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PONE-D-23-34994Cuproptosis Genes in Predicting the Occurrence of Allergic Rhinitis and Pharmacological TreatmentPLOS ONE

Dear Dr. Yi,

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 11 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,

Salman Sadullah Usmani, Ph.D.

Academic Editor

PLOS ONE

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Additional Editor Comments:

The manuscript requires revisions to address few major concerns, including the need for a more focused introduction, updated citations, improved presentation of results, and clearer explanations in the methodology. Additionally, specific attention should be given to figure quality, molecular docking result discussions, and establishing connections between cytokine responses and identified genes.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Cuproptosis Genes in Predicting the Occurrence of Allergic Rhinitis and Pharmacological Treatment

The structure of the paper was well structured. But it is having following corrections

1. Proofread the entire manuscript.

2. Draw a graphical abstract to your study.

3. Compare your study with previous works.

4. Explain the novelty of the proposed approach.

Reviewer #2: In the current study, seasonal allergic rhinitis was investigated. Public microarray data were utilized for the analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Several selection algorithms were employed to identify signature genes, resulting in the identification of four such genes. Additional validation datasets were used to establish predictive efficiency. Consensus cluster analyses were performed to further categorize the seasonal allergic rhinitis (SAR) or cuprotosis genes into subsets. Finally, the SAR signature genes were utilized as targets for drug prediction and molecular docking to identify candidate drugs that may impact SAR.

Several major concerns have been addressed and should improve in the revised version.

1. The introduction section is too general. It should be objective-oriented and highlight what bioinformatics applications have already been accomplished, what updates are necessary, and what has been applied in the current article.

2. The data used in this article were published in 2015, and since then, many research groups have utilized it in their studies. However, those articles were not cited, and the results were not compared.

3. Author should provide the results such as DE analysis, pathway enrichment analysis and others in the supplementary table.

4. The limitation mentioned, "Due to constraints in time and human resources, no further experimental verification has been conducted," is not satisfactory.

5. Overall, the writing is of low quality. The sentence structure lacks consistency.

6. The sentence and logic should be corrected as follows:

"Differentially expressed genes (DEGs) between controls and SAR patients were analyzed using the limma package in R, as previously described [25]. DEGs were defined as genes with a fold change (FC) ≥ 1.3 and a p-value < 0.05. The dataset GSE118243 was employed as an independent validation set."

Additionally, the citation [25] in this context may be inappropriate, as it doesn't provide sufficient information about the implications of the limma package. The original limma package should be cited for clarity and accuracy.

7. In the subsection "2.2 Cuproptosis and immune-related genes," the collection method for cuproptosis genes is mentioned, but crucial details, such as the rationale behind selecting this gene set and the objectives for its utilization, are missing.

8. Figure 1D: A heatmap illustrating the correlation would be clearer than a circus. The author mentions, "Correlation analysis showed a strong correlation between these 10 SAR/cuprotosis genes." However, the importance of this correlation analysis and the implications of the results are not discussed and should be addressed.

9. In the results section, it is reported that there are 10 overlapped genes between the 478 DEGs and the 347 cuproptosis genes. However, the statistical significance level of this overlap is not reported.

10. In the result section, only the terms of the pathways are reported for the GO and KEGG pathway analysis. However, there is a lack of discussion regarding the association of these pathways with Allergic Rhinitis.

11. Lines 265-276: The gene MRPS30 is primarily associated with breast cancer or tumors, with no direct relation to Allergic Rhinitis. The author attempts to establish a distant connection, which may be challenging to substantiate experimentally. The same comment applies to the other three signature genes.

Reviewer #3: The study by Ting Yi et al. explores the new territory of cuproptosis, a novel programmed cell death mechanism, in the context of seasonal allergic rhinitis (SAR). The study leverages a comprehensive bioinformatics approach, combining differential gene analysis, algorithm-based identification of SAR signature genes, and subsequent exploration of their interactions with immune genes. Furthermore, the research hunts into the potential therapeutic implications by identifying candidate drugs through molecular docking. While the study is very interesting and adds up the knowledge to the current literature and has the potential to be a very nice resource in the field, I did have a few concerns about the current version, as detailed below:

• Many figures suffer from poor quality, appear blurry and difficult to read, and need to change with high resolution ones.

• The molecular docking results should be presented and discussed with clear justifications for the selection of 1,5-isoquinolinediol and gefitinib as potential SAR treatments, considering factors like binding affinity and specificity.

• There is no apparent connection between the discussed paragraphs (line numbers 250-264) and the context of SAR and associated cytokine responses. There is a noticeable gap, and the authors have not adequately addressed the association of these responses with the identified genes. Proper transition is needed to bridge the gap between SAR, cytokines response and identified genes.

