Even in the western tradition, the earliest methods of mnemonics tied ideas to locations, from whence we get the ideas of loci communes (in Latin) and thence commonplaces and commonplace books. The idea of loci communes was koinos topos in Greek from whence we have derived the word 'topic'.

Was this a carryover from other local oral traditions or a new innovation? Given the prevalence of very similar Indigenous methods around the world, it was assuredly not an innovation. Perhaps it was a rediscovery after the loss of some of these traditions locally in societies that were less reliant on orality and moving towards more reliance on literacy for their memories.

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

Some timber circle sites to look into: - Secotan in North Carolina circa 1585 - Poverty Point - Hopewell timber circles (Moorehead Circle and Stubbs Earthworks) in Ohio - Cahokia

Artist, illustrator and mapmaker John White painted a watercolor in July 1585 of a group of Native Americans in the Secotan village in North America. Both he and chronicler Thomas Harriot described a gathering of Indigenous peoples gathered in the Algonquian village as part of Sir Walter Raleigh's Roanoke Colony expedition. They describe a festival with participants holding a dance at a timber circle, the posts of which were carved with with faces.

Harriot wrote that participants had come from surrounding villages and that "every man attyred in the most strange fashion they can devise havinge certayne marks on the backs to declare of what place they bee."

This evidence would generally support some of Lynne Kelly's thesis in Knowledge and Power. A group of neighboring peoples gathering, possibly for the Green Corn Ceremony, ostensibly to strengthen social ties and potentially to strengthen and trade knowledge.

Would we also see others of her list of markers in the area?

Read references: - Daniels, Dennis F. "John White". NCpedia. Retrieved 2017-12-19. - Tucker, Abigal (December 2008). "Sketching the Earliest Views of the New World". Smithsonian Magazine. Retrieved 2017-12-19. - "A Selection of John White's Watercolors : A festive dance". Encyclopedia Virginia. Retrieved 2017-12-19.

Mahase, E. (2022). Covid-19: Is the UK heading for another omicron wave? BMJ, 376, o738. https://doi.org/10.1136/bmj.o738

Discussion, revision and decision

Decision - Verified with reservations

Charles A. Schumpert: Verified manuscript

Max Shokhirev: Verified with reservations

Author response and revisions

Author response to reviewer Max Shokhirev

Dear Dr Shokhirev,

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

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

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

Are the conclusions adequately supported by the results? No

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

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

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

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

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

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

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

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

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

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

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

Section 1.4

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Section 2.3

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

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

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

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

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

Section 2.5-2.9,3

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

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

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

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

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

Reviewer response

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

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

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

Author response to reviewer Charles A. Schumpert

Dear Dr Schumpert,

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

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

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

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

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

personal trust networks - a part of personal learning networks? the internal and the external benefit are no longer seperatable - one always comes together with the other

Are these graphic and memorable stories strikingly similar because of the underlying packages of orality and memory used in these cultures?

This is one of my primary motivations for reading this text.

Indigenous sciences are highly interconnected while Western sciences tend to be highly sub-divided into ever smaller specializations.

Are Indigenous sciences naturally interconnected or do they form that way because of the associative memory underlying the cultural orality by which they are formed and transmitted? (I would suspect so, but don't yet have the experience to say definitively. Evidence for this should be collected.)

Lorenzo Nigro indicates that the "kothon" of Motya in southern Sicily was a pool of Baal whose surface may have been used to observe and map the stars. He also indicates that the Phoenicians adored the stars potentially as gods or deceased ancestors. This is an example of a potentially false assumption often seen in archaeology of Western practitioners misconstruing Indigenous practices based on modern ideas of religion and culture.

I might posit that this sort of practice is more akin to that of the science of Indigenous peoples who used oral and mnemonic methods in combination with remembering their histories and ancestors.

Cross reference this with coming reading in The First Astronomers (to come) which may treat this in more depth.

Leonardo da Vinci documented the attributes of standing water for studying the night sky.

