Peer Review History
Original SubmissionAugust 30, 2020 |
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Pécs, Hungary October 13, 2020 PONE-D-20-27215 Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells PLOS ONE Dear Dr. Burman, 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 by the Reviewers, listed below. Please submit your revised manuscript by Nov 28 2020 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:
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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Joseph Najbauer, 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 2. Thank you for including your ethics statement: 'Ethics approval for the study was granted by the University of Cape Town (UCT) Faculty of Health Sciences Human Research Ethics Committee (HREC REF. 380/2009 and 434/2011), and was renewed annually, incorporating amendments to the project protocol where necessary. All methods were carried out in accordance with the guidelines approved by the Ethics Committee. Participants were recruited from the Neurogenetics clinic at Groote Schuur Hospital in Cape Town. Informed consent was obtained from all participants prior to their enrolment in the study.' Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. 3. Thank you for stating the following in the Acknowledgments Section of your manuscript: 'Funding for this work was provided by Ataxia UK, Commonwealth Scholarship Commission (UK), John Fell OUP Fund, National Research Foundation (South Africa), National Research Foundation (South Africa, Competitive Programme for Rated Researchers CPR20110624000019696), Medical Research Council (South Africa), Harry Crossley Foundation, Deutscher Akademischer Austausch Dienst, University of Cape Town Research Council, Wellcome Trust, Parkinson’s Disease UK, Medical Research Council UK, Blue Brain Project, and the James Martin 21st Century School.' We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 'The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.' Please include the updated Funding Statement in your cover letter. We will change the online submission form on your behalf. [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 Reviewer #2: Partly Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: No ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes Reviewer #3: I Don't Know Reviewer #4: Yes Reviewer #5: 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: No Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: 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 Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: 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 authors describe the electrofisiological and molecular features in iPS derivated cells derived from 2 SCA7 patients and 1 control. Although, the results could be interesting the manuscript contains a lot of errors and lacks some fundamental data and results. 1. Errors in references. In the page 7 the authors cite the reference 16 what is not their previous article and is not related to the text. 2. Material and methods. Retinal differentiation lack some fundamental details. It is not clear until which day of differentiation toward retinal cells, the cells were maintained. 3. The Supplementary Fig 2 should include the sequencing results to confirm the the disease genotype 4. Page 7. The authors claim” the reprogramming Sendai virus, were confirmed by immunocytochemistry (antibodies listed in S1-2 Tables). The expression of selected pluripotency genes (OCT4, SOX2, NANOG) was determined by quantitative PCR. All results related to confirmation of silencing of the virus (RT-PCR is normally used) and expression of the endogenous pluripotent genes should be shown in manuscript. Also the shape of the colonies. The alkaline phosphate assay is missing of undifferentiated cells. Also panel should include differentiation capacity to three embryonic layers at least for 2 markers for each layer. And this all for 3 generated lines. Fingerprint analysis of generated lines is missing. Other pluripotency markers are missing for immune in S3 Figure. S3 B Hoecht staining is of low quality for the first figure. Immunocytochemistry has to be shown for all three lines (the best clon of each) It is not clear what C1, C2 and others mean. Different clones of the same patient and Control lines??? It is strange that C2 and P2b does not express OCT2. Are they pluripotent? It is not clear why the authors continu the differentiation with iPS lines with no expression of pluripotent markers. Or the authors did not include tha data to confirm a full pluripotency of the generated lines. No data which representative iPS line is shown in S3 The data is lacking. 