Queueing theory model of mTOR complexes’ impact on Akt-mediated adipocytes response to insulin

Sylwester M. Kloska; Krzysztof Pałczyński; Tomasz Marciniak; Tomasz Talaśka; Marissa Miller; Beata J. Wysocki; Paul H. Davis; Ghada A. Soliman; Tadeusz A. Wysocki

doi:10.1371/journal.pone.0279573

Peer Review History

Original SubmissionJuly 6, 2022
22 Sep 2022 Decision Letter - Irina U Agoulnik, Editor PONE-D-22-19018Queueing theory model of mTOR complexes’ impact on Akt-mediated cell response to insulinPLOS ONE Dear Dr. Kloska, 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. Even after downloading a high resolution of figure 1, it is impossible to read and understand the flow of the signaling. Please also clearly describe, which tissues/cells you are modeling for and why, as the insulin receptor signaling is vastly different in WAT, BAT, liver, muscle, adipose, pancreatic and other cells. As suggested by the reviewer, please clearly separate introductory background description from the original research performed for this manuscript. Please provide additional clarifications and descriptions, requested by the reviewer. Please submit your revised manuscript by Nov 06 2022 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 plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Irina U Agoulnik, Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following in the Acknowledgments Section of your manuscript: “This work was supported by the National Science Center (NCN) of Poland in terms of Opus-17 290 Program [2019/33/B/ST6/00875].” We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “This work was supported by the National Science Center (NCN) of Poland (https://www.ncn.gov.pl/) in terms of Opus-17 Program [2019/33/B/ST6/00875 awarded to TAW]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. [Note: HTML markup is below. Please do not edit.] 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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A ****** 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: No ****** 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 ****** 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 authors/laboratory have previously described the computational simulation of cellular GLU4 translocation due to insulin secretion. They have also shown other applications of the method, including the initiation of immune response. Here, they expand the previous model to include the interaction of mTOR complexes on PI3K/AKT insulin signalling. However, the authors need to do more to showcase the previous work (not just reference it), while explaining how the present manuscript builds on/is different from what they (and others?) have already published. The authors may choose to present the work as a validation of already-available information via other methods that could potentially yield novel information, but it is important to be clear on what the current goal is, how much of the goal has been achieved in this manuscript and what future perspective the authors envision. From Line 62 to 104, the authors have did well to explain the historical and current use of “Queueing theory”. The methodology section also attempts to explain the detailed equations, constants, concentrations and algorithms used to compute the model. However, the authors should consider defining the theory itself, and the hypothesis upon which its viability is predicated. In the methodology and result sections, it is important to be clear about where the authors are showcasing already-available information and where they are discussing their methods/findings, else, they risk presenting a descriptive paper that may not be strongly showcasing their contribution to knowledge. Summarily, the presentation of the results here is not laid out in a way that a reader can follow in a step wise manner. In modelling specific points in a pathway, it is important for the reader to know what sequence the authors are following in describing their results, especially when it is all tied up in a theory, else the work becomes entirely descriptive and it becomes difficult to differentiate published work from new findings. If it helps, the authors may consider separating the results from the discussion section so that they can explore each section individually and help the reader arrive at a logical conclusion of whether their claims are valid or not. Minor Points. Line 92-94: Fig 1 is presented as a low resolution image, making it difficult/impossible to review. Line 106: It seems intuitive to simple state that “The endpoints of the signaling pathway..”, but the authors may consider stating which pathway they are refereeing to. Line 198-207: The effect of lowering mTORC1 activity is described here, but the authors should consider leveraging evidences from literature to bolster their findings. Line 214-220: These points here (as in many parts of the write-up) are available in literature and may not be the results for this manuscript. It is therefore important to appropriately reference them, as this is ethically required and further helps the reader to differentiate between the authors results and evidences in literature (even if those evidences were reported by the authors). Line 226: “Insulin signaling pathway, disease and treatment strategies”. The authors have majorly discussed mTORC1 activity here, so it is not clear how the subtitle fits the section. Line 228-229: “The equations described in the model are based on the mass action law”. Please clarify which model is been referred to; the model used by Sonntag et al. or the model used in this study? Data availability: The authors state that “Yes - all data are fully available without restriction”, is this by request or in a publicly available platform? ****** 6. 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: Yes: Olawande C. Olagoke, PhD. ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0279573.r001
Revision 1
