludes some valuable context for drawing conclusions. Full tables of KEGG pathway enrichment outputs should be provided in supplementary materials. Input gene lists should also be uploaded as supplementary data files. 

Both output and input files are included in this submission as additional files.

Fig 1A. - Only n=5 participants were used for this analysis, explanation of the exclusion criteria for the other participants would be useful. 

As Figure 1A is a schematic, we assume the reviewer is referring to Figure 1B. We’ve provided a flow chart of subject inclusion/exclusion in Figure S2.

Fig 2. - For circadian transcriptome analysis only n=4 participants were used - what criteria was used to exclude individuals, and why were only these individuals used in the end? 

As patient recruitment was interrupted by COVID, we selected samples where we had sufficient serum to effectively carry out the RNA seq experiment and control for age and sex.

Line 322 - How many replicates were excluded in the end for each group? Providing this information would strengthen the claim that the ability of both old and young serum to drive 24h oscillations in fibroblasts is robust and not only individual. 

Each serum was tested in triplicate in two individual runs of the experiment. Of the 15 serum samples, on one of the runs, a triplicate for each of two serum samples (one old, one young) was excluded. Given that only one technical replicate in one run of the experiment had to be excluded for one old and one young individual out of all the samples assayed, this supports the idea that young and old serum drive robust oscillations.

Line 373 - Should list which active interaction sources were used for analysis. 

In this manuscript we used STRING (search tool for retrieval of interacting genes) analysis to identify relevant pathways. We do not present any STRING networks in the paper.

Line 68 - "These novel findings suggest that it may be possible to treat impaired circadian physiology and the associated disease risks by targeting blood borne factors." This is a completed overstatement that are cannot be sustained by the limited findings provided by the authors. 

We’ve modified this statement to avoid overstating results.

(1) Pagani, L. et al. Serum factors in older individuals change cellular clock properties. Proceedings of the National Academy of Sciences 108, 7218–7223 (2011).

(2) Pagani, L. et al. Serum factors in older individuals change cellular clock properties. Proc Natl Acad Sci U S A 108, 7218–7223 (2011).

(3) Lee, Y. et al. G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLOS Biology 17, e3000228 (2019).

(4) Tomasetti, C. et al. Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence. Proceedings of the National Academy of Sciences 116, 20482–20488 (2019).

(5) Cela, O. et al. Clock genes-dependent acetylation of complex I sets rhythmic activity of mitochondrial OxPhos. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1863, 596–606 (2016).

(6) Scrima, R. et al. Mitochondrial calcium drives clock gene-dependent activation of pyruvate dehydrogenase and of oxidative phosphorylation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1867, 118815 (2020).

(7) Lesnefsky, E. J. & Hoppel, C. L. Oxidative phosphorylation and aging. Ageing Research Reviews 5, 402–433 (2006).

(8) Greco, M. et al. Marked aging-related decline in efficiency of oxidative phosphorylation in human skin fibroblasts. The FASEB Journal 17, 1706–1708 (2003).

(9) Federico, A. et al. Mitochondria, oxidative stress and neurodegeneration. Journal of the Neurological Sciences 322, 254–262 (2012).

Hablando desde una perspectiva amplia este es un proceso en donde observamos suficiente evidencia para reaccionar con base a la comunicación con su estado puro.

clocks weren't used to tell time which is interesting because now that's all we use it for.

why did charles martel stoped the muslims from conquering france?

The contrast in resources available to children from different income levels really highlights the systemic barriers that perpetuate educational inequality. It raises important questions about how society can create more equitable opportunities for all children regardless of their family income. Addressing these gaps is essential for fostering a more just and inclusive educational landscape

I agree , those children in higher income status have a higher probability of have education support at home, this includes having a personal tutor, being involved in other activities , having extra curriculums, having parents who achieved a higher education guide them, throughout their school years.

I agree with this statement, children can be more focused in school when they don’t have issues at home. These issues can impact their behaviors at school , for example they might be more anti social, develop imposter syndrome, become easily distracted. I think this is unfortunate because not only does it impact children right now but also in their future sometimes limits their opportunities for higher education .

I thinks it’s interesting that this study highlights a significant achievement gap in early literacy skills based on family income. Children from families in the top 20% of income outperform those from the bottom 20% by 106 points when they start kindergarten. This gap is notably larger than the difference in reading skills among racial groups. The disparity persists and even widens by fifth grade with silica gaps observed in mathematics.

I can relate to this because for the first couple of years growing up, my mother was the only parent in my life. me and my brother watched our mother struggle on her own to provide for us. their would be moments where my brother and i were home alone for most of the day because my mother would be working late. when my mother married my step-father, her burden was reduced and she was more happy.

This is a great point! Family dynamics and academic success are strongly related; children who grow up in a stable, encouraging home often show better behavioral and emotional control, which helps them to succeed academically. Parent-child relationships can become tense regardless of their socio-economic background. Under such circumstances, parents could find it difficult to keep warmth and patience, which would result in more severe methods of raising children. These dynamics might compromise children's well-being, therefore affecting their ability to focus and thrive in the classroom.

This makes sense to me. Families who are financially well-off may afford to make investments in healthy food, better child care, and better learning conditions. Lower-income households sometimes lack these tools, which lays a solid foundation for academic achievement. Having access to safe environments and great early childhood education will help a child be ready for school and succeed academically in the long run. Families experiencing financial difficulties may cause parents to be more prone to suffer with stress, sadness, or exhaustion, which may impact their interactions with their children and reduce the time available for assistance, educational involvement, and nurturing. Children from low-income homes suffer a doubled strain from these emotional dynamics and lack of financial means, which limits their school performance relative to their higher-income counterparts.

This chapter raises a quite interesting subject. The success of a child in school depends on many variables. The example of Alexander and Anthony provides an excellent illustration of the students' socioeconomic background as well as their parents' educational history, which helps to influence the academic success of the children.

I think kids do better in school when they can focus, get along with others, and aren’t weighed down by problems at home. For children from low-income families, outside factors can make it really hard to thrive. Things like family stress, lack of access to healthcare, or emotional struggles can slow down their physical and mental development. When kids are distracted by issues like financial strain or tension at home, it affects not only their academic performance but also their overall well-being.

This shows how greatly family income and socioeconomic background affect school results. From access to better schools to lots of resources for extracurricular activities, Alexander's family wealth and suburban surroundings give him major benefits that help him succeed in his academics and in life. Anthony's family, on the other hand, battles lower educational achievement and financial uncertainty, which reduces chances for academic excellence and parental participation in his schooling. The disparity in family structure is also quite important since Alexander gains from the presence of both parents, which not only raises household income but also improves the availability of parental time and support.

This stands out to me so much because of how parenting is reflected based on everything that happens in life. In a household with constant worries and stress the parent tends to reflect those worries on their kids. It is either shown through a parents anger and always responding as if they're annoyed, yelling, and just anxious, which that tends to affect their kids behavior in school or wherever they may be. We look at things different when it comes to spending money.

I wonder how many more different ways of printing the world invented before making the printer as we know it today.

I wonder what they did before things like these were invented and how they might've looked like.

because a problem or question occurred and if they couldnt ind it through their already established knowledge they had to investigate science more

wonder why they think its non science based?

# EL IS 10 -METALEGIS

(((( listen, as money comes alive; people--and starts doing your work for you, telling you how to run your government better; and making sure that you can't pay for what you aren't supposed to get. ))))

https://chatgpt.com/share/67044ea2-c080-8008-ae4c-3418e95a74f2

watch, as the worthlessness of Bitcoin without "smartcontracts" ripples across the multiverse; even if "ECC" encryption looks like it's a sound explanation for why Orion doesn't move in the sky ...if you can can recall ... that particuar conversation.

https://chatgpt.com/share/6702da44-7e84-8008-8187-dcfd8e30ddba

Congestion effects. One thing a regulator (e.g. taxi cab controller) may manage better than the "market" given it is an obvious externality.

I listen to music all the time and I never knew that this is how sound waves are created. It's crazy how all the sound information is just saved onto a number.

Résumé de la vidéo [00:00:01][^1^][1] - [00:24:02][^2^][2]:

Cette vidéo est une introduction à la pensée complexe, mettant en avant son importance pour transformer la société de manière écologique et juste. Les intervenants discutent de leurs expériences et de la manière dont la pensée complexe influence leurs actions.

Moments forts: + [00:00:01][^3^][3] Introduction à la table ronde * Importance de la pensée complexe * Objectif de transformation sociale * Présentation des invités + [00:01:52][^4^][4] Xavier Normand sur la pensée complexe * Expérience personnelle avec Edgar Morin * Application dans la politique locale * Importance de la participation citoyenne + [00:12:56][^5^][5] Nathalie Molinaire sur la crise et le changement * Utilisation de la crise pour le changement * Approche systémique en pédopsychiatrie * Importance de la réflexivité et de la reliance + [00:20:30][^6^][6] Exemple concret de changement * Cas d'une élue locale * Stratégies pour susciter le changement * Importance de poser des limites et de se ressourcer

Résumé de la vidéo [00:24:06][^1^][1] - [00:46:39][^2^][2]:

Cette vidéo explore la pensée complexe et son application dans divers contextes, notamment les crises écologiques et les entreprises. Elle met en lumière l'importance de la réflexion et de l'action dans un monde complexe.

Points forts : + [00:24:06][^3^][3] La crise comme potentiel de changement * Observer et réfléchir * Optimisme volontaire * Écologie de l'action + [00:25:01][^4^][4] La pensée complexe dans les entreprises * Gestion des services d'eau chez Suez * Difficultés de la pensée complexe * Importance de la transmission + [00:30:01][^5^][5] Stratégie et incertitude * Importance de la stratégie * Connaissance et analyse des biais * Adaptation à la complexité + [00:37:00][^6^][6] Transition écologique et sociale * Expériences de terrain * Importance des communs * Défis économiques et sociaux + [00:42:00][^7^][7] Financement des écosystèmes coopératifs * Importance de financer les métiers intermédiaires * Solidarité et coopération * Développement des territoires ruraux

Résumé de la vidéo [00:46:41][^1^][1] - [00:58:24][^2^][2]:

Cette vidéo traite de la pensée complexe et de la manière dont elle peut être appliquée pour créer des valeurs immatérielles et renforcer la coopération entre les parties prenantes dans une communauté.