Where was this and what did it actually entail?

In 1998, Ben Shneiderman wrote "The danger of working at "internet time" is that hasty decisions may be poor, and rapid changes may cause troubling turbulence for many users." He's essentially admonishing against the dangerous and anti-social idea of what Mark Zuckerberg would later encourage at Facebook when he said "move fast and break things."

The idea that refinement is a social process is a powerful one, but it is limited by the society's power structures, scale, and access to the original material and least powerful person's ability to help refine it.

Nice that he takes this sort of inclusive approach so early in the evolution of the internet.

https://vi.to/hubs/micro-camp-march-2022/pages/micro-camp-march-2022-town-hall-mp4?sidebar=shown&v=%2Fvideos%2F4859

==>l’échantillon de l’étude est est extrêmement limité, l’étude n’est pas répliqué et elle ne permet pas de retirer de résultats concluants

Kill two birds with one stone.

Reichel, C. (2022, March 1). Please Keep Your Masks On. Bill of Health. http://blog.petrieflom.law.harvard.edu/2022/02/28/please-keep-your-masks-on/

Wu, K. J. (2021, December 1). What J&J Can Still Teach Us. The Atlantic. https://www.theatlantic.com/science/archive/2021/12/vaccine-durability-annual-covid-boosters/620863/

An economic diversion of this scale would make it far more likely that humanity will not be able to prevent, but indeed accelerate planetary tipping points! Hence the urgency of this crisis for the climate movement. This implies that the climate movement and the antiwar movement must now synchronize resources and form a coherent, unified strategy

Ideas fill their spaces.

When writing it can be daunting to see a long blank screen and feel like you've got to fill it up with ideas de novo.

From the other perspective if you're starting with a smaller space like a Twitter input box or index card you may find that you write too much and require the ability to edit things down to fit the sparse space.

I do quite like the small space provided by Hypothes.is which has the ability to expand and scroll as you write so that it has the Goldilocks feel of not too small, not too big, but "just right".

Micro.blog has a feature that starts with a box that can grow with the content. Once going past 280 characters it also adds an optional input box to give the post a title if one wants it to be an article rather than a simple note.

Link to idea of Occamy from the movie Fantastic Beasts and Where to Find Them that can grow or shrink to fit the available space: https://harrypotter.fandom.com/wiki/Occamy

Each highlighted statement expresses political talking points aligned to induce trump-like support.

Trump introduced new marketing and strategy, formulated using concepts and metrics mastered by Reality TV and Hollywood and then paired with advertising propaganda and "selling" techniques to create a "Brand". This is after-all Donald Trump, this is what he does, has done and is the only way he has found to make money. Trump built the "brand" (just barely) while teetering on self destruction.

His charismatic persona became "the glue" that allowed creative narratives to stick to certain types of people in-spite of risk. Trump learned OTJ how to capture a specific type of audience.

The mistake people make about Trump is assuming his audience to be "Joe Six-Pack", redneck's with limited education! This assumption does not have merit on its own.<br /> * There is a common "follower" theme among his audience that is exploited by those who: * Bought the "licensing rights" to the master-class Trump "how-to" course.

... assuming you're a Rubyist and you have gem and ruby installed.

Inasaridze, K. (2022). COVID-19-related symptoms’ assessment tool. PsyArXiv. https://doi.org/10.31234/osf.io/wf8rv

https://apnews.com/article/ketanji-brown-jackson-supreme-court-whats-next-bf806d8993ffd585a6ed8166d235990a

Google translation:

9/8g The Zettelkasten technique is based on experience: You can't think without writing—at least not in contexts that require selective access to memory.

That also means: you can't think without notching differences.

There's something interesting about the translation here of "notching" occurring on an index card about ideas which can be linked to the early computer science version of edge-notched cards. Could this have been a subtle and tangential reference to just this sort of computing?

The idea isn't new to me, but in the last phrase Luhmann tangentially highlights the value of the zettelkasten for more easily and directly comparing and contrasting the ideas on two different cards which might be either linked or juxtaposed.