5. Results: Fig 1B the immune staining is low quality. The cells have no neuronal forms. Fig 1C It is strange that expression of PAX6 is so low and it is early neural marker. Fig 1 D n=2 for these kind of data is too low. 6. Fig4. All cells are recoverin positive. Normally this protocol generates small yield of recoverin positive cells. It is no clear how many baches of differentiation protocol were used for statistical analysis. In conclusion, the manuscript does not have sufficient technical level for publication in PLOS ONE. Experiments, statistics, and other analyses are not performed to a high technical standard and are not described in sufficient detail Reviewer #2: Manuscript by Burman, Watson, Smith et al. is a very interesting and valuable study of SCA7 pathology in patient-derived cell lines. These cell lines include iPSCs, reprogrammed from human fibroblasts, as well as cell lines obtained by neuronal differentiation. Neuronal cells were assessed for electrophysiological properties and examined for transcriptional aberrations. Cell lines were characterized comprehensively, both iPSCs and neuronal cell lines. My major concern is about the number of cell lines generated and analyzed. I do understand that generation and characterization of this kind of cell lines is difficult and often troublemaking. But the issue here is whether the use of this number of cell lines is enough for conclusions made. In numerous studies isogenic cell lines are used, which is more proper approach when only small number of cell lines can be used (due to complicated experimental setup etc.). I would find the results more convincing if the experiments were performed for more cell lines. For example the results presented in the Figure 3E, although the tendency of change is not consistent for SCA7 cell lines, is shown as statistically significant lowering of the measured parameter in Fig. 3F. The same refers to results presented in Fig. 3 G and H. First of all, it is not quite clear from the lines 107-108 and 127-128 how many control cell lines were generated. I see in Fig. S1 that two clones of control cell line were analyzed, but lines 127-128 could be rephrased to state this clearly. For results presented in Fig. 1D, n is 2 for control samples, but actually two clones of the same cell line were used. Were the results very consistent for these clones? If so treating them as two control cell lines is a bit misleading. If no – why? Lines 316-317: Again naming two clones of iPSC line as “two separated iPSC lines” is misleading. Other major comments: - Images in figure 1F for SCA7 and control cell line do not look like performed with identical settings. Also for better comparison they should be at the same magnification. - I cannot see reference to Fig. 1F in the text, whereas reference to Fig. 1E is only in the discussion. The same refers to Fig. 2 A-D. This is confusing. Minor comments: - Line 119: “quantitative RT-PCR” should be mentioned (RT – reverse transcription), instead of “quantitative PCR” (and throughout the text: RT-qPCR or qRT-PCR, instead of qPCR) - I found some essential references missing, like recent review papers: PMID: 31792895, 31432449; as well as experimental ones: 27999335, 31859031 - Table S1: it is valuable also to mention catalogue numbers as some suppliers have several antibodies for specific protein - Fig. 1A: green word “NESTIN” is hardly visible when placed at the image. The same refers to Fig. 4 A-C. - Line 406: two patients can be named a “cohort”? Reviewer #3: Burman et al present the novel generation of patient-derived iPSC models of SCA7. Differentiation of iPSCs to neurons and photoreceptors enabled the finding of electrophysiological immaturity in SCA7 neurons and transcriptional alterations resulting from ATXN7 repeat expansions. The work is original and well carried out and the manuscript is very well written. I am supportive of its publication in PLOS ONE, with some minor consideration for the authors. 1) Please can you clarify the number of batches of retinal cells used in Fig 4H (line 386). Is this 2 batches of patient cells relative to 1 control batch, or are both clones represented? I would say that two batches are minimum for this type of analysis. 2) Please can you expand upon the iPSC culture conditions. Line 114. KOSR percentage, bFGF concentration. How were the colonies manually passaged? 3) Line 150 – how many days of induction was performed before NSCs were produced? How many passages were NPCs cultured for before neural induction. Was this consistent between controls and patients? Neural and glial potential can shift with prolonged NSC passaging and maybe this is worth mentioning in the discussion? 4) Consider a statistics section. I am unsure why Fig 2E used Chi-squared, Fig 3C used Kruskal Wallis and Fig 3E/G used ANOVA. Minor Line 342 please correct iPS to iPSC Line 365 please correct sentence, e.g. is “we asked” missing? Line 427 please correct sentence, e.g. is “are significant” missing? Reviewer #4: The manuscript by Burman et al. assesses molecular and electrophysiological features of neurons and retinal photoreceptor cells derived from induced pluripotent stem cells (iPSCs) that were reprogrammed from fibroblasts from two unrelated patients suffering from spinocerebellar ataxia type seven (SCA-7), and compared them with iPSC-derived cells from one healthy control donor. Authors report transcriptional aberrations in SCA-7 patient derived neural stem cells as well as photoreceptor cells, and differences in resting membrane potential and input resistance between control and SCA-7 patient derived neurons. Although the study is mainly descriptive due to the low number of subjects (2 patients and 1 healthy control), it is scientifically sound and the results are relevant for future studies on iPSC-based phenotyping of neurodegenerative diseases. I recommend resolving only two very minor issues before publication: 1. The references to some of the figures in the main text is incorrect, and – in those cases – does not correspond to the figure legends (lines 280, 282, 294, 295). 