SNP associations in the L-citrulline metabolic pathway and vascular aging in the Japanese population

Dai Nogimura; Kazuki Moriyasu; Sachiko Ishida; Masakazu Kohda; Takayuki Yazawa; Masahiko Morita

doi:10.1371/journal.pone.0323778

Peer Review History

Original SubmissionNovember 19, 2024
19 Nov 2024 Author Response https://doi.org/10.1371/journal.pone.0323778.r001
17 Jan 2025 Decision Letter - Asif Jan, Editor PONE-D-24-52040SNPs on the L-citrulline metabolic pathway are associated with specific health characteristics related to vascular aging in the Japanese populationPLOS ONE Dear Dr. Morita, 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 Mar 03 2025 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. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. 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: Yes ****** 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: Minor comments:-The manuscript titled "SNPs on the L-citrulline Metabolic Pathway Are Associated with Specific Health Characteristics Related to Vascular Aging in the Japanese Population" presents an intriguing study on the genetic factors influencing vascular aging. The focus on nitric oxide production and L-citrulline's role in improving vascular function is highly relevant to cardiovascular research. The integration of both candidate gene and genome-wide association approaches strengthens the findings. However, the manuscript can benefit from clearer articulation of the clinical implications of these findings. The discussion should expand on how these genetic associations can be translated into personalized interventions for vascular aging. Additionally, the limitations section is comprehensive, but it would be helpful to discuss potential future directions, such as validating these findings in other populations. Overall, this is a well-conducted study with significant potential, but further refinement in linking the genetic associations to practical applications will enhance the manuscript’s impact. Reviewer #2: 1. Clinical Relevance and Practical Implications The manuscript provides significant findings on SNPs associated with vascular aging, but the discussion should emphasize how these genetic markers can be translated into clinical practice. For instance, the authors could elaborate on the potential for genotype-based supplementation of L-citrulline to improve vascular health in aging populations. Including more practical applications would make the study more impactful. 2. Broader Applicability of Findings The study focuses exclusively on the Japanese population. It would be beneficial to discuss the generalizability of these findings to other ethnic groups. The authors could also mention the importance of validating these results in diverse populations to ensure broader applicability. 3. GWAS Results Interpretation The manuscript includes genome-wide association study (GWAS) findings, but the interpretation of the identified SNPs could be more detailed. The authors should clarify the functional relevance of these SNPs and how they impact downstream nitric oxide signaling, particularly for the newly identified associations. 4. Methodological Details While the methodology is described in detail, some sections could benefit from additional clarity. For example, the selection criteria for the traits used in association analyses should be more explicitly explained. Additionally, the rationale behind using both candidate gene and GWAS approaches should be stated more clearly. Title The title is informative but could be refined for clarity. Consider simplifying it to: “SNP Associations in the L-Citrulline Pathway and Vascular Aging in the Japanese Population.” 2. Abstract The abstract is comprehensive but slightly dense. Simplifying some of the terminology for a broader audience would improve readability. Additionally, the abstract should briefly highlight the practical implications of the study findings. 3. Figures and Tables The figures and tables are well-organized, but the legends could be more descriptive. Providing additional context for each figure would help readers better understand the results at a glance. 4. Terminology Consistency Ensure consistency in using abbreviations and technical terms throughout the manuscript. For example, "L-citrulline" should be consistently abbreviated as "Cit" after its first use. ****** 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: Yes: DR.WAHEED ALI SHAH ******** [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.0323778.r002
Revision 1