• It is advised that the authors should define abbreviations at least in the first instance. E.g. GEO in abstract, please check for other in entire manuscript.

• There are a lot of definite and indefinite articles missing along with some grammatical errors, also please correct the manuscript for undefined spaces.

• Number of spelling mistakes/typo errors.

• Citations and references must be in the correct and uniform format, Italics missing in some places.

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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

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[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.

PONE-D-23-34994R1Cuproptosis Genes in Predicting the Occurrence of Allergic Rhinitis and Pharmacological TreatmentPLOS ONE

Dear Dr. Yi,

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 Jun 01 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,

Salman Sadullah Usmani, Ph.D.

Academic Editor

PLOS ONE

[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 #2: (No Response)

Reviewer #3: All comments have been addressed

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

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

Reviewer #2: Partly

Reviewer #3: Yes

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

Reviewer #2: N/A

Reviewer #3: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

Reviewer #3: (No Response)

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: No

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The response from the author is unsatisfactory. The reviewer attempted to identify gaps and deficiencies so that the

authors could improve them, making the manuscript more understandable for readers upon publication.

However, it appears the author lacks the inclination to enhance the manuscript. I and reviewer 3 suggested

improvements to the writing. In response, the author stated, "Before submission, I had already enlisted the help

of a friend who is a native English speaker from the USA to assist in polishing my article."

However, having a native speaker from a different field revise a research article may not be sufficient.

Additionally, the discussion of the results is inadequate. I recommend discussing the GO and KEGG pathway

enrichment results to establish connections between the disease and the identified pathways.

I did not ask an experimental study for the GO and KEGG pathway.

The author's overall response likely avoids the reviewer's query

Reviewer #3: The authors have effectively considered and incorporated the concerns highlighted earlier. The revisions made by the authors have substantially improved the manuscript. I think, the modified version now appears well-prepared for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

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[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.

PONE-D-23-34994R2Cuproptosis Genes in Predicting the Occurrence of Allergic Rhinitis and Pharmacological TreatmentPLOS ONE

Dear Dr. Yi,

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 Oct 21 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,

Salman Sadullah Usmani, 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.

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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 #2: (No Response)

Reviewer #4: (No Response)

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

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

Reviewer #2: No

Reviewer #4: Yes

**********

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

Reviewer #2: N/A

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 #2: No

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 #2: (No Response)

Reviewer #4: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The response from the author to the first review was neither complete nor satisfactory. Most of my comments from the first review were ignored, which I also mentioned in the second review. If the author thoroughly addresses those comments and fills the gaps, I can consider the submission positively. Otherwise, I will have to reject it.

Reviewer #4: The authors have investigated the relationship between cuproptosis genes and allergic rhinitis (SAR) using bioinformatics analysis. It identifies four signature genes (MRPS30, CLPX, MRPL13, MRPL53) as potential biomarkers for SAR, with strong predictive accuracy. The study also suggests potential drugs (1,5-isoquinolinediol and gefitinib) for SAR treatment based on molecular docking analysis. The research contributes new insights into SAR pathogenesis and potential therapeutic targets. However, I have the following minor comments, before considering the manuscript for publication:

1. Rephrase the sentence in the abstract: "Cuproptosis is a novel mechanism of programmed cell death that has not been studied about allergic rhinitis" to improve clarity. Suggestion: "Cuproptosis is a novel form of programmed cell death, and its role in allergic rhinitis has not yet been explored."

2. In the introduction, add a clearer transition between the description of allergic rhinitis and the relevance of cuproptosis to strengthen the connection between the two topics.

3. In the results section, explain why combining the signature genes (MRPS30, CLPX, MRPL13, and MRPL53) significantly improves the AUC values in predicting SAR, emphasizing the added value of the combination.

4. Ensure that the versions of bioinformatics tools (such as R packages or Enrichr) are mentioned in the methods section for reproducibility and transparency.

5. In the discussion, elaborate on the connection between cuproptosis and immune responses in allergic rhinitis, offering a brief explanation of how cuproptosis might influence immune cells involved in the allergic reaction.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #4: Yes: Sumeet Patiyal

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[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.

Cuproptosis Genes in Predicting the Occurrence of Allergic Rhinitis and Pharmacological Treatment

PONE-D-23-34994R3

Dear Dr. Yi,

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,

Vinay Kumar, 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 #2: (No Response)

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

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

Reviewer #2: No

**********

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

Reviewer #2: N/A

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

**********

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 #2: No

**********

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 #2: I appreciate the author's effort; however, I feel it does not fully resolve my key concerns, leaving important aspects of the manuscript unaddressed.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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