Points forts : + [00:46:41][^3^][3] La dialogie et la coopération * Les antagonismes et complémentarités * Importance de la communication * Création de valeurs immatérielles + [00:48:00][^4^][4] La confiance et la coopération * Confiance entre les acteurs * Coopération pour l'intérêt collectif * Développement des valeurs partagées + [00:50:02][^5^][5] Financement et résilience * Nouveaux véhicules financiers * Capitaux patients à intérêt modéré * Importance de la rentabilité sociale et écologique + [00:54:00][^6^][6] Implication des citoyens * Collecte de fonds citoyenne * Difficultés de financement institutionnel * Importance de la fraternité et de la gouvernance partagée + [00:56:02][^7^][7] Agir en complexité * Posture de doute et d'apprentissage * Importance de la réflexivité collective * Coopération avec toutes les parties prenantes

low-income students that have their natural skills recognized and affirmed, are often able to produce favorable academic results—that is, pass tests or graduate—like their high income counterparts. But for children from poor families especially, the educational system sometimes ignores and undervalues their strengths in favor of compliance and conformity. The author's own experience of being called one of the "good ones" due of conformity shows how frequently schools reward behavior that conforms with dominant standards. This hinders the ability of other low income student because they aren't promoting intellect or creativity.

I agree with this. In low income households, kids don't have access to books generally because they can't afford them or the parents have poor reading skills. this negatively affects the children and hinders their ability to improve their reading skills.

I can relate to this as I was also raised by my mother and I adopted her values and motivations. she worked many hours and I would be alone with my brother a lot. I understood from a young age that we had to be good and work hard if we wanted to be successful in life. I think that is what drove me to come to college and get a higher education

I feel like this is common among low income students. As a low income student as well, I feel pride in knowing I am studying here and proving that anyone can get an education.

machine learning and natural language processing provide science education researchers means to combine exploratory capabilities of qualitative research methods with the systematicity of quantitative methods.

Computability theory and algorithms history - Algorithms date back to Classical Greece and 9th century Persia. - Formal mathematical definition of effective computability proposed in the 20th century.

Provability and undecidability in mathematics - False statements being provable leads to serious consequences. - True statements that are not provable can be frustrating, especially in mathematical problem-solving.

Introduction to propositions as types and natural deduction by Gensen - Gensen introduced natural deduction as the main form of logic we use today - He also developed sequent calculus and introduced the use of '∀' as upside-down 'A' for 'for all'

Understanding implications in proofs - Implications are about assuming and not proving - Different rules for concluding A and B in proofs

Direct proof simplifies proof process - Substitution may add nodes but simplifies by removing sub-formulas - Consistency ensured by absence of proof of false in logic

Introduction to Simply Typed Lambda Calculus - Church developed Simply Typed Lambda Calculus to establish a consistent system. - Lambda calculus includes functions, pairs, and the ability to build various data types.

Propositions in logic correspond to types in a programming language - Proofs in the logic correspond to terms programs in the programming language - Simplification of proofs corresponds to evaluation of programs

Curry Howard is a foundational concept for various fields - It applies to intuitionistic logic and all areas of logic - Logicians and computer scientists independently discovered similar concepts

Lambda calculus may be a universal programming language for aliens. - Lambda calculus could be easier for aliens to decipher than other programming languages due to its logical foundation. - It is speculated that aliens could potentially understand Lambda calculus as it is rooted in fundamental logic principles.

The strength of the weak electron force is crucial for the existence of matter and life. - If the electron force was slightly stronger, matter wouldn't form and life wouldn't exist. - Multiple universes could have different electron forces and gravities, but a universe without logic is hard to imagine.

Exploring correspondence between logic and programming features - Linear Logic corresponds to session Types for concurrency - Category theory considered as the third column linking multiple concepts

Computer science impacts knowledge discovery - Logicians often make discoveries before computer scientists due to their experience. - Linear logic and concurrency had early correspondence, leading to joint discoveries.

Résumé de la vidéo [00:00:08][^1^][1] - [00:31:21][^2^][2]:

Cette vidéo est une introduction à la pensée complexe, présentée dans le cadre de l'Université Populaire Edgar Morin pour la Métamorphose. Elle aborde les concepts clés de la pensée complexe et leur pertinence pour une transformation profonde de la société.

Moments forts: + [00:00:08][^3^][3] Introduction et contexte * Présentation du projet citoyen * Importance de la pensée complexe * Objectifs de la séance + [00:06:02][^4^][4] Pertinence de la pensée complexe * Dimension cognitive de la métamorphose * Nécessité de changer nos modes de pensée * Citation d'Einstein sur la résolution des problèmes + [00:11:56][^5^][5] Organisation et fonctionnement * Groupes de recherche-action * Importance de l'auto-organisation * Rôle des réseaux distribués + [00:20:50][^6^][6] Concepts clés * Auto-organisation et écho-organisation * Importance de la diversité des acteurs * Tolérance à l'ambiguïté + [00:26:09][^7^][7] Projets et objectifs * Définition des projets des groupes * Importance de la créativité * Partage d'un objectif commun

Résumé de la vidéo [00:31:23][^1^][1] - [01:05:44][^2^][2]:

Cette vidéo présente une introduction à la pensée complexe, en mettant l'accent sur l'importance des représentations et des analogies dans la compréhension du monde.

Moments forts : + [00:31:23][^3^][3] Présentation des intervenants * Jean, ingénieur et docteur en sciences * Leonardo Rodriguez, sociologue * Importance de la diversité des visions + [00:33:01][^4^][4] Importance des représentations * Distance entre le monde et notre manière de le penser * Utilisation des analogies pour la pédagogie * Exemple de la pipe de Magritte + [00:45:00][^5^][5] Complexité et réalité * Distinction entre le monde et nos perceptions * Importance de la pensée complexe * Représentations et leur impact sur notre compréhension + [00:58:00][^6^][6] Exemple du verre de vin * Michel Cassé et sa vision complexe du monde * Importance des représentations dans la perception de la réalité * Curiosité et ouverture d'esprit

Résumé de la vidéo [01:05:48][^1^][1] - [01:39:30][^2^][2]:

Cette partie de la vidéo explore la pensée complexe, en mettant l'accent sur les concepts de naturalisme, d'intériorité humaine, et de rationalisation. Elle discute également de la modernité et de la nécessité de repenser nos approches intellectuelles et organisationnelles.

Moments forts : + [01:05:48][^3^][3] Intériorité et naturalisme * Différence entre l'intériorité humaine et animale * Importance de la culture dans l'intériorité humaine * Critique du naturalisme par rapport à la pensée de Morin + [01:13:03][^4^][4] Rationalisation et modernité * Impact de la rationalisation sur la société * Critique de la modernité et de la rationalisation excessive * Importance de la réflexivité et de la pensée critique + [01:20:08][^5^][5] Allégorie de la rationalisation * Histoire de l'homme cherchant ses clés sous un lampadaire * Métaphore de la pensée limitée par la rationalisation * Nécessité de la pensée complexe pour dépasser ces limites + [01:28:02][^6^][6] Rationalisation dans divers domaines * Impact sur la médecine et l'éducation * Critique de la réduction de l'humain à une ressource * Importance de repenser les structures éducatives et médicales + [01:32:01][^7^][7] Métamorphose et pensée complexe * Besoin de transformation systémique profonde * Importance de la pensée complexe pour cette transformation * Référence à Jean-Louis Pes et son influence

.Résumé de la vidéo [01:39:34][^1^][1] - [01:57:18][^2^][2]:

Cette vidéo explore la pensée complexe à travers les œuvres et les idées d'Edgar Morin. Elle aborde ses contributions à la sociologie, son engagement politique, et son approche interdisciplinaire.

Moments forts: + [01:39:34][^3^][3] Introduction à la pensée complexe * Analyse de la mort et du cinéma * Importance de la réflexivité * Influence de la Résistance + [01:42:01][^4^][4] Engagement et réflexivité * Exclusion du parti communiste * Importance de l'autocritique * Maintien des idéaux fraternitaires + [01:45:01][^5^][5] Œuvres et découvertes * Livres recommandés * Découvertes en Californie * Importance de la méthode + [01:47:02][^6^][6] Critique du marxisme * Provincialisation de Marx * Intégration des dimensions symboliques * Rejet du déterminisme économique + [01:51:01][^7^][7] Connaissance interdisciplinaire * Connaissance des sciences de la matière * Importance de la pensée systémique * Découverte de la cybernétique

Résumé de la vidéo [00:00:42][^1^][1] - [00:36:02][^2^][2]:

Cette vidéo est une introduction à la pensée complexe, abordant les concepts clés et les objectifs pédagogiques de ce cycle d'enseignement.

Moments forts: + [00:01:10][^3^][3] Introduction et calendrier * Présentation du calendrier des séances * Importance de l'interdisciplinarité * Conférences et groupes de recherche-action + [00:04:16][^4^][4] Objectifs pédagogiques * Accès à la pensée complexe * Méthode et contenu * Importance de la réflexion collective + [00:10:03][^5^][5] Représentations et paradigmes * Identification des représentations * Influence des paradigmes dominants * Importance de la réflexion sur les modes de pensée + [00:17:01][^6^][6] Méthode de connaissance * Besoin d'une méthode de connaissance * Critique des représentations simplifiées * Importance de la complexité dans la compréhension du réel + [00:25:01][^7^][7] Biais cognitifs * Exemples de biais cognitifs * Importance de la prise de conscience des biais * Impact des biais sur la perception et la mémoire

Résumé de la vidéo [00:36:06][^1^][1] - [01:15:13][^2^][2]:

Cette partie de la vidéo explore la pensée complexe, en mettant l'accent sur les paradigmes de disjonction et de conjonction, ainsi que sur l'importance des relations et des processus dans la compréhension de la complexité.

Moments forts : + [00:36:06][^3^][3] Paradigme de disjonction * Séparation entre raison et émotion * Impact sur la représentation dominante * Exemple historique du droit de vote des femmes + [00:40:07][^4^][4] Cas de Phineas Gage * Accident et changement de comportement * Lien entre lésions cérébrales et comportement * Importance de la région préfrontale + [00:47:00][^5^][5] Définition de la complexité * Tissu de constituants hétérogènes * Interaction et rétroaction * Nécessité de mettre de l'ordre dans les phénomènes + [00:56:02][^6^][6] Processus et continuité * Réel comme processus permanent * Difficulté à saisir la globalité * Importance de la perception et du langage + [01:07:08][^7^][7] Dimension relationnelle * Relation au premier plan * Conception individualiste vs. relationnelle * Importance des relations pour comprendre la complexité

Résumé de la vidéo [01:15:15][^1^][1] - [01:52:48][^2^][2]:

Cette vidéo explore la pensée complexe, en mettant l'accent sur les relations économiques et sociales, la résonance, et la critique de l'individualisme.