Link to:

• Graeber and Wengrow ideas of storytelling

• Shield of Achilles and ekphrasis thesis

• https://hypothes.is/a/I-VY-HyfEeyjIC_pm7NF7Q With the further context of the full quote including "with selective access to memory" Luhmann seemed to at least to make space (if not give a tacit nod?) to oral traditions which had methods for access to memories in ways that modern literates don't typically give any credit at all. Johannes F.K .Schmidt certainly didn't and actively erased it in Niklas Luhmann’s Card Index: The Fabrication of Serendipity.

https://www.ifthencollection.org/

https://threadreaderapp.com/thread/1494369809538195456.html

Link to : https://fivethirtyeight.com/features/universities-say-they-want-more-diverse-faculties-so-why-is-academia-still-so-white/

https://www.baltimoresun.com/opinion/editorial/bs-ed-0220-sun-racial-reckoning-apology-online-20220218-qp32uybk5bgqrcnd732aicrouu-story.html

The Baltimore Sun begins grappling with its dark history.

Boundary work is the practice of a group that sets the rules to determine who is and isn't good enough to join the group.

Link to Groucho Marx quote, "I refuse to join any club that would have me as a member."

Can symbol that represents one thing change over a long period of time to mean something different?

Why was the apple chosen as the representation of temptation?

A Theory of signs and symbols that deals especially with there function in both artificially constructed and natural languages.

Brief description of what the LARA system does.

https://www.unige.ch/callector/lara

example: https://www.issco.unige.ch/en/research/projects/callector/le_petit_prince_abc2vocabpages/hyperlinked_text.html

https://threadreaderapp.com/thread/1494102154839306240.html

On Yale not giving tenure to Michael W. Kraus...

Disagree. Sounds plenty bad.

I think that making sure the apps and website we use are accessible to everyone is really important. I liked how this reading broke down the different levels in terms language accessibility and internet access. Sometimes I think teachers can overlook that aspect and accidentally have students trailing behind.

Dame Adjin-Tettey, T. (2022). Combating fake news, disinformation, and misinformation: Experimental evidence for media literacy education. Cogent Arts & Humanities, 9(1), 2037229. https://doi.org/10.1080/23311983.2022.2037229

It's interesting to see how far back exaggeration in the media has been a relevant thing. Today we have different social media sites, blogs, and podcasts, etc. that modernly display "yellow journalism", and that's just something that I thought wasn't a thing during the 1800s and 1900s.

I think that it's very interesting how a drawing/cartoon can be so powerful and have such an impact that it brings upon changes.

By its own definition, insight cannot be forced, much less forced in a particular direction.

Let's be honest that there are certainly methods for doing all of this within our brains and not needing to rely on external structures. This being said, using writing, literacy, and external structures does allow us to process things faster than before.

Can we calculate what the level of greater efficiency allows for doing this? What is the overall throughput difference in being able to forget and write? Not rely on communication with others? What does a back of the envelope calculation for this look like?

Prof. Akiko Iwasaki. (2022, January 27). Vaccines that reduce infection & disease are needed to combat the pandemic. Here, @tianyangmao @BenIsraelow et al. Describe our new mucosal booster strategy, Prime and Spike, to induce such immunity via nasal delivery of unadjuvanted spike vaccine 🧵 (1/) https://biorxiv.org/content/10.1101/2022.01.24.477597v1 https://t.co/bcB5MFph9F [Tweet]. @VirusesImmunity. https://twitter.com/VirusesImmunity/status/1486510697332842498

If house flipping is viewed as a driver of inequality in crowded housing markets in larger cities, what spurs it on? What do the economics look like and how can the trend be combatted?

What effect does economic speculation have?

Have they considered consolidation? Abandon three or four cities to aggregate into one?

