A novel approach to interrogating the effects of chemical warfare agent exposure using organ-on-a-chip technology and multiomic analysis

Tyler D. P. Goralski; Conor C. Jenkins; Daniel J. Angelini; Jennifer R. Horsmon; Elizabeth S. Dhummakupt; Gabrielle M. Rizzo; Brooke L. Simmons; Alvin T. Liem; Pierce A. Roth; Mark A. Karavis; Jessica M. Hill; Jennifer W. Sekowski; Kyle P. Glover

doi:10.1371/journal.pone.0280883

Peer Review History

Original SubmissionMarch 10, 2022
27 Jul 2022 Decision Letter - Timothy J Garrett, Editor PONE-D-22-07224A Novel Approach to Interrogating the Effects of Chemical Warfare Agent Exposure Using Organ-on-a-Chip Technology and Multiomic AnalysisPLOS ONE Dear Dr. Goralski, 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 clear responses to each of the reviewer comments. It is important to be very clear of the research nature of the study given the subject matter and the general public. ============================== Please submit your revised manuscript by Sep 10 2022 11:59PM. 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Thank you for stating the following in the Acknowledgments Section of your manuscript: “Funding for this project was provided by the Defense Advanced Research Projects Agency (DARPA) and Defense Threat Reduction Agency (DTRA)-Joint Science and Technology Office (JSTO) for Chemical and Biological Defense.” 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: “KG CB10735 Defense Threat Reduction Agency https://www.dtra.mil/ The funders played a role in the decision to publish. KG BQ5066 Defense Advanced Research Projects Agency https://www.darpa.mil/ The funders played a role in the decision to publish.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4. 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. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. 5. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. 6. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. [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: Yes Reviewer #2: Partly Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes Reviewer #3: No ****** 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 Reviewer #3: 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: No Reviewer #2: Yes Reviewer #3: 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: I fully admit I am not familiar with the methods used in this research and cannot assess if they were properly executed. The manuscript seems to present a new and ethical way to study the effects of VX on organ systems; it also presents novel effects of VX on liver tissue. However, the use of jargon, combined with problematic sentence structure and poor grammar, made several parts of the results and discussion/conclusions sections difficult to follow. Further, the organization of these sections could be improved. Notably, what the authors consider "method validation" and what they consider new findings are not clearly differentiated. Reviewer #2: 1. Methods, Hepatocyte Matrigel Overlay (line 432). Authors describe the use of Matrigel for the culturing of their organ-on-a-chip system, but don’t discuss the potential interference in the metabolomics from this highly complex media or if the Matrigel was effectively washed/removed prior to extraction. 2. Discussion (line 316). Authors compare the organ-on-a-chip results as comparable to in vivo results but fail to show sufficient evidence that the low extraction had sufficient metabolic information to derive physiological information relative to the toxicity treatment. More direct comparisons are needed to determine that this system and low extraction are sufficient. 3. Discussion (line 351). Authors again discuss how the results are comparable to the in vivo results but do not show this sufficiently with the interference of the plasticizers. 4. Identifications referenced in Figure 3 are hard to see. Reviewer #3: This article describes the use of an organ-on-a-chip system to study VX exposure via metabolomics, proteomics, and transcriptomics. The experiments themselves (the proteomics, transcriptomics, and metabolomics) were well-described and experimentally sound. The presentation of the results and the discussion struck me as confusing and incomplete. Statistical analysis was performed, but not presented or discussed in sufficient detail. As a result, the paper needs major revisions prior to publication. Major Comments: • Why were the RP negative, HILIC positive, and HILIC negative results not presented or discussed? • Method details on the partial least squares and the linear regression analysis need to be included. Include an explanation of the color scale in the heat maps • The metabolomics results description was confusing in that a “top 10” was mentioned, but then only 3 were said to be dysregulated. Please elaborate. • The phrase “sPLS-DA was performed incorporating time of day” is confusing because time of day is not mentioned previously. Do the authors mean days post-exposure? • The results/discussion for the plasticizer contamination was unclear. Were