PONE-D-23-18580Stochastic modeling of a gene regulatory network driving B cell development in germinal centersPLOS ONE

Dear Dr. Crauste,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’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.

Your manuscript, "Stochastic modeling of a gene regulatory network driving B cell development in germinal centers" (PONE-D-23-18580), has been assessed by our reviewers. Although it is of interest, we are unable to consider it for publication in its current form. The reviewers have raised a number of mains points that we believe would improve the manuscript and may allow a revised version to be published in PLOS ONE.

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Nihad A.M Al-Rashedi

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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

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

PLOS ONE 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

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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: The manuscript by Alexey Koshkin et al. deals with the investigation of the gene regulatory networks (GRNs) associated with germinal center (GC) cell development and differentiation based on public available single-cell (SC) transcriptomic data. Including three key gene regulators (BCL6, IRF4, BLIMP1), influenced by two external stimuli signals (surface receptors BCR and CD40), a model was established that qualitatively recapitulates mRNA distributions corresponding to GC and plasmablast stages of B cell differentiation, which can be used in validating the GRN in physiological and pathophysiological conditions.

The manuscript is written well and meets almost all criterias for publishing in PlosOne:

Comments:

The validation (testing) of the model on a test-data set (for example the sc-RNA data set from the same sample source but also an external data set would highly improve the quality of the paper.

Reviewer #2: In this paper the authors use stochastic modeling of a gene regulatory network to fit single cell expression data related to B cell differentiation in germinal centers. This is an important problem which can lead to better understanding of malignancies in B cells. The work is technically sound, and the paper is well-written with the mathematical descriptions and the figures doing a good job of clearly presenting the work to the readers. I would like to point out some revisions that are still needed.

- The benefit of using a stochastic model over a kinetic model, as also the improvements of using Version III over Version II are not fully clear without including a figure like Figure 2 each for the latter two parameter tune cases. For example, in version III PB_PC improves for two genes, however the GC performance becomes worse. So plots showing the mRNA counts like in Figure 2 would show how close the total model predictions are to the observed values.

- Some of the parameters depicted in 4-6 are not present later, for example beta_i, gamma, k^min, k^max. It needs to be clarified how they are replaced (e.g. maybe by k_init) or not used anymore.

- In Pages 6 and 7, line 146-154, the ranges for some parameters are not given, e.g. theta_{1,1}, H_{1,1}, etc. In line 152, aren't there 6 H_{j,i} interactions and 11 theta_{i,j} interactions? The values in Line 153 do not match, so that section needs to corrected so that the number of parameter combinations adds up.

- Why is CD40 stimuli upto 61 instead of 60?

- In Figures 4, 5, S3, some further details about the y axis scale are needed for the reader.

- In Figure 1 caption, k_{off,i} is not shown to be dependent on P_j and theta_ji in the text, only k_{on,i}, so those should match. Also autoactivation loop for BCL6 needs to be mentioned, as it is mentioned just for IRF4.

- Error in Line 363 (antibody producing, not antigen producing) should be corrected.

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Reviewer #1: No

Reviewer #2: No

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Stochastic modeling of a gene regulatory network driving B cell development in germinal centers

PONE-D-23-18580R1

Dear Dr. Crauste,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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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 onepress@plos.org.

Kind regards,

Nihad A.M Al-Rashedi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

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 #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: (No Response)

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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: (No Response)

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

PLOS ONE 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: (No Response)

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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 manuscript by Alexey Koshkin et al. deals with the investigation of the gene regulatory networks (GRNs) associated with germinal center (GC) cell development and differentiation based on public available single-cell (SC) transcriptomic data. Including three key gene regulators (BCL6, IRF4, BLIMP1), influenced by two external stimuli signals (surface receptors BCR and CD40), a model was established that qualitatively recapitulates mRNA distributions corresponding to GC and plasmablast stages of B cell differentiation, which can be used in validating the GRN in physiological and pathophysiological conditions.

The manuscript is written well and meets almost all criterias for publishing in PlosOne. My concern was

taken into account and the response was accepted by the reviewer. Therefore, the paper is fit for publication in "Plos ONE"

Reviewer #2: (No Response)

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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.

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 #1: No

Reviewer #2: Yes: Gourab Ghosh Roy

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