17 Feb 2025 Author Response Dear Prof. Emily Chenette, Editor-in-Chief, PLoS ONE Manuscript Number: PONE-D-24-52040 Title: SNPs on the L-citrulline metabolic pathway are associated with specific health characteristics related to vascular aging in the Japanese population Authors: Dai Nogimura, Kazuki Moriyasu, Sachiko Ishida, Masakazu Kohda, Takayuki Yazawa, Masahiko Morita We would like to thank the two reviewers for their valuable comments, which we have used to revise our manuscript accordingly. These comments have helped us significantly improve our paper. Please see our revised manuscript and point-by-point response to the reviewers’ comments. We are writing the modified parts in red, and these parts were checked by a native English speaker. The authors felt the revised manuscript is a suitable response to the comments and has significantly improved over the initial submission. Thank you very much for your consideration and kind assistance. Sincerely yours, Masahiko Morita, Ph. D. Institute of Health Sciences, Kirin Holdings Company, Ltd. 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan Phone No: +81-90-3063-2127 Email Address: Masahiko_Morita@kirin.co.jp Response to the reviewers’ comments. Comment from Reviewer #1 The discussion should expand on how these genetic associations can be translated into personalized interventions for vascular aging. AND, Comment from Reviewer #2 1. Clinical Relevance and Practical Implications The manuscript provides significant findings on SNPs associated with vascular aging, but the discussion should emphasize how these genetic markers can be translated into clinical practice. For instance, the authors could elaborate on the potential for genotype-based supplementation of L-citrulline to improve vascular health in aging populations. Including more practical applications would make the study more impactful. Response: We strongly agree with the reviewer that the practical implications of the genetic associations in this study need to be considered. As you indicated, the results of this study support the validity of genotype-based Cit supplementation in the future, which might make personalized supplements beneficial. We have added a statement including the possibility of further research development in the final paragraph of the Discussion section (page 20-21, lines 472–476, 480, and 482–486). Comment from Reviewer #1 The limitation section is comprehensive, but it would be helpful to discuss potential future directions, such as validating these findings in other populations. AND, Comment from Reviewer #2 2. Broader Applicability of the Findings The study focuses exclusively on the Japanese population. It would be beneficial to discuss the generalizability of these findings to other ethnic groups. The authors could also mention the importance of validating these results in diverse populations to ensure broader applicability. Response: Thank you for your comments. As you indicated, future validation in different populations and races is needed to better ensure the association between the SNPs found in this study and the symptoms of vascular aging. We have added this point in the seventh paragraph of the Discussion section (page 20, lines 449–453). Comment from Reviewer #2 3. GWAS Results Interpretation The manuscript includes the genome-wide association study (GWAS) findings, but the interpretation of the identified SNPs could be more detailed. The authors should clarify the functional relevance of these SNPs and the way they impact downstream nitric oxide signaling, particularly for the newly identified associations. Response: Thank you for pointing this out. The interpretation of the SNPs identified in the GWAS is provided in paragraph 6 of the Discussion section. We have already discussed PRMT6 in depth for its involvement with the NO signaling pathway. In response to your suggestion, we have also added the gene for the other identified SNP (HSD17B11) on page 19, lines 439 to 444, regarding its possible association with vascular aging. However, as mentioned on the same page in lines 444 to 446, no association with the Cit and NO action pathways has been reported. Comment from Reviewer #2 4. Methodological Details While the methodology is described in detail, some sections could benefit from additional clarity. For example, the selection criteria for the traits used in association analyses should be more explicitly explained. Additionally, the rationale behind using both the candidate gene and GWAS approaches should be stated more clearly. Response: Thank you for this suggestion. I will first reply to the first half of your point. We used POMS2 and SF-36v2 and our visual analog scale (VAS) to determine the trait of association analysis in this study. We have added the detailed reasons for selecting each investigation method and the case/control selection criteria in the Trait definition section on page 6-8 to make it clearer. We will then respond to the latter part of your comment. Although candidate gene analysis has high power and is useful for finding associations between SNPs in specific genes and symptoms, it may miss other important SNPs. Therefore, we also performed GWAS to more broadly analyze SNPs across genes related to Cit/NO metabolism and the trait. We have added the rationale for using the candidate gene and the GWAS approach in the sixth paragraph of the Discussion section (page 18, lines 408–410). Comment from Reviewer #2 Title The title is informative but could be refined for clarity. Consider simplifying it to “SNP Associations in the L-Citrulline Pathway and Vascular Aging in the Japanese Population.” Response: Thank you for pointing this out. We have revised the title based on your suggestion to make it simpler. Comment from Reviewer #2 Abstract The abstract is comprehensive but slightly dense. Simplifying some of the terminology for a broader audience would improve readability. Additionally, the