PONE-D-24-57016Carbohydrate sulfotransferase 14 gene deletion induces dermatan sulfate deficiency and affects collagen structure and bowel contractionPLOS ONE

Dear Dr. Yoshizawa,

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 17 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,

Nikos K Karamanos, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. To comply with PLOS ONE submissions requirements, in your Methods section, please provide additional information regarding the experiments involving animals and ensure you have included details on (1) methods of sacrifice, (2)and  efforts to alleviate suffering.

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.

Additional Editor Comments:

It is an interesting and well contacted experiment study. Points given by rev I are valid and well could improve the quality of this study further. Therefore authors may revise the manuscript accordingly. It may be useful that authors give recent refs in the theme,

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Partly

**********

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

Reviewer #1: 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

**********

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

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

Reviewer #1: Yes

**********

5. Review Comments to the Author

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

Reviewer #1: The work by Fumiko Ono aimed To determine the effects of DS deficiency on the gastrointestinal tract. The experimental procedures outlined in the manuscript provide a comprehensive approach to investigating the effects of dermatan sulfate (DS) deficiency on colonic structure and function in Chst14 knockout mice. The authors performed a variety of experiments, including histological analyses, collagen fibril assessments, and a dextran sulfate sodium (DSS) colitis model, to evaluate the physiological and pathological consequences of DS deficiency.

Support for Conclusions:

- Collagen Structure: The results indicate that collagen fibrils in the colon of Chst14-/- mice were abnormally arranged and exhibited smaller diameters compared to wild-type mice, which supports the conclusion that DS deficiency affects collagen assembly.

- Colonic Function: The findings of increased colonic contraction and shorter colon length in Chst14-/- mice suggest that DS plays a role in regulating colonic physiology. However, the lack of significant differences in defecation volume, food intake, and gastrointestinal transit time implies that physiological function may not be severely impacted in the same way it is in humans with mcEDS.

- DSS Colitis Model: The study found no significant aggravation of colitis in Chst14-/- mice compared to wild-type mice, suggesting that DS deficiency does not worsen inflammation or healing in the colonic context.

Critiques:

- In-depth Mechanistic Studies: The study could benefit from further mechanistic investigations to elucidate the specific pathways through which DS affects collagen assembly and colonic contraction. This could include exploring the molecular interactions between DS and collagen or other extracellular matrix components.

- Broader Physiological Assessments: Additional experiments assessing other aspects of gastrointestinal function, such as motility patterns or responses to food intake, could provide a more complete picture of how DS deficiency affects the colon.

- Longitudinal Studies: Conducting longitudinal studies could help determine if the observed effects in Chst14-/- mice change over time or with age, which may provide insights into the progression of symptoms that occur in patients with mcEDS.

- Inclusion of Female Mice: The study primarily used male mice to avoid gender-related variations. Including female mice in future experiments could provide more comprehensive data and help understand any potential gender differences in DS function.

- Comparative Studies with Human Tissue: Comparing the findings in mouse models with human tissue samples from mcEDS patients could validate the translational relevance of the animal model and refine the conclusions drawn from the study.

Overall, while the experimental procedures and results support the conclusions, the study could be strengthened by addressing the critiques and incorporating the suggestions mentioned above to provide a deeper understanding of DS's role in colonic physiology and pathology.

**********

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:  Mauro Sergio Pavao

**********

[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.

Carbohydrate sulfotransferase 14 gene deletion induces dermatan sulfate deficiency and affects collagen structure and bowel contraction

PONE-D-24-57016R1

Dear Dr. Yoshizawa,

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,

Nikos K Karamanos, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: