Review Reports - Advances in Flavonoid Research: Sources, Biological Activities, and Developmental Prospectives

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper is a comprehensive review titled "Advances in Flavonoid Research: Sources, Biological Activities, and Developmental Perspectives." It covers various aspects of flavonoids, including their structural characteristics, classification, sources, and a wide range of biological activities such as antioxidant, anti-inflammatory, anti-tumor, antidiabetic, and antibacterial effects. The review also discusses the challenges and opportunities in flavonoid research, emphasizing the need for further study on biosynthesis pathways, cell synthesis techniques, and the development of novel drug delivery systems to overcome issues like poor solubility and bioavailability. The paper aims to provide technical and strategic references for future research on flavonoids, highlighting their potential in drug development and healthcare applications. However, both the presentation and the writing of the manuscript require significant enhancements. Therefore, I can’t recommend it for publication. Comments and suggestions are shown below:

1. Please consistently show the structures in Table 1.

2. It’s confusing that the structures shown in Table 1, are they the skeletons or the representative compound?

3. Please re-draw the structures, the resolution is really low.

4. There are many grammar errors and inconsistent writing, please carefully double-check the whole text.

5. Please show the stereochemistry of all the structures, such as the sugar moiety.

6. Figure 4, what are the compounds D-H?

7. “7 > 4′ ≈ 3 > 3′ >> 5” hard to understand.

8. Where are figures 5D and 5E?

9. “Through the 18S rDNA sequence amplification of the isolated strain AG-10 , combined with the morphological characteristics of the colony and conospores, the endophytic fungal metabolites were identified as Fusarium sp.” confusing sentences, the fungal metabolites were identified as Fusariumm sp.?

10. Figure 6, the chemical synthesis figure also included, should be removed.

11. Figure 7 should be improved. The figure legend should be corrected.

12. Please cite the references when you talk about the existing limitations.

Comments on the Quality of English Language

Extensive editing of English language required.

Author Response

Response to Reviewer 1:

Dear Reviewer,

Thank you very much for your careful and comprehensive review of our paper. Based on your comment and suggestion, we revised the relevant part in manuscript. The responses answering every question are as follows. All the lines and pages mentioned in responses are form the revised manuscript in review mode (Word version).

Comments and Suggestions.

Response: Thank you for your careful and rigorous review of the article and your affirmation of our work. We have read your comments and suggestions carefully. We will carefully revise the article according to the comments and suggestions you listed. Thank you!

Comment 1. Please consistently show the structures in Table 1.

Response: Thank you for your comment. Classification and chemical structure of naturally derived flavonoid compounds are shown in Table1. The structures are the skeletons of different classification flavonoids.

Comment 2. It’s confusing that the structures shown in Table 1, are they the skeletons or the representative compound?

Response: Thank you for your comment. They are the skeletons of different classification flavonoids. We have made the necessary modifications.

Comment 3. Please re-draw the structures, the resolution is really low.

Response: Thank you for your comment and suggestion. We have uniformly used ChemDraw software to draw the chemical structure according to your suggestion.

Comment 4. There are many grammar errors and inconsistent writing, please carefully double-check the whole text.

Response: Thank you for your comments and suggestions. we have carefully polished and modified the language of the manuscript.

Comment 5. Please show the stereochemistry of all the structures, such as the sugar moiety.

Response: Thank you for your comment and suggestion. We have followed your suggestion and used ChemDraw software to unify the chemical structure for the manuscript.

Comment 6. Figure 4, what are the compounds D-H?

Response: Thank you for your comment . We apologize for the for the confusion in inserting Figures 4 and 5. We have carefully checked and reinsert in the correct position.

Comment 7. “7 > 4′ ≈ 3 > 3′ >> 5” hard to understand.

Response: Thank you for your comment . This represents the different effects of hydroxyl introduction sites on the activity of flavonoids . The number represents the number of carbon atoms in the skeleton of flavonoids, as shown in Figure 2.

Comment 8. Where are figures 5D and 5E?

Response: Thank you for your comment . We have reinserted Figures 4 and 5 into the manuscript, and provided detailed explanations of the differences between 5D and 5E in the text.

Comment 9. “Through the 18S rDNA sequence amplification of the isolated strain AG-10 , combined with the morphological characteristics of the colony and conospores, the endophytic fungal metabolites were identified as Fusarium sp.” confusing sentences, the fungal metabolites were identified as Fusariumm sp.?

Response: Thank you for your comment . We have revised this sentence to“Through the 18S rDNA sequence amplification of the isolated strain AG-10 , combined with the morphological characteristics of the colony and conospores , the endophytic fungal were identified as Fusarium sp.”

Comment 10. Figure 6, the chemical synthesis figure also included, should be removed.

Response: Thank you for your comment . Figure 6 shows the biosynthetic pathways of flavonoids . Some compounds have been shown in the text, but others have not . To maintain consistency , the figure uses compounds containing chemical structures . In addition , the biosynthetic pathways of flavonoids can be further understood from the changes in chemical structures . Thank you again for your good suggestion .

Comment 11. Figure 7 should be improved. The figure legend should be corrected.

Response: Thank you for your comment . Figure 7 has been redrawn and improved, and the legend has also been modified .

Comment 12. Please cite the references when you talk about the existing limitations.

Response: Thank you for your comment . Following your suggestion, we have added relevant references.

Comments on the Quality of English Language

Extensive editing of English language required.

Response: Thank you for your comment. We have checked and revised the language of the manuscript. Thank you again for your insightful suggestion.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The paper submitted to CIMB presents review information about flavonoids in order to characterize their biological activity along with their mechanisms of action. On the whole the issue is interesting but authors did not present innovative information. The issue was presented many times in various journals. I leave the decision on acceptance to the editor. There is no glarring errors but please see my comments:

In my opinion, the section 4 and 5 should be joined. The mechanisms of action presented in section 5 should be added to section 4 as additional subsections. This would be a significant help when analyzing activity presented in section 4.

3.2. Chemical Synthesis and Structural Modification: please provide at leat two additional references in part 118-137 lines.

Figure 7. ‘Microotganisms synthesis strategy of flavonoids using genetic engineering tech nology’. Should be: Microorganisms synthesis strategy of flavonoids using genetic engineering technology’

7.1. Existing Limitations and Constraints: please provide additional references for lines 925-926; 976-986;988-998 Additionally please provide full reference information (number of reference) for ‘In order to solve the problem of poor solubility and bioactivity, Islam et al. developed water-soluble micellar formulations containing single and multiple flavonoids using the biocompatible surface-active ionic liquid choline oleate, and investigated the effect of dosage form change on their food preservation properties using luteolin, naringin and quercetin as models of bioactive compounds.’

7.2. Focus and Strategies in Future Research: tehre is only one reference. Please provide more references.

Conclusions: please provide

Methodology:please provide information about selection of references. Presentation in form of diagarm will be acceptable.

Author Response

Response to Reviewer 2:

Dear Reviewer,

Comments and Suggestions.

Comment 1. In my opinion, the section 4 and 5 should be joined. The mechanisms of action presented in section 5 should be added to section 4 as additional subsections. This would be a significant help when analyzing activity presented in section 4.

Response: Thank you for your suggestion. This is a great suggestion, but due to the ongoing discovery of the biological activity of flavonoids and the inconsistent in-depth research on the mechanisms of action of different biological activities, some of the mechanisms of action of biological activities are being analyzed and studied. It may be more reasonable to choose to elaborate on them separately in the article. Thank you again for your suggestion.

Comment 2. Chemical Synthesis and Structural Modification: please provide at leat two additional references in part 118-137 lines.

Response: Thank you for your suggestion. We have added and supplemented relevant references.

Comment 3. Figure 7. ‘Microotganisms synthesis strategy of flavonoids using genetic engineering tech nology’. Should be: Microorganisms synthesis strategy of flavonoids using genetic engineering technology’

Response: Thank you for your suggestion. We have made modifications according to your suggestions.

Comment 4. 7.1. Existing Limitations and Constraints: please provide additional references for lines 925-926; 976-986; 988-998 Additionally please provide full reference information (number of reference) for ‘In order to solve the problem of poor solubility and bioactivity, Islam et al. developed water-soluble micellar formulations containing single and multiple flavonoids using the biocompatible surface-active ionic liquid choline oleate, and investigated the effect of dosage form change on their food preservation properties using luteolin, naringin and quercetin as models of bioactive compounds.’

Response: Thank you for your suggestion. We have supplemented relevant references.

Comment 5. 7.2. Focus and Strategies in Future Research: tehre is only one reference. Please provide more references.

Response: Thank you for your suggestion. We have supplemented relevant references.

Comment 6. Conclusions: please provide

Response: Thank you for your suggestion. We have added the conclusion section.

Comment 7. Methodology: please provide information about selection of references. Presentation in form of diagarm will be acceptable.

Response: Thank you for your comment and suggestion. This manuscript comprehensively reviews the current research and application status of flavonoids from the sources, biological activities, drug action mechanisms and clinical applications. The selection of references is based on the basic principle of the latest research related to flavonoids, almost half of the literature sources are from 2021 to the present, and the manuscript comprehensively reviews the latest research progress and existing opportunities and challenges of flavonoids from 7 aspects.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors are presenting an extensive review on the topic of flavonoids. Below they can find several suggestions for their manuscript.

Although the FDA is a very popular abbreviation, please, introduce it in L52 A list of abbreviations is not in compliance with the journal's template. The same applies for the other abbreviations.

How were the chemical structures used in the manuscript plotted, if software was used indicate it, or state the source of the image

Use the same font in the figures as it is in the manuscript

Revise title in section 7

The manuscript's logic is hard to follow. Please, think about making it more reader-friendly.

Comments on the Quality of English Language

Please, try to use comprehensible sentences and check for typo mistakes. The length of the sentence does not make it better.

Author Response

Response to Reviewer 3:

Dear Reviewer,

Comments and Suggestions for Authors.

The authors are presenting an extensive review on the topic of flavonoids. Below they can find several suggestions for their manuscript.

Response: Thank you for your comments and suggestions. We have read your comments carefully and attentively revised relevant part according your advice. Thank you again for your careful and rigorous review of the article and your affirmation of our work. We will keep working hard in the future. Thank you!

Comment 1. Although the FDA is a very popular abbreviation, please, introduce it in L52 A list of abbreviations is not in compliance with the journal's template. The same applies for the other abbreviations.

Response: Thank you for your comment and suggestion. We have added the full name of FDA as per your suggestion and made modifications to the abbreviation section according to the journal format. And other abbreviations in the article have been uniformly modified.

Comment 2. How were the chemical structures used in the manuscript plotted, if software was used indicate it, or state the source of the image

Response: Thank you for your suggestion. We have followed your suggestion and used ChemDraw software to unify the chemical structure for the manuscript.

Comment 3.Use the same font in the figures as it is in the manuscript

Response: Thank you for your suggestion. We have made unified modifications to use the same font as in the manuscript in the figure.

Comment 4. Revise title in section 7

Response: Thank you for your suggestion. We have revised the title in Section 7.

Comment 5. The manuscript's logic is hard to follow. Please, think about making it more reader-friendly.

Response: Thank you for your comment and suggestion. The principal line of our review is the discovery of the sources of flavonoids, exploration of their biological activities, analysis of their mechanisms of action, implementation of clinical applications, and opportunities and challenges for further research. We have made necessary modifications to the article to enhance its logic and readability.

Comments on the Quality of English Language

Please, try to use comprehensible sentences and check for typo mistakes. The length of the sentence does not make it better.

Response: Thank you for your comments and suggestions. we have carefully polished and modified the language of the manuscript.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript submitted to me for review entitled “Advances in Flavonoid Research: Sources, Biological Activities, and Developmental Prospectives” provides an update on the state of research on the well-known flavonoids. Such reviews will always be interesting, because nature is an inexhaustible source of bioactive substances and we will not stop getting to know it. The authors have summarized results of state-of-the-art research on both the chemistry and human health benefits of this class of compounds in their review. Almost half of the literature sources are from 2021 to the present. The work is comprehensive and well structured. My remarks are solely about the layout of the manuscript.

1. Table 1 repeats Table 2 to some extent. The two tables could be merged. Additionally, compound structures are missing in the "chemical structure" column.