abstract should briefly highlight the practical implications of the study findings. Response: Thank you for pointing this out. We have simplified the sentences and phrases to make the Abstract more readable and added a note of the practical implications of the study findings at the end. Comment from Reviewer #2 Figures and Tables The figures and tables are well-organized, but the legends could be more descriptive. Providing additional context for each figure would help readers better understand the results at a glance. Response: In response to your suggestion, we have added background explanations to the legend of each figure for better understanding by the reader. In Fig 1 legend, we have added a brief description of the main purpose of the figure and the results. In Fig 2 legend, we have added a description of the role of the genes encoded by SNPs observed to be associated with the Cit and NO pathways in our study. Comment from Reviewer #2 Terminology Consistency Ensure consistency in using abbreviations and technical terms throughout the manuscript. For example, "L-citrulline" should be consistently abbreviated as "Cit" after its first use. Response: Thank you very much for your direction. Again, we have checked the consistency of terminology throughout the manuscript and corrected the inadequacies. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0323778.r003
10 Mar 2025 Decision Letter - Asif Jan, Editor PONE-D-24-52040R1SNP associations in the L-citrulline metabolic pathway and vascular aging in the Japanese populationPLOS ONE Dear Dr. Morita, 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 Apr 24 2025 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, Asif Jan, 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.] [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.0323778.r004
Revision 2
31 Mar 2025 Author Response In addition to our previous response, we have added a statement regarding updating reference information. ________________________________________________ Dear Prof. Emily Chenette, Editor-in-Chief, PLoS ONE Manuscript Number: PONE-D-24-52040 Title: SNPs on the L-citrulline metabolic pathway are associated with specific health characteristics related to vascular aging in the Japanese population Authors: Dai Nogimura, Kazuki Moriyasu, Sachiko Ishida, Masakazu Kohda, Takayuki Yazawa, Masahiko Morita We would like to thank the two reviewers for their valuable comments, which we have used to revise our manuscript accordingly. These comments have helped us significantly improve our paper. Please see our revised manuscript and point-by-point response to the reviewers’ comments. We are writing the modified parts in red, and these parts were checked by a native English speaker. The authors felt the revised manuscript is a suitable response to the comments and has significantly improved over the initial submission. Thank you very much for your consideration and kind assistance. Sincerely yours, Masahiko Morita, Ph. D. Institute of Health Sciences, Kirin Holdings Company, Ltd. 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan Phone No: +81-90-3063-2127 Email Address: Masahiko_Morita@kirin.co.jp Response to the reviewers’ comments. Comment from Reviewer #1 The discussion should expand on how these genetic associations can be translated into personalized interventions for vascular aging. AND, Comment from Reviewer #2 1. Clinical Relevance and Practical Implications The manuscript provides significant findings on SNPs associated with vascular aging, but the discussion should emphasize how these genetic markers can be translated into clinical practice. For instance, the authors could elaborate on the potential for genotype-based supplementation of L-citrulline to improve vascular health in aging populations. Including more practical applications would make the study more impactful. Response: We strongly agree with the reviewer that the practical implications of the genetic associations in this study need to be considered. As you indicated, the results of this study support the validity of genotype-based Cit supplementation in the future, which might make personalized supplements beneficial. We have added a statement including the possibility of further research development in the final paragraph of the Discussion section (page 20-21, lines 472–476, 480, and 482–486). Comment from Reviewer #1 The limitation section is comprehensive, but it would be helpful to discuss potential future directions, such as validating these findings in other populations. AND, Comment from Reviewer #2 2. Broader Applicability of the Findings The study focuses exclusively on the Japanese population. It would be beneficial to discuss the generalizability of these findings to other ethnic groups. The authors could also mention the importance of validating these results in diverse populations to ensure broader applicability. Response: Thank you for your comments. As you indicated, future validation in different populations and races is needed to better ensure the association between the SNPs found in this study and the symptoms of vascular aging. We have added this point in the seventh paragraph of the Discussion section (page 20, lines 449–453). With