28 Sep 2022 Author Response Dear Dr Irina U Agoulnik, Thank you for giving us the opportunity to submit a revised draft of our manuscript titled “Queueing theory model of mTOR complexes’ impact on Akt-mediated cell response to insulin” to PLOS ONE. We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on my manuscript. We are grateful to the reviewers for their insightful comments on my paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. We have highlighted the changes within the manuscript. Here is a point-by-point response to the reviewers’ comments and concerns. Comments from the Editor Even after downloading a high resolution of figure 1, it is impossible to read and understand the flow of the signaling. Response: Thank you for pointing this out. We agree with your point and we refined mentioned figure in order to improve its quality and readability. Please also clearly describe, which tissues/cells you are modeling for and why, as the insulin receptor signaling is vastly different in WAT, BAT, liver, muscle, adipose, pancreatic and other cells. Response: Thank you for pointing this out. As suggested, we have added an explanation that presented model refers to human adipocytes (lines 118-119). As suggested by the reviewer, please clearly separate introductory background description from the original research performed for this manuscript. Please provide additional clarifications and descriptions, requested by the reviewer. Response: Thank you for these suggestions. We have adapted our work to the guidance and feedback provided in the review. Comments from Reviewer 1 • Comment 1: The authors need to do more to showcase the previous work (not just reference it), while explaining how the present manuscript builds on/is different from what they (and others?) have already published. The authors may choose to present the work as a validation of already-available information via other methods that could potentially yield novel information, but it is important to be clear on what the current goal is, how much of the goal has been achieved in this manuscript and what future perspective the authors envision. However, the authors should consider defining the theory itself, and the hypothesis upon which its viability is predicated. Response: Thank you for pointing this out. We agree with this comment. Therefore, we have added the following comments in the Introduction section: “The research hypothesis of this work is the ability to simulate the cellular response to insulin and track changes in the concentrations of proteins involved in this response using queueing theory based simulation model. The presented model shows the mechanism of mTORC1 influence on mobilization of GLUT4 particles. Since mTORC1 has been reported in literature as having an impact on glucose uptake (20,21).” “Since then the mTORC1 signaling pathway connections with Akt-mediated insulin response has been described (22,23). This work presents a model where those connections have been included.”. • Comment 2: In the methodology and result sections, it is important to be clear about where the authors are showcasing already-available information and where they are discussing their methods/findings, else, they risk presenting a descriptive paper that may not be strongly showcasing their contribution to knowledge. Response: Thank you for this feedback. We have divided the Results and Discussion section into two separate sections, making our results more clearly marked. In this way, the results of the research we conducted are more visible. • Comment 3: The presentation of the results here is not laid out in a way that a reader can follow in a step wise manner. In modelling specific points in a pathway, it is important for the reader to know what sequence the authors are following in describing their results, especially when it is all tied up in a theory, else the work becomes entirely descriptive and it becomes difficult to differentiate published work from new findings. If it helps, the authors may consider separating the results from the discussion section so that they can explore each section individually and help the reader arrive at a logical conclusion of whether their claims are valid or not. Response: Thank you for your suggestion. We have separated the Results and Discussion sections so that the visibility of the results obtained from our research is more emphasized. Minor points: • Line 92-94: Fig 1 is presented as a low resolution image, making it difficult/impossible to review. Response: We have revised figures in the paper. We agree with your point and we refined mentioned figure in order to improve its quality and readability. • Line 106: It seems intuitive to simple state that “The endpoints of the signaling pathway..”, but the authors may consider stating which pathway they are refereeing to. Response: Thank you for pointing this out. As suggested, we have added an explanation that we meant ‘Akt-mediated insulin signaling pathway’ in this sentence. • Line 198-207: The effect of lowering mTORC1 activity is described here, but the authors should consider leveraging evidences from literature to bolster their findings. Response: Thank you for pointing this out. We have added a piece of information in which we refer to literature results that support the results we obtained. “Similar conclusions can be drawn from the results presented by Rajan et al. (39) and Veilleux et al. (40) which confirms the validity of the method we presented.” • Line 214-220: These points here (as in many parts of the write-up) are available in literature and may not be the results for this manuscript. It is therefore important to appropriately reference them, as this is ethically required and further helps the reader to differentiate between the authors results and evidences in literature (even if those evidences were reported by the authors). Response: Thank you for raising this issue. We have corrected the indicated fragment to more clearly show the findings of another research team and have cited the work of that team accordingly (lines 226-227). • Line 226: “Insulin signaling pathway, disease and treatment strategies”. The authors have majorly discussed mTORC1 activity here, so it is not clear how the subtitle fits the section. Response: Thank you for pointing this out. We have decided to remove subsections, because we divided Results and Discussion sections. • Line 228-229: “The equations described in the model are based on the mass action law”. Please clarify which model is been referred to; the model used by Sonntag et al. or the model used in this study? Response: Thank you for pointing this out. We added an explanation which model is been referred to. • Data availability: The authors state that “Yes - all data are fully available without restriction”, is this by request or in a publicly available platform? Response: Thank you for your question. The data will be available in the online version of the paper (tables with values of literature concentrations used in the model and reaction equations and kinetic constants used in the model). The source code is freely available for download at https://github.com/UTP-WTIiE/IrsMtorcQueuesSimulation, implemented in C# supported in Linux or MS Windows. We have also generated a DOI for our GitHub repositorium, which can be accessed here: https://doi.org/10.5281/zenodo.7117138. We look forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have. Sincerely, Sylwester Michał Kloska on behalf of all co-authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0279573.r002