Moments forts: + [01:15:15][^3^][3] Relations économiques et sociales * Relations intéressées et superficielles * Échange économique et individualisme * Critique de la marchandisation des relations + [01:17:01][^4^][4] Concept de résonance * Résonance selon le sociologue allemand * Importance de l'affection et de l'émotion * Absence de résonance dans les relations marchandes + [01:20:06][^5^][5] Critique de l'individualisme * Exacerbation de l'individualisme depuis les années 80 * Évolution des rémunérations des dirigeants * Héroïsation des individus riches + [01:26:02][^6^][6] Notion de mérite * Critique de la notion de mérite * Étude des joueurs de hockey canadiens * Influence des facteurs institutionnels et sociaux + [01:37:00][^7^][7] Démarche analytique vs systémique * Préceptes de la démarche analytique * Limites de la décomposition et recomposition * Importance de la pensée systémique et de la finalité

Résumé de la vidéo [01:52:53][^1^][1] - [02:09:17][^2^][2]:

Cette vidéo explore la pensée complexe, en se concentrant sur les concepts de causalité et de téléologie, et leur application dans la compréhension des systèmes et des relations humaines.

Points forts : + [01:52:53][^3^][3] Causalité et téléologie * Causalité : Pourquoi en un mot * Téléologie : Pourquoi en deux mots * Importance de comprendre les finalités + [01:54:11][^4^][4] Perspective systémique * Analyse des relations plutôt que des individus * Projeter vers l'avenir * Sélectionner des éléments pertinents + [01:57:02][^5^][5] Modélisation analytique et systémique * Optimisation et adéquation * Pertinence de l'optimisation * Propriétés émergentes des systèmes + [02:00:04][^6^][6] Exemples concrets * Bataille de Camerone * Résistance des légionnaires * Importance de l'auto-organisation + [02:03:00][^7^][7] Groupes de recherche-action * Auto-organisation des groupes * Importance de la créativité et de la liberté * Accompagnement des groupes pour éviter l'essoufflement

Exploring notational design in computer science - Episode 17 delved into philosophical aspects, while this episode focuses on practical applications. - Addressing the need for operational semantics and elegance in reasoning and design, alongside listener questions.

Work environment and shift in focus - The department was initially conducive for mathematically oriented work and founded by three mathematicians. - The focus shifted over time and became less favorable for the speaker.

Elegance is about concise expressibility - Definition of elegance involves simplicity and mathematics we already know - Elegance does not mean familiarity or subjectivity, opposite to what is commonly perceived

Mathematics values concise expressions and reusability. - Mathematicians value expressing things concisely in core mathematic field. - Abstract algebra is a pragmatic tool derived from the need for reusability in mathematics.

Capitalism promotes short-term value work - Values of capitalism lead to focusing on immediate results without considering long-term impact. - Precise simplicity is essential for understanding complexity and elegance in theories.

MIT shifted from teaching Scheme to Python due to industry demand - Python is favored by companies for hiring programmers. - MIT's switch to Python reflects the influence of capitalism over academic values.

Courage to go beyond easy solutions - Being uncomfortable with proposed solutions but lacking a better one - Importance of speaking up and listening in decision-making processes

Choosing personal responsibility and honesty in values - Choosing not to prioritize promotions and raises by avoiding rocking the boat - Recognizing the brief window of opportunity to make an impact in the world

Scientific method emphasizes experimentation and progress towards truth - Experimentation measures theories against reality and guides where to look and what to test for - Capitalism focuses on short-term value, individuals must prioritize work of lasting value by making strategic choices and being skeptical of established norms and technologies.

Choosing work of lasting value over short-term gain requires sacrifice and dedication - Prioritizing meaningful work over maximizing bonuses and raises can be challenging but rewarding - Agreeing with Dan on valuing elegance in science and using objective criteria for progress

Complex questions must be formally checked for trustworthiness. - Complicated questions are likely false and can fool most people. - Questions that cannot be formally checked must be approached with simplicity and pragmatism.

Elegance is a duality of simplicity and cost - Simplicity requires mental effort and is difficult to find - Complexity results in usage cost for the user and creation cost for the creator

Elegance and easily formalizable values discussed - Dan and the speaker share similar values on elegance - Elegance should be easily formalizable and objective to avoid self-deception

Occasionally compelling theories may be disproven by measurements - Mistakes in measurements can lead to disagreement with theories - Compelling theories may prompt reevaluation and remeasurement to verify accuracy

Proof prevents self-dilution and ensures arrival at truth - Proof tells us if we haven't finished the proof or if we have truly reached the truth, unlike informal arguments - The cost of proof is the cost of knowing we are right, which outweighs the detraction from performance

Proof is essential for optimizing performance in software engineering. - Without proof, optimization can lead to self-defeating results and shaky correctness. - Engineers prioritize reliability and efficiency, with energy efficiency being a key aspect in modern software development.

Proper documentation in proof states reveals and corrects mistakes. - Proof not only confirms correctness but also helps constructively identify and correct mistakes. - Would you rather appear right or become right? Proof is key to becoming right and challenges the idea of already being right.

Code documentation must include proofs for understanding - The statement of the theorem represents the functionality of the software - The proof ensures the implementation details are correct

Elegance is key for simplicity and value in theorems and proofs - Simple and precise theorems provide more value to users than complex specifications, leading to practical benefits. - Striving for elegance in proofs reduces unnecessary complexity and effort, ensuring a better outcome.

Creating high value and cost-effective solutions with efficiency and sustainability - Balancing high value with cost-effectiveness and efficiency to create sustainable solutions. - Emphasizing the importance of simplicity, correctness, and elegance in delivering value to end users.

Analogy between compositional semantics and homomorphic design. - The essence is the same but in a more specific form. - Computers are analog, made out of nature, and cannot run at Nature's Own rate.

Nature's discreetness is impossible to achieve in this universe. - The discreetness of nature at the plank level is interesting but impractical in software or hardware implementation. - Even hardware built in this universe cannot achieve the required sampling rate set by nature.

Digital abstraction is about bits and bit patterns. - Digital abstraction involves interpreting data as bits and patterns, not numbers, trees, or graphs. - Using precise and truthful analogies, such as homomorphism in mathematics, is essential for accurate representation.

Groups and their relation in engineering - Groups like real numbers and symmetry groups serve as a basis in engineering. - Monoids, such as natural numbers and strings, are also used in programming.

Logarithms provide precise analogies between multiplication and addition - Log of a product is the sum of the logs (log a + log b) - Logarithms allow computation by turning multiplication into addition

Creating an implementation to add natural numbers using machine - Describing the need for dependable and efficient implementation - Resolving the challenge of using a machine that deals with bits, not numbers

Understanding the three-step process of converting numbers to binary and interpreting output - First step involves converting a number to binary before interpretation - Second step includes interpreting the binary using a mathematical function to get the number output

Denotational design ensures consistent results from input to output. - Correctness in denotational design means getting the same result from different paths. - Denotational design aims for a beautiful and elegant formulation of implementations and correctness proofs.

Implementing homomorphic data representations using different mathematical structures. - Utilizing the same vocabulary for data representations to maintain homomorphism. - Exploring various mathematical structures like monoids, groups, rings, and vector spaces in relation to machine learning and linear algebra.

Linear algebra deals with vector spaces over a ring with scalars. - Scalars form a ring, which can also be a commutative ring or a field. - Vectors can be added and scaled by scalars, forming the basis of linear algebra.

Matrices encode linear maps - Using currying, matrices represent functions from vectors to vectors - Matrices describe linear functions, making it easier to prove properties

Matrix multiplication is associative - Matrix multiplication involves matching up rows and columns, multiplying corresponding elements, and adding them up. - Associativity in matrix multiplication means the order of multiplication doesn't affect the result.

Understanding the purpose of a matrix as denoting a linear transformation - A matrix represents the mapping from a matrix to a linear function - Linear algebra is about functions that are linear, not about matrices

Matrices are a more efficient representation of linear functions. - Matrix multiplication follows a completely systematic denotational design. - Choosing the right representation, such as matrices, is crucial for success.

Matrix multiplication must be a perfect analogy to function composition. - Linear Maps and matrices speak the same language. - Composition is the main motivation for matrix multiplication in linear algebra.

Matrix composition is equivalent to interpreting matrices as linear maps and then composing them. - Correct matrix multiplication is necessarily associative. - Defining equality for matrices and linear functions is crucial for consistency.

Proving algebraic properties is not necessary for understanding concepts. - Algebraic properties are symptoms of superficial understanding. - Properties can be assumed to hold without explicit proof, as they follow from discipline.

Clear interpretation of linear maps and matrices is crucial for correct implementation. - Linear algebra is not about computers but using them as tools for visualization. - It is essential to understand the analogy between linear maps and matrices for accurate implementation.

Specification drives towards simplicity, implementation towards efficiency. - Using functions for linear maps is simpler than matrices to avoid errors in interpretation. - Introducing denotation helps reconcile different interpretations of matrices, ensuring correctness.

Specifications and implementations should be pulled in opposite directions - Specifications should be simple and free of detail, while implementations should be full of clever tricks and optimized for the specific hardware - The flaw in operational semantics is that it tries to put specifications and implementations together, rather than allowing them to be different

Correctness proofs emphasize simplicity for valuable theorems - Denotation simplifies theorem proof by removing operational complexities - Efficient implementation requires consideration of modern processing elements like GPU, ASIC

Understanding function composition and associative properties. - Importance of both formal and informal reasoning in relation to function composition. - Distinguishing between operational implementations for better performance and theoretical theorems for proofs.

Identifying linear operations and their presence in algebra - Linear operations include left and right projection of a pair, and appending zero to the pair - Exploring the existence of these operations within an algebraic structure, such as vector spaces and categories

Denotational design and linear maps in category theory - Linear maps and building blocks of denotational design - Understanding the mathematical realm and implementing the linear transformations

Showing type safety through operational semantics - Operational semantics used to demonstrate correctness of a computable language - Type safety proven through strong normalization and proper type relations

Operational semantics is a means to an end, not the goal. - Using operational semantics to solve problems definable outside of technology. - Creating a language with a type system to implement mathematical concepts in computing.

Designing programming interfaces vs. languages - I don't design languages, I design programming interfaces and implementations. - Programming languages have two parts: descriptions and gluing things together.

Choose one host language and embed domain-specific vocabularies to avoid constant language creation. - Peter Landin suggests embedding all vocabularies in a host language, distinguishing between domain-independent and domain-specific components. - This approach leads to pragmatic benefits and helps in avoiding the constant reinvention of programming languages.

Don't design languages - Existing imperative languages like C, C++, JavaScript are not conducive to adding new features easily. - Functional languages, particularly non-strict function languages, and dependently typed languages are better at hosting other vocabularies.

Operational and denotational semantics in language designing - Choosing between operational and denotational semantics for libraries - Challenges in separating operational and denotational semantics in some cases

Understanding denotational design in mathematical manipulation - Differentiating essential hard work from inessential hard work in math proofs - Exploring representations and operations in linear algebra and polynomial manipulation

Automatic differentiation is about functions that are differentiable - Definition and importance of differentiable functions in automatic differentiation - The connection between automatic differentiation and denotational design

Discussion on full abstraction and notational semantics - The conversation revolves around the impressive notational semantics and its relation to full abstraction. - The discussion also involves a comparison between concrete models and the challenges in achieving full abstraction in sequential and parallel computation.

Full abstraction is a key concept for equivalence - Observable operational equivalence means matching in all contexts - Many current languages lack full abstraction, which is historically accidental

Exploring the concept of parallelism in computational functions - It involves understanding PCF partial computable functions and Lambda calculus - The implementation challenge arises from deciding the evaluation order when dealing with false arguments

Differentiating between operational and denotational semantics in defining discourse - Operational semantics should not dictate denotational semantics - We should question and challenge the legitimacy of paradigms defining discourse

Imperative knowledge crucial for realistic 21st-century program implementation. - Declarative programs in high-level languages still need to meet the machine for practical interest. - Care about implementation involves proof, specification, correctness, and elegance.

Emphasizing the importance of proof in efficient specifications - Discussion on the necessity of detailed proofs for efficiency - Highlighting the comparison between operational and denotational approaches in linear algebra

Prevention through higher-level language and rich type systems - Higher-level language with a simple denotational model is expressive and aids in preventing errors - Focus on a small subset of machine behaviors that reflect correct execution of simple programming notions

Handling errors and exceptions in programming - Errors are things that cannot be captured in the semantic domain, leading to exceptions - A failure of the type system can result in errors, showing a need for a better system like in C or Pascal

Dependent types provide equivalent reasoning to foundations of mathematics and logic. - Dependent types offer a general solution for proofs and encoding in a self-consistent logical framework. - The entry barrier for learning advanced concepts like dependent types can be intimidating but crucial for ecosystem development.

Bridging familiarity and elegance in programming paradigms - Discussing the balance between familiarity and elegance in programming paradigms - Emphasizing the importance of making small tweaks to familiar paradigms for easier adoption

Challenging existing paradigms in computation - Exploring fundamental weaknesses in current computational paradigms - Adapting to the deceleration of Moore's Law and the need for innovation

Contributing to existing paradigms may bring short-term popularity but leads to dead ends - Choosing to contribute to existing paradigms may result in short-term popularity, kudos, and raises. - However, it also involves expending life energy, a non-renewable and precious resource, into something that is a dead end.

Learning negotiation and mediation from Roger Carl - Reflecting the other person's point of view to their satisfaction - Listening deeply and connecting with the other person's perspective

Facilitating heart-to-heart communication. - The facilitator observes and guides the process. - The dialogue creates a deeper connection and understanding between the individuals involved.

Belief clings but Faith lets go - Belief is the insistence that the truth is what one would wish it to be - Faith is an unreserved opening of the mind to the truth, without preconceptions

note

key

Luttwak's enthusiasm for this set up visible in his IDF book

I find it pretty interesting how someone can input these options into a form that is completely off topic. Whoever created these forms was most likely not paying attention and really screwed up. How did someone not catch any of these mistakes before uploading the form?

veni vidi vici

and still we stand inside this box; and still we cannot escape tartarus; between here and there and "sam i am" there is no way to know if we are "looking for dolphins who have been made by kangaroos" or staring at the koala, staring at alachua ...

staring at falafel

fa la la la la, la la la la

between polaris flickering though, and aristotle pondering whether or not "let there be light" and "i think therefore i am" has something to do with "roe v wade" or whether or not the hypocratic oath really means something to the people of araboth, we are staring at the "pledge of alegiance" and wondering if the crates of socrates and the socratic ...

if there's a reason we all need to be here; to ensure that "nobody loses" while we are watching the power of two conquer odinheim and jotunheim in one "swoosh" of the bifrost;

literally staring at the bifrost; wondering if we all "found the bridge" and know it has something to do with "holy sabbath" and ...

literally if it's in boca, or in miami; or if it's moved it's entire construction to the Xerox^2 PaRQ I'm sitting in; and if it's got anything to do with why Silicon Valley said that's where Microsoft and Apple came from; or the Newton;

falling from Eton or Eden or "standing on the shoulders of giants" ... staring at us all; looking back at the ... Google + network and the Grassy Knoll

and what's that got to do with "Omniscience?"

ad astra per scientam

This is kind of mentioned out of nowhere.

Explaining the question: what do you want if everything will always be (the same). When everything is a never ending process, what do you want to do with it?

Uses magic school bus like adventure through the biology of ear canals to scientifically explain the process of hearing.

a procedure designed to model and simulate the experience of acoustic phenomena

Basically, listening uses the entire body.

Common verbs used throughout the verse and poem. Repeated constantly.

Finished and ends contradictory thoughts with the same words of "inside/outside"

Good ending sentence for the learning first word streak. Conclusion to learning is birth.

Good simile describing the process of growth.

fecund definition: producing or capable of producing an abundance of offspring or new growth; fertile.

Author enjoys using the words "sentient beings" to describe the living.

Mother nature?

The author not only repeats concepts in detail, but repeats generally while using the same words multiple times in a verse.

Author likes to repeat concepts twice, expanding on the thought the second time

oh how fucking scary it is gravitron still goes unnoticed the iss fails to spin wheels and mir has wunderfallen

the days of the shuttle run long forgot between yesteryear and yetser dear "still i pearce the blue blue sky"

https://songmeanings.com/songs/view/14918/

and still we haven't sailed across the sun made it out of the "milky way" or transposed andromeda veritae still we haven't even tried to call NIST

the light of a star, the light of a day still stuck inside this strange unearthen play on a stage, talking about wormholes unable to see the light from the "stay"

https://translate.google.com/?sl=la&tl=de&text=the%20light%20is%20bright&op=translate

When we sit in our personal silence and ponder all the things in our life we feel we can't change because society told us we can't, most will feel defeated and discouraged, and this is where philosophy can pick you back up and encourage you to push past the barriers created for us to find alternatives in a world full of standard living.

I believe that a person who enriches their lives as a philosopher might will be able to accomplish anything they are searching for. Philosophy is not just about writing and thinking logically (which is very crucial skill to obtain), but also going out of our comfort zone and exploring parts of us we have yet to see.

Starting off the reading by saying "Picture yourself as a young mother with two children", encourages the audience to put themselves in shoes we may be lucky enough to never have to wear. It's a great way to introduce philosophy since philosophy as a whole is about understanding all perspectives.

I think this is true and it highlights how valuable philosophy is to society. Philosophy helps people question things around them, and through questioning uncover new truths and solutions to problems.

I think that while she may be bettered by philosophy, it is not good that her daily life is "largely unchanged". A college degree is one of the best paths to upwards social mobility, and a young mother with two children would almost definitely have her life improved from more money. While philosophy undoubtedly helped her develop valuable skills, she may have been more pragmatic by choosing to major in something else, while still taking philosophy classes.

A warm wash comes over the stage, the light is dim but everything can still be seen clearly.

https://www.skyquestt.com/report/business-intelligence-software-market

from - https://hyp.is/-g32gITnEe--sr9oB-mhTg/book.peergos.org/architecture/spec.html?highlight=libp2p

libp2p

from: https://book.peergos.org/architecture/spec.html?highlight=libp2p

The bottom of the first page and the top paragraph of the second page is about how these small crime can get you locked up.

Industralization and basically all the rights of humans being abused at the time. (E.g. hazardous work place)

The Birth of the Working Class

This was done by Otto von Bismark , First Chancellor of Germany

This was especially true in Scotland

peergos book says so

Russell's paradox (1901) in set theory can be stated as:

If $$P$$ is the set of all sets, one can form the set $$Q = {A \in P | A \notin A}$$ which can lead to the contradiction $$Q \in Q$$ iff $$Q \notin Q$$.

This can be done by dividing P into two non-empty subsets, $$P_1 = {A \in p | A \notin A}$$ and $$P_2={A \in P | A \in A}$$. We then have the contradiction $$P_1 \in P_1$$ iff $$P_1 \notin P_1$$.

The paradox happens when we allow as sets A for which $$A \in A$$. It can be remedied by agreeing that no collection can be a set which would be an element of itself.

---

Relation to Groucho Marx's quote (earliest 1949) about resigning membership of a club which would have him as a member: https://hypothes.is/a/3_zAfITjEe-H5-PlfOlK8A

In 1963 Paul Cohen completed the work of Gödel by proving the independence of the axiom of choice and the continuum hypothesis from the Zermelo-Fraenkel set theory axioms. He did this by showing that neither could be deduced from the existing axioms and specifically by showing that the negation of each could be added to ZF consistently.

Gödel's breakthrough in 1940 was to prove that one could extend the axioms of set theory to include the axiom of choice or the continuum hypothesis without introducing contradictions.

Willard, Stephen. General Topology. Addison-Wesley Series in Mathematics. Addison-Wesley Publishing Company, Inc., 1970.

Annotation url: urn:x-pdf:eb874067e68a720ea298d18714fcd41e

Alternate annotations at: https://jonudell.info/h/facet/?user=chrisaldrich&max=100&exactTagSearch=true&expanded=true&url=urn%3Ax-pdf%3Aeb874067e68a720ea298d18714fcd41e

Important tip! Need to remember for exam

The approach benefits those with more resources like college-bound kids from richer home, and disparaging lower-income students by letting students choose their own courses with little or no assistance from counselors. Often advised by informed and involved parents, the children from wealthy homes are better able to negotiate the process and select challenging and interesting courses with tough teachers. Poorer students, especially those from underprivileged "flatland" neighborhoods, are more prone to choose simpler courses or teachers with less demands, therefore reducing their academic development and future possibilities.

I've experienced self-scheduling to a lesser extent. we were allowed to choose elective courses for our next year but we still had our GE courses assigned to us. This process seems unfair to students who have no guidance.

The chapter asks an important question regarding the dichotomy between Berkeley High's progressive values and their contribution in growing the racial achievement gap. The school's structural policies still reflect racial disparities despite the fact it is in a community that values diversity and provides courses in African American studies and ethnic studies. Could it be due to to systematic racism? Or could it be due to cultural and social expectations?

This has always been an issue that has been known. In this diverse society the teachers themselves pick and choose who they want to help out and see succeed. Big public schools have always to be known to segregate people of color because they do not think they have the same capacity as thers to be able to educationally succeed. On the other hand, in a school very diverse majority of the time we all tend to push very hard but because of the feeling of being let down and not having support we tend to slack off and not do the full potential.

My Spanish teacher used an analogy one time about how you have a file cabinet in your brain for language. She said that rather than having multiple files for multiple languages that you should think about it as having one large file that contains all your languages and to not try and think about translating a phrase or sentence from language to another. If you are trying to speak Spanish it is a lot more beneficial to fill in words that you don't know with words you do in English/other languages. She referred to this as "Spanglish" and this is a word that has stuck with me ever since.

I feel like it's really helpful and important to provide students opportunities to display any kind of knowledge that they have mastered. Even beginner conversations like 'como estas' can do a lot for one's confidence. I think once people know they've completed a topic, they realize they have the abilities to understand language and move on to the next.

https://quoteinvestigator.com/2011/04/18/groucho-resigns/

ref: 1949 October 20, Dunkirk Evening Observer, In Hollywood by Erskine Johnson, Page 22, Column 5, Dunkirk, New York. (NewspaperArchive)

Talk about this a lot with teaching piano/ jazz. Learning how to practice/ learn is one of the most beneficial aspects of lessons. Same idea with learning another language

Thinking in this way is beneficial but in reality, most people are past this opportunity. How can we draw from what we gained here to learn more?

rallying americans together to help fight the british and end the kings rein. Oppression has taken over the world, freedom has been expelled from every nation in danger.

Without a ruler, there are no wars. The pride of kings confuses mankind and makes them angry.

The way we started out was as man and women, not kings and subjects. He is critiquing the monarchy by saying that the ruling of the king is unfair and unjust. The king is selfish in the way he puts himself above the rest.

since mankind started out as equal, it is our policies and views of the world that made a difference between rich and poor. Oppression is usually the consequence in our world.

This made me think about how in different languages they have different phrases/words for the sounds that animals make, something that I find really interesting. For example, if I was trying to communicate this way with someone from a Spanish speaking country and I said "bark" trying to explain that I'm looking for a dog, they might be confused because they would say "guau" which means bark/woof. It's just really interesting to me how the sounds that animals make, which is generally universal, are different across languages.

This made me think a lot about the difference that forms of multimodality can make in terms of comprehension in conversations. For example, someone could have a friend that has a history of lying to them but is asking something, promising they can trust them. Although in other circumstances, their behaviors, words, tone, and body language might cause you to fulfill their request, the past actions of this friend can play a huge role in how you intake their communication. Sometimes when people are describing something to set a scene attached to negative emotions or create an image that excites or will make the other person happy, the whole conversation can convince someone of something without even having to really ask.

I think this is why a lot of people struggle to actually learn when only doing something like Duolingo. I've tried that route before, and I barely remember anything that I learned from attempting to learn solely through apps - people overestimate their skills even though they probably have never actually used the language in real life.

I thought that this was a really great analogy. I have never really thought of my brain as a separate entity when "training it," I have never really been conscious of it. If I'm working my body out by doing something like a chest exercise I think about it as training my chest like in the ringmaster example. Training my brain in this same way isn't something I have thought about but this has given me a new perspective and will help me when I'm studying or in any way I'm actively using my brain.

Edits function like Google Doc comments: inline, subtle, like feedback from a friend. Beautiful!

I have and currently struggle with this scenario when it comes to language learning. When I was in Spanish classes and was actively using and practicing everyday I didn't have to think about simple conjugations or when I would use formal/informal language for example. But now since speaking and learning the language is out of my routine I struggle to answer even very basic questions in Spanish. This was very apparent to me when we had to say to people during class in another language. Someone asked me a few very basic questions in Spanish and I had to really stop and think about my answers that I otherwise would have been able to answer immediately if Spanish was still apart of my daily routine.

There's so many little examples of how you need to try and fail in order to learn and master something. School literally exists to learn, which will never be a perfect process, so why would one out of so many classes hold people back. I feel like for me, I'm scared of messing up because language is such an important part of people's cultures and identities.

if philosophy doesnt recognize that these issues are social, it only pokes at the surface level of the issue

Greek influence of not knowing without knowing the essence

Boa tarde autores!

Como o tema me instigou a curiosidade, resolvi tecer algumas sugestões e apontamentos que acredito que possa ser de relevante contribuição. Na introdução foi apresentado um bom panorama sobre o tema, mas poderia ser mais concisa e clara para facilitar a compreensão do leitor. Há alguns pontos que podem ser ajustados para melhorar o fluxo do texto e reduzir a redundância. O texto poderia ser melhor estruturado com parágrafos mais curtos, cada um focando em uma ideia ou tema específico. Isso ajudaria a melhorar a leitura e interpretação. Poderiam também ser utilizadas palavras de transição para melhorar a fluidez entre as ideias. Por exemplo, ao introduzir novos conceitos ou estudos, utilizasse expressões como "Além disso", "Por outro lado", ou "Em contraste". As referências (como “GALLO; WAITT, 2011”) poderiam ser melhor formatadas de forma consistente ao longo do texto. Isso inclui a padronização na citação de autores e datas. Analisando a gramática e a ortografia, por exemplo, "professoras e professores do" deveria ser corrigido para "professoras e professores do". Também poderia remover redundâncias, para evitar repetições desnecessárias de ideias. Por exemplo, a ideia de que "a ciência cidadã é um processo formativo" e "a ciência cidadã exige conscientização" poderia ser consolidada. Nas considerações finais observa-se um resumo detalhado dos resultados, mas poderia ainda ser otimizada para garantir maior clareza e objetividade.

unclear why this is on here, theres no mention of a boat further up, if you want people to know about boat vibes and invite them on, mention it further up, and again, not as a collapsed section.

get a photo of yourself on here?

space man thing doesnt really fit with the image you are going for?

kind of cheesy, im not sure many folk wll get the geocites vibes?

way too much padding.

not really pro?

even more mentions

too whimsey, and too many mentions of this love and peace vibe.

these bits are the main core of your content, expand by default?

too whimsy imho.

feels tacked on, have 2 different pages for events and helping start ups?

doesnt feel in the vibe

put images here ?

not really necc and doesnt say what the site is about

This was fascinating to learn about I never knew there were limitations on the internet at that time. I thought it was anything goes and it’s nice to know that there was some sort of morals and ethics happening.

I remember this time. I had friends that used Blogger and I remember thinking how cool it was to connect and hear what was happening in my friends lives without actually talking to them. It was like getting to hear an unfiltered version of what was happening in their life. At that time I remember not having the patience to read everything and I would just end of calling to talk to my friends.

doesnt sound like you are fun/approchable?

Name the title. What is the humanities.

are

is

is

it

C´est un article sur une érosion de leur autonomie collective, qui demandent cinq: exemple´autonomie du métier, évaluée, le contrôle direct etc.

no more for the common good

extremism became accepted, no moderation. change in rationality, definition

war brings out peeoples gritty natures

the excuse of killing for the nation allowed people to abuse it, kill for any reason was accepted, utter violece agasint eachother

Pelo take Cor ships and return home

C'est une petite magazine Il parle de communication, il aide les enterprises C'est un texte informatif

C'est une petite magazine Il parle de communication, il aide les enterprises C'est un texte informatif

Observation: How the America systems is unfair and display their power and dominates towards minorities through laws, oppression humans and enslaving humans while taking away honest wages etc<br /> Interpretation: Describes the mistreatment in America that Black Americans have to endure while experiencing the oppression, laws being in place towards them that doesn't benefit them but only keep African American oppressed because of laws.

Observation: The heaviness that the slaves felt from being in slavery and wanting justice and being shown mercy and wanted to ask Thomas Jefferson Questions.

Interpretation:This sentence in the letter was describing the emotion that the anonymous slave felt and also others that was slaves which was feeling burden and wanting to seek justice while also want to experience mercy.

Observation: a compass is being used to described the angle of the rivers that is being observed.

Interpretation: observing the rivers while knowing the distance between the two rivers.

Observation: Noticed a letter being written which discuss the waterways on a Friday morning

Interpretation: How Lewis or Clark describe their journey exploring the rivers and observing the trees as well.

• 2015 -> Volkswagen selling diesel cars as environmentally friendly and fuel efficient which caused high levels of air pollution

• Weiwei incident

• Unlike theft, robbery involves stealing a property while a victim is involved, but the distinction is left to the police

• Fraud example -> Scam emails that asks for our personal information

• Another example of fraud is ponzi's scam

• Wayfair was accused of smuggling children and selling them on the market, but it's not grounded in credible evidence

• 2020

• Happened for the protection of sex workers, but forced them to go to underground sex-work

• Prevented easier screener in part of the sex worker

• Eg. Chemical dependency, grooming through a false sense of love and obligation, etc.

• Exploits the human need for connection, even when there's exploitation and abuse involved

• Stockholm syndrome -> Captive develops a bond with their captor as a defense mechanism under extreme defense

• Trafficking involves trafficking transporting people to another country without their consent, for the purpose of forcing them to be involved in sex trades or in forced labour

• What, why, and how are the three elements of human trafficking

• Smuggling involves transporting people to another country consensuallly, often by means of coercion and deception.

• Smuggling victims are often involved due to unsafe environments in their home country and seeking a better help elsewhere

• Engaging in collective behavior for mutual benefit
• Eg. Challenger Explosion in 1986 ->

• Perpetrated by the government, individuals in the government, or an individual in the government
• Eg. War crimes Real life example: Residential schools of Canada
• State crimes occur mostly for money

• Business-relate crime such as stealing money from employer -> Embezzlement
• Eg. Ponzi scheme -> Taking advantage of people in what seems to be a legitimate business

• Group of organization or individuals in that organization engages in illegal acts
• Eg. bribing, insider trading
• Real life example: Jordan Belfort who commited stock price fixing

this is crazy! Charleigh practice annotate

woop woop it works

Case: patient is named case #2, male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Hyperammonemia (HP:0001987), oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), neonatal onset(HP:0003623), Hyperglutaminemia (HP:0003217)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA was isolated from lymphocytes. To examine the small mutations in the coding region of the OTC gene, all 10 exons and their flanking intron regions were amplified using PCR, and the nucleotide sequences of the amplified products were determined. To determine the intron 5 sequence of case 2, PCR was performed using primers OTCex5F and OTCint5R, and primers OTCint5F and OTCex6R (Table 1, Fig. 3). The amplified products were subcloned into the pT7 vector and the inserted DNA was sequenced using an automated DNA sequencer. Allopurinol test

Supplemental Data: TABLE 1, Notes:

Variant: NM_000531.6: c.540+265G>A

ClinVarID: NA

CAID: CA658658977

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Reviewer #2 (Public review):

Goldstein et al. provide a thorough characterization of the interaction of attention and eye movement planning. These processes have been thought to be intertwined since at least the development of the Premotor Theory of Attention in 1987, and their relationship has been a continual source of debate and research for decades. Here, Goldstein et al. capitalize on their novel urgent saccade task to dissociate the effects of endogenous and exogenous attention on saccades towards and away from the cue. They find that attention and eye movements are, to some extent, linked to one another but that this link is transient and depends on the nature of the task. A primary strength of the work is that the researchers are able to carefully measure the time course of the interaction between attention and eye movements in various well-controlled experimental conditions. As a result, the behavioral interplay of two forms of attention (endogenous and exogenous) are illustrated at the level of tens of milliseconds as they interact with the planning and execution of saccades towards and away from the cued location. Overall, the results allow the authors to make meaningful claims about the time course of visual behavior, attention, and the potential neural mechanisms at a timescale relevant to everyday human behavior.

