Review Reports - The Roles of Calcium Ions in Parkinson’s Disease: Calcium Channel Inhibitors as a Novel Agents?

Round 1

Reviewer 1 Report

I have some comments on the manuscript entitled “Calcium Channel Inhibitors as a novel approach for the management of Parkinson’s disease”

1. Why there is a hyphen between the word “management” in the manuscript title.

2. Brief mechanism of action behind calcium channel inhibitor on PD should be included in the manuscript.

3. Limitations of your manuscript should be included in the last line of abstract section.

4. Include some more signalling component in figure no 1, 2 and 3.

5. Your objective and approaches regarding role of calcium channel blocker in PD should be elaborated in the last paragraph of introduction section.

6. A table regarding role of different medicinal plant and its bioactive components on calcium channel inhibitor and its role in PD should be included in the manuscript.

7. Discuss Anti-Parkinsonian role of Mucuna pruriens, ursolic acid and chlorogenic acid in MPTP intoxicate mouse model in your manuscript along with Anti-apoptotic role of Withania somnifera in Maneb and Paraquat induced mouse model.

8. Authors own input should be included at the end of every required paragraph.

9. Complete editorial checking will be needed to correct the grammatical and punctuation mistakes.

Author Response

Comment 1	Why there is a hyphen between the word “management” in the manuscript title.
Response	In revised manuscript, it has changed.
Comment 2	Brief mechanism of action behind calcium channel inhibitor on PD should be included in the manuscript.
Response	It has included in the revised manuscript.
Comment 3	Limitations of your manuscript should be included in the last line of abstract section.
Response	It has been corrected in the revised manuscript.
Comment 4	Include some more signalling component in figure no 1, 2 and 3.
Response	It has been added in the revised manuscript.
Comment 5	Your objective and approaches regarding role of calcium channel blocker in PD should be elaborated in the last paragraph of introduction section.
Response	Thanks for your comment. It has been enlarged in the revised manuscript
Comment 6	table regarding role of different medicinal plant and its bioactive components on calcium channel inhibitor and its role in PD should be included in the manuscript.
Response	It has been added in the revised manuscript
Comment 7	Discuss Anti-Parkinsonian role of Mucuna pruriens, ursolic acid and chlorogenic acid in MPTP intoxicate mouse model in your manuscript along with Anti-apoptotic role of Withania somnifera in Maneb and Paraquat induced mouse model.
Response	Thanks for your comment. It has been added in the revised manuscript.
Comment 8	Authors own input should be included at the end of every required paragraph
Response	It has included as per your comment.
Comment 9	Complete editorial checking will be needed to correct the grammatical and punctuation mistakes.
Response	All authors have checked and corrected it.

Reviewer 2 Report

Review report on the manuscript titled ‘Calcium Channel Inhibitors as a novel approach for the management of Parkinson’s disease’ by Alam R et al., submitted to Journal of Molecular Pathology

Manuscript ID: jmp-1886417

Dear Authors,

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by but not limited to motor dysfunction. In this original manuscript, entitled ‘Calcium Channel Inhibitors as a novel approach for the management of Parkinson’s disease’, by Alam R and Colleagues reviewed the potential use of r- and t-type calcium channel inhibitors for prevention of PD progression.

The main strength of this manuscript is that the authors attempt to summarize the current knowledge of calcium homeostasis, mitochondria, calcium channel, and calcium channel blockers in the search of novel therapeutic agents for PD.

In general, I think the idea of this review is really valuable and the author’s fascinating observations on this timely topic may be of interest to the readers of Journal of Molecular Pathology. However, some comments as well as some crucial evidence that should be included to support the authors’ argumentation, and that need to be addressed to improve the quality of the article, its adequacy, and its readability prior to the publication in the present form.

My overall judgment is to publish this article after the authors have carefully considered my suggestions below, reshaping parts of the introduction and conclusion sections by adding more evidence. In general, I recommend the authors to use more evidence to back their claims, especially in the introduction of the article, which I believe is currently insufficient. Thus, I advise the authors to attempt to deepen the subject of this manuscript, as the bibliography is too concise: nonetheless, in my opinion, less than 150 articles for a review paper are insufficient. Currently the authors cite only 57 papers, and they are dramatically low. Therefore, I suggest focusing their efforts on researching relevant literature: I believe that adding more studies will help to provide better and more accurate background to this paper.

