Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome: A public databases-based study

Li Wu; Qi Wang; Qi-chao Gao; Gao-xiang Shi; Jing Li; Fu-rong Fan; Jing Wu; Pei-Feng He; Qi Yu

doi:10.1371/journal.pone.0298447

Peer Review History

Original SubmissionAugust 1, 2023
25 Oct 2023 Decision Letter - Gurudeeban Selvaraj, Editor PONE-D-23-23956Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome : a public databases-based studyPLOS ONE Dear Dr. Yu, 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 submit your revised manuscript by Dec 09 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. 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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 financial disclosure: "This project was supported by grants from the Shanxi Province key research and development program (No. 201903D311011; 201803D31067)." Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. 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. 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 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 ****** 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 ****** 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: Regarding the manuscript entitled" Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome : a public databases-based study. The manuscript is interesting, but the quality of the figures should be improved. Reviewer #2: Please provide the flowchart of study in a separate figure. In the introduction section please provide brief description about WGCNA method. Reading the paper PMID: 37636389 is suggested. " GSE55235, GSE55457, GSE1919, GSE110169, GSE84844, GSE23117, GSE40611, and GSE84844" are data series not data set please revise related sentences. In the senetence "The co-expression network was built using microarray dataset GSE55235 and dataset GSE84844 to obtain the RA and pSS-associated modules" did the authors perform WGCNA on selected genes of data series . How did they screen genes for WGCNA? In sentence "An adjusted p < 0.05 in GO terms or KEGG pathways was considered statistically significant and visualized using the “GOplot” package " please mention GOplot package under R software . ****** 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: Shahram Teimourian Reviewer #2: 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.0298447.r001
Revision 1
31 Oct 2023 Author Response Dear editors and reviewers: Thank you very much for your careful review of our manuscript entitled “Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome: a public databases-based study”. We have carefully considered the reviewers’ professional comments and made a point to point response as follows: To Reviewer 1： 1. Regarding the manuscript entitled “Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome : a public databases-based study” . The manuscript is interesting, but the quality of the figures should be improved. Response：Thank you for your professional suggestions. Later, I will re-upload high-resolution figures in the manuscript that meet the requirements of the magazine. To Reviewer 2： 1. Please provide the flowchart of study in a separate figure. Response：Thank you for your professional suggestions. Fig 1 in the manuscript is the flow chart of this study, and I will upload a separate flow chart again in the system. 2. In the introduction section please provide brief description about WGCNA method. Reading the paper PMID: 37636389 is suggested. Response: Thank you for your professional suggestions. We describe the WGCNA approach in the introduction section. Weighted Gene Co-expression Network Analysis (WGCNA) is a computational biology method used to explore patterns of gene correlations among different samples. It can be used to cluster gene modules that exhibit highly coordinated changes in various biological processes and correlate these gene modules with clinical feature data [1, 2]. By analyzing the results, important core modules and molecules can be identified. The introduction of co-expression networks has facilitated a network-based gene selection method, which can be used in basic medical research to identify specific candidate biomarkers [3] or immunotherapy targets [4]. The main computational process of WGCNA involves raising correlation values between genes to a power, resulting in a topological overlap matrix network that better fits the characteristics of a scale-free network [5]. Its characteristic is the strengthening of strong correlations and weakening of weak correlations. In this study, the expression profile data of RA and pSS were analyzed using the WGCNA analysis method. After calculating and analyzing the correlation between gene modules and clinical feature data, the relationship between each gene module and clinical features was clarified. Combined with the analysis of differentially expressed genes, the biological functions and target genes of RA and pSS were identified. References 1. Zhang T, Wong G. Gene expression data analysis using Hellinger correlation in weighted gene co-expression networks (WGCNA). Computational and structural biotechnology journal. 2022;20:3851-63. 2. Liu K, Chen S, Lu R. Identification of important genes related to ferroptosis and hypoxia in acute myocardial infarction based on WGCNA. Bioengineered. 2021;12(1):7950-63. 3. Ye H, Wang R, Wei J, Wang Y, Zhang X, Wang L. Bioinformatics Analysis Identifies Potential Ferroptosis Key Gene in Type 2 Diabetic Islet Dysfunction. Frontiers in endocrinology. 2022;13:904312. 4. Afshar S, Leili T, Amini P, Dinu I. Introducing novel key genes and transcription factors associated with rectal cancer response to chemoradiation through co-expression network analysis. Heliyon. 2023;9(8):e18869. 5. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559. 3. "GSE55235, GSE55457, GSE1919, GSE110169, GSE84844, GSE23117, GSE40611, and GSE84844" are data series not data set please revise related sentences. Response：Thank you for your professional suggestions. Finally, we downloaded the data series numbered GSE55235, GSE55457, GSE1919, GSE110169, GSE84844, GSE23117, GSE40611, and GSE84844. 4. In the senetence "The co-expression network was built using microarray dataset GSE55235 and dataset GSE84844 to obtain the RA and pSS-associated modules" did the authors perform WGCNA on selected genes of data series . How did they screen genes for WGCNA? Response：Thank you for your professional suggestions. We performed WGCNA on selected genes of data series GSE55235 and GSE84844. We used the R package “WGCNA” to identify disease trait-related modules and hub genes. First, the gene expression data was clustered to determine the optimal soft threshold (β) based on the average connectivity and scale-free topology fit index (R2). Multiple gene modules and hierarchical clustering trees were constructed. Then, Pearson correlation analysis was performed between genes to obtain a relationship matrix, and the module with the highest correlation was selected as the key gene module. Based on the criteria of a soft-thresholding power of 10 (scale free R2 = 0.85), a cut height of 0.25, and a minimum module size of 50, calculations were made to achieve scale-free topology for the dataset GSE55235. For the dataset GSE84844, we specified a soft-thresholding power of 4, a cut height of 0.4, and a minimum module size of 50 to confirm the co-expression modules. The genes selected for further analysis were those with strong correlation coefficients with clinical characteristics. We identified key modules in RA and pSS using Pearson correlation coefficients and the p-value of each eigengene and disease trait. Afterward, the genes in these key modules that were positively associated with RA and pSS were identified as shared genes. 