PONE-D-22-11884Cutaneous expression of Growth-Associated Protein 43 is not a compelling marker for human nerve regeneration after chronic focal nerve injuryPLOS ONE

Dear Dr. Schmid,

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PLOS ONE

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"ABS is supported by a Wellcome Trust Clinical Career Development Fellowship (222101/Z/20/Z) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The Oxford carpal tunnel cohort was supported by an advanced postdoc mobility fellowship from the Swiss National Science Foundation (P00P3-158835 to ABS) and an early career research grant from the International Association for the Study of Pain (to ABS). GB is supported by Diabetes UK (19/0005984). This research was funded in whole, or in part, by the Wellcome Trust [222101/Z/20/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission."

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Manuscript number: PONE-D-22-11884

Title: Cutaneous expression of Growth-Associated Protein 43 is not a compelling marker for human nerve regeneration after chronic focal nerve injury.

Overview and general recommendation:

GAP43 is a well-known marker for neuronal development/growth in embryo and regeneration after neuronal injury in adult rodent animal. Capral tunnel syndrome (CTS) is a typical model both for human sensory nerve degeneration due to nerve compression and regeneration after surgery decompression. The strength of the paper is that Carrol et al choose the optimized model to investigate the difference of GAP43+ immune-positive cutaneous nerve fibers before and after surgery and whether GAP43 expression is related to after surgery regeneration; The authors provided the meaningful and realistic results of GAP43+ fiber regeneration in chronic nerve injury of CTS in patients. This article is acceptable for publication after the. following points are addressed.

The major concerns:

Title: As this study only investigates the carpal tunnel syndrome patient’s index finger skin sample with average symptom duration 37.6 months, which belongs to chronic neuronal injury, it should be cautioned to expand the conclusion to all chronic focal nerve injury which may involve different mechanisms. I suggest that the title should be specified to carpal tunnel syndrome only.

The GAP43 immunofluorescence staining image: The study measures and expresses the GAP43+ fiber in a reasonable scientific way (Fig 1 and 2) with matched statistics calculation. I strongly suggest the authors provide data from PGP9.5 and GAP43 staining to show the audience that both fibers are effectively detected.

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Reviewer #1: No

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Attachments

Attachment

Submitted filename: 05.14.22 Plos one review .docx

PONE-D-22-11884R1Cutaneous expression of Growth-Associated Protein 43 is not a compelling marker for human nerve regeneration in carpal tunnel syndromePLOS ONE

Dear Dr. Schmid,

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. I agree with the reviewer that adding more images to Fig. 2 would be beneficial (especially those that show nerve terminals). 

Please submit your revised manuscript in 45 days after this decision letter. 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,

Michal Hetman

Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: 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 #1: Partly

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

Reviewer #1: Yes

**********

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

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Reviewer #1: Yes

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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 #1: Yes

**********

6. Review Comments to the Author

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

Reviewer #1: 08.15.22 Resubmission review

1. Title. I really appreciate that the author changed the title to make it specific to carpal tunnel syndrome.

2. The GAP43 immunofluorescence staining image needs minor revise. In figure 2, the PGP9.5 staining appears correct, however the GAP43 staining presents minor problem. Most of the GAP43 Cy3 color overlaps with PGP9.5 (AlexaFluor-488) and fails to show the difference between the two nociceptors. Consideration It is true that most GAP43+ fibers are usually positive for PGP9.5, even they might be different nociceptors, derived from different types of DRG neuron, thus they should have their own unique morphology. The overlapped immunofluorescence staining is a weakness of this image. Another weakness of this figure is the nerve bundle traveling inside the dermis is well presented, however, the axon terminals located inside the epidermis which is the most important part to distinguish the different type of nociceptor are not well stained. Therefore, it is difficult to discern the two types of nociceptors. Overall, considering the weakness of figure 2, I would suggest the author provide additional PGP9.5 and GAP43 double staining image with the emphasis on the fiber located within epidermis as a minor revise.

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Reviewer #1: No

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Attachments

Attachment

Submitted filename: 08.15.22 2nd review final 2.docx

Cutaneous expression of Growth-Associated Protein 43 is not a compelling marker for human nerve regeneration in carpal tunnel syndrome

PONE-D-22-11884R2

Dear Dr. Schmid,

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.

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Kind regards,

Michal Hetman

Academic Editor

PLOS ONE

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