Dear Dr. Gelens,

Thank you very much for submitting your manuscript "Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

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Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Attila Csikász-Nagy

Associate Editor

PLOS Computational Biology

Mark Alber

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: This is nice work that is entirely suitable for publication in PLoS Comp Biol.

The authors have already made most of the changes that I recommended in an earlier review of the paper for a different journal.

A necessary revision: the authors should create a table that lists all the parameter values used in the calculations in the figures. For example, I wanted to check Fig. 3, and it took me a little bit of trial-and-error to figure out the parameter values used for the model in this figure.

An optional revision: In the Discussion, the authors say "It would be valuable to study a model of the form... Eq. (7)". They don't have to put this off to a future publication, because they are already set up to do so using the two-param bifurcation diagram in Fig 3D. In the attached file, I present an implementation of Eq. (7) that produces limit cycle oscillations. When XT(t) and a(t) are projected onto Fig. 3D, the limit cycle sweeps diagonally across the bistable domain (the blue region), alternately flipping X(t) into the high and low states of the bistable switch. It would be a nice example of how to analyze a system with time-scale separations.

Reviewer #2: The idea presented in this manuscript is very interesting, but I think it can be improved:

- The introduction is broad and it doesn't focus on the main ideas stated in the abstract. It would be nicer to have more details about dynamical stability than explain bistable switches in the cell cycle... which they have been broadly covered.

- At the end of section 2.1, there is explained that the NEBD is another example, but it is not supported by any analysis or bibliography covering the dynamical changes on bistable switches when including NEBD.

- Fig 2C. It is difficult to follow together with the description in the main test. It would be nice to have some kind of guidance when walking through the different plots within the test. Besides, the colours are misleading, as one can think that blue curve is the complex cycB-CDK1 and Cdc25 is red (based on the diagram on Fig 2A). Choose another colour scheme would be helpful .

- Section 2.2. seems completely irrelevant for the purpose of the manuscript. The system explained here can de added into the next 2 sections, as it seems to be the original work described in the manuscript.

- Apart from section 2.1, there is no extra connection with cell cycle, either in the switches or the oscillatory behaviour. The toy examples used to explain the idea are quite useful, but I am missing a relation between these examples and the real players of the cell cycle (out of the brief explanation on the discussion).

- The title of the work oversells the content of the manuscript. If kept, I will consider to make a strong point based on the previous comment.

Reviewer #3: attached

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: No: Must give param values so readers can reproduce all figures in the paper.

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions, please see http://journals.plos.org/compbiol/s/submission-guidelines#loc-materials-and-methods

Attachments

Attachment

Submitted filename: Gelens.docx

Attachment

Submitted filename: Review_Rombouts&Gelens.pdf

Dear Dr. Gelens,

Thank you very much for submitting your manuscript "Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions" for consideration at PLOS Computational Biology. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. 

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Attila Csikász-Nagy

Associate Editor

PLOS Computational Biology

Mark Alber

Deputy Editor

PLOS Computational Biology

***********************

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #2: The authors have addressed most of my suggestions properly. The ones that were not addressed were reasoned accordingly.

Reviewer #3: The authors have addressed most of concerns in the revision. However, according to the new result, the description for the main results needs to be more clear. The authors newly performed the stochastic simulations for the case when the slow variable also fluctuates (Fig 4I, J, Fig 5G, and Fig S1 and S3). According to these new results, the advantage of dynamic switch overs the static switch is not clear. Even dynamic switch leads to more unstable oscillations than the static switch when Omega=50 and 100 (e.g. red and green line; Fig S3 left lowest panel). Thus, the current results indicate that the dynamic switch leads to robustness (stability) over the static switch “under the condition that the noise of the slow variable, which leads to the dynamic switch (i.e. XT), is negligible”. However, such limitation seems not clearly descried in the current text including intro and conclusion. Providing the clear condition when the dynamic switch is robust will improve the impact of the manuscript and be more helpful for readers when they want to use the results.

**********

Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #2: Yes

Reviewer #3: Yes

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/ploscompbiol/s/submission-guidelines#loc-materials-and-methods

Dear Dr. Gelens,

We are pleased to inform you that your manuscript 'Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions' has been provisionally accepted for publication in PLOS Computational Biology.

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

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.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

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

Best regards,

Attila Csikász-Nagy

Associate Editor

PLOS Computational Biology

Mark Alber

Deputy Editor

PLOS Computational Biology

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