https://orcid.org/0009-0004-3254-6144
Peer Review History
| Original SubmissionDecember 22, 2025 |
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-->PONE-D-25-65980-->-->Integrated NEK7-inflammasome and platelet signature delineates a diagnostic model in heart failure-->-->PLOS One Dear Dr. Dai, 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 21 2026 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: 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, Xuebo Zhang, 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. Please note that PLOS One has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, all author-generated code must be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. 3. 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Thank you for stating the following financial disclosure: This study was funded by the National Natural Science Foundation of China (Grant Nos. 82260079, 82360079, and 82400468) and the Guizhou Provincial Science and Technology Projects (Grant No. Guizhou Science and Technology Cooperation Support Program [2024] General 160). Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 6. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 7. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor’s input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. 8. Please remove your figures from within your manuscript file, leaving only the individual TIFF/EPS image files, uploaded separately. These will be automatically included in the reviewers’ PDF. 9. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service. The American Journal Experts (AJE) (https://www.aje.com/) is one such service that has extensive experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. Please note that having the manuscript copyedited by AJE or any other editing services does not guarantee selection for peer review or acceptance for publication. Upon resubmission, please provide the following The name of the colleague or the details of the professional service that edited your manuscript A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a *supporting information* file) A clean copy of the edited manuscript (uploaded as the new *manuscript* file) 10. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. [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: Yes ********** -->2. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes Reviewer #2: Yes ********** -->3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: Yes Reviewer #2: Yes ********** -->4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.--> Reviewer #1: Yes Reviewer #2: Yes ********** -->5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: Dear Authors, The manuscript addresses an important question and uses appropriate multi-omics and machine-learning approaches; however, major revision is required before it can be considered for publication. Please reduce the length of the manuscript, particularly the Results section. Several downstream analyses (e.g., extensive pseudotime analysis, cell–cell communication, TF–miRNA networks, and molecular docking) can be condensed or moved to the Supplementary Materials. The diagnostic model requires stronger validation. The very high AUC suggests potential overfitting; external validation or robust cross-validation should be performed and clearly reported. Tone down mechanistic and causal claims, especially regarding the NEK7–platelet–fibrosis axis, and clearly frame conclusions as associative or hypothesis-generating where appropriate. The link to platelet activation is indirect; this limitation should be explicitly acknowledged, and conclusions adjusted accordingly. The animal experiment sample size (n=3/group) is limited; please discuss its impact on statistical power and interpretation, particularly for ISLR, which shows non-significant changes. Clearly report multiple-testing corrections for immune infiltration and regulatory network analyses. Provide full model parameters (coefficients and intercept) for the nomogram to ensure reproducibility. Add a concise Limitations subsection in the Discussion addressing dataset size, overfitting risk, and the correlational nature of the analyses. No concerns regarding data availability, ethics, or dual publication were identified. These revisions will substantially improve clarity, rigor, and suitability for publication. Reviewer #2: Performance reporting in the external validation cohort This manuscript presents a technically rigorous and well-integrated multi-omics investigation into the molecular architecture of heart failure, identifying a fibroblast-centered gene signature that links NEK7-mediated inflammasome activation, platelet signaling, and TGF-β–associated fibrosis. The study is methodologically strong and addresses an important gap in current heart failure research by moving beyond single-gene biomarkers toward a systems-level, biologically coherent signature. A major strength of the work is its layered analytical design, combining bulk RNA-seq from independent cohorts, single-cell transcriptomic analysis, network-based approaches (WGCNA), complementary machine-learning feature selection methods (LASSO and SVM-RFE), and experimental validation in an established murine heart failure model. The convergence of results across these independent methodologies substantially strengthens the credibility of the findings and reduces the likelihood that the identified signature is dataset- or method-specific. minor comments The manuscript reports an exceptionally high diagnostic performance for the nomogram (AUC = 0.993; Fig. 5C, Results section, pp. 32–33). While impressive, it is not sufficiently clear whether this performance refers to the training cohort (GSE116250) or the independent validation cohort (GSE57338). To strengthen confidence in generalizability, the authors should explicitly report, for the validation