2. The sentence in line 365 on p. 18 is incomplete. Reviewer #5: Within the manuscript Burman et al. generated iPSCs from two SCA7 patients and one control, differentiated iPSCs into iPSC-derived neurons and photoreceptors and analysed the molecular and electrophysiological properties of these cells. Unfortunately, the inaccurate and incomplete experimental setup does not allow to draw any final conclusions. This has mainly two major reasons: - The line to line variability independent from the disease background is to high to only use 2 control lines (derived from the same individual) and 2 patient lines. The authors claim that SCA7 patients show electrophysiological differences, although the electrophysiological results are variable and inconclusive towards a maturation phenotype. Timing of electrical maturation can greatly vary among different iPSC lines. Therefore, in order to compare control to diseased neurons, analysis of multiple electrophysiological parameters might be more predictive. To confirm a developmental functional phenotype analysis of multiple control and patient lines especially at different time points during the differentiation is absolutely essential. - the characterisation of differentiated cells (neurons and retinal photoreceptors) is too inaccurate. Thereforem it is unclear if line to line differences only occur due to different compositions of cell types and/or different differentiation stages (cultivation artefact). Detailed comments: Electrophysiology: - In general there are nearly no differences between the control (C1a / C1b) and the matching patient line (P2b) Inconsistent data: 298 - the spiking response of a cell to current injection can be used to determine the maturation stage of a differentiating neuron 424 - Despite the presence of significant differences in spiking responses between the four cell lines, we did not observe a reliable trend between the control and patient derived neurons. - No differences of SCA7 neurons in neuronal maturity as determined by the occurrence of single and multiple action potentials (Fig 2E) 310 - The resting membrane potentials (Vm) of cells varied significantly across each cell line. The Vm derived from SCA7 patient lines was significantly more hyperpolarised compared to the control cell lines. - No explanation within the text on how resting membrane potential is relevant or indicative for impaired neuronal health or maturation. - Generally, increasingly hyperpolarized resting membrane potentials are a hallmark of maturation. In this respect, pooled SCA7 patient lines show a more mature phenotype. 332 - Next, we performed voltage-clamp recordings of the neurons in order to measure the input resistance as well as the voltage-gated sodium and potassium currents (Fig 3A-B). A lower input resistance is associated with neurite outgrowth and increased numbers of ion channels inserted into the plasma membrane during the process of neuronal maturation. (…). Cells derived from SCA7 patient lines had a significantly higher mean input resistance than cells from the control lines (Fig 3D, p = 0.01, Mann-Whitney U test). - Generally, neurons change developmentally with a decrease in input resistance. In this respect, pooled SCA7 patient lines show a more immature phenotype 341 - (Fig 3) Sodium and potassium currents in neurons differentiated from control and patient iPS cell lines 360 - When pooled together, however, we noted that both the Max IK and Max INa were significantly smaller in the cell lines coming from SCA7 patients compared to the control cell lines. - High variance between patient lines, only significantly different from controls when pooled together - Increasing max sodium and potassium currents reflect the process of electrical maturation. In this regard, SCA7 patient lines show a more immature phenotype Expression analysis: - Why were only NPCs used for the analysis in Fig. 1D? What about iPSC-derived neurons? - It is unclear how the qPCR results were normalized (two control lines?) - High variance in Fig. 4 D-G between the two control lines. How was this normalized in Fig. 4H? General comments: - In depth characterisation of iPSCs is missing (Suppl. Fig.) - Where multiple housekeeping genes used for qPCR quantification? - p15, l282: Fig 2G-H: data not shown, Fig. 1? - The type of generated neurons is unclear (any marker? glutamatergic, GABAergic, regional identity?) - Which lines were used for the representative images of the ICC stainings? - p19, ll 375-376: Obvious difference: The expression of CRX in control and SCA7 cells seems to be different (Fig. 4B) ********** 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 Reviewer #4: No Reviewer #5: 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. |
Revision 1 |
Pécs, Hungary December 28, 2020 PONE-D-20-27215R1 Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells PLOS ONE Dear Dr. Burman, Thank you for submitting your manuscript (R1 version) 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 by Reviewer #2 and Reviewer #5, listed below. Please submit your revised manuscript by Feb 13 2021 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:
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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Joseph Najbauer, 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 #1: All comments have been addressed Reviewer #2: (No Response) Reviewer #3: All comments have been addressed Reviewer #4: All comments have been addressed Reviewer #5: (No Response) ********** 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: Yes Reviewer #2: Partly Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: No ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: No ********** 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 #1: Yes Reviewer #2: No Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: 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 #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: 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: The authors addressed properly all my concerns. They replied correctly. Reviewer #2: The majority of my comments was sufficiently addressed, except for the comment concerning interpretation of the results based on two SCA7 cell lines analyzed. First of all, I am not convinced by explanation for not generating isogenic cell lines by comparison with DMPK gene. I know that the CRISPR/Cas-9-based strategy is difficult to be applied for repeated tracts and its application for this study would take a long time. Still, there are studies like PMID: 28238795 and 32182692 which show application of such strategy for huntingtin, where CAG repeat tract is also present in ORF. It can be referred and commented instead. Unfortunately, in attached files I could not access current version of Fig. 3. (zip files contained only main figures 1 and 4) which was changed as I see in this figure legend and the interpretation. Reviewer #3: The authors have satisfactorily addressed my comments. I recommend that this manuscript is appropriate for publication. Reviewer #4: (No Response) Reviewer #5: Unfortunately the revised manuscript "Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells" does not lead to any improvement in either of the two main critical points. 1.) Since the line to line variability is too high, no conclusive results can be obtained. 2.) Even more important, the identity of differentiated cell types (either neurons or retinal photoreceptors) is still more or less unknown. As the authors stated in their response: "The low cell numbers and heterogeneity of mature neuronal cultures proved a challenge to obtaining significant biological material to perform reliable expression analysis." If even such an analysis was not possible, then the results of the electrophysiological recordings are inappropriate. The maturity and the cellular composition/identity of differentiated neurons determines the electrophysiological properties. Therefore, it can not be excluded that the "features of functional aberrations" in SCA7 iPSC-derived neurons are a cell culture artefact rather than a consequence of the mutation. Without any additional experiments to prove the identity of differentiated neurons (proportion of GABAergic vs. glutamatergic neurons / neuronal subtype specification) and photoreceptors no conclusive findings can be formulated. ********** 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 #1: No Reviewer #2: No Reviewer #3: No Reviewer #4: No Reviewer #5: 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. |
Revision 2 |
Pécs, Hungary February 7, 2021 Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells PONE-D-20-27215R2 Dear Dr. Burman, We’re pleased to inform you that your manuscript (R2 version) 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, Joseph Najbauer, Ph.D. Academic Editor PLOS ONE ------------------------------------------------------ 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: All comments have been addressed Reviewer #5: (No Response) ********** 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: Yes Reviewer #5: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Reviewer #5: 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: Yes Reviewer #5: 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: Yes Reviewer #5: 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 #2: (No Response) Reviewer #5: I fully understand that under the current COVID 19-crisis it is difficult to perform the necessary experiments to address my two main points of criticism (line to line variability, missing characterization of differentiated cells). I still believe that analyzing patients to controls without knowing the identity and potential differences of the differentiated cell type is a major error which makes any interpretation of the existing data difficult. Nevertheless this study may be a good starting point for the establishment of a patient-derived model to investigate pathogenic mechanism in SCA7. ********** 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 #5: No |
Formally Accepted |
PONE-D-20-27215R2 Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells Dear Dr. Burman: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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. Joseph Najbauer Academic Editor PLOS ONE |
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