the addition of this description, paper #55, which indicates that GWAS results are not always replicated in other populations or races, was newly added to the reference list. Comment from Reviewer #2 3. GWAS Results Interpretation The manuscript includes the genome-wide association study (GWAS) findings, but the interpretation of the identified SNPs could be more detailed. The authors should clarify the functional relevance of these SNPs and the way they impact downstream nitric oxide signaling, particularly for the newly identified associations. Response: Thank you for pointing this out. The interpretation of the SNPs identified in the GWAS is provided in paragraph 6 of the Discussion section. We have already discussed PRMT6 in depth for its involvement with the NO signaling pathway. In response to your suggestion, we have also added the gene for the other identified SNP (HSD17B11) on page 19, lines 439 to 444, regarding its possible association with vascular aging. With the addition of this description, paper #54, which indicates that gene expression of HSD17B11 was significantly reduced by nitroglycerin, known to have vasodilating properties, was newly added to the reference list. However, as mentioned on the same page in lines 444 to 446, no association with the Cit and NO action pathways has been reported. Comment from Reviewer #2 4. Methodological Details While the methodology is described in detail, some sections could benefit from additional clarity. For example, the selection criteria for the traits used in association analyses should be more explicitly explained. Additionally, the rationale behind using both the candidate gene and GWAS approaches should be stated more clearly. Response: Thank you for this suggestion. I will first reply to the first half of your point. We used POMS2 and SF-36v2 and our visual analog scale (VAS) to determine the trait of association analysis in this study. We have added the detailed reasons for selecting each investigation method and the case/control selection criteria in the Trait definition section on page 6-8 to make it clearer. We will then respond to the latter part of your comment. Although candidate gene analysis has high power and is useful for finding associations between SNPs in specific genes and symptoms, it may miss other important SNPs. Therefore, we also performed GWAS to more broadly analyze SNPs across genes related to Cit/NO metabolism and the trait. We have added the rationale for using the candidate gene and the GWAS approach in the sixth paragraph of the Discussion section (page 18, lines 408–410). Comment from Reviewer #2 Title The title is informative but could be refined for clarity. Consider simplifying it to “SNP Associations in the L-Citrulline Pathway and Vascular Aging in the Japanese Population.” Response: Thank you for pointing this out. We have revised the title based on your suggestion to make it simpler. Comment from Reviewer #2 Abstract The abstract is comprehensive but slightly dense. Simplifying some of the terminology for a broader audience would improve readability. Additionally, the abstract should briefly highlight the practical implications of the study findings. Response: Thank you for pointing this out. We have simplified the sentences and phrases to make the Abstract more readable and added a note of the practical implications of the study findings at the end. Comment from Reviewer #2 Figures and Tables The figures and tables are well-organized, but the legends could be more descriptive. Providing additional context for each figure would help readers better understand the results at a glance. Response: In response to your suggestion, we have added background explanations to the legend of each figure for better understanding by the reader. In Fig 1 legend, we have added a brief description of the main purpose of the figure and the results. In Fig 2 legend, we have added a description of the role of the genes encoded by SNPs observed to be associated with the Cit and NO pathways in our study. Comment from Reviewer #2 Terminology Consistency Ensure consistency in using abbreviations and technical terms throughout the manuscript. For example, "L-citrulline" should be consistently abbreviated as "Cit" after its first use. Response: Thank you very much for your direction. Again, we have checked the consistency of terminology throughout the manuscript and corrected the inadequacies. Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.docx https://doi.org/10.1371/journal.pone.0323778.r005
15 Apr 2025 Decision Letter - Asif Jan, Editor SNP associations in the L-citrulline metabolic pathway and vascular aging in the Japanese population PONE-D-24-52040R2 Dear Dr. Morita, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Asif Jan, Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0323778.r006
Formally Accepted
Acceptance Letter - Asif Jan, Editor PONE-D-24-52040R2 PLOS ONE Dear Dr. Morita, 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 You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days 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. Asif Jan Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0323778.r007

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