Comments:

1. Title: As the description of calcium channel blockers are limited to the section 3.5., I suggest rephrasing the title such as ’The Roles of Calcium Iones in Parkinson’s Disease: Calcium Channel Inhibitors as a Novel Agents?’.

2. Abstract: Please present the background, the rationale, the objectives, the summary, and the conclusion of this review proportionally. Please expand all abbreviations in the first appearance in the abstract.

3. Keywords: I suggest listing ten keywords and using as many keywords as possible in the first two sentences of the abstract.

4. Introduction: The Introduction is well written and nicely presented, leading to the purpose of this study. Nevertheless, I believe that more information on pathophysiology and core features of PD will provide a better and more accurate background, because as it stands, this information is not highlighted in the text. In this regard, I would suggest adding more information on the pathogenesis of PD including neurodevelopmental, environmental, dietary factors including tryptophan and kynurenines, reduced stress resilience, mitochondria impairment, inflammation, aging, pathology, involvement of the gut microbiota, imaging diagnosis, antioxidants as preventive and therapeutic measures, and novel treatment such as deep brain stimulation, among others (doi: 10.1007/s00702-022-02513-5; https://doi.org/10.3390/ijms22168726; https://doi.org/10.3390/biom12070998; doi: 10.20944/preprints202010.0172.v2; https://doi.org/10.3390/ijms21249338; https://doi.org/10.3390/biomedicines9101310; https://doi.org/10.3390/cells9112476; https://doi.org/10.3390/ijms21072431; https://doi.org/10.3390/ijms23136991; https://doi.org/10.3390/cells11162607; https://doi.org/10.1186/s41983-022-00460-2; https://doi.org/10.3390/microorganisms9112281; https://doi.org/10.3390/biom12040507; https://doi.org/10.3390/jpm12010089; doi:10.3390/antiox10030453; https://doi.org/10.3390/diagnostics12041001).

5. In the current text, information on the main elements stays solitary and the connection between the elements which potentially exists, remains loose. That said, I recommend that the authors present a brief introductory description regarding the main elements, such as mitochondria, calcium homeostasis, calcium channel, and calcium channel blockers, leading to the rationale and the purpose of this review.

6. Introduction: I suggest adding more information on pathological neural substrates of cognitive symptoms in PD, specifically on frontal lobe dysfunction, and on related effects on patients’ cognitive impairments: evidence from recent studies provides a deeper understanding of human learning neural networks, particularly on human crucial role in prefrontal cortex, proposing a theoretical model to conceptualize these psychophysiological processes, the neurovisceral integration model of fear (NVI-f) that can be impaired in the context of psychiatric disorder (https://doi.org/10.1016/j.tins.2022.04.003; (https://doi.org/10.1111/psyp.14122) that might also contribute to the advancement of alternative, more precise and individualized treatments for PD. For most recent literature on rTCS, please refer to the following papers: https://doi.org/10.3390/ijms23126850; https://doi.org/10.3390/biomedicines10030627; https://doi.org/10.3390/brainsci11111532; https://doi.org/10.3390/biomedicines9070783).

7. Discussion: Here, the authors present their expert opinion by developing argument based on the previous sections. Furthermore, the authors develop this section with significance of the current study, the weaknesses or the limitation in the present review, the potentials, the ultimate goal, research or knowledge needed to achieve, the biggest challenge in this goal, and future research direction, among others.

8. I believe that a ‘Conclusion’ paragraph would benefit from some thoughtful as well as in-depth considerations by the author, because as it stands, it is very descriptive but not enough theoretical to adequately convey what the authors believe is the take-home message of their study. Therefore, please provide a synthesis of the data presented in the paper as well as possible keys to advancing research and understanding calcium channels as potential targets and calcium channel blockers as potential therapeutic agents.

9. References: I strongly recommend citing more references to present background information, supports the rationale of this study, and develop convincing discussion, preferably consisting of more than 150 references.

The manuscript contains three figures, no table, and 57 references. I hope that, after these careful revisions, the manuscript can meet the Journal’s high standards for publication. The manuscript potentially carries important value reviewing calcium channel blockers as potential therapeutic agents for PD.