2. Let the formulas be written in the same way and size. (I mean that the CH₃-group can also be written with just a dash.)

3. Let the compounds in line 135 and the reagents in Figure 1 be written correctly.

4. The descriptions of Figures 4 and 5 have been interchanged.

5. The authors report antibacterial activity of flavonoids in section 4.7. It is logical to add in part 5 information about the mechanism of this action. For their reference, I offer the following rеview: Ireneusz Go´rniak, Rafał Bartoszewski, Jarosław Kro´liczewski Comprehensive review of antimicrobial activities of plant flavonoids Phytochem Rev (2019) 18:241–272 https://doi.org/10.1007/s11101-018-9591-z

Author Response

Response to Reviewer 4:

Dear Reviewer,

Comments and Suggestions.

Response: Thank you for your comments. Your recognition of our work gives us great encouragement. Thank you!

Comment 1. Table 1 repeats Table 2 to some extent. The two tables could be merged. Additionally, compound structures are missing in the "chemical structure" column.

Response: Thank you for your suggestion. This is a good suggestion, but the themes presented in Tables 1 and 2 are different. Table 1 mainly shows 14 different classifications of flavonoids, while Table 2 mainly shows representative compounds and their chemical structures and plant sources in different flavonoids, excluding all 14 flavonoids. And the merged tables will appear crowded and not very distinct. Therefore, it may be more reasonable to display them separately. We have checked and supplemented the chemical structure of flavonoids.

Comment 2. Let the formulas be written in the same way and size. (I mean that the CH3-group can also be written with just a dash.)

Response: Thank you for your comment and suggestion. We have standardized the size and style of the structure.

Comment 3. Let the compounds in line 135 and the reagents in Figure 1 be written correctly.

Response: Thank you for your comment and suggestion. We have made the modifications.

Comment 4. The descriptions of Figures 4 and 5 have been interchanged.

Response: Thank you for your comment and suggestion. We apologize for the confusion in inserting Figures 4 and 5. We have carefully checked and reinsert in the correct position.

Comment 5. The authors report antibacterial activity of flavonoids in section 4.7. It is logical to add in part 5 information about the mechanism of this action. For their reference, I offer the following rеview: Ireneusz Go´rniak, Rafał Bartoszewski, Jarosław Kro´liczewski Comprehensive review of antimicrobial activities of plant flavonoids Phytochem Rev (2019) 18:241-272 https://doi.org/10.1007/s11101-018-9591-z

Response: Thank you for your comment and suggestion. We have added and supplemented this reference.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have not made substantial revisions to the manuscript, leaving lots of issues unaddressed. I would not recommend it for publication until it undergoes thorough revision.

1. Table 1, if you want to show the skeleton carbon, why there are R groups?

2. Table 2, the structures look weird, please re-draw them.

3. Please cite the appropriate references, such as the first paragraph in section 3.1.

4. The authors showed Figure 4 but did not talk about it in the main text.

5. All the compound numbers should be bolded.

6. Please show the stereochemistry of the structures if they are shown in the literature.

7. Please revise Figures 6 and 7.

Comments on the Quality of English Language

English is hard reading.

Author Response

Response to Reviewer 1:

Dear Reviewer,

Comments and Suggestions.

The authors have not made substantial revisions to the manuscript, leaving lots of issues unaddressed. I would not recommend it for publication until it undergoes thorough revision.

Response: Thank you for your careful review of the manuscript and your affirmation of our work. We have read your comments and suggestions carefully. We will carefully revise the article according to the comments and suggestions you listed. Thank you!

Comment 1. Table 1, if you want to show the skeleton carbon, why there are R groups?

Response: Thank you for your comment. We have redrawn the skeletons structure of homoisoflavones and made modifications.

Comment 2. Table 2, the structures look weird, please re-draw them.

Response: Thank you for your comment and suggestion.We have redraw the chemical structure according to your suggestion.

Comment 3. Please cite the appropriate references, such as the first paragraph in section 3.1.

Response: Thank you for your suggestion. We have added and supplemented relevant references in section 3.1. [10. Zuo, J.; Ma, P.; Geng, S.; Kong, Y.; Li, X.; Fan, Z.; Zhang, Y.; Dong, A.; Zhou, Q. Optimization of the extraction process of flavo-noids from Trollius ledebouri with natural deep eutectic solvents. J Sep Sci. 2022, 45, 717-727. 11. Ahmad, R.; Alqathama, A.; Aldholmi, M.; Riaz, M.; Eldin, S.M.; Mahtab, Alam,M.; Abdelmohsen, S.A.M. Ultrasonic-assisted ex-traction of fenugreek flavonoids and its geographical-based comparative evaluation using green UHPLC-DAD analysis. Ultrason Sonochem. 2023, 95, 106382. ]

Comment 4. The authors showed Figure 4 but did not talk about it in the main text.

Response: Thank you for your comments and suggestions. In lines 183-201, we provided a detailed description of Figure 4. Thank you again for your suggestion. “Figure 4 shows some common flavonoid chelation sites with metal ions. The introduction of halogenated elements into flavonoid molecules can improve the biological activity of flavonoids, and the introduced elements are mainly fluorine, chlorine and bromine. The order of activity of introduced substances is usually fluorine greater than chlorine greater than bromine [48,50]. The introduction of reactive groups are mainly methyl, acyl and hydroxyl groups. The introduction of different active groups into flavonoid molecules can change the conformation of flavonoid molecules, enhance their biological activities, and even generate new physiological functions. Copmans et al. [49,51] investigated the effects of naringenin, kaempferol, and their three methylated derivatives on epileptic seizures (PTZ-induced) in zebrafish, and the results showed that the methylated flavanone NRGdm was very effective against PTZ-induced epileptic seizures in zebrafish larvae. The introduction of the hydroxyl group can increase the water solubility and antioxidant activity of flavonoids, and its introduction site has different effects on the activity of flavonoids, and the relationship between the relative activity and the introduction site is as follows: 7 > 4′≈ 3 > 3′ >> 5 [50,52].” Thank you!

Comment 5. All the compound numbers should be bolded.

Response: Thank you for your suggestion. All the compound numbers had been bolded.

Comment 6. Please show the stereochemistry of the structures if they are shown in the literature.

Response: Thank you for your comment. We have redraw the chemical structure according to your suggestion.

Comment 7. Please revise Figures 6 and 7.

Response: Thank you for your comment and suggestion. We have redrawn and modified Figures 6 and 7.

Comments on the Quality of English Language

English is hard reading.

Response: Thank you for your comment. We have revised the language of the manuscript.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Authors did not add significant improvement to the paper. The most important syggestion was based on poor and hard to read structure of paper which did not include the most important information along with superficial information which can be find in numeorus review articles based on flavonoids. Additionally, the response:

thank you for your comment and suggestion. This manuscript comprehensively reviews the current research and application status of flavonoids from the sources, biological activities, drug action mechanisms and clinical applications. The selection of references is based on the basic principle of the latest research related to flavonoids, almost half of the literature sources are from 2021 to the present, and the manuscript comprehensively reviews the latest research progress and existing opportunities and challenges of flavonoids from 7 aspects.

is insufficient. In this case authors should present detail information (in paper) about the process of literature searching.

Additionally, conclusions are superficial and did not bring new information.

Comments on the Quality of English Language

is insufficient. In this case authors should present detail information (in paper) about the process of literature searching.

Additionally, conclusions are superficial and did not bring new information.

Author Response

Response to Reviewer 2:

Dear Reviewer,

Thank you very much for your comprehensive review of our manuscript. The responses answering every question are as follows.

Comments and Suggestions.

Response: Thank you for your comment and suggestion. Nature is an inexhaustible source of bioactive substances and we will not stop getting to know it. We provides an update on the state of research on the well-known flavonoids. The review summarizes the latest research progress on flavonoids, existing problems in the therapeutic efficacy, and how these issues can be solved with the research of flavonoids. And we have reorganized and revised the conclusion section. Thank you again for your careful and rigorous review of the manuscript and your affirmation of our work. We will keep working hard in the future. Thank you!

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

You have written responses to my recommendations but have not implemented them in your manuscript. Additionally, using track changes is the standard, most appropriate way to send a revised version of a manuscript.

Comments on the Quality of English Language

Extensive English language editing is required!

Author Response

Response to Reviewer 3:

Dear Reviewer,

Comments and Suggestions for Authors.

Response: Thank you for your comments and suggestions. We have made comprehensive revisions to the 6 modification suggestions for you proposed, and all modifications have been made in revision mode. Thank you again for your careful and rigorous review of the manuscript and your affirmation of our work. We will keep working hard in the future. Thank you!

Response: Thank you for your comment and suggestion. We have added the full name of FDA in L67 as per your suggestion and made modifications to the abbreviation section according to the journal format. And other abbreviations in the article have been uniformly modified.

Comment 2. How were the chemical structures used in the manuscript plotted, if software was used indicate it, or state the source of the image

Response: Thank you for your suggestion. We have followed your suggestion and redraw the chemical structure for the manuscript.

Comment 3.Use the same font in the figures as it is in the manuscript

Response: Thank you for your suggestion. We have made unified modifications to use the same font as in the manuscript in the figure.

Comment 4. Revise title in section 7

Response: Thank you for your suggestion. We have revised the title in Section 7.

Comment 5. The manuscript's logic is hard to follow. Please, think about making it more reader-friendly.

Comments on the Quality of English Language

Please, try to use comprehensible sentences and check for typo mistakes. The length of the sentence does not make it better.

Response: Thank you for your comments and suggestions. we have carefully polished the language of the manuscript.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The authors have made the necessary corrections. They failed to correct only the writing of NH4SCN, BF4N2Ar and TfOIAr2 (line 169), as well as BF4N2Ar and TfOIAr2 in Figure 3 indexes 4,4,2,2, etc. This is important from a chemical point of view.

Author Response

Response to Reviewer 4:

Dear Reviewer,

Comments and Suggestions.

Response: Thank you for your comments. We have revised the writing of these compounds and redrawn Figure 3，and checked the entire text. Thank you again for your suggestion.

Author Response File: Author Response.pdf

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

The authors addressed some issues, however, there are still some obvious issues.

1. In Table 2, please draw the exact structure that matches the name you list in the table, for example, for hesperidin, what's the sugar moiety? For catechin, what's the absolute configuration? some structures look weird, need to re-draw them, like eupatilin.

2. Figure 7 is weird, and needs to be re-drawn.

3. Double-check the compound names, hespridin should be hesperidin.

Author Response

Response to Reviewer 1:

Dear Reviewer,

Comments and Suggestions for Authors.

The authors addressed some issues, however, there are still some obvious issues.

Response: Thank you for your comments and suggestions. We have made comprehensive revisions for you proposed, and all modifications have been made in revision mode. Thank you again for your careful and rigorous review of the manuscript and your affirmation of our work. We will keep working hard in the future. Thank you!

Comment 1. In Table 2, please draw the exact structure that matches the name you list in the table, for example, for hesperidin, what's the sugar moiety? For catechin, what's the absolute configuration? some structures look weird, need to re-draw them, like eupatilin.

Response: Thank you for your comment and suggestion. We have checked the compound names and chemical structures in Table 2, and we have uniformly used ChemDraw software to re-draw the chemical structures of some compounds according to your suggestion, including Hesperidin, Catechins, Eupatilin, etc. Thank you again!

Comment 2. Figure 7 is weird, and needs to be re-drawn.

Response: Thank you for your suggestion. We have followed your suggestion and redraw the Figure 7.

Comment 3. Double-check the compound names, hespridin should be hesperidin.

Response: Thank you for your suggestion. We have carefully checked and made modifications to the compound names throughout the entire text.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

thank you for manuscript improvement. The paper can be accepted in present form.

Author Response

Response to Reviewer 2:

Dear Reviewer,

Thank you very much for your careful and comprehensive review of our paper. Thank you again!

Comments and Suggestions.

thank you for manuscript improvement. The paper can be accepted in present form. Response: Thank you for your comments. Thank you again for your careful and rigorous review of the manuscript and your affirmation of our work. We will keep working hard in the future. Thank you!

Author Response File: Author Response.pdf