Reviewer #3 (Public review):

The present study used an experimental procedure involving time-pressure for responding, in order to uncover how the control of saccades by exogenous and endogenous attention unfolds over time. The findings of the study indicate that saccade planning is influenced by the locus of endogenous attention, but that this influence was short-lasting and could be overcome quickly. Taken together, the present findings reveal new dynamics between endogenous attention and eye movement control and lead the way for studying them using experiments under time-pressure.

The results achieved by the present study advance our understanding of vision, eye movements, and their control by brain mechanisms for attention. In addition, they demonstrate how tasks involving time-pressure can be used to study the dynamics of cognitive processes. Therefore, the present study seems highly important not only for vision science, but also for psychology, (cognitive) neuroscience, and related research fields in general.

I think the authors' addressed all of the reviewers' points successfully and in detail, so that I don't have any further suggestions or comments.

Author response:

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

Reviewer #1 (Public Review):

The main research question could be defined more clearly. In the abstract and at some points throughout the manuscript, the authors indicate that the main purpose of the study was to assess whether the allocation of endogenous attention requires saccade planning [e.g., ll.3-5 or ll.247-248]. While the data show a coupling between endogenous attention and saccades, they do not point to a specific direction of this coupling (i.e., whether endogenous attention is necessary to successfully execute a saccade plan or whether a saccade plan necessarily accompanies endogenous attention).

Thanks for the suggestion. We have modified the text in the abstract and at various points in the text to make it more clear that the study investigates the relationship between attention and saccades in one particular direction, first attentional deployment and then saccade planning.

Some of the analyses were performed only on subgroups of the participants. The reporting of these subgroup analyses is transparent and data from all participants are reported in the supplementary figures. Still, these subgroup analyses may make the data appear more consistent, compared to when data is considered across all participants. For instance, the exogenous capture in Experiments 1 and 2 appears much weaker in Figure 2 (subgroup) than Figure S3 (all participants). Moreover, because different subgroups were used for different analyses, it is often difficult to follow and evaluate the results. For instance, the tachometric curves in Figure 2 (see also Figure 3 and 4) show no motor bias towards the cue (i.e., performance was at ~50% for rPTs <75 ms). I assume that the subsequent analyses of the motor bias were based on a very different subgroup. In fact, based on Figure S2, it seems that the motor bias was predominantly seen in the unreliable participants. Therefore, I often found the figures that were based on data across all participants (Figures 7 and S3) more informative to evaluate the overall pattern of results.

Indeed, our intent was to dissociate the effects on saccade bias and timing as clearly as possible, even if that meant having to parse the data into subgroups of participants for different analyses. We do think conceptually this is the better strategy, because the bias and timing effects were distinct and not strongly correlated with specific participants or task variants. For instance, the unreliable participants were somewhat more consistently biased in the same direction, but the reliable participants also showed substantial biases, so the difference in magnitude was relatively modest. This can be more easily appreciated now that the reliable and unreliable participants are indicated in Figures 3 and 5. The impact of the bias is also discussed further in the last paragraphs of the Results, which note that the bias was not a reliable predictor of overall success during informed choices.

Reviewer #3 (Public Review):

(1) In this experimental paradigm, participants must decide where to saccade based on the color of the cue in the visual periphery (they should have made a prosaccade toward a green cue and an antisaccade away from a magenta cue). Thus, irrespective of whether the cue signaled that a prosaccade or an antisaccade was to be made, the identity of the cue was always essential for the task (as the authors explain on p. 5, lines 129-138). Also, the location where the cue appeared was blocked, and thus known to the participants in advance, so that endogenous attention could be directed to the cue at the beginning of a trial (e.g., p. 5, lines 129-132). These aspects of the experimental paradigm differ from the classic prosaccade/antisaccade paradigm (e.g. Antoniades et al., 2013, Vision Research). In the classic paradigm, the identity of the cues does not have to be distinguished to solve the task, since there is only one stimulus that should be looked at (prosaccade) or away from (antisaccade), and whether a prosaccade or antisaccade was required is constant across a block of trials. Thus, in contrast to the present paradigm, in the classic paradigm, the participants do not know where the cue is about to appear, but they know whether to perform a prosaccade or an antisaccade based on the location of the cue.

The present paradigm keeps the location of the cue constant in a block of trials by intention, because this ensures that endogenous attention is allocated to its location and is not overpowered by the exogenous capture of attention that would happen when a single stimulus appeared abruptly in the visual field. Thus, the reason for keeping the location of the cue constant seems convincing. However, I wondered what consequences the constant location would have for the task representations that persist across the task and govern how attention is allocated. In the classic paradigm, there is always a single stimulus that captures attention exogenously (as it appears abruptly). In a prosaccade block, participants can prioritize the visual transient caused by the stimulus, and follow it with a saccade to its coordinates. In an antisaccade block, following the transient with a saccade would always be wrong, so that participants could try to suppress the attention capture by the transient, and base their saccade on the coordinates of the opposite location. Thus, in prosaccade and antisaccade blocks, the task representations controlling how visual transients are processed to perform the task differ. In the present task, prosaccades and antisaccades cannot be distinguished by the visual transients. Thus, such a situation could favor endogenous attention and increase its influence on saccade planning, even though saccade planning under more naturalistic conditions would be dominated by visual transients. I suggest discussing how this (and vice versa the emphasis on visual transients in the classic paradigm) could affect the generality of the presented findings (e.g., how does this relate to the interpretation that saccade plans are obligatorily coupled to endogenous attention? See, Results, p. 10, lines 306-308, see also Deubel & Schneider, 1996, Vision Research).

Great discussion point. There are indeed many ways to set up an experiment where one must either look to a relevant cue or look away from it. Furthermore, it is also possible to arrange an experiment where the behavior is essentially identical to that in the classic antisaccade task without ever introducing the idea of looking away from something (Oor et al., 2023). More important than the specific task instructions or the structure of the event sequence, we think the fundamental factors that determine behavior in all of these cases are the magnitudes of the resulting exogenous and endogenous signals, and whether they are aligned or misaligned. Under urgent conditions, consideration of these elements and their relevant time scales explains behavior in a wide variety of tasks (see Salinas and Stanford, 2021). Furthermore, a recent study (Zhu et al., 2024) showed that the activation patterns of neurons in monkey prefrontal cortex during the antisaccade task can be accurately predicted from their stimulus- and saccade-related responses during a simpler task (a memory guided saccade task). This lends credence to the idea that, at the circuit level, the qualities that are critical for target selection and oculomotor performance are the relative strengths of the exogenous and endogenous signals, and their alignment in space and time. If we understand what those signals are, then it no longer matters how they were generated. The Discussion now includes a paragraph on this issue.

(2) Discussion (p. 16, lines 472-475): The authors suppose that "It is as if the exogenous response was automatically followed by a motor bias in the opposite direction. Perhaps the oculomotor circuitry is such that an exogenous signal can rapidly trigger a saccade, but if it does not, then the corresponding motor plan is rapidly suppressed regardless of anything else.". I think this interesting point should be discussed in more detail. Could it also be that instead of suppression, other currently active motor plans were enhanced? Would this involve attention? Some attention models assume that attention works by distributing available (neuronal) processing resources (e.g., Desimone & Duncan, 1995, Annual Review of Neuroscience; Bundesen, 1990, Psychological Review; Bundesen et al., 2005, Psychological Review) so that the information receiving the largest share of resources results in perception and is used for action, but this happens without the active suppression of information.

The rebound seen after the exogenously driven changes is certainly interesting, and we agree that it could involve not only the suppression of a specific motor plan but also enhancement of another (opposite) plan. However, we think that, given the lack of prior data with the requisite temporal precision, further elaboration of this point would just be too speculative in the context of the point that we are trying to make, which is simply that the underlying choice dynamics are more rapid and intricate than is generally appreciated.

(3) Methods, p. 19, lines 593-596: It is reported that saccades were scored based on their direction. I think more information should be provided to understand which eye movements entered the analysis. Was there a criterion for saccade amplitude? I think it would be very helpful to provide data on the distributions of saccade amplitudes or on their accuracy (e.g. average distance from target) or reliability (e.g. standard deviation of landing points). Also, it is reported that some data was excluded from the analysis, and I suggest reporting how much of the data was excluded. Was the exclusion of the data related to whether participants were "reliable" or "unreliable" performers?

The reported results are based on all saccades (detected according to a velocity threshold) that were produced after the go signal and in a predominantly horizontal direction (within ± 60° of the cue or non-cue), which were the vast majority (> 99%). Indeed, most saccades were directed to the choice targets, with 95% of them within ± 14.2° of the horizontal plane. The excluded (non-scored) trials were primarily fixation breaks plus a small fraction of trials with blinks, which compromised saccade determination. There was no explicit amplitude criterion; applying one (for instance, excluding any saccades with amplitude < 2°) produced minimal changes to the data. Overall, saccade amplitudes were distributed unimodally with a median of 7.7° and a 95% confidence interval of [3.7°, 9.7°], whereas the choice targets were located at ± 8° horizontally. This is now reported in the Methods.

As far as data exclusion, analyses were based on urgent trials (gap > 0); non-urgent (gap < 0) trials were excluded from calculation of the tachometric curves simply because they might correspond to a slightly different regime (go signal after cue onset) and to long processing times in the asymptotic range (rPT in 200–300 ms) or beyond, which are not as informative. However, including them made no appreciable difference to the results. No data were excluded based on participant performance or identity; all psychometric analyses were carried out after the selection of trials based on the scoring criteria described above. This is now stated in the Methods.

(4) Results, p. 9, lines 262-266: Some data analyses are performed on a subset of participants that met certain performance criteria. The reasons for this data selection seem convincing (e.g. to ensure empirical curves were not flat, line 264). Nevertheless, I suggest to explain and justify this step in more detail. In addition, if not all participants achieved an acceptable performance and data quality, this could also speak to the experimental task and its difficulty. Thus, I suggest discussing the potential implications of this, in particular, how this could affect the studied mechanisms, and whether it could limit the presented findings to a special group within the studied population.

The ideal (i.e., best) analysis for determining the cost of an antisaccade for each individual participant (Fig. 4c) was based on curve fitting and required task performance to rise consistently above chance at long rPTs in both pro and anti trials. This is why the mentioned conditions on the fits were imposed. This is now explained in the text. This ideal analysis was not viable for all tachometric curves not necessarily because of task difficulty but also because of high variability or high bias in a particular experiment/condition. It is true that the task was somewhat difficult, but this manifested in various ways across the dataset, so attempting to draw a clean-cut classification of participants based on “difficulty” may not be easy or all that informative (as can be gleaned from Fig. S1). There simply was a range of success levels, as one might expect from any task that requires some nontrivial cognitive processing. Also note that no participants were excluded flat out from analysis. Thus, at the mentioned point in the text, we simply note that a complementary analysis is presented later that includes all participants and all conditions and provides a highly consistent result (namely, Fig. 7e). Then, in the last section of the Results, where Fig. 7 is presented, we point out that there is considerable variance in performance at long rPTs, and that it relates to both the bias and the difficulty of the task across participants.   

Reviewer #1 (Recommendations For The Authors):

(1) I have some questions related to the initial motor bias:

a) Based on Figure S3, which shows the tachometric curves using data from all participants, there only seems to be a systematic motor bias in Experiments 1 and 3 but no bias in Experiments 2 and 4. It is unclear to me why this is different from the data shown in Figure 7.

For the bars in Fig. 7, accuracy (% correct) was computed for each participant and then averaged across participants, whereas for the data in Fig. S3, trials were first pooled across participants and then accuracy was computed for each rPT bin. The different averaging methods produce slightly different results because some participants had more trials in the guessing range than others, and different biases.  

b) Based on Figure 7 (and Figure S3), there was no motor bias in Experiment 4. Based on the correlations between motor bias and time difference between pro and antisaccades, I would expect that the rise points between pro and antisaccades would be more similar in this Experiment. Was this the case?

No. Figs. 3c and S3d show that the rise times of pro and anti trials for Experiment 4 still differ by about 30 ms (around the 75% correct mark), and the rest of the panels in those figures show that the difference is similar for all experiments. What happens is that Figs. 7 and S3 show that on average the bias is zero for Experiment 4, but that does not mean that the average difference in rise times is zero because there is an offset in the data (correlation is not the same as regression). The most relevant evidence is in Fig. 6c, which shows that, for an overall bias of zero, one would still expect a positive difference in rise times of about 25–30 ms. This figure now includes a regression line, and the corresponding text now explains the relationship between bias and rise times more clearly. Thanks for asking; this is an important point that was not sufficiently elaborated before.

c) If I understand correctly, the initial motor bias was predominantly observed in participants who were classified as 'unreliable performers' (comparing Figure S2 and Figure 2). Was there a correlation between the motor bias and overall success in the task? In other words: Was a strong motor bias generally disadvantageous?

Good question. Participants classified as ‘unreliable’ were somewhat more consistently biased in the same direction than those classified as ‘reliable’, but the distinction in magnitude was not large. This can be better appreciated now in Fig. 5 by noting the mix of black (reliable) and gray labels (unreliable) along the x axes. The unreliable participants were also, by definition, less accurate in their asymptotic performance in at least one experiment (Fig. S1). In general, however, this classification was used simply to distinguish more clearly the two main effects in the data (timing cost and bias). In fact, the motor bias was not a reliable predictor of performance during informed choices: across all participants, the mean accuracy in the asymptotic range (rPT > 200 ms) had a weak, non-significant correlation with the bias (ρ = ‒0.07, p = 0.7). So, no, the motor bias did not incur an obvious disadvantage in terms of overall success in the task. Its more relevant effect was the asymmetry in performance that it promoted between pro- and antisaccade trials (Fig. 6c). This is now explained at the end of the Results.

(2) One of the key analyses of the current study is the comparison of the rPT required to make informed pro and antisaccades (ll.246 ff). I think it would be informative for readers to see the results of this analysis separately for all four experiments. For instance, based on Figure 4a and b, it looks like the rise points were actually very similar between pro and antisaccades in Experiment 1.

We agree that the ideal analysis would be to compute the performance rise point for pro- and antisaccade curves for each experiment and each participant, but as is now noted in the text, this requires a steady and substantial rise in the tachometric curve, which is not always obtained at such a fine-grained level; the underlying variability can be glimpsed from the individual points in Fig. 7a, b. Indeed, in Fig. 4a, b the mean difference between pro and anti rise points appears small for Experiment 1 — but note that the two panels include data from only partially overlapping sets of participants; the figure legend now makes this more clear. Again, this is because the required fitting procedure was not always reliable in both conditions (pro and anti) for a given subject in a given experiment. Thus, panels a and b cannot be directly compared. The key results are those in Fig. 4c, which compare the rise points in the two conditions for the same participants (11 of them, for which both rise points could be reliably determined). In that case the mean difference is evident, and the individual effect consistent for 9 of the 11 participants (as now noted).

A similar comparison for Experiments 1 or 2 individually would include fewer data points and lose statistical power. However, on average, the results for Experiments 1 and 2 (separately) were indeed very similar; in both cases, the comparison between pro and anti curves pooled across the same qualifying participants as in Fig. 4c produced results that were nearly identical to those of Fig. 4d (as can be inferred from Fig. 2a, b). Furthermore, results for the four individual experiments pooled across all participants are presented in Figure S3, which shows delayed rises in antisaccade performance consistent with the single participant data (Fig. 4c).

(3) Figure 3: It would be helpful to indicate the reliable performers that were used for Figure 3a in the bar plots in Figure 3b. Same for Figures 3c and d.

Done. Thanks for the suggestion.

(4) Introduction: The literature on the link between covert attention and directional biases in microsaccades seems relevant in the context of the current study (e.g., Hafed et al., 2002, Vision Res; Engbert & Kliegl, 2003, Vision Res; Willett & Mayo, 2023, Proc Natl Acad Sci USA).

Yes, thanks for the suggestion. The introduction now mentions the link between attentional allocation and microsaccade production.

(5) ll.395ff & Figure 7f: Please clarify whether data were pooled across all four experiments for this analysis.

Yes, the data were pooled, but a positive trend was observed for each of the four experiments individually. This is now stated.

(6) ll.432-433: There is evidence that the attentional locus and the actual saccade endpoint can also be dissociated (e.g., Wollenberg et al., 2018, PLoS Biol; Hanning et al., 2019, Proc Natl Acad Sci USA).

True. We have rephrased accordingly. Thanks for the correction.

(7) ll.438-440: This sentence is difficult to parse.

Fixed.

Reviewer #2 (Recommendations For The Authors):

The manuscript is well-written and compelling. The biggest issue for me was keeping track of the specifics of the individual experiments. I think some small efforts to reinforce those details along the way would help the reader. For example, in the Figure 3 figure legend, I found the parenthetical phrase "high luminence cue, low luminence non-cue)" immensely helpful. It would be helpful and trivial to add the corresponding phrase after "Experiment 4" in the same legend.

Thanks for the suggestion. Legends and/or labels have been expanded accordingly in this and other figures.

Line 314: "..had any effect on performance,..." Should there be a callout to Figure 2 here?

Done.

It wasn't clear to me why the specific high and low luminance values (48 and 0.25) were chosen. I assume there was at least some quick perceptual assessment. If that's the case or if the values were taken from prior work, please include that information.

Done.

Reviewer #3 (Recommendations For The Authors):

Minor points. Please note that the comments made in the public review above are not repeated here.

(1) Introduction, p. 2, lines 41-45: It is mentioned that the effects of covert attention or a saccade can be quite distinct. I suggest specifying in what way.

Done.

(2) Introduction, p. 2, lines 46-47: It is said that the relation between attention and saccade planning was still uncertain and then it is stressed that this was the case for more natural viewing conditions. However, the discussed literature and the experimental approach of the current study still rely on experimental paradigms that are far from natural viewing conditions. Thus, I suggest either discussing the link between these paradigms and natural viewing in more detail or leaving out the reference to natural viewing at this point (I think the latter suggestion would fit the present paper best).

We followed the latter suggestion.

(3) Introduction (e.g. p. 3, lines 55-58): The authors discuss the effects that sustaining fixation might have on attention and eye movements. Recently, it has been found that maintaining fixation can ameliorate cognitive conflicts that involve spatial attention (Krause & Poth, 2023, iScience). It seems interesting to include this finding in the discussion, because it supports the authors' view that it is necessary to study fixation and eye movements rather than eye movements alone to uncover their interplay with attention and decision-making.

Thanks for the reference. The reported finding is certainly interesting, but we find it somewhat tangential to the specific point we make about strong fixation constraints — which is that they suppress internally driven motor activity, including biases, that are highly informative of the relationship between attention and saccade planning (lines 466‒472, 541‒561). Whether fixation state has other subtle consequences for cognitive control is an intriguing, important issue, for sure. But we would rather maintain the readers’ focus on the reasons why less restrictive fixation requirements are relevant for understanding the deployment of attention.

(4) Results, p. 9, lines 264-266: It is reported that "The rise points were statistically the same across experiments for both prosaccades (p=0.08, n=10, permutation test)...", but the p-value seems quite close to significance. I suggest mentioning this and phrasing the sentence a bit more carefully.

We now refer to the rise points as “similar”.

(5) Figure 7 a-d: It might help readers who first skim through the figures before reading the text to use other labels for the bins on the x-axis that spell out the name of the phase in the trial. It might also help to visualize the bins on the plot of a tachymetric function (in this case, changing the labels could be unnecessary).

Thanks for the suggestion. We added an insert to the figure to indicate the correspondence between labels and time bins more intuitively.

(6) Methods, p. 18, lines 566-567: On some trials, participants received an auditory beep as a feedback stimulus. As this could induce a burst of arousal, I wondered how it affected the subsequent trials.

This is an interesting issue to ponder. We agree that, in principle, the beep could have an impact on arousal. However, what exactly would be predicted as a consequence? The absence of a beep is meant to increase the urgency of the participant, so some effect of the beep event on RT would be expected anyway as per task instructions. Thus, it is unclear whether an arousal contribution could be isolated from other confounds. That said, three observations suggest that, at most, an independent arousal effect would be very small. First, we have performed multisensory experiments (unpublished) with auditory and visual stimuli, and have found that it is difficult to obtain a measurable effect of sound on an urgent visual choice task unless the experimental conditions are particularly conducive; namely, when the visual stimuli are dim and the sound is loud and lateralized. None of these conditions applies to the standard feedback beep. Second, because most trials are on time, the meaningful feedback signal is conveyed by the absence of the beep. But this signal to alter behavior (i.e., respond sooner) has zero intensity and is therefore unlikely to trigger a strong exogenous, automatic response. Finally, in our data, we can parse the trials that followed a beep (the majority) from those that did not (a minority). In doing so, we found no differences with respect to perceptual performance; only minor differences in RT that were identical for pro- and antisaccade trials. All this suggests to us that it is very unlikely that the feedback alters arousal significantly on specific trials, somehow impacting the tachometric curve (a contribution to general arousal across blocks or sessions is possible, of course, but would be of little consequence to the aims of the study).

(7) Methods, p. 18, lines 574-577: I suggest referring to the colors or the conditions in the text as it was done in the experiments, just to prevent readers being confused before reading the methods.

We appreciate the thought, but think that the study is easier to understand by pretending, initially, that the color assignments were fixed. This is a harmless simplification. Mentioning the actual color assignments early on would be potentially more confusing and make the description of the task longer and more contrived.

(8) Methods, p. 18, Table 1: Given that the authors had a spectrophotometer, I suggest providing (approximate) measurements for the stimulus colors in addition to the luminance (i.e. not just RGB values).

Unfortunately, we have since switched the monitor in our setup, so we don’t have the exact color measurements for the stimuli used at the time. We will keep the suggestion in mind for future studies though.

References

Oor EE, Stanford TR, Salinas E (2023) Stimulus salience conflicts and colludes with endogenous goals during urgent choices. iScience 26:106253.

Salinas E, Stanford TR (2021) Under time pressure, the exogenous modulation of saccade plans is ubiquitous, intricate, and lawful. Curr Opin Neurobiol 70:154-162.

Zhu J, Zhou XM, Constantinidis C, Salinas E, Stanford TR (2024) Parallel signatures of cognitive maturation in primate antisaccade performance and prefrontal activity. iScience.  doi: https://doi.org/10.1016/j.isci.2024.110488.

Interesting that backpropagation really is just the chain rule over and over again. I wonder why it took us so long to realize the strengths of DL.

It's interesting that you do not see many Taylor series approaches in the context of deep neural networks. The idea that you can create nonlinear decision boundaries with nested perceptrons, but we do not use Taylor series, which appear powerful enough to do that too is interesting. Is it computational limits?

like observing the glacier collapse/melting at certain point that no one would expect to happen

key points

It's quite like the process of scholars doing research since we all are supposed to conduct our own research on the basis of preexisting findings. That's exactly why we want to do literature review.

issue of bias

Welcome back.

In this lesson, I'll be talking about Network Address Translation, or NAT, a process of giving a private resource outgoing only access to the internet.

And a NAT gateway is the AWS implementation that's available within WPC.

There's quite a bit of theory to cover, so let's get started.

So what is NAT?

Well, it stands for Network Address Translation.

This is one of those terms which means more than people think that it does.

In a strict sense, it's a set of different processes which can adjust ID packets by changing their source or destination IP addresses.

Now, you've seen a form of this already.

The internet gateway actually performs a type of NAT known as static NAT.

It's how a resource can be allocated with a public IP version for address, and then when the packets of data leave those resources and pass through the internet gateway, it adjusts the source IP address on the packet from the private address to the public, and then sends the packet on, and then when the packet returns, it adjusts the destination address from the public IP address to the original private address.

That's called static NAT, and that's how the internet gateway implements public IP version for addressing.

Now, what most people think of when they think of NAT is a subset of NAT called IP Masquerading.

And IP Masquerading hides a whole private side IP block behind a single public IP.

So rather than the one private IP to one public IP process that the internet gateway does, NAT is many private IPs to one single IP.

And this technique is popular because IP version 4 addresses are running out.

The public address space is rapidly becoming exhausted.

IP Masquerading, or what we'll refer to for the rest of this lesson as NAT, gives a whole private range of IP addresses outgoing only access to the public internet and the AWS public zone.

I've highlighted outgoing because that's the most important part, because many private IPs use a single public IP.

Incoming access doesn't work.

Private devices that use NAT can initiate outgoing connections to internet or AWS public space services, and those connections can receive response data, but you cannot initiate connections from the public internet to these private IP addresses when NAT is used.

It doesn't work that way.

Now, AWS has two ways that it can provide NAT services.

Historically, you could use an EC2 instance configured to provide NAT, but it's also a managed service, the NAT gateway, which you can provision in the VPC to provide the same functionality.

So let's look at how this works architecturally.

This is a simplified version of the Animals for Life architecture that we've been using so far.

On the left is an application tier subnet in blue, and it's using the IP range 10.16.32.0/20.

So this is a private only subnet.

Inside it are three instances, I01, which is using the IP 10.16.32.10, I02, which is using 32.20, and I03, which is using 32.30.

These IP addresses are private, so they're not publicly routable.

They cannot communicate with the public internet or the AWS public zone services.

These addresses cannot be routed across a public style network.

Now, if we wanted this to be allowed, if we wanted these instances to perform certain activities using public networking, for example, software updates, how would we do it?

Well, we could make the subnet's public in the same way that we've done with the public subnets or the web subnets, but we might not want to do that architecturally.

With this multi-tier architecture that we're implementing together, part of the design logic is to have tiers which aren't public and aren't accessible from the public internet.

Now, we could also host some kind of software update server inside the VPC, and some businesses choose to do that.

Some businesses run Windows update services, all Linux update services inside their private network, but that comes with an admin overhead.

NAT offers us a third option, and it works really well in this style of situation.

We provision a NAT gateway into a public subnet, and remember, the public subnet allows us to use public IP addresses.

The public subnet has a route table attached to it, which provides default IP version 4 routes pointing at the internet gateway.

So, because the NAT gateway is located in this public web subnet, it has a public IP which is routable across the public internet, so it's now able to send data out and get data back in return.

Now, the private subnet where the instances are located can also have its own route table, and this route table can be different than the public subnet route table.

So, we could configure it so that the route table that's on the application subnet has a default IP version 4 route, but this time, instead of pointing at the internet gateway, like the web subnet users, we configure this private route table so that it points at the NAT gateway.

This means when those instances are sending any data to any IP addresses that do not belong inside the VPC, by default, this default route will be used, and that traffic will get sent to the NAT gateway.

So, let's have a look at how this packet flow works.

Let's simulate the flow packets from one of the private instances and see what the NAT gateway actually does.

So, first, instance 1 generates some data.

Let's assume that it's looking for software updates.

So, this packet has a source IP address of instance 1's private IP and a destination of 1.3.3.7.

For this example, let's assume that that's a software update server.

Now, because we have this default route on the route table of the application subnet, that packet is routed through to the NAT gateway.

The NAT gateway makes a record of the data packet.

It stores the destination that the packet is for, the source address of the instance sending it, and other details which help it identify the specific communication in future.

Remember, multiple instances can be communicating at once, and for each instance, it could be having multiple conversations with different public internet hosts.

So, the NAT gateway needs to be able to uniquely identify those.

So, it records the IP addresses involved, the source and destination, the port numbers, everything it needs, into a translation table.

So, the NAT gateway maintains something called a translation table which records all of this information.

And then, it adjusts the packet to the one that's been sent by the instance, and it changes the source address of this IP packet to be its own source address.

Now, if this NAT appliance were anywhere for AWS, what it would do right now is adjust the packet with a public routable address. - Hi. - Let's do this directly.

But remember, all the inside of the IPC really has directly attached to it a public IP version 4 address.

That's what the internet gateway does.

So, the NAT gateway, because it's in the web subnet, it has a default route, and this default route points at the internet gateway.

And so, the packet is moved from the NAT gateway to the internet gateway by the IPC router.

At this point, the internet gateway knows that this packet is from the NAT gateway.

It knows that the NAT gateway has a public IP version 4 address associated with it, and so, it modifies the packet to have a source address of the NAT gateway's public address, and it sends it on its way.

The NAT gateway's job is to allow multiple private IP addresses to masquerade behind the IP address that it has.

That's where the term IP masquerading comes from.

That's why it's more accurate.

So, the NAT gateway takes all of the incoming packets from all of the instances that it's managing, and it records all the information about the communication.

It takes those packets, it changes the source address from being those instances to its own IP address, its own external-facing IP address.

If it was outside AWS, this would be a public address directly.

That's how your internet router works for your home network.

All of the devices internally on your network talk out using one external IP address, your home router uses NAT.

But because it's in AWS, it doesn't have directly attached a real public IP.

The internet gateway translates from its IP address to the associated public one.

So, that's how the flow works.

If you need to give an instance its own public IP version for address, then only the internet gateway is required.

If you want to give private instances outgoing access to the internet and the AWS public services such as S3, then you need both the NAT gateway to do this many-to-one translation and the internet gateway to translate from the IP of the NAT gateway to a real public IP version for address.

Now, let's quickly run through some of the key facts for the NAT gateway product that you'll be implementing in the next demo lesson.

First, and I hope this is logical for you by now, it needs to run from a public subnet because it needs to be able to be assigned a public IP version for IP address for itself.

So, to deploy a NAT gateway, you already need your VPC in a position where it has public subnets.

And for that, you need an internet gateway, subnets configured to allocate public IP version for addresses and default routes for those subnets pointing at the internet gateway.

Now, a NAT gateway actually uses a special type of public IP version for address that we haven't covered yet called an elastic IP.

For now, just know that these are IP version for addresses, which is static.

They don't change.

These IP addresses are allocated to your account in a region and they can be used for whatever you want until you reallocate them.

And NAT gateways use these elastic IPs, the one service which utilizes elastic IPs.

Now, they're talking about elastic IPs later on in the course.

Now, NAT gateways are an AZ resilient service.

If you read the AWS documentation, you might get the impression that they're fully resilient in a region like an internet gateway.

They're not, they're resilient in the AZ that they're in.

So they can recover from hardware failure inside an AZ.

But if an AZ entirely fails, then the NAT gateway will also fail.

For a fully region resilient service, so to mirror the high availability provided by an internet gateway, then you need to deploy one NAT gateway in each AZ that you're using in the VPC and then have a route table for private subnets in that availability zone, pointing at the NAT gateway also in that availability zone.

So for every availability zone that you use, you need one NAT gateway and one route table pointing at that NAT gateway.

Now, they aren't super expensive, but it can get costly if you have lots of availability zones, which is why it's important to always think about your VPC design.

Now, NAT gateways are a managed service.

You deploy them and AWS handle everything else.

They can scale to 45 gigabits per second in bandwidth and you can always deploy multiple NAT gateways and split your subnets across multiple provision products.

If you need more bandwidth, you can just deploy more NAT gateways.

For example, you could split heavy consumers across two different subnets in the same AZ, have two NAT gateways in the same AZ and just route each of those subnets to a different NAT gateway and that would quickly allow you to double your available bandwidth.

With NAT gateways, you'll build based on the number that you have.

So there's a standard hourly charge for running a NAT gateway and this is obviously subject to change in a different region, but it's currently about four cents per hour.

And note, this is actually an hourly charge.

So partial hours are billed as full hours.

And there's also a data processing charge.

So that's the same amount as the hourly charge around four cents currently per gigabyte of processed data.

So you've got this base charge that a NAT gateway consumes while running plus a charge based on the amount of data that you process.

So keep both of those things in mind for any NAT gateway related questions in the exam.

Don't focus on the actual values, just focus on the fact they have two charging elements.

Okay, so this is the end of part one of this lesson.

It's getting a little bit on the long side, and so I wanted to add a break.

It's an opportunity just to take a rest or grab a coffee.

Part two will be continuing immediately from the end of part one.

So go ahead, complete the video, and when you're ready, join me in part two.