Best regards,

Reviewer

Author Response

Comment 1	Title: As the description of calcium channel blockers are limited to the section 3.5., I suggest rephrasing the title such as ’The Roles of Calcium Iones in Parkinson’s Disease: Calcium Channel Inhibitors as a Novel Agents?’
Response	In revised manuscript, it has been changed.
Comment 2	Abstract: Please present the background, the rationale, the objectives, the summary, and the conclusion of this review proportionally. Please expand all abbreviations in the first appearance in the abstract.
Response	It has been included in the revised manuscript.
Comment 3	Keywords: I suggest listing ten keywords and using as many keywords as possible in the first two sentences of the abstract.
Response	It has been added in the revised manuscript.
Comment 4	Introduction: The Introduction is well written and nicely presented, leading to the purpose of this study. Nevertheless, I believe that more information on pathophysiology and core features of PD will provide a better and more accurate background, because as it stands, this information is not highlighted in the text. In this regard, I would suggest adding more information on the pathogenesis of PD including neurodevelopmental, environmental, dietary factors including tryptophan and kynurenines, reduced stress resilience, mitochondria impairment, inflammation, aging, pathology, involvement of the gut microbiota, imaging diagnosis, antioxidants as preventive and therapeutic measures, and novel treatment such as deep brain stimulation, among others.
Response	Needful done.
Comment 5	In the current text, information on the main elements stays solitary and the connection between the elements which potentially exists, remains loose. That said, I recommend that the authors present a brief introductory description regarding the main elements, such as mitochondria, calcium homeostasis, calcium channel, and calcium channel blockers, leading to the rationale and the purpose of this review.
Response	Needful done
Comment 6	Introduction: I suggest adding more information on pathological neural substrates of cognitive symptoms in PD, specifically on frontal lobe dysfunction, and on related effects on patients’ cognitive impairments: evidence from recent studies provides a deeper understanding of human learning neural networks, particularly on human crucial role in prefrontal cortex, proposing a theoretical model to conceptualize these psychophysiological processes, the neurovisceral integration model of fear (NVI-f) that can be impaired in the context of psychiatric disorder (https://doi.org/10.1016/j.tins.2022.04.003; (https://doi.org/10.1111/psyp.14122) that might also contribute to the advancement of alternative, more precise and individualized treatments for PD. For most recent literature on rTCS, please refer to the following papers: https://doi.org/10.3390/ijms23126850; https://doi.org/10.3390/biomedicines10030627; https://doi.org/10.3390/brainsci11111532; https://doi.org/10.3390/biomedicines9070783)..
Response	Thanks for your comment and in revised manuscript we have added as per your suggestion.
Comment 7	Discussion: Here, the authors present their expert opinion by developing argument based on the previous sections. Furthermore, the authors develop this section with significance of the current study, the weaknesses or the limitation in the present review, the potentials, the ultimate goal, research or knowledge needed to achieve, the biggest challenge in this goal,and future research direction, among others.
Response	It has been added in revised manuscript.
Comment 8	I believe that a ‘Conclusion’ paragraph would benefit from some thoughtful as well as in-depth considerations by the author, because as it stands, it is very descriptive but not enough theoretical to adequately convey what the authors believe is the take-home message of their study. Therefore, please provide a synthesis of the data presented in the paper as well as possible keys to advancing research and understanding calcium channels as potential targets and calcium channel blockers as potential therapeutic agents.
Response	Thank you for your comment. It has been added in revised manuscript.
Comment 9	References: I strongly recommend citing more references to present background information, supports the rationale of this study, and develop convincing discussion, preferably consisting of more than 150 references. The manuscript contains three figures, no table, and 57 references. I hope that, after these careful revisions, the manuscript can meet the Journal’s high standards for publication. The manuscript potentially carries important value by reviewing calcium channel blockers as potential therapeutic agents for PD.
Response	Needful done.

Author Response File: Author Response.docx

Reviewer 3 Report

Figures 2 and 3: draw better arrows. Shaky lines do not look good.

In the topic: 3.4. Role of calcium channels in Parkinson’s disease. The author could also mention the channel BKCa.

