Exploring the most promising anti ‐ Depressant drug targeting Microtubule Affinity Receptor Kinase 4 involved in Alzheimer’s Disease through molecular docking and molecular dynamics simulation

S. Rehan Ahmad; Md. Zeyaullah; Abdullah M. AlShahrani; Mohammad Suhail Khan; Khursheed Muzammil; Faheem Ahmed; Adam Dawria; Ali Mohieldin; Haroon Ali; Abdelrhman A. G. Altijani

doi:10.1371/journal.pone.0301179

Peer Review History

Original SubmissionNovember 3, 2023
19 Jan 2024 Decision Letter - Sajjad Ahmad, Editor PONE-D-23-35218Exploring a Promising Anti-Depressant Drug Targeting Microtubule Affinity Receptor Kinase 4 Inhibition in Alzheimer's Disease through Molecular Docking and Dynamics SimulationPLOS ONE Dear Dr. Ahmad, 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. ============================== The manuscript overall quality is good but still needs major changes as suggested by the reviewer. ============================== Please submit your revised manuscript by Mar 04 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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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. 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. Thank you for stating the following financial disclosure: “Deanship of Scientific Research at King Khalid University, Kingdom of Saudi Arabia , Research Project Grant Number RGP2/355/44.” 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. 4. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement. 5. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. 6. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical. 7. Please upload a copy of Supplementary 1. which you refer to in your text on page 15. Additional Editor Comments: The reviewer raised some concerns on the methodology of the manuscript. However, i still think the paper has the potential to be published. I will give one chance to the authors to improve the manuscript in light of the reviewer comments and send the manuscript for second round of revisions after incorporating all the changes. [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: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No ****** 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 ****** 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: Overall, the study presents a well-structured and comprehensive investigation into the potential of antidepressants as a treatment for Alzheimer's disease (AD). The authors have clearly identified a need for more effective AD therapies and have explored a promising therapeutic target, MARK4, which is involved in both AD and cancer progression. The use of molecular docking, molecular dynamics simulation, and MMGBSA to assess the binding affinity and potential efficacy of various antidepressants is a rigorous approach that provides valuable insights. However, there are a few areas which need to be addressed The selection of 24 antidepressants for this study warrants further explanation. The authors rely heavily on a 2013 study that itself drew from outdated references, raising concerns about the study's novelty and the relevance of the chosen antidepressants. The 2013 study, which served as the primary basis for selecting the antidepressants, appears to have cherry-picked compounds based on limited evidence and without considering more recent advancements in antidepressant research. Given the significant advancements in antidepressant development over the past decade, it is surprising that the authors chose to exclusively rely on compounds identified in a 2013 study. Moreover, the authors should conduct additional literature reviews to identify newer and more relevant evidence supporting their choice of antidepressants. This could involve examining recent studies that have investigated the potential of antidepressants in treating Alzheimer's disease or exploring the mechanisms by which these compounds interact with MARK4. The authors' reliance on ADMET analysis to narrow down the pool of potential antidepressants is also a significant concern. While ADMET studies provide valuable insights into the pharmacokinetic and toxicological properties of compounds, they should not be used solely as exclusionary criteria to filter out potential drug candidates. The authors' reliance on molecular docking to identify promising antidepressants warrants further scrutiny. While molecular docking provides a valuable starting point for identifying potential drug interactions, it is essential to carefully validate the results to ensure their robustness and reproducibility. The authors should compare the predicted binding modes from docking with those obtained from X-ray crystallography as reported in PDB. This will help to establish the accuracy of the docking simulations and ensure that the proposed binding interactions are biologically plausible. Justifiy in details the criteria for selecting the top six antidepressants for molecular dynamics simulation and MMGBSA. Provide a more detailed comparison of the molecular dynamics and MMGBSA results for the six antidepressants. ****** 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: Shafi Ullah Khan ******** [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. https://doi.org/10.1371/journal.pone.0301179.r001
Revision 1