they increased in the Day 7 samples as one might expect? • Regarding days post-exposure, the authors speculated that “One possible answer is that basal level activity within the tissues could mature the longer they are in the chips.” Can’t the untreated controls be used to normalize for such age-associated changes? • The authors should double check the p-value thresholds. Figure 8, for example, is described as both p=0.005 (caption) and p<0.05 (text) • My understanding of S-plots was that the extremes were interesting (upper right and lower left). The 10 points highlighted in figure 2 seem to be randomly scattered in the S-plot. Therefore, I do not understand what I am supposed to conclude from the plot and how it relates to the highlighted points. Minor comments: • The method section on VX solution preparation cuts off mid sentence • The caption in figure 4 has B and C backwards • Page 8: incidents or incidence? • Page 4: compliments or complements? • Page 12: “While we observed high p-values”…should this be low p values? ****** 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: No Reviewer #2: No Reviewer #3: No ******** [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.0280883.r001
Revision 1
12 Sep 2022 Author Response PLOS ONE (PONE-D-22-07224) Response to Reviewers Authors: Goralski TDP, Jenkins CC, Angelini DJ, Horsmon JR, Dhummakupt ES, Rizzo GM, Simmons BL, Liem AT, Roth PA, Sekowski JW, Glover KP Title: A Novel Approach to Interrogating the Effects of Chemical Warfare Agent Exposure Using Organ-on-a-Chip Technology and Multiomic Analysis ID #: PONE-D-22-07224 Comments from the Editor: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. All style requirements have been met. 2. Please ensure you have included in your Methods section full information regarding the origin (supplier or manufacturer) of all materials used in this study. This includes in particular the origin of the VX chemical warfare agent. Full information regarding the origin of all materials used in this study, including the supplier and manufacturer, have been included in the manuscript. The origin of the VX chemical warfare agent has been included, as well as the purity of the sample. 3. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Funding information was removed from the Acknowledgements section of the manuscript. The information provided in the review is correct. 4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. All data sets have been uploaded to repositories, and we are awaiting accession numbers. The transcriptomics data were uploaded to Gene Expression Omibus through NCBI, the proteomics data were uploaded to the PRIDE Proteomics Identification Database, and the metabolomics data were uploaded to the Metabolights Database. We will provide you with the accession numbers as soon as possible. 5. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. The data availability statement will remain the same. See above comment. 6. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. Figure S1 was added to the manuscript, which shows the LDH cytotoxicity data described. Reviewer(s)' Comments to Author: Reviewer: 1 Comments to the Author 1. The use of jargon, combined with problematic sentence structure and poor grammar, made several parts of the results and discussion/conclusions sections difficult to follow. Further, the organization of these sections could be improved. Notably, what the authors consider "method validation" and what they consider new findings are not clearly differentiated. The manuscript was revised to tone down, or better explain the use of jargon, and correct all problematic sentence structure and poor grammar. Method validation and novel findings were defined in the discussion section. The manuscript states that through validation of this novel methodology, we were able to identify both previously implicated and unique pathways associated with VX exposure. Reviewer: 2 Comments to the Author 1. Methods, Hepatocyte Matrigel Overlay (line 432). Authors describe the use of Matrigel for the culturing of their organ-on-a-chip system, but don’t discuss the potential interference in the metabolomics from this highly complex media or if the Matrigel was effectively washed/removed prior to extraction. The chips were washed 3X with DPBS before the tissues were removed for downstream processing and analysis. All chips, including those that were untreated, received the same lot of Matrigel purchased from Corning (9119020), so any effects on the metabolomics would be equally observed in both control and treated chips. Therefore, these potential effects would not stand out as off target dysregulations in the VX exposed chips. 2. Discussion (line 316). Authors compare the organ-on-a-chip results as comparable to in vivo results but fail to show sufficient evidence that the low extraction had sufficient metabolic information to derive physiological information relative to the toxicity treatment. More direct comparisons are needed to determine that this system and low extraction are sufficient. We noted multiple times throughout the manuscript that some of the results obtained from the chip exposures match the dysregulations observed in vivo, with references to previous studies using animal models for VX exposures and downstream omics analysis. We believe that this is validation of our low extraction method. 