Author Response

Comment 1	This is a review article about an interesting topic: the calcium channel blockers as a novel treatment approach for Parkinson’s disease. The structure is generally good, but English language besides some orthographic errors, has also some grammatical and syntactical issues that sometimes make it difficult for the reader to exactly understand the meaning of a sentence. For example, in line 11 the term “result in motor impairment” could be rephrased to “which results in motor impairment”. In line 30 the term “are first appeared” should be rephrased to “first appear”. The word “dysfunctioning”, mentioned in lines 39, 64, 103, 126 and 137 should be corrected to “dysfunction” and in lines 240-41 the term “subarachnoidal hemorrhage” should be rephrased to ““subarachnoid hemorrhage”. In line 264 the term “there is needed” should be replaced by either “there is the need” or “it is necessary”.
Response	In revised manuscript, it has been corrected.
Comment 2	The introduction section describes the background of the current review in a fairly comprehensive manner.
Response	It has been described in revised manuscript.
Comment 3	To my opinion, the authors should add a paragraph, describing the method they used for their literature review.
Response	It has been corrected in the revised manuscript.
Comment 4	Results are interesting and well presented.
Response	It has been added in the revised manuscript.
Comment 5	Conclusion section could be rewritten in a more detailed and critical manner, focusing more on possible aims of relative future studies.
Response	It has been enlarged in the revised manuscript

Author Response File: Author Response.docx

Reviewer 4 Report

This is a review article about an interesting topic: the calcium channel blockers as a novel treatment approach for Parkinson’s disease.

The structure is generally good, but English language besides some orthographic errors, has also some grammatical and syntactical issues that sometimes make it difficult for the reader to exactly understand the meaning of a sentence.

For example, in line 11 the term “result in motor impairment” could be rephrased to “which results in motor impairment”. In line 30 the term “are first appeared” should be rephrased to “first appear”. The word “dysfunctioning”, mentioned in lines 39, 64, 103, 126 and 137 should be corrected to “dysfunction” and in lines 240-41 the term “subarachnoidal hemorrhage” should be rephrased to ““subarachnoid hemorrhage”. In line 264 the term “there is needed” should be replaced by either “there is the need” or “it is necessary”.

The introduction section describes the background of the current review in a fairly comprehensive manner.

To my opinion, the authors should add a paragraph, describing the method they used for their literature review.

Results are interesting and well presented.

Conclusion section could be rewritten in a more detailed and critical manner, focusing more on possible aims of relative future studies.

Author Response

Comment 1	This is a review article about an interesting topic: the calcium channel blockers as a novel treatment approach for Parkinson’s disease. The structure is generally good, but English language besides some orthographic errors, has also some grammatical and syntactical issues that sometimes make it difficult for the reader to exactly understand the meaning of a sentence. For example, in line 11 the term “result in motor impairment” could be rephrased to “which results in motor impairment”. In line 30 the term “are first appeared” should be rephrased to “first appear”. The word “dysfunctioning”, mentioned in lines 39, 64, 103, 126 and 137 should be corrected to “dysfunction” and in lines 240-41 the term “subarachnoidal hemorrhage” should be rephrased to ““subarachnoid hemorrhage”. In line 264 the term “there is needed” should be replaced by either “there is the need” or “it is necessary”.
Response	In revised manuscript, it has been corrected.
Comment 2	The introduction section describes the background of the current review in a fairly comprehensive manner.
Response	It has been described in revised manuscript.
Comment 3	To my opinion, the authors should add a paragraph, describing the method they used for their literature review.
Response	It has been corrected in the revised manuscript.
Comment 4	Results are interesting and well presented.
Response	It has been added in the revised manuscript.
Comment 5	Conclusion section could be rewritten in a more detailed and critical manner, focusing more on possible aims of relative future studies.
Response	It has been enlarged in the revised manuscript

Round 2

Reviewer 1 Report

The manuscript is revised as per my suggestions.

Author Response

Comment 1	The manuscript is revised as per my suggestions.
Response	Thanks sir for considering our review paper for publication.

Author Response File: Author Response.docx

Reviewer 2 Report

The 2^nd review report on the manuscript titled ‘Calcium Channel Inhibitors as a novel approach for the management of Parkinson’s disease’ by Alam R et al., submitted to Journal of Molecular Pathology

Manuscript ID: jmp-1886417

Dear Authors,

I am pleased to see that the authors did an excellent work extensively revising the manuscript but solving issues partially, which I have raised in the previous round of the review session. Currently, this paper is a timely piece of research and reviewing the potential use of r- and t-type calcium channel inhibitors for prevention of Parkinson’s disease (PD) progression. That said, I suggest some points below, which the authors deserve to reconsider for the betterment of this manuscript and thus, the manuscript will meet the high standard of the journal.

