Long-term exposure to low concentrations of polycyclic aromatic hydrocarbons and alterations in platelet indices: A longitudinal study in China

Jing Cui; Ting Zhang; Chao Zhang; Zhenwei Xue; Durong Chen; Xiaona Kong; Caili Zhao; Yufeng Guo; Zimeng Li; Xiaoming Liu; Jiefang Duan; Wenjie Peng; Xiaolin Zhou; Hongmei Yu

doi:10.1371/journal.pone.0276944

Peer Review History

Original SubmissionJune 13, 2022
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The paper investigates the low-concentration exposure to PAHs and alterations in platelet indices in the Chinese population based on the longitudinal dataset using UPAHM as biomarkers of exposure. I wish to point out only some modifications to shape up the manuscript. 1. PAHs abbreviation must be explained at its first mention (in the abstract). 2. The abstract of the manuscript is required to be upgraded. 3. At an end of the introduction, authors should add in detail objective of the work. 4. Why authors selected more female participants? Any specific reason. 5. The authors should be uniformed the units and symbols according to journal format. 6. Improve the quality of the figures. 7. In discussion section, authors should cite recent references with more detail discussion. 8. Grammatical mistakes pervade the manuscript. I suggest the authors to carefully correct them. 9. References must be formatted according to the standard style of materials letters journal. [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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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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: I have reviewed the manuscript entitled “Long-term exposure to low concentrations of polycyclic aromatic hydrocarbons and alterations in platelet indices: A longitudinal study in China”. The paper investigates the low-concentration exposure to PAHs and alterations in platelet indices in the Chinese population based on the longitudinal dataset using UPAHM as biomarkers of exposure. I wish to point out only some modifications to shape up the manuscript. 1. PAHs abbreviation must be explained at its first mention (in the abstract). 2. The abstract of the manuscript is required to be upgraded. 3. At an end of the introduction, authors should add in detail objective of the work. 4. Why authors selected more female participants? Any specific reason. 5. The authors should be uniformed the units and symbols according to journal format. 6. Improve the quality of the figures. 7. In discussion section, authors should cite recent references with more detail discussion. 8. Grammatical mistakes pervade the manuscript. I suggest the authors to carefully correct them. 9. References must be formatted according to the standard style of materials letters journal. ****** 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. 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Revision 1
18 Sep 2022 Author Response Dear Dr. Govarthanan Muthusamy; We thank the Editors and Reviewers for their accurate and insightful comments, and for the careful attention that they have paid to our manuscript. We have carefully revised the manuscript in response to all the comments. Our point-by-point responses to the Editors and Reviewers’ comments are listed below. We hope that this new draft addresses all of your concerns, and that our manuscript is now suitable for publication in your journal. Sincerely, Hongmei Yu Reviewer #1: Comment 1: PAHs abbreviation must be explained at its first mention (in the abstract). Response: We thank the Reviewer for pointing this out. We added the PAHs abbreviation. Specific revisions are as follows. “Abstract Long-term exposure to low polycyclic aromatic hydrocarbon (PAH) concentration may ave detrimental effects, including changing platelet indices. ” Comment 2: The abstract of the manuscript is required to be upgraded. Response: We thank the Reviewer for this constructive comment. We have carefully revised the abstract. Specific revisions are as follows. “Abstract(page 2) Long-term exposure to low polycyclic aromatic hydrocarbon (PAH) concentration may ave detrimental effects, including changing platelet indices. Effects of chronic exposure to low PAH concentrations have been evaluated in cross-sectional, but not in longitudinal studies, to date. We aimed to assess the effects of long-term exposure to the low-concentration PAHs on alterations in platelet indices in the Chinese population. During 2014 - 2017, we enrolled 222 participants who had lived in a village in northern China, 1-2 km downwind from a coal plant, for more than 25 years, but who were not employed by the plant or related businesses. During three follow-ups, annually in June, demographic information and urine and blood samples were collected. Eight PAHs were tested: namely 2-hydroxynaphthalene, 1-hydroxynaphthalene, 2-hydroxyfluorene, 9-hydroxyfluorene (9-OHFlu), 2-hydroxyphenanthrene (2-OHPh), 1-hydroxyphenanthrene (1-OHPh), 1-hydroxypyrene (1-OHP), and 3-hydroxybenzo [a] pyrene. Five platelet indices were measured: platelet count (PLT), platelet distribution width (PDW), mean platelet volume (MPV), platelet crit, and the platelet-large cell ratio. Generalized mixed and generalized linear mixed models were used to estimate correlations between eight urinary PAH metabolites and platelet indices. Model 1 assessed whether these correlations varied over time. Models 2 and 3 adjusted for additional personal information and personal habits. We found the following significant correlations: 2-OHPh (Model1 β_1 = 18.06，Model2 β_2 = 18.54, Model3 β_3 = 18.54), 1-OHPh (β_1 = 16.43, β_2 = 17.42, β_3 = 17.42), 1-OHP (β_1 = 13.93, β_2 = 14.03, β_3 = 14.03) with PLT, as well as 9-OHFlu with PDW and MPV (odds ratio or Model3 〖OR〗_PDW [95%CI] = 1.64[1.3-2.06], 〖OR〗_MPV [95%CI] = 1.33[1.19-1.48]). Long-term exposure to low concentrations of PAHs, indicated by2-OHPh, 1-OHPh, 1-OHP, and 9-OHFlu, as urinary biomarkers, affects PLT, PDW, and MPV. 9-OHFlu increased both PDW and MPV after elimination of the effects of other PAH exposure modes. Comment 3: At an end of the introduction, authors should add in detail objective of the work. Response: We thank the Reviewer for this insightful comment. We have carefully revised the introduction. Specific revisions are as follows. “Introduction (page 5, paragraph 1) Thus, we assessed the effects of long-term exposure to low-concentration PAHs and alterations in platelet indices in the Chinese population. Longitudinal datasets were collected to study the effects of long-term exposure to low concentrations of PAHs on platelet indices among adults who were not occupationally exposed. We then estimated the correlations among eight representative urinary PAH metabolites (UPAHMs) and five platelet indices, under the effect of covariates, aiming to assess low-concentration exposure to PAHs and alterations in platelet indices in the Chinese population based on a longitudinal dataset using UPAHM as biomarkers of exposure.” Comment 4: Why authors selected more female participants? Any specific reason. Response: We thank the Reviewer for pointing this out. In the Methods section, as we pointed out in the original manuscript, all participants had resided for more than 25 years in a village located downwind and 1-2 km from a coal plant but were not employed by the plant or related businesses. Therefore, large numbers of men were excluded from the study because men are more likely to be employed by the plant or related businesses. Table 1 shows gender did not differ by year of recruitment into the study. We added this into the Discussion section of our manuscript. “Discussion (page 16, paragraph 3) The number of female participants was larger than that of male participants, which may have resulted from the inclusion and exclusion criteria. For more than 25 years, all participants had resided in a village located 1–2 km downwind, from a coal plant, but were not employed by the plant or related businesses. Therefore, a large number of men were excluded from the study because men were more likely to be employed by the coal plant or related businesses.” Comment 5: The authors should be uniformed the units and symbols according to journal format. Response: We thank the Reviewer for pointing this out. We have carefully added the units in Table 2 and 3, while change the symbols of paragraph after Table 3. Table 2. The fixed effect among platelet indices and UPAHM based on GMMs UPAHM PLT/F1(%) PDW(fL) MPV(fL) PCT(%) P-LCR(%) 2-OHNa(ng/g·cr-1) 0.34 (0.5627) 3.03 (0.0826) 3.07 (0.0806) 2.36 (0.1253) 0.21 (0.6497) 1-OHNa(ng/g·cr-1) 5.22 (0.0228)* 0.23 (0.6332) 0.13 (0.7201) 0.44 (0.5060) 0.10 (0.7527) 9-OHFlu(ng/g·cr-1) 3.75 (0.0534) 6.01 (0.0146)* 6.26 (0.0127)* 0.01 (0.9270) 4.37 (0.0372)* 2-OHFlu(ng/g·cr-1) 5.45 (0.0200)* 0.21 (0.6469) 0.42 (0.5165) 0.53 (0.4652) 1.20 (0.2744) 2-OHPh(ng/g·cr-1) 4.71 (0.0306)* 0.16 (0.6922) 0.22 (0.6399) 1.74 (0.1884) 2.10 (0.1480) 1-OHPh(ng/g·cr-1) 5.45 (0.0200)* 0.31 (0.5761) 0.41 (0.5227) 0.77 (0.3806) 0.62 (0.4314) 1-OHP(ng/g·cr-1) 6.17 (0.0134)* 0.30 (0.5862) 0.16 (0.6854) 0.67 (0.4133) 2.65 (0.1040) 3-OHBaP(ng/g·cr-1) 0.01 (0.9050) 1.57 (0.2112) 0.77 (0.3811) 2.03 (0.1549) 0.61 (0.4339) Table 3. Dose-reposed effect of PAH exposure on PLT Level of UPAHM Model 1 Model 2 Model 3 1-OHNa(ng/g·cr-1) Con(β[P value]) 6.65[0.052] 6.54[0.057] 6.54[0.057] 1 0.95(0.916-0.986)* 0.951(0.916-0.987)* 0.95(0.916-0.986)* 2 0.945(0.9-0.993)* 0.946(0.9-0.993)* 0.943(0.897-0.991)* 3 0.962(0.924-1.001) 0.962(0.924-1.002) 0.961(0.923-1.001) 4 1 1 1 AIC -286.9 -268.9 -251 BIC -266.5 -248.5 -230.6 2-OHFlu(ng/g·cr-1) Con(β[P value]) 22.37[<0.001] 22.8[<0.001] 22.8[<0.001] 1 0.966(0.928-1.005) 0.966(0.928-1.006) 0.967(0.928-1.007) 2 0.961(0.923-1) 0.961(0.922-1) 0.961(0.923-1.001) 3 1.008(0.969-1.049) 1.007(0.967-1.049) 1.007(0.967-1.049) 4 1 1 1 AIC -286.2 -268.2 -249.6 BIC -265.8 -247.8 -229.2 2-OHPh(ng/g·cr-1) Con(β[P value]) 18.06[<0.001] 18.54[<0.001] 18.54[<0.001] 1 0.941(0.904-0.979)* 0.941(0.904-0.98)* 0.941(0.904-0.98)* 2 0.939(0.904-0.976)* 0.939(0.904-0.977)* 0.94(0.904-0.977)* 3 0.951(0.912-0.991)* 0.95(0.911-0.99)* 0.949(0.91-0.99)* 4 1 1 1 AIC -290.1 -272.2 -253.8 BIC -269.7 -251.8 -233.4 1-OHPh(ng/g·cr-1) Con(β[P value]) 16.43[<0.001] 17.42[<0.001] 17.42[<0.001] 1 0.958(0.92-0.997) 0.958(0.92-0.997)* 0.957(0.919-0.996)* 2 0.958(0.924-0.993)* 0.958(0.924-0.994)* 0.958(0.924-0.994)* 3 0.992(0.944-1.042) 0.991(0.943-1.041) 0.99(0.942-1.04) 4 1 1 1 AIC -285.4 -267.5 -249.2 BIC -265 -247.1 -228.8 1-OHP(ng/g·cr-1) Con(β[P value]) 13.93[0.001] 14.03[0.001] 14.03[0.001] 1 0.948(0.902-0.996) 0.949(0.903-0.997)* 0.949(0.903-0.997)* 2 0.99(0.942-1.04) 0.992(0.944-1.043) 0.992(0.944-1.043) 3 0.988(0.942-1.035) 0.989(0.944-1.037) 0.99(0.944-1.038) 4 1 1 1 AIC -285.4 -267.8 -249.4 BIC -265 -247.3 -228.9 “Model 1: β1[P value]= 0.48 [< 0.001], Model 2 β2[P value]= 0.49 [< 0.001], Model 3 β3[P value]= 0.49 [< 0.001]) correlated with PDW and with MPV (β1[P value]= 0.28 [< 0.001], β2[P value]= 0.28 [< 0.001], β3[P value]= 0.28 [< 0.001]), and with P-LCR (β1[P value]= 0.58 [0.458], β2[P value]= 0.57 [0.463], β3[P value]= 0.57 [0.463]) in all three models, all of which had an increasing effect on platelet indices.” “For MPV, participants without exposure to second-hand smoke exhibited a dose–response trend at the second and third levels, in which the second exposure level (ORwithout =0.958; 95%CI [0.924–0.994]) and the second exposure level (ORwithout= 1.049; 95%CI[1.013–1.086]) differed from the highest exposure level.” Comment 6: Improve the quality of the figures. Response: We thank the Reviewer for this constructive comment. We re-uploaded the clear figures. And changed them into PDF documents. Comment 7: In discussion section, authors should cite recent references with more detail discussion. Response: We thank the Reviewer for pointing this out. We have carefully revised the discussion. “ 28. Zhang, H., L. Yuan, J. Xue and H. Wu, Polycyclic aromatic hydrocarbons in surface water and sediment from Shanghai port, China: spatial distribution, source apportionment, and potential risk assessment. Environ Sci Pollut Res Int, (2022). doi:10.1007/s11356-022-22706-5. 