PCSY-D-23-00009

Rules, hypergraphs, and probabilities: the three-level analysis of chemical reaction systems and other stochastic stoichiometric population processes

PLOS Complex Systems

Dear Dr. Smith,

Thank you for submitting your manuscript to PLOS Complex Systems. After careful consideration, we feel that it has merit but does not fully meet PLOS Complex Systems's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

While the journal accepts manuscripts of any length, we encourage you to present and discuss your findings concisely. The paper is extremely long, which would reduce readership if accepted at this length.

Please submit your revised manuscript within 60 days Jul 20 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at complexsystems@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcsy/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Wilson Wen Bin Goh, PhD

Academic Editor

PLOS Complex Systems

Journal Requirements:

1. We ask that a manuscript source file is provided at Revision. Please upload your manuscript file as a .doc, .docx, .rtf or .tex.

Additional Editor Comments (if provided):

Overall, reviewers have provided favorable feedback. Nonetheless, the manuscript's extensive length has raised concerns among multiple reviewers. I encourage you to revise the paper, aiming to meet the journal's length requirements while enhancing conciseness and addressing reviewer comments.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does this manuscript meet PLOS Complex Systems’s publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: N/A

Reviewer #3: N/A

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3. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Complex Systems does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall, this is an interesting contribution that provides a fairly

comprehensive theory of a large class of population-based model that

includes in particular chemical reaction networks. The sheer length of the

manuscript might be a frightening, but the breadth of the material,

covering both flows and proabilities and their relationship to rule based

formulations of the model itself probably does not lend itself to a much

shorter presentation. The detailed descriptions of application examples,

mostly taken from metabolism, are certainly helpful to understand the

material. In summary, I recommend publication, with a few cosmetic changes

that the authors can be trusted to perform without the need for re-review.

I did not find any errors in the mathematical derivations.

Occasionally, e.g. (22) I'm not sure whether formal results are really new

or whether they parallel observations that were made in previous work in

a more restricted setting.

Minor

Abs I'm not sure I understand what exactly

"most potentially combinatorial reaction systems used by biochemistry"

means.

209. The explanation "stoichiometric, meaning that (...) some set is

removed (...) and some other set is added (...)" appears a bit

vague. The term "stoichiometric" usually seems to imply that

something [mass, net composition] is conserved during this

replacement.

325. What is the notational difference between \\sim and \\approx?

611. $\\alpha_k$ instead $\\alpha^k$ in (26) ?

624. Notation is confusing here. It seems you mean something different

here with the i\\in{1,2} then the i in the reaction (ij). Also why

\\alpha^k versus \\alpha_k in l.613 ? (Use \\alpha_k^+, \\alpha_k^- ?)

641. Capitalization on headings?

826. What is a supporting graph?

836. Am I supposed to reads this with precedence rules of

"multiplications" before "sums", i.e., as (2 AlKe) + (PHL . AL) ?

Is this going to be some algebraic structure that I should care

about, or just some convenient shorthand notation?

1143. I can't parse the meaning of the section heading 1. Hartely ...

1153. provide*s* a

1363. what exactly is the '--> above SS' supposed to mean

mathematically? Is this a limit ?

1792. it seem you are using Einstein sum convention from here on, but only

explain this in 1814. (97)

1888. f_i instead of fi and appendix C. The notation fi looks awkward.

2382 (E2) you probably mean H3PO4 as in (E1)

2383 (E3) typeseetting of H3PO4

Reviewer #2: In this manuscript, the authors develop a theoretical framework to study the functional analysis and evolution of combinatorial chemical reaction networks. The authors categorize this framework into three layers and elaborate on the meaning and mechanism of each layer. In particular, the authors apply frontier mathematical theories to chemical research and achieve very rich results, which is rare in chemical research. This kind of research, which fully combines mathematical and chemical mechanisms, is very novel and interesting. I think this article can be accepted by PLOS Complex Systems, but of course, some problems should be noticed.

1. The theoretical framework presented by the authors is ponderous and it may be very helpful for the reader to understand the authors' work if the authors could provide a schematic diagram.

2. The authors have given very informative theoretical results which have been verified by a biological sugar-phosphate chemical model. We are more interested in whether this theory has practical significance. It would be helpful to verify the authors' theoretical results if they could provide some experimental data as an aid or illustrate them with the help of existing experimental results.

3. The form of references is not uniform; some journal titles are presented in abbreviated form and some do not take this form.

Reviewer #3: The manuscript is a long, but interesting description of a set of analytical and computational approaches to describe arbitrary biochemical networks.

What makes this manuscript quite fascinating is the multitude of links towards adjacent concepts and formalisms.

The interplay of the three levels is interesting and well described. The authors distinguish between the abstract rules, the formal models of these rules and the explicit stochastic processes yielding trajectories in state space. This formal distinction has some advantages, as the authors can illustrate, how choices on one level affect the others.

Some of the links to adjacent fields (and extensions of the core formalism the authors present) are, however, not really brought to practical applications (or at least discussed in the context of their relevance for understanding biochemical, metabolic systems), which, for the reader, creates the unfortunate impression to plow through a vast book-keeping exercise.

From my perspective, for a journal like PLOS Complex Systems striving for article-type submissions, the manuscript is too long by a factor of 8-10 (the submitted pdf has 160 pages!). It should be shortened substantially before publication.

Should the authors wish to keep the manuscript at this length, I wonder, whether a journal like Physics Reports is the better choice.

A few additional points:

(1) The application examples are very instructive and I can imagine researchers invested in these metabolic subsystems to benefit from this discussion. These examples should be the core of a shortened manuscript.

(2) I am wondering, to which extend these considerations are already covered by the rich formalism of metabolic control analysis (MCA). In fact, some aspects of what is discussed throughout the manuscript remind me of summation theorems and connectivity theorems. Similarly to the research agenda of the manuscript, MCA has the goal of relating the local features of metabolic systems (as captured, e.g., by elasticities) to the global features (as given by control coefficients).

(3) In spite of its considerable length the manuscript relies heavily on jargon only specialists in that domain are likely to understand. This is not a good strategy for a journal, as PLOS Complex System, which aims at communicating principles of complex systems to a broader scientific community.

Summarizing, in its present form I suggest rejection of the manuscript. I would be happy, though, to re-review a substantially shortened, more concise and less jargon-ridden version of the manuscript.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Rules, hypergraphs, and probabilities: the three-level analysis of chemical reaction systems and other stochastic stoichiometric population processes

PCSY-D-23-00009R1

Dear Dr. Smith,

We are pleased to inform you that your manuscript 'Rules, hypergraphs, and probabilities: the three-level analysis of chemical reaction systems and other stochastic stoichiometric population processes' has been provisionally accepted for publication in PLOS Complex Systems.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow-up email from a member of our team. 

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact complexsystems@plos.org.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Complex Systems.

Best regards,

Luis M. Rocha, Ph.D.

Section Editor

PLOS Complex Systems

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Reviewer Comments (if any, and for reference):

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

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2. Does this manuscript meet PLOS Complex Systems's publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #3: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #3: I don't know

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4. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Complex Systems does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have extensively rewritten the text, mostly in compliance with another reviewer's comments on the overall length of the manuscript. I'm not convinced that the current variant - with most of the technical point moved to appendices - really makes the manuscript better or easier to comprehend. I'm not going to the ask the authors to revert to previous format in the interest of convergence. My specific comments have been addresses and I did not spot any new technical problems. Also, I found the reply letter convincing.

Reviewer #3: Structural changes of the manuscript have been essentially the transfer of material to the appendices. In line numbers (which do not count equations and figures) this reads as follows:

In the previous version:

main text ends at: 2053

appendices start at: 2054

appendices end at: 2816

In the current version:

main text ends at: 1237

appendices start at: 1238

appendices end at: 2722

I still believe that the length of the manuscript is prohibitive, but this is up to the editor to decide (and hence my formal decision of 'reject', which the editor should override in case they think differently about this point). I still see a journal like Physics Reports as the better choice of a manuscript of this length.

Regarding my comment about metabolic control analysis, the authors adequately incorporated a discussion of this approach in their manuscript.

Regarding my suggestions to build a shorter manuscript around specific applications to make the material more tangible, the authors prefer to do this in follow-up publications.

I also acknowledge the author's effort to make the main text clearer with the more jargon-ridden parts being confined to the appendices.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

Do you want your identity to be public for this peer review? If you choose “no”, your identity will remain anonymous but your review may still be made public.

For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

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