Comments:

1. Authors: Please add asterisk to the corresponding author and place ‘and’ in front of the last author.

2. Abstract: Please abridge the abstract to 200 words according to the guidelines of the journal. Please expand ‘R-‘.

1. I believe that more information on pathophysiology and core features of PD will provide a better and more accurate background, because as it stands, this information is not highlighted in the text. In this regard, I would suggest adding more information on the pathogenesis of PD including neurodevelopmental, environmental, dietary factors including tryptophan and kynurenines, reduced stress resilience, mitochondria impairment, inflammation, aging, pathology, involvement of the gut microbiota, imaging diagnosis, antioxidants as preventive and therapeutic measures, and novel treatment such as deep brain stimulation, among others (doi: 10.1007/s00702-022-02513-5; https://doi.org/10.3390/ijms22168726; https://doi.org/10.3390/biom12070998; doi: 10.20944/preprints202010.0172.v2; https://doi.org/10.3390/ijms21249338; https://doi.org/10.3390/biomedicines9101310; https://doi.org/10.3390/cells9112476; https://doi.org/10.3390/ijms21072431; https://doi.org/10.3390/ijms23136991; https://doi.org/10.3390/cells11162607; https://doi.org/10.1186/s41983-022-00460-2; https://doi.org/10.3390/microorganisms9112281; https://doi.org/10.3390/biom12040507; https://doi.org/10.3390/jpm12010089; doi:10.3390/antiox10030453; https://doi.org/10.3390/diagnostics12041001).

2. In the current text, information on the main elements stays solitary and the connection between the elements which potentially exists, remains loose. That said, I recommend that the authors present a brief introductory description regarding the main elements, such as mitochondria, calcium homeostasis, calcium channel, and calcium channel blockers, leading to the rationale and the purpose of this review.

3. Introduction: I suggest adding more information on pathological neural substrates of cognitive symptoms in PD, specifically on frontal lobe dysfunction, and on related effects on patients’ cognitive impairments: evidence from recent studies provides a deeper understanding of human learning neural networks, particularly on human crucial role in prefrontal cortex, proposing a theoretical model to conceptualize these psychophysiological processes, the neurovisceral integration model of fear (NVI-f) that can be impaired in the context of psychiatric disorder (https://doi.org/10.1016/j.tins.2022.04.003; (https://doi.org/10.1111/psyp.14122) that might also contribute to the advancement of alternative, more precise and individualized treatments for PD. For most recent literature on rTCS, please refer to the following papers: https://doi.org/10.3390/ijms23126850; https://doi.org/10.3390/biomedicines10030627; https://doi.org/10.3390/brainsci11111532; https://doi.org/10.3390/biomedicines9070783).

4. I believe that a ‘Conclusion’ paragraph would benefit from some thoughtful as well as in-depth considerations by the author, because as it stands, it is very descriptive but not enough theoretical to adequately convey what the authors believe is the take-home message of their study. Therefore, the authors develop this section with significance of the current study, the weaknesses or the limitation in the present review, the potentials, the ultimate goal, research or knowledge needed to achieve, the biggest challenge in this goal, and future research direction, among others.

5. Figures: Please add the titles and the captions under the figures.

6. Table 1: Please place the title above the table.

The manuscript contains three figures, one table, and 157 references. In the rebuttal, I expect the authors address their response adequately enough to describe the revision they made, their intention, the rationale, or their opinions if they do not agree to let the reviewer convinced that the quality of the manuscript has improved. The manuscript potentially carries important value reviewing calcium channel blockers as potential therapeutic agents for PD. I hope that, after these careful revisions, the manuscript will meet the Journal’s high standards for publication.

Best regards,

Reviewer

Author Response

Response to comment on the research paper entitled: “The Roles of Calcium Ions in Parkinson’s Disease: Calcium Channel Inhibitors as a Novel Agents?”

Reviewer 2:

I am pleased to see that the authors did an excellent work extensively revising the manuscript but solving issues partially, which I have raised in the previous round of the review session. Currently, this paper is a timely piece of research and reviewing the potential use of r- and t- type calcium channel inhibitors for prevention of Parkinson’s disease (PD) progression. That said, I suggest some points below, which the authors deserve to reconsider for the betterment of this manuscript and thus, the manuscript will meet the high standard of the journal.

Comment 1	Comments: 1. Authors: Please add asterisk to the corresponding author and place ‘and’ in front of the last author. 2. Abstract: Please abridge the abstract to 200 words according to the guidelines of the journal. Please expand ‘R-‘.
Response	In revised manuscript, it has been changed.
Comment 2	I believe that more information on pathophysiology and core features of PD will provide a better and more accurate background, because as it stands, this information is not highlighted in the text. In this regard, I would suggest adding more information on the pathogenesis of PD including neurodevelopmental, environmental, dietary factors including tryptophan and kynurenines, reduced stress resilience, mitochondria impairment, inflammation, aging, pathology, involvement of the gut microbiota, imaging diagnosis, antioxidants as preventive and therapeutic measures, and novel treatment such as deep brain stimulation, among others (doi: 10.1007/s00702-022-02513-5; https://doi.org/10.3390/ijms22168726; ttps://doi.org/10.3390/biom12070998; doi: 10.20944/preprints202010.0172.v2; https://doi.org/10.3390/ijms21249338; https://doi.org/10.3390/biomedicines9101310; https://doi.org/10.3390/cells9112476; https://doi.org/10.3390/ijms21072431; https://doi.org/10.3390/ijms23136991; https://doi.org/10.3390/cells11162607; https://doi.org/10.1186/s41983-022-00460-2; https://doi.org/10.3390/microorganisms9112281; https://doi.org/10.3390/biom12040507; https://doi.org/10.3390/jpm12010089; doi:10.3390/antiox10030453; https://doi.org/10.3390/diagnostics12041001).
Response	It has been included in the revised manuscript.
Comment 3	In the current text, information on the main elements stays solitary and the connection between the elements which potentially exists, remains loose. That said, I recommend that the authors present a brief introductory description regarding the main elements, such as mitochondria, calcium homeostasis, calcium channel, and calcium channel blockers, leading to the rationale and the purpose of this review.
Response	It has been added in the revised manuscript.
Comment 4	Introduction: I suggest adding more information on pathological neural substrates of cognitive symptoms in PD, specifically on frontal lobe dysfunction, and on related effects on patients’ cognitive impairments: evidence from recent studies provides a deeper understanding of human learning neural networks, particularly on human crucial role in refrontal cortex, proposing a theoretical model to conceptualize these psychophysiological processes, the neurovisceral integration model of fear (NVI-f) that can be impaired in the context of psychiatric disorder (https://doi.org/10.1016/j.tins.2022.04.003; (https://doi.org/10.1111/psyp.14122) that might also contribute to the advancement of alternative, more precise and individualized treatments for PD. For most recent literature on rTCS, please refer to the following papers: https://doi.org/10.3390/ijms23126850; https://doi.org/10.3390/biomedicines10030627; https://doi.org/10.3390/brainsci11111532; https://doi.org/10.3390/biomedicines9070783).
Response	Needful done.
Comment 5	I believe that a ‘Conclusion’ paragraph would benefit from some thoughtful as well as in-depth considerations by the author, because as it stands, it is very descriptive but not enough theoretical to adequately convey what the authors believe is the take-home message of their study. Therefore, the authors develop this section with significance of the current study, the weaknesses or the limitation in the present review, the potentials, the ultimate goal, research or knowledge needed to achieve, the biggest challenge in this goal, and future research direction, among others.
Response	Needful done
Comment 6	Figures: Please add the titles and the captions under the figures.
Response	Thanks for your comment and in revised manuscript we have added as per your suggestion.
Comment 7	Table 1: Please place the title above the table.
Response	It has been added in revised manuscript.

Author Response File: Author Response.pdf

Reviewer 4 Report

This is a generally well revised manuscript. Most of the comments have been appropriately addressed. However, as I have previously said, a paragraph describing the method that authors used for their literature review would, to my opinion, further improve the quality of this review.

Author Response

Comment 1	This is a generally well revised manuscript. Most of the comments have been appropriately addressed. However, as I have previously said, a paragraph describing the method that authors used for their literature review would, to my opinion, further improve the quality of this review.
Response	In revised manuscript, it has been added as per your comment.

Author Response File: Author Response.docx