dataset (GSE57338; Methods, p. 14): AUC with 95% confidence intervals Calibration metrics (e.g., calibration slope/intercept or calibration plot) Sensitivity and specificity at a prespecified decision threshold Precision–recall AUC, particularly if class imbalance is present Reporting validation-specific performance metrics would address concerns that the near-perfect AUC may reflect optimism rather than true external discrimination. Clarification of batch effects and platform harmonization The study integrates datasets generated from different platforms (GSE116250 vs. GSE57338; Methods, p. 14). However, the manuscript does not clearly state how batch effects or platform-specific biases were handled. The authors should clarify whether they: Normalized datasets independently, Applied batch-correction methods (e.g., ComBat or similar), ensuring no outcome information was used, or Used rank-based or pathway-level scoring approaches to mitigate platform effects This clarification is important to exclude the possibility that technical differences contributed to the strong discrimination. Model transparency and reproducibility For clinical and translational interpretability, the manuscript would benefit from explicitly reporting: Logistic regression coefficients (β values) and intercept for the nomogram The exact scoring rule used in the nomogram (Results, Fig. 5A, p. 32) A supplementary table or code snippet enabling reproduction of the diagnostic model Providing these details would substantially enhance reproducibility and downstream utility. Moderation of translational claims While the identified four-gene signature shows strong diagnostic potential, the language in the Discussion and Conclusion (pp. 39–40) would benefit from slight moderation. Referring to the model as a “candidate diagnostic signature” rather than a ready diagnostic tool would more accurately reflect the current level of validation. Similarly, the molecular docking results (Results, Fig. 9, pp. 39–40) should be clearly framed as hypothesis-generating, rather than as evidence of therapeutic efficacy. ********** -->6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.--> Reviewer #1: No Reviewer #2: Yes: A.abbasi ********** [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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. |
| Revision 1 |
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-->PONE-D-25-65980R1-->-->Integrated NEK7-inflammasome and platelet signature delineates a diagnostic model in heart failure-->-->PLOS One Dear Dr. Dai, 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. It should be noted that the authors should not consider any citations from reviewers' requests. Please submit your revised manuscript by Mar 23 2026 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: 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, Xuebo Zhang, Ph.D. Academic Editor PLOS One Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. [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 #3: All comments have been addressed ********** -->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 Reviewer #3: Yes ********** -->3. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes Reviewer #3: 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 #1: Yes Reviewer #3: 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 #3: 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: This manuscript presents a comprehensive multi-omics investigation into a NEK7-associated fibro-inflammatory gene signature in heart failure. The integrative analytical framework—combining bulk RNA-seq, single-cell analysis, machine learning, and experimental validation—is methodologically solid and addresses a biologically relevant question. The convergence of findings across independent datasets strengthens the credibility of the identified four-gene signature. However, several issues warrant attention. The exceptionally high training AUC suggests potential overfitting, and although external validation was performed, the reported poor calibration in the validation cohort raises concerns regarding model generalizability. This should be transparently reported and discussed rather than minimized. The animal validation is limited by small sample size (n=3/group) and lack of protein-level confirmation, reducing biological robustness. In addition, immune infiltration and regulatory network analyses were conducted without formal multiple-testing correction, which increases the risk of false-positive findings. Mechanistic interpretations of the NEK7–platelet–fibrosis axis remain largely correlational and should be framed cautiously. No concerns regarding dual publication, research ethics, or competing interests are apparent based on the materials provided. Overall, the study is scientifically interesting and potentially publishable after minor-to-moderate revision focusing on transparency, calibration reporting, and cautious interpretation of translational implications. Reviewer #3: Review of Manuscript PONE-D-25-65980: "Integrated NEK7-inflammasome and platelet signature delineates a diagnostic model in heart failure" Overall Assessment: This is a well-conceived and comprehensive study that integrates multi-omics data and machine learning to identify a novel four-gene signature (TIMP2, COL16A1, MDK, ISLR) associated with NEK7-mediated inflammation and platelet activation in heart failure (HF). The work is analytically robust, employs appropriate and sophisticated bioinformatic methodologies, and presents a compelling narrative linking fibrosis, inflammation, and thrombosis in HF pathogenesis. The construction of a high-accuracy diagnostic nomogram (AUC=0.993) is a significant finding. However, several major and minor concerns must be addressed to strengthen the manuscript’s validity, clarity, and translational impact before publication. --- Major Concerns 1. Validation and Overfitting Risk: The reported diagnostic accuracy (AUC 0.993) is exceptionally high. While internal validation is performed on GSE57338, this is still a retrospective, public dataset. There is a significant risk of model overfitting to the specific cohorts used (GSE116250 for training/feature selection). The authors must: Explicitly discuss the potential for overfitting in the Limitations section. Provide more robust validation. Ideally, this should involve an independent, prospective clinical cohort with blood or tissue samples to test the signature’s diagnostic performance in a real-world setting. If this is not feasible within the current study, the limitations section must strongly emphasize this as a critical next step and temper claims of immediate clinical translatability. Perform cross-validation (e.g., leave-one-out or repeated k-fold) during the model-building process in the training set and report those metrics. 2. Functional Link Between Signature and Platelet Activation: The core hypothesis links the gene signature to platelet activation. However, the evidence for this link is primarily bioinformatic (correlation with a platelet gene set). There is a lack of direct experimental or causal evidence connecting the upregulation of TIMP2, COL16A1, MDK, or ISLR in cardiac fibroblasts to platelet hyperactivity or its consequences in HF. The authors should either: Acknowledge this as a key limitation and frame the signature as "associated with a platelet activation gene program" rather than implying a direct mechanistic role in platelet biology. Or, propose and (if possible, preliminarily) test a more direct connection. For example, could conditioned media from fibroblasts overexpressing these genes activate platelets in vitro? Are protein levels of these markers correlated with plasma markers of platelet activation (e.g., soluble P-selectin, PF4) in available patient serum/plasma data? 3. Animal Model Validation: The in vivo validation is limited to mRNA expression in an Ang-II model (n=3/group). The sample size is very small, limiting statistical power. More importantly, protein-level validation (western blot, immunohistochemistry) of the key genes in the murine hearts and, if possible, in human HF tissue samples is crucial to confirm the bioinformatic predictions. The non-significant result for Islr (P=0.5691) is appropriately discussed but warrants deeper investigation. Is this due to species differences, timing, or post-transcriptional regulation? IHC could clarify if ISLR protein is localized differently or expressed in a relevant cell type. 4. Diagnostic Utility and Clinical Context: The discussion comparing the nomogram’s AUC (0.993) to BNP/NT-proBNP (AUC ~0.95-0.99 for HF vs. healthy) requires more nuance. The critical clinical challenge is not distinguishing severe HF from healthy controls, but early detection, differential diagnosis (e.g., HFpEF vs. pulmonary disease), or prognostication. The authors should: Test or discuss how their signature performs in these more challenging, clinically relevant scenarios using available data (e.g., stratifying within HF subgroups). Clarify the intended clinical specimen for this test. Is it intended for cardiac tissue (limiting utility) or is there evidence these genes are detectable in peripheral blood (e.g., in circulating fibroblasts, extracellular vesicles, or as soluble proteins)? Minor Concerns 1. Methods Clarity: WGCNA Parameters: Please specify the network type (signed/unsigned) chosen for WGCNA and the rationale. Single-cell Analysis: For Seurat analysis, state the normalization method used (`LogNormalize` or `SCTransform`). The criteria for selecting 30 PCs should be better justified (e.g., elbow plot shown in Suppl.). Molecular Docking: Briefly describe the preparation steps for the protein structures (e.g., missing loops, protonation state). The threshold Vina score ≤ -5.0 kcal/mol is acceptable but consider that stronger binders typically have scores < -7.0 kcal/mol; comment on the predicted binding affinities. 2. Results Presentation: Figure 2G: The heatmap shows module-trait correlations. Please ensure the color scale is clearly labeled, and the statistical significance (p-values) for the key turquoise module correlation with both traits is indicated in the figure or legend. Immune Infiltration: The positive correlation between NEK7 and CD56dim NK cells is interesting. Could the authors speculate briefly in the discussion on the potential role of this immune subset in the NEK7-inflammasome-platelet axis? CellChat Analysis: The finding of MIF-(CD74+CD44) as a key ligand-receptor pair is notable. Is MIF expression part of the identified gene signature or upregulated in HF fibroblasts? A brief comment would connect this communication finding back to the core signature. 3. Discussion & Limitations: The limitations section is good but should be expanded as per the major points above (overfitting, lack of functional platelet link, preliminary animal data). The therapeutic implications (β-Heparin/MDK, WZ4002/NEK7) are speculative but interesting. Acknowledge that molecular docking is a predictive starting point requiring extensive experimental validation. 4. Writing and Formatting: Minor grammatical errors and typos are present (e.g., "offers" should be "offer" in Conclusion, Page 10 line 43; "data abases" Page 21). A thorough proofread is needed. Ensure all figure and table citations in the text are correct (e.g., reference to S1-S4 Figs., S1-S19 Tables). The Data Availability Statement is slightly confusing and repetitive. It mentions Figshare deposition "under moderation" and a Mendeley Data DOI. Please consolidate to one definitive, publicly accessible repository and provide the final, working DOI/accession. Decision:Major Revision Required. The manuscript presents a novel and potentially important finding in HF research. The analytical approach is strong. However, the concerns regarding overfitting, the indirect nature of the platelet activation link, and the preliminary nature of the experimental validation are substantial and must be adequately addressed through textual revisions, additional analyses where possible, and a more balanced discussion of limitations and future directions. With satisfactory revisions, this work could make a valuable contribution to the field. ********** -->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 #3: 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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. |
| Revision 2 |
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-->PONE-D-25-65980R2-->-->Integrated NEK7-inflammasome and platelet signature delineates a diagnostic model in heart failure-->-->PLOS One Dear Dr. Dai, 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 14 2026 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: 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. As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only the individual author can complete the verification step; PLOS staff cannot verify ORCID iDs on behalf of authors. We look forward to receiving your revised manuscript. Kind regards, Austin W.T. Chiang Academic Editor PLOS One Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Additional Editor Comments: The authors have made some useful revisions, including adding another public dataset, expanding the limitations section, and softening some mechanistic wording. However, several major concerns remain insufficiently addressed. – The additional validation dataset, GSE5406, is not adequately justified, and the authors do not clearly explain whether it is comparable to the model-development dataset. The risk of overfitting also remains because the authors have not provided sufficient additional validation analyses, such as repeated cross-validation, bootstrap optimism correction, or detailed calibration assessment across datasets. – The animal validation also remains weak because it is based on n=3 animals per group and mRNA-level qPCR only. The authors did not increase the sample size or provide protein-level validation. Therefore, the animal data should be described as preliminary support rather than confirmatory validation. – In addition, the proposed link between the four-gene signature and platelet activation remains mainly correlative. The manuscript should avoid causal or mechanistic claims unless supported by direct functional evidence. Because the manuscript presents a diagnostic model, the authors must also address the requirements for utility, validity, and availability. At present, the model’s clinical utility is not established because it is based on cardiac tissue datasets and has not been validated in prospective cohorts, blood-based samples, or clinically relevant diagnostic settings. Therefore, before further consideration, the authors should either provide stronger validation and additional analyses to support the diagnostic-model claim, or substantially reframe the manuscript as a hypothesis-generating transcriptomic study rather than a validated diagnostic tool. [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 #3: All comments have been addressed ********** -->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 #3: Yes ********** -->3. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes Reviewer #3: 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 #1: Yes Reviewer #3: 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 #3: 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 manuscript has been substantially improved following revision. It is methodologically sound and presents a robust multi-omics analysis of a relevant question in heart failure. Major concerns, including overfitting risk, lack of multiple-testing correction, and mechanistic overinterpretation, have been adequately addressed. Statistical rigor has been strengthened, additional validation has been provided, and interpretations have been appropriately tempered. Remaining limitations are clearly acknowledged and do not compromise the overall validity. The manuscript is suitable for publication, with no concerns regarding ethics, data availability, or competing interests. Reviewer #3: The author’s response to the review comments is comprehensive, detailed, and highly constructive. They not only made targeted revisions to the manuscript, but more importantly, demonstrated a profound understanding of the limitations of the research and a commitment to scientific rigor during the revisions. The addition of external validation, cautious wording of core hypotheses, and clear planning for future research directions have all substantially improved the quality of the manuscript. This manuscript currently meets the publishing standards of PLOS ONE. The author perfectly answered the vast majority of questions raised by the reviewers and made convincing revisions to the manuscript. ********** -->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? 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| Revision 3 |
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Integrated NEK7-inflammasome and platelet transcriptomic signature generates mechanistic hypotheses in heart failure PONE-D-25-65980R3 Dear Dr. Dai, 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. For questions related to billing, please contact billing support. 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, Austin W.T. Chiang Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: |
| Formally Accepted |
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PONE-D-25-65980R3 PLOS One Dear Dr. Dai, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Wan-Tien Chiang Academic Editor PLOS One |
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