28 Nov 2022 Decision Letter - Irina U Agoulnik, Editor PONE-D-22-19018R1Queueing theory model of mTOR complexes’ impact on Akt-mediated cell response to insulinPLOS ONE Dear Dr. Kloska, 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. Please provide requested references and corrections requested by the reviewer. Please also consider adding a statement to your discussion describing the limitations of your model. Please submit your revised manuscript by Jan 12 2023 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 plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Irina U Agoulnik, Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] 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: (No Response) ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A ****** 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 ****** 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 ****** 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 done well to respond to the suggestions. They have correctly shown in the methodology that their model and supporting (referenced) experimental result is in adipocytes. They may choose to also let this reflect in the title and/or abstract so as to guide readers to the specificity of their work. Also, appropriate referencing should be made for line 31-36, 63-67 and 121-122. Furthermore, the authors may choose to reword their conclusion as the novelty of their work doesn’t seem to be that “manipulating mTORC1 kinase affects GLUT 4 translocation and glucose entry”, but that queuing theory can effectively model the process. Importantly, the authors have alluded to the improvement of queuing theory over ODE’s. are there any drawbacks to modelling with the theory, especially in relation to mTORC1 mediated GLUT 4 translocation? ****** 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: Yes: Olawande Olagoke, PhD. ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0279573.r003
Revision 2
29 Nov 2022 Author Response Dear Dr Irina U Agoulnik, Thank you for giving us the opportunity to submit a revised draft of our manuscript titled “Queueing theory model of mTOR complexes’ impact on Akt-mediated adipocytes response to insulin” to PLOS ONE. We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on my manuscript. We are grateful to the reviewers for their insightful comments on my paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. We have highlighted the changes within the manuscript. Here is a point-by-point response to the reviewers’ comments and concerns. Comments from the Editor Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Response: Thank you for these notifications. We have checked references and we believe there is no retracted paper what we refer to. We have made every effort to ensure that the list of references is complete and meets the requirements of the Journal. Comments from Reviewer 1 • The authors have done well to respond to the suggestions. They have correctly shown in the methodology that their model and supporting (referenced) experimental result is in adipocytes. They may choose to also let this reflect in the title and/or abstract so as to guide readers to the specificity of their work. Response: Thank you for your suggestions. We have changed the manuscript title and abstract. They now clearly show that the paper is related to adipocytes response to insulin. • Also, appropriate referencing should be made for line 31-36, 63-67 and 121-122. Response: Thank you for pointing this out. We have added new references in the mentioned lines. • Furthermore, the authors may choose to reword their conclusion as the novelty of their work doesn’t seem to be that “manipulating mTORC1 kinase affects GLUT 4 translocation and glucose entry”, but that queuing theory can effectively model the process. Response: Thank you for pointing this out. We agree with the comment. The relevant statement has been included in the Conclusions section. • Importantly, the authors have alluded to the improvement of queuing theory over ODE’s. are there any drawbacks to modelling with the theory, especially in relation to mTORC1 mediated GLUT 4 translocation? Response: The presented model has several limitations. It does not take into account other signaling pathways or individual reactions that are also connected to and influence signaling proteins. This is especially true for the Akt protein, which is the central node in the presented signaling model. Moreover, a model based on literature data will only be as good as the available data. However, we do not question the reliability of other research teams and their published results. Another of the limitations is that in queueing theory, each simulation gives one realization of the stochastic process, while ODE gives an averaged solution. Therefore, a limitation is that depending on the number of cells for which one runs simulations and then averages them, this is how accurate the result will be. Therefore, the model presented here is for averaged results for 50 cells. We look forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have. Sincerely, Sylwester Michał Kloska on behalf of all co-authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0279573.r004
12 Dec 2022 Decision Letter - Irina U Agoulnik, Editor Queueing theory model of mTOR complexes’ impact on Akt-mediated adipocytes response to insulin PONE-D-22-19018R2 Dear Dr. Kloska, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Irina U Agoulnik, Ph.D. 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 ******** 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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: Yes: Olawande Olagoke, PhD. ******** https://doi.org/10.1371/journal.pone.0279573.r005

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