29. Sopian, N.A., J. Jalaludin, S. Abu Bakar, T.R. Hamedon and M.T. Latif, Exposure to Particulate PAHs on Potential Genotoxicity and Cancer Risk among School Children Living Near the Petrochemical Industry. Int J Environ Res Public Health, (2021). 18. doi:10.3390/ijerph18052575. 30. Oliveira, M., K. Slezakova, C. Delerue-Matos, M.C. Pereira and S. Morais, Children environmental exposure to particulate matter and polycyclic aromatic hydrocarbons and biomonitoring in school environments: A review on indoor and outdoor exposure levels, major sources and health impacts. Environ Int, (2019). 124: p. 180-204. doi:10.1016/j.envint.2018.12.052. 31. Xu, P., Z. Chen, Y. Chen, L. Feng, L. Wu, D. Xu, et al., Body burdens of heavy metals associated with epigenetic damage in children living in the vicinity of a municipal waste incinerator. Chemosphere, (2019). 229: p. 160-168. doi:10.1016/j.chemosphere.2019.05.016. 32. Ailijiang, N., X. Cui, A. Mamat, Y. Mamitimin, N. Zhong, W. Cheng, et al., Levels, source apportionment, and risk assessment of polycyclic aromatic hydrocarbons in vegetable bases of northwest China. Environ Geochem Health, (2022). doi:10.1007/s10653-022-01369-8. 33. Zalata, A., S. Yahia, A. El-Bakary and H.M. Elsheikha, Increased DNA damage in children caused by passive smoking as assessed by comet assay and oxidative stress. Mutat Res, (2007). 629: p. 140-7. doi:10.1016/j.mrgentox.2007.02.001. 34. Beyoglu, D., T. Ozkozaci, N. Akici, G.Z. Omurtag, A. Akici, O. Ceran, et al., Assessment of DNA damage in children exposed to indoor tobacco smoke. Int J Hyg Environ Health, (2010). 213: p. 40-3. doi:10.1016/j.ijheh.2009.10.001. 35. Chunjie, Yuan, Jian, Hou, Yun, Zhou, et al., Dose-response relationships between polycyclic aromatic hydrocarbons exposure and platelet indices. Environmental Pollution, (2018). 36. Jones, R.H., Bayesian information criterion for longitudinal and clustered data. Stats in Medicine, (2011). 30. 37. Sanquetta, C.R., A.P.D. Corte, A. Behling, L.R.D.O. Piva and M.N.I. Sanquetta, Selection criteria for linear regression models to estimate individual tree biomasses in the Atlantic Rain Forest, Brazil. Carbon Balance Management, (2018). 13.” Comment 8: Grammatical mistakes pervade the manuscript. I suggest the authors to carefully correct them. Response: We thank the Reviewer for pointing this out. This new manuscript has been edited extensively by professional editing group. Comment 9: References must be formatted according to the standard style of materials letters journal. Response: We thank the Reviewer for pointing this out. We have edited the style of the reference. Journal Requirements: Comment 1: Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Response: We thank the Editors for pointing this out. We have edited the names of Table and Figure(eg.Fig 1; S1 Table). Comment 2: Please provide additional details regarding participant consent. Response: We thank the Editors for pointing this out. We have added the ethics approval and the informed consent form as S2 and S3 Figs. Comment 3: We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. Response: We thank the Editors for pointing this out. And we make the consistency of funding number. The work has been approved by the Institutional Review Board of China Institute for Radiation Protection (CIRP). The funding number is 21111011101EHSM(2019)SX-03. Comment 4: Please state what role the funders took in the study. Response: We thank the Editors for pointing this out. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. And add this into the cover letter. Comment 5: PLOS journals require that the minimal data set be made fully available. Response: We thank the Editors for pointing this out. We have added the minimal data set as S6 Table. Comment 6: PLOS requires an ORCID ID for the corresponding author in Editorial Manager on papers submitted Response: We thank the Editors for pointing this out. We have log in and connected the ORCID ID of corresponding author. Comment 7: Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Response: We thank the Editors for pointing this out. We have carefully revised the part. “Supporting information S1 Fig. Correlations among demographic information and urinary metabolite levels S2 Fig. Ethics approval S3 Fig. Informed consent form S4 Fig. language editing certification S1 Table. The GMM Model of PAH and blood routine indexes. S2 Table. The GLMM Model of PAH and PLT. Notes, the confidence and 95% confidence interval result of the models have listed in this each cell of the table, by the order from Model 1 to Model 3. S3 Table. The GLMM Model of 9-OHFlu and three platelet indices. Notes, the confidence and 95% confidence interval result of the models have been listed in each cell of the table, by the order from Model 1 to Model 3. S4 Table. The variables collected from all 222 participants. Note, we collected the variables from each of the 222 patients in these three aspects. The variables in the latter two aspects have been collected three times for repeated measures. While list their full names, their acronyms have been listed in the brackets for the convenience of further use. S5 Table. The variates of platelet indices and UPAHM among times. Note, PLT is short for the count of platelet, while PDW for Platelet distribution width, MPV for mean platelet volume, PCT for platelet crit, P-LCR for large platelet ratio, 2-OHNa for 2-hydroxynaphthalene, 1-OHNa for 1-hydroxynaphthalene, 2-OHFlu for 2-hydroxyfluorene, 9-OHFlu for 9-hydroxyfluorene, 2-OHPh for 2-hydroxyphenanthrene, 1-OHPh for 1-hydroxyphenanthrene, 1-OHP for 1-hydroxypyrene, 3-OHBaP for 3-hydroxybenzo[a]pyrene. Listing the geometric mean± geometric standard error for each following-up time of each index, the p values according to Mauchly's test of sphericity have been recorded in the fourth row of each group with "ST" for short. The last row of each group listed the results of ANOVA for repeated measurement (MANOVA) or traditional ANOVA analysis while their P values have been displayed in the brackets after F values. * stands for the statistical significance with α=0.05. S6 Table. The minimal data set S1 file. Generalized Linear Mixed Model and Generalized Mixed Model: The description of both modeling methods.” Comment 8: Please review your reference list to ensure that it is complete and correct. Response: We thank the Editors for pointing this out. We have carefully revised the reference part. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0276944.r002
18 Oct 2022 Decision Letter - Govarthanan Muthusamy, Editor Long-term exposure to low concentrations of polycyclic aromatic hydrocarbons and alterations in platelet indices: A longitudinal study in China PONE-D-22-17020R1 Dear Dr. Yu, 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 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, Govarthanan Muthusamy Academic Editor PLOS ONE Additional Editor Comments (optional): 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: 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 ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript has been improved after revision, according to the reviewer's comments. I recommend the paper to be published. ****** 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 ******** https://doi.org/10.1371/journal.pone.0276944.r003
Formally Accepted
24 Oct 2022 Acceptance Letter - Govarthanan Muthusamy, Editor PONE-D-22-17020R1 Long-term exposure to low concentrations of polycyclic aromatic hydrocarbons and alterations in platelet indices: A longitudinal study in China Dear Dr. Yu: 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. Govarthanan Muthusamy Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276944.r004

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