5. In sentence "An adjusted p < 0.05 in GO terms or KEGG pathways was considered statistically significant and visualized using the “GOplot” package " please mention GOplot package under R software. Response：Thank you for your professional suggestions. An adjusted p < 0.05 in GO terms or KEGG pathways was considered statistically significant and visualized using the “GOplot” package under R 4.2.1 version. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0298447.r002
27 Dec 2023 Decision Letter - Gurudeeban Selvaraj, Editor PONE-D-23-23956R1Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome : a public databases-based studyPLOS ONE Dear Dr. Yu, 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 submit your revised manuscript by Feb 10 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at 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, Gurudeeban Selvaraj 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 #3: All comments have been addressed Reviewer #4: 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 #3: Yes Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes Reviewer #4: 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 #3: Yes Reviewer #4: 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 #3: Yes Reviewer #4: 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 #3: 1- This study reports on the findings of the original research. Researchers have used public databases and bioinformatics techniques to identify potential mechanisms and drug predictions for RA and pSS. This new study can contribute to our understanding of the structural molecular mechanisms of these diseases. 2- This study is based on standards and detailed analysis. The authors used rigorous methods to examine the data and find common genes, pathways, and therapeutic targets. These methods include weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, and functional enrichment analysis. 3- The data presented in the article confirm the conclusion. By combining data from different studies, the authors discovered four hub genes (CXCL10, GZMA, ITGA4, and PSMB9). It was found that these genes are upregulated in both RA and pSS, which supports these findings. Reviewer #4: The contents of the article and the topic are interesting, and the revision had considered of the first reviewer's recommendation. However, I suggest that improving the quality of the figures in the article would be better. They are obscure that I cannot see them clearly. ****** 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 #3: Yes: Masoud Ghorbani Reviewer #4: 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.0298447.r003
Revision 2
11 Jan 2024 Author Response Dear editors and reviewers: Thank you very much for your careful review of our manuscript entitled “Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome: a public databases-based study”. We have carefully considered the reviewers’ professional comments and made a point to point response as follows: To Reviewer 3： 1. (1) This study reports on the findings of the original research. Researchers have used public databases and bioinformatics techniques to identify potential mechanisms and drug predictions for RA and pSS. This new study can contribute to our understanding of the structural molecular mechanisms of these diseases. (2) This study is based on standards and detailed analysis. The authors used rigorous methods to examine the data and find common genes, pathways, and therapeutic targets. These methods include weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, and functional enrichment analysis. (3) The data presented in the article confirm the conclusion. By combining data from different studies, the authors discovered four hub genes (CXCL10, GZMA, ITGA4, and PSMB9). It was found that these genes are upregulated in both RA and pSS, which supports these findings. Response： Thank you for your encouraging feedback on our research. We are grateful for your positive assessment of our work and appreciate your constructive suggestions for improvement. Your insights will undoubtedly help us to further refine and strengthen our study. We will carefully consider and address all of your comments in the revised manuscript. Thank you once again for your support and guidance. To Reviewer 4： 1. The contents of the article and the topic are interesting, and the revision had considered of the first reviewer's recommendation. However, I suggest that improving the quality of the figures in the article would be better. They are obscure that I cannot see them clearly. Response：We appreciate the feedback regarding the image quality issue, and we have re-uploaded clearer images. It is important to note that the merged version of figures seen during the peer review process may have undergone system compression, leading to a decrease in image quality. This could be the primary reason for the diminished image quality. We will promptly address this issue by providing the responsible editor with high-resolution images that meet the journal’s requirements. We appreciate your constructive criticism and assure you that we are committed to improving the quality of our manuscript in response to your feedback. Thank you very much for your attention and time. Look forward to hearing from you. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0298447.r004
25 Jan 2024 Decision Letter - Gurudeeban Selvaraj, Editor Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren’s Syndrome : a public databases-based study PONE-D-23-23956R2 Dear Dr. Yu, 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, Dr. Gurudeeban Selvaraj, 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 #4: 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 #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #4: 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 #4: 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 #4: 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 #4: The authors has revised the problems that I proposed in the previous recommendations. Thus I suggest to accept this article. ****** 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 #4: No ******** https://doi.org/10.1371/journal.pone.0298447.r005
Formally Accepted
6 Feb 2024 Acceptance Letter - Gurudeeban Selvaraj, Editor PONE-D-23-23956R2 PLOS ONE Dear Dr. Yu, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Gurudeeban Selvaraj Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0298447.r006

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