This sounds great, but what are the "costs" on the other side? How does one balance out the economics of this sort of housing situation versus amenities supplied by a community in terms of culture, health, health care, interaction, etc.? Is there a maximum on a curve to be found here? Certainly in some places one is going to overpay for this basket of goods (perhaps San Francisco?) where in others one may underpay. Does it have anything to do with the lifecycle of cities and their governments? If so, how much?

US government moves to end daily COVID-19 death reporting by hospitals. (n.d.). World Socialist Web Site. Retrieved February 2, 2022, from https://www.wsws.org/en/articles/2022/01/15/hhhs-j15.html

Overall the webpage is clean and uncluddered. A user can view each section in th order. Allowing for efficient keyboard navigation.

Highlighting this, but really the whole section is almost perfectly written. Hardest is achieving your desired inner discipline and then having to fight with people who don't understand this shit (because their performance never matters, or they don't give a damn).

Tech solutionism is the presumption that technology (usually by itself) can fix a variety of social, cultural, and structural problems.

It fits into a category of problem that when one's tool is a hammer then every problem looks like a nail.

Many tech solutionism problems are likely ill-defined to begin with. Many are also incredibly complex and difficult which also tends to encourage bikeshedding, which is unlikely to lead us to appropriate solutions.

Discussion, revision and decision

Discussion and Revision

Author

Reviewer 1 (Takehiko Ogawa, Yokohama City University, ogawa@yokohama-cu.ac.jp ):

We had already suggested in the "Limitations" section on page 10 of the manuscript-PDF testis transplantation experiments to test biological functionality for future studies: https://www.biorxiv.org/content/10.1101/2021.10.12.464060v1.full.pdf

However, these experiments will require new cell lines, new funding, more resources, more logistics, and new ethics approval which we are considering for future studies. We believe that the observations described in our manuscript are valuable to the scientific community and are a basis to conduct further studies.

Reviewer 2 (Dr. Pradeep G Kumar, Rajiv Gandhi Centre for Biotechnology, and kumarp@rgcb.res.in )

There are no line numbers in the manuscript-PDF but the pages are numbered: https://www.biorxiv.org/content/10.1101/2021.10.12.464060v1.full.pdf Since the pages of the manuscript-PDF are numbered, we think that citation of the manuscript is unproblematic. The text of the manuscript has been checked by multiple experienced authors and found not to require the suggested changes.

Reviewer (Takehiko Ogawa)

I think that authors admit the limit of the study, which I think is serious. I think the paper has its own value with limitation as almost always in most cases. I would like to take “verified with reservation” as my final decision.

Decision

Takehiko Ogawa: Verified with reservations

Pradeep G Kumar: Verified manuscript

Verified with reservations

Discussion, revision and decision

Revision

The research question of this article is not clear enough, and this paper is more like a report than a research paper. Since a lot of research about retraction haven been published, many characteristics of retraction have been analysed. There seem not enough new messages comes from this article.

The objective of the paper was not to address a research question but to report on a more recent set of PubMed retractions due to insufficient/old information available in the papers published on this subject(PubMed, not WoS retracted articles). One of the initial objectives was to analyze the dynamic of image related retractions(a relatively new subject), a subject for which the information is at least scarce if non existing. We have also studied the impact of retracted research via two citations databases (Google Scholar and Dimensions) and tried to represent the variability of this impact when the author country is being considered. At this time, the paper is the second biggest serie of PubMed retracted articles.

In addition, as ‘exploratory research’ defined by the title, the use of full data for analysis is more in line with the objectives of the title, instead of excluding other disciplines and restricting the analysis to human health. If the author’s goal is to analyse the characteristics of human health-related retractions, it is recommended to limit it in the title. The current topic is too general.*

There was an error from our part, thank you very much for pointing this.

It is recommended that the author properly point out what have and haven’t been done in this topic, and their specific contribution to the existing knowledge, so as to show the innovation of the research.*

We have revised the article and added the informations related to previous research on this subject. Thank you so much for this suggestion.

Discussion, revision and decision

Discussion and Revision

Author response

We would like to thank the reviewers for their valuable comments. Below we provide pointwise response and the changes made in the revised manuscript.

To Dr. Jyotsnamayee Sabat

Pt-13: I want to know how the representative sequences were selected for different states. Is it based on no. of sequences submitted or positivity rate of a particular region?

All the Indian isolates available in GISAID for the period 27th Jan – 27th May 2020 were download and considered for analysis. NO state-wise selection was done.

To Dr Parvin Abraham

Pt-12: The dataset is only from 27th Jan – 27th May 2020. Maybe they can include more Numbers.

The period of data collection was restricted to 27th Jan – 27th May 2020 to basically understand the variations observed across different states of the country during the early phase of pandemic. Also, we are interested in assessing the impact of lockdown in containing the spread of COVID19 and state-specific subclusters, if any.

To Hurng-Yi Wang:

Pt-13: Agarwal and Parekh analyzed 685 SARS-CoV-2 isolates collected during 27th Jan - 27th May 2020 from India and described the distribution of virus strains and mutations across the country. While the information might be valuable to some local readers, the results are mainly descriptive and the data are a bit out of date. In addition, I have the following comments.

The period of data collection is restricted to 27th Jan – 27th May 2020 to basically understand the variations observed across different states of the country during the early phase of pandemic. Also, we are interested in assessing the impact of lockdown in containing the spread of COVID19 and state-specific subclusters, if any.

1. Some details of the methods are lacking. For example, the MUpro provides two methods, it is necessary to specify which method was used in the analysis. The confidence score of each prediction should also be provided. Besides, some results from I-Mutant and MUpro were conflicting, the authors may want to discuss the discrepancy.

   In the revised manuscript we give the sign of DDG predicted using the tools I-Mutant2.0 and the MUpro along with the respective confidence scores. In I-Mutant2.0, the sign of protein stability change predicted and reliability index (which provides confidence to the prediction) are now incorporated in Table-1. Similarly, the sign change and confidence scores given by MUpro on using SVM and NN based models have been incorporated. We expect all the models to give same results, except in cases where the predictions may be hard to make. This has now been explicitly mentioned in the Materials and Methods section: “In I-Mutant2.0, the sign of DDG is based on SVM classifier, and the associated confidence score is given by the reliability index. On the other hand, MUpro provides sign change prediction using two models, one SVM-based and the other using Neural Networks. InTable-1, the predicted sign of DDG by I-Mutant2.0 and MuPRO along with the respective confidence scores is reported.”

2. The “Analysis of the Mutational Profile of Indian Isolates” should be moved to Materials and Methods.

   There indeed was some redundancy in the information available in the Materials and Methods section and in the section “Analysis of the Mutational Profile of Indian Isolates”. We have now edited the Materials and Methods section appropriately and deleted the para under the above- mentioned section.

3. The authors provided lengthy discussion about the effect of each mutation in some lineages, such as 20A and I/A3i. However, as these mutations are tightly linked, the effect of each individual mutation is difficult to access. It is possible that some of the mutations are just hitchhikers. They may want to address this alternative point.

   For 20A we define the haplotype comprising four co-occurring mutations D614G, C241T, C3037T, and C14408T. Similarly, six co-occurring mutations C6312A, C13730T, C23929T, C28311T, C6310A (S2015R) and C19524T are shown to be associated with subclade I/A3i. Together as a set, these are useful in identifying clusters or group of isolates with similar mutational profile. However, those that are non-synonymous mutations are likely to have some individual impact on the overall stability of the respective protein. And so, we have presented both these results. To address this point, we have added a sentence at the end of Materials and Methods section and is reproduced below: “While we report individual effects of mutations on protein stability, some of the mutations in a haplotype may not be under natural selection and are just hitchhiking mutations.”

4. Several figures are confusing and lack detail. The diversity plots of Figure 3 and Figure 8 are hard to be precisely compared to the mutations that occurred among different plots. Phylogenetic trees, as well as their figure legends, are confusing, especially Figure 9 and Figure 10. For Figure 9, it is impossible to tell which mutation site had changed from C to T. For Figure 10, spots depicted in yellow are both position 29827 A>T and position 29830 G>T, green spot only notes as G, but A29827 is not mentioned in the figure. Furthermore, the mutation position of blue spot C cannot be found.

   We have now redrawn the diversity plots in Figure 3 and Figure 8, (labelled Figure 2 and Figure 4, respectively, in the revised manuscript) and are shown below. We have introduced horizontal lines to show the height of the divergence line at variant positions discussed in the manuscript, and these are also marked with the same colour in corresponding subplots for comparison.

In the revised manuscript, Figures 9 and 10 are now Supplementary Figures 2c and 2d respectively. The new figure legends are: Supplementary Figure 2: The sequences carrying the mutations a) C5700A b) C23929T c) C18877T d) G29830T are depicted in yellow colour. Figure 10 (now Supplementary Figure 2(d)) is now re-plotted, and we have removed the blue dot corresponding to ‘C’ since no samples from India had this variation.

1. Figure 9 and Figure 10 were not mentioned inside the text.

   It has now been added in the manuscript: Supplementary Figure 2(c) – On Pg-9, in the first line under the heading “Identification of novel subclade I/GJ-20A and unique mutations in Maharashtra”. Supplementary Figure 2(d) – On Pg-11, in the last paragraph under the heading “Identification of novel subclade I/GJ-20A and unique mutations in Maharashtra”.

2. The Top 10 mutations in PCA analysis are the mutations in 20A and I/A3i. It is reasonable to observed a clear association of the clusters with the clades. It is not clear, however, how these distribution correlate with lockdown, contact tracing and quarantine measures.

   From Supplementary Figure 1 clade 20A (shown in ‘Green’) is predominantly observed in Gujarat (178/201) and the distribution of clade 19A (shown in ‘Blue’) is high in Telangana (75/97), followed by Delhi (55/76), Maharashtra (31/80), and Tamil Nadu (19/34). Four mutations, C6312A, C13730T, C23929T, and C28311T are reported to be associated with subclade I/A3i, which is India-specific subclade of 19A. These co-occurring mutations are found in ~32% of Indian samples sequenced (till 31st May 2020). Only 5 isolates of this subclade were observed after May in India with the last one dated 13th June 2020 (according to data available in Nextstrain). This indicates that the spread of subclade I/A3i had been largely contained during lockdown with efforts of contact tracing and quarantining the infected individuals. Also, Telangana and Delhi isolates cluster together due to shared I/A3i mutations, primarily due to the Tablighi Jamaat congregation that occurred just before lockdown was announced. Similarly, clade 20A defining mutations were observed to occur in ~ 90% of Gujarat samples. Due to the countrywide lockdown from 25th March 2020, this clade and its sub-clusters were localized in the state, defined by Gujarat-specific mutations, e.g., I/GJ-20A.

Hurng-Yi Wang:

I agree to change to Verified manuscript.

Decision

Verified manuscript

Dr. Abraham: Verified manuscript

Dr. Sabat: Verified manuscript

Dr. Wang: Verified manuscript

https://people.com/tv/main-characters-in-satc-revival-and-just-like-that-are-same-age-as-the-golden-girls/

https://www.nytimes.com/2022/01/19/style/andre-leon-talley-dead.html

Foolish constraint.

Serwer, A. (2022, January 14). The Culture War Has Warped the Supreme Court’s Judgment. The Atlantic. https://www.theatlantic.com/ideas/archive/2022/01/biden-worker-vaccine-mandate-scotus-osha-standard/621249/

Nash, D. (n.d.). The CDC Got Lost Trying to Follow the Science. Retrieved January 14, 2022, from https://www.barrons.com/articles/cdc-guidance-covid-isolation-pandemic-51641847943

CDC studies confirm mask-wearing in schools reduces spread of COVID-19. (2021, September 27). New Atlas. https://newatlas.com/health-wellbeing/cdc-mask-mandate-children-schools-coronavirus-effective/

https://www.ft.com/content/83a14261-598d-4601-87fc-5dde528b33d0

Almost like saying that "man cannot live by bread alone"...

Every element receives its value based on the network of links and connections it has with other elements. This is just as true for ideas on index cards in a zettelkasten as it is for people within a society.

idea/index card:zettelkasten :: person:society

What other elements in complex systems is this analogy true for? Is it a truism for all elements in complex systems? What other examples can we come up with?

Continuing on the analogy between addresses for zettels/index cards and for people, the differing contexts for cards and ideas is similar to the multiple different publics in which people operate (home, work, school, church, etc.)

Having these multiple publics creates a variety of cross links within various networks for people which makes their internal knowledge and relationships more valuable.

As societies grow the number of potential interconnections grows as well. Compounding things the society doesn't grow as a homogeneous whole but smaller sub-groups appear creating new and different publics for each member of the society. This is sure to create a much larger and much more complex system. Perhaps it's part of the beneficial piece of the human limit of memory of inter-personal connections (the Dunbar number) means that instead of spending time linearly with those physically closest to us, we travel further out into other spheres and by doing so, we dramatically increase the complexity of our societies.

Does this level of complexity change for oral societies in pre-agrarian contexts?

What would this look like mathematically and combinatorially? How does this effect the size and complexity of the system?

How can we connect this to Stuart Kauffman's ideas on complexity? (Picking up a single thread creates a network by itself...)

Definitely worth keeping in mind, even for my own work. Providing an evidential structure for claims will be paramount.

Is there a well-named cognitive bias for the human tendency to see everything as nails when one has a hammer in their hand?

There is certainly social lubrication of visiting people from time to time which can help and advance societies, but this regular visiting can also be seen as a means of reinforcing one's oral cultural history through spaced repetition.

It can be seen as "trade" but in a way that anthropologists have generally ignored for lack of imagination for what may have been actually happening.

Is it also possible that these items may have served the purpose of mnemonic devices as a means of transporting (otherwise invisible) information from one area or culture to another?

Can we build evidence for this from the archaeological record?

Relate this to the idea of expanding the traditional "land, labor, capital" theory of economics to include "information" as a basic building block

Compare this with the Indigenous idea of Skywoman in the opening chapter of Braiding Sweetgrass: Indigenous Wisdom, Scientific Knowledge, and the Teachings of Plants by Robin Wall Kimmerer, which tells a dramatically different story.

medical and dental tourism

Reviewed Work: Knowledge and Power in Prehistoric Societies: Orality, Memory, and the Transmission of Culture by LYNNE KELLY Review by: Asa R. https://www.jstor.org/stable/26337970

The imagery of exploration and sea travel was a popular subject in the literature of the Elizabethan-Jacobean era. It was the Age of Discovery, and John Donne himself also had experience in sea travel. The heroic adventure stories of the people who fulfilled the Renaissance curiosity through their expedition were fascinating enough to stir the imagination of the writers of the time.

Exploration is a process of understanding a wider world, but Speaker is no more interested in it since he has already found the perfect world in his little room with his lover.

In Galen's medicine, disease and death were the consequence of a disproportion in one's constituent elements, the 4 humors: black bile, yellow bile, blood, and phlegm.

https://blog.nationalmuseum.ch/en/2021/11/birth-of-the-gods/

This is a good example of the default "ancestor worship" and "rituals" label on archeological finds of ancient peoples

What is the actual basis for assigning these labels? Is there any real evidence or is it just become the default in the literature.

Personally I'm building evidence towards a more comprehensive thesis for what these practices may have been used for.

There are alternative models to global capitalism to rapid scaling, and a lot more equitable. Elore cosmolocal production: https://clreader.net/. This model could disrupt the Speed and Scale model.

https://www.kron4.com/news/bay-area/car-broken-into-with-family-members-toddlers-inside-near-san-franciscos-lombard-street/

Garrido-Vásquez, P., & Rock, T. (2021). Judgments of truth are independently modulated by affect and repetition. PsyArXiv. https://doi.org/10.31234/osf.io/qajkb

Classroom carbon dioxide levels three times above guidelines. (2021, November 26). https://schoolsweek.co.uk/classroom-carbon-dioxide-levels-three-times-above-watchdog-guidelines/

FDA authorizes Pfizer-BioNTech, Moderna boosters for all adults. (2021). Washington Post. Retrieved November 22, 2021, from https://www.washingtonpost.com/health/2021/11/19/fda-clears-pfizer-biontech-moderna-booster-shots-all-adults/

Rappelle certains points du rapport Éduquer au numérique.

Puis, lien possible aux collègues des collèges, via Una Daly (CCCOER): https://hyp.is/LydNYEfpEey9gTODlHd8XQ/oer.pressbooks.pub/oeg2021/chapter/english/

The current incarnation of the tutorial (https://raw.githubusercontent.com/akkartik/mu/7195a5e88e7657b380c0b410c8701792a5ebad72/tutorial/index.md) starts by describing "Prerequisites[:] You will need[...]", and then goes on to list several things, including various software packages—assuming a Linux system, etc.

This is the idea I'm trying to get across with the self-containedness I've been pursuing (if not with triple scripts then at least with LP docs).

That prerequisites list should be able to replace with two requirements, i.e.:

"You will need: (1) this document, and (2) the ability to read it (assuming you have an appropriate viewer [which in 2021 is nowhere close to the kind of ask of the old world])"

"burden"

well-being of all. On the other side was another woman with a garden and a tree. But for tasting its fruit, she was banished from the garden and the gates clanged shut behind her. That mother of men was made to wander in the wilderness and earn her bread by the sweat of her brow, not by filling her mouth with the sweet juicy fruits that bend the branches low. In order to eat, she was instructed to subdue the wilder-ness into which she was cast.

Its amazing how two origin stories with such similarities lead us to such different cultures and civilizations. The founder effects can be incredibly powerful.

The Western word "ceremony" is certainly not the best word for describing these traditions. It has too much baggage and hidden meaning with religious overtones. It's a close-enough word to convey some meaning to those who don't have the cultural background to understand the underlying orality and memory culture. It is one of those words that gets "lost in translation" because of the dramatic differences in culture and contextual collapse.

Most Western-based anthropology presumes a Western idea of "religion" and impinges it upon oral cultures. I would maintain that what we would call their "religion" is really an oral-based mnemonic tradition that creates the power of their culture through knowledge. The West mistakes this for superstitious religious practices, but primarily because we can't see (or have never been shown) the larger structures behind what is going on. Our hubris and lack of respect (the evils of the scala naturae) has prevented us from listening and gaining entrance to this knowledge.

I think that the archaeological ideas of cultish practices or ritual and religion are all more likely better viewed as oral practices of mnemonic tradition. To see this more easily compare the Western idea of the memory palace with the Australian indigenous idea of songline.

Fauci, A. (2021). Victories against AIDS have lessons for COVID-19. Nature, 600(7887), 9–9. https://doi.org/10.1038/d41586-021-03569-1

Kit Yates. (2021, November 26). European centres for disease prevention and control has designated B.1.1.259 as a variant of concern. Fast work. Https://t.co/f6JiWVvjJC [Tweet]. @Kit_Yates_Maths. https://twitter.com/Kit_Yates_Maths/status/1464285136137170947

Include this in a comparative analysis of other methodologies such as Hoornweg, Hachaichi, R3.0 Thresholds and Allocations, etc.

Rhodes, E. (2021, September 10). “We need to flex our mental and emotional muscles outside the point of desperation” | The Psychologist. https://thepsychologist.bps.org.uk/we-need-flex-our-mental-and-emotional-muscles-outside-point-desperation