8 Feb 2024 Author Response 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: No ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No ________________________________________ 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 ________________________________________ 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: Overall, the study presents a well-structured and comprehensive investigation into the potential of antidepressants as a treatment for Alzheimer's disease (AD). The authors have clearly identified a need for more effective AD therapies and have explored a promising therapeutic target, MARK4, which is involved in both AD and cancer progression. The use of molecular docking, molecular dynamics simulation, and MMGBSA to assess the binding affinity and potential efficacy of various antidepressants is a rigorous approach that provides valuable insights. However, there are a few areas which need to be addressed We would like to thanks the reviewer for spending value time and effort in reviewing the manuscript. We modified the manuscript based on the comment and we also modified conclusion to have better clarity and removed extra MMGBSA figure (Figure 11) to avoid confusion The selection of 24 antidepressants for this study warrants further explanation. The authors rely heavily on a 2013 study that itself drew from outdated references, raising concerns about the study's novelty and the relevance of the chosen antidepressants. The 2013 study, which served as the primary basis for selecting the antidepressants, appears to have cherry-picked compounds based on limited evidence and without considering more recent advancements in antidepressant research. Given the significant advancements in antidepressant development over the past decade, it is surprising that the authors chose to exclusively rely on compounds identified in a 2013 study. Answer 1- We would like to thanks the reviewer for valuable comment. We selected 24 anti-depressants based on their mode of action as well as commonly used in the global market. We added one column in the table related to mode of action in Table 1. Moreover, the authors should conduct additional literature reviews to identify newer and more relevant evidence supporting their choice of antidepressants. This could involve examining recent studies that have investigated the potential of antidepressants in treating Alzheimer's disease or exploring the mechanisms by which these compounds interact with MARK4. Answer 2 - Thanks for the valuable comment. Based on the comment we added the sentence “Based on the recent meta-analysis finding, sertraline and mirtazapine can be considered as an alternative treatment for depression in AD [18]. Even the combination of antipsychotics (such as risperidone and quetiapine) and mirtazapine can be used for the management of AD [19,20]”. The authors' reliance on ADMET analysis to narrow down the pool of potential antidepressants is also a significant concern. While ADMET studies provide valuable insights into the pharmacokinetic and toxicological properties of compounds, they should not be used solely as exclusionary criteria to filter out potential drug candidates. Answer 3 - Thanks for valuable comment and we apologize for the confusion. We filter out the drugs based on the binding affinities not on ADMET studies. We plotted the radar plot only for top 6 drugs which we got from molecular docking and donepezil. Based on the comment we even added a ADMET analysis table as supplementary 2 and modified the sentence in methodology “As 24 SSRI drugs are already in the market, but still we performed ADMET analysis with the SWISS ADME server which is shown in supplementary 2 and we even plotted the radar graph for the the binding affinity of the top six drugs and donepezil. Even we made changes in result section “In this study, we generated radar plots for the binding affinity of the top six drugs (CID ID - 4184, 2771, 4205, 5533, 4543, and 2160) lies between -9 to -8.2 kcal/mol as well as radar plot of Donepezil which is already approved for AD”. The authors' reliance on molecular docking to identify promising antidepressants warrants further scrutiny. While molecular docking provides a valuable starting point for identifying potential drug interactions, it is essential to carefully validate the results to ensure their robustness and reproducibility. The authors should compare the predicted binding modes from docking with those obtained from X-ray crystallography as reported in PDB. This will help to establish the accuracy of the docking simulations and ensure that the proposed binding interactions are biologically plausible. Answer 4 - Based on the comment we added “The conformation of docked Sertraline, Fluoxetine, Escitalopram, Fluvoxamine, Paroxetine and Citalopram with the MARK4 is shown in the Figure 2. The suitable docked pose was selected by mimicking the crystal structure of the MARK4 complex with pyrazolopyrimidine inhibitor (PDB: 5ES1). The docked complex where Sertraline, Fluoxetine, Escitalopram, Fluvoxamine, Paroxetine and Citalopram was present at the same position occupied by pyrazolopyrimidine inhibitor in the crystal structure, was selected for further analysis. Binding free energy of Sertraline, Fluoxetine, Escitalopram, Fluvoxamine, Paroxetine and Citalopram to the MARK4 was found to be - 9 kcal/mol,-8.7kcal/mol, -8.4kcal/mol, -8.3kcal/mol, -8.2 kcal/mol and -8.2 kcal/mol respectively. All six drugs forms several close interactions to active site residues of MARK4 such as Ile62, Lys85, Val116, Met132, Tyr134, Ala135, Leu185, Ala195 and Asp196, and forming one hydrogen bonds with Lys85, and several non-covalent interactions such as Alkyl, Pi-Alkyl and Van der Waals interactions offered by the protein MARK4. It is found that all six drugs are placed at the same position where co-crystal ligand pyrazolopyrimidine inhibitor is placed and it is interacting with the same active site residues, to which co-crystal ligand pyrazolopyrimidine inhibitor is interacting with. The analysis of docked conformations clearly indicates that all six drugs binds deeper into the cavity, and perhaps decrease the accessibility of MARK4 which may be responsible modulation of its biological functions “in the result section of molecular docking. Justifiy in details the criteria for selecting the top six antidepressants for molecular dynamics simulation and MMGBSA. Answer 5. Based on the comment, we added “Based on the top six binding free energy of Sertraline, Fluoxetine, Escitalopram, Fluvoxamine, Paroxetine and Citalopram to the MARK4 which was found to be -9 kcal/mol,-8.7kcal/mol, -8.4kcal/mol, -8.3kcal/mol, -8.2 kcal/mol and -8.2 kcal/mol respectively from 24 drugs, we proceed towards further analysis which include molecular dynamics simulations at 100ns followed by MMGBSA” in the result section of molecular dynamics. Provide a more detailed comparison of the molecular dynamics and MMGBSA results for the six antidepressants. Answer 6 Based on the comment we modified the MMGBSA result “After analysing the MMGBSA plot, it was observed that for most of the protein-ligand complexes, the values ranged between -40-50 region as shown in orange colour in the plot. Based on the MMGBSA result we can observe that the binding value for both 2771 and 4205 is between -30 -40 which is very similar to the 5SE1-3152 controlled compound whose MMGBSA binding value also ranged between -30-40, respectively. The binding value for 4184, 5533, 4543 and 2160 ranged between -40-50 which is not close to the control drug (donepezil). The MMGBSA result is shown in Figure 11.” We removed the Figure 11 related to MMGBSA to avoid confusion. ________________________________________ 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. Attachments Attachment Submitted filename: Response to Reviewer.docx https://doi.org/10.1371/journal.pone.0301179.r002
8 Mar 2024 Decision Letter - Sajjad Ahmad, Editor PONE-D-23-35218R1Exploring the most promising Anti - Depressant Drug targeting Microtubule Affinity Receptor Kinase 4 involved in Alzheimer’s Disease Through Molecular Docking and Molecular Dynamics SimulationPLOS ONE Dear Dr. Ahmad, 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. ============================== Most of the comments are addressed. Minor revisions needed to improve the figures quality. ============================== Please submit your revised manuscript by Apr 22 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Sajjad Ahmad Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Minor revisions needed. Improve figures quality. [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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: (No Response) ****** 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: While the author has addressed previous reviewer comments and their work is suitable for publication, the figures require revision due to insufficient resolution, making it difficult to decipher details like legends and color schemes. ****** 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: Yes: Shafi Ullah Khan ******** [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. https://doi.org/10.1371/journal.pone.0301179.r003
Revision 2
11 Mar 2024 Author Response Respected Editor Sir, We have uploaded all figure as separate file. Please find the attachments and do the needful. with regards Dr. S Rehan Ahmad Assistant Professor , Department of Zoology , Hiralal Mazumdar Memorial College for Women , Govt. Aided College , Govt. of West Bengal Dakshineswar , Kolkata , West Bengal , India -700035 Mobile No. +91-8335999175 / +91-9332094070 E-Mail : zoologist.rehan@gmail.com Scopus Id : 57226372929 Attachments Attachment Submitted filename: Response to Reviewer.docx https://doi.org/10.1371/journal.pone.0301179.r004
13 Mar 2024 Decision Letter - Sajjad Ahmad, Editor Exploring the most promising Anti - Depressant Drug targeting Microtubule Affinity Receptor Kinase 4 involved in Alzheimer’s Disease Through Molecular Docking and Molecular Dynamics Simulation PONE-D-23-35218R2 Dear Dr. Ahmad, 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 http://www.editorialmanager.com/pone/ 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, Sajjad Ahmad Academic Editor PLOS ONE Additional Editor Comments (optional): The authors all the concerns and the paper is ready for publication. Reviewers' comments: https://doi.org/10.1371/journal.pone.0301179.r005
Formally Accepted
8 Apr 2024 Acceptance Letter - Sajjad Ahmad, Editor PONE-D-23-35218R2 PLOS ONE Dear Dr. Ahmad, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks 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. 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. Sajjad Ahmad Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0301179.r006

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