3. Discussion (line 351). Authors again discuss how the results are comparable to the in vivo results but do not show this sufficiently with the interference of the plasticizers. Additional comments were made to the Discussion section to address the potential for plasticizer interference. “Given that the plasticizers are a likely byproduct of the organ chip systems, it is improbable that these off target effects would be observed in multiomics data sets obtained from similar exposures in vivo. However, in our assessment, effects that would implicate the specific plasticizers identified by omics analysis were not reflected in our data. 4. Identifications referenced in Figure 3 are hard to see. Figure 3 identifications were edited for clarity. Reviewer: 3 Major Comments to the Author 1. Why were the RP negative, HILIC positive, and HILIC negative results not presented or discussed? HILIC Positive sPLS-DA data was included in the manuscript. All acquisitions are included as supplemental data files. 2. Method details on the partial least squares and the linear regression analysis need to be included. Include an explanation of the color scale in the heat maps. The sPLS-DA methodology is built into the search engine utilized for the metabolomics experiments. Compound Discoverer’s sPLS-DA algorithem is based on the paper entitled Sparse PLS discriminant analysis: biologically relevant feature selection and graphical displays for multiclass problems. This reference has been added to the manuscript. The color mapping of the heatmaps has been declared in the figure legend. 3. The metabolomics results description was confusing in that a “top 10” was mentioned, but then only 3 were said to be dysregulated. Please elaborate. We have clarified this by stating that out of the ten discriminating compounds, only three were found to be significantly dysregulated. 4. The phrase “sPLS-DA was performed incorporating time of day” is confusing because time of day is not mentioned previously. Do the authors mean days post-exposure? This was revised in the manuscript. 5. The results/discussion for the plasticizer contamination was unclear. Were they increased in the Day 7 samples as one might expect? This was revised in the results section, and the octyl isocyanate boxplot was added to the supplemental. 6. Regarding days post-exposure, the authors speculated that “One possible answer is that basal level activity within the tissues could mature the longer they are in the chips.” Can’t the untreated controls be used to normalize for such age-associated changes? 7. The authors should double check the p-value thresholds. Figure 8, for example, is described as both p=0.005 (caption) and p<0.05 (text). The manuscript was revised to reflect that the p-value was 0.005. 8. My understanding of S-plots was that the extremes were interesting (upper right and lower left). The 10 points highlighted in figure 2 seem to be randomly scattered in the S-plot. Therefore, I do not understand what I am supposed to conclude from the plot and how it relates to the highlighted points. The sPLS-DA algorithem in Compound discoverer places additional factors into its identification of sPLS-DA compounds. It takes into account feature presence across all sample groups and the extremes are some features that appear in few or none of the samples in a sample group thus skewing the discrimination capabilities. Minor Comments to Author 1. The method section on VX solution preparation cuts off mid sentence • The methods section on VX solution preparation was revised. 2. The caption in figure 4 has B and C backwards. Figure 4 caption was revised 3. Page 8: incidents or incidence? Changed to incidence. 4. Page 4: compliments or complements? Changed to complements. 5. Page 12: “While we observed high p-values”…should this be low p values? Changed to low p-values. Attachments Attachment Submitted filename: PONE-D-22-07224 Rebuttal Letter.docx https://doi.org/10.1371/journal.pone.0280883.r002
15 Nov 2022 Decision Letter - Timothy J Garrett, Editor PONE-D-22-07224R1A Novel Approach to Interrogating the Effects of Chemical Warfare Agent Exposure Using Organ-on-a-Chip Technology and Multiomic AnalysisPLOS ONE Dear Dr. Goralski, 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. ==============================The remaining comments should be readily addressed. Please respond and provide the necessary edits ============================== Please submit your revised manuscript by Dec 30 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, Timothy J Garrett, PhD 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) Reviewer #2: All comments have been addressed Reviewer #3: 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: Partly Reviewer #2: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 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: Yes Reviewer #3: 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 Reviewer #2: Yes Reviewer #3: 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: I agree with the authors that organ-on-a-chip technology has tremendous potential in this space. I still have concerns regarding the discussion of method validation in this paper. It seems the claim that the organ-on-a-chip design is valid and accurate for assessing the effects of VX on liver tissue is based on general similarity of some results with generally established effects of VX. For a proof-of-concept study, I would expect some outlining of explicit parameters, as established a priori, to assess method performance relative to more established cell-line and in vivo methods. While similarity of some results with expected results is good, it is unclear if unexpected results are informative – especially given the high variation observed for the untreated chips and findings regarding carcinogenic plastic contamination. While I do not think the fact that these questions were not answered by the study is in and of itself a problem, I do think the repeated language that the study showed the method is valid and accurate and reveals effects of VX not previously established by other methodologies is problematic. Further, the authors seem to frame this method as a substitute or surrogate for in vivo studies, which is not the intent of organ-on-a-chip technology. It is typically viewed as a bridge between cell lines and in vivo studies. In sum, the study is promising and innovative, and possible issues are admittedly mentioned, but the authors have used strong language in their conclusions that should be tempered or nuanced at this stage. Reviewer #2: (No Response) Reviewer #3: No comments. This feature does not seem to be working; the system forced me to enter comments and exceed the 100 character limit.: "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." ****** 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: No Reviewer #3: No ******** [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.0280883.r003
Revision 2
19 Dec 2022 Author Response Reviewer(s)' Comments to Author: Reviewer: 1 Comments to the Author 1. I agree with the authors that organ-on-a-chip technology has tremendous potential in this space. I still have concerns regarding the discussion of method validation in this paper. It seems the claim that the organ-on-a-chip design is valid and accurate for assessing the effects of VX on liver tissue is based on general similarity of some results with generally established effects of VX. For a proof-of-concept study, I would expect some outlining of explicit parameters, as established a priori, to assess method performance relative to more established cell-line and in vivo methods. While similarity of some results with expected results is good, it isunclear if unexpected results are informative - especially given the high variation observed for the untreated chips and findings regarding carcinogenic plastic contamination. While I do not think the fact that these questions were not answered by the study is in and of itself a problem, I do think the repeated language that the study showed the method is valid and accurate and reveals effects of VX not previously established by other methodologies is problematic. Further, the authors seem to frame this method as a substitute or surrogate for in vivo studies, which is not the intent of organ-on-a-chip technology. It is typically viewed as a bridge between cell lines and in vivo studies. In sum, the study is promising and innovative, and possible issues are admittedly mentioned, but the authors have used strong language in their conclusions that should be tempered or nuanced at this stage. The manuscript was revised to remove and amend all language that would suggest this study was a validation of the method, as well as language which would indicate the method was fully accurate, or proof of concept. Reviewer: 2 No Comments to the Author Reviewer: 3 No Comments to the Author Attachments Attachment Submitted filename: PONE-D-22-07224 Rebuttal Letter.docx https://doi.org/10.1371/journal.pone.0280883.r004
11 Jan 2023 Decision Letter - Timothy J Garrett, Editor A Novel Approach to Interrogating the Effects of Chemical Warfare Agent Exposure Using Organ-on-a-Chip Technology and Multiomic Analysis PONE-D-22-07224R2 Dear Dr. Goralski, 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, Timothy J Garrett, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0280883.r005
Formally Accepted
3 Feb 2023 Acceptance Letter - Timothy J Garrett, Editor PONE-D-22-07224R2 A Novel Approach to Interrogating the Effects of Chemical Warfare Agent Exposure Using Organ-on-a-Chip Technology and Multiomic Analysis Dear Dr. Goralski: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Timothy J Garrett Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0280883.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .