Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A MULTIPLEX CENTRALITY METRIC FOR COMPLEX SOCIAL NETWORKS: SEX, SOCIAL STATUS, AND FAMILY STRUCTURE PREDICT MULTIPLEX CENTRALITY IN RHESUS MACAQUES
Review round: 2
Reviewer: 1

Output:
Basic reporting: The manuscript is clearly written and structured well. The Introduction provides a useful overview of the potential benefits of adopting a multilayer approach, clearly explains why consensus ranking may be useful for situations other multilayer centrality metrics may be ill-equipped to handle, and shows how rhesus macaques offer a useful testbed. Coverage of the literature is good throughout.

The figures and captions have been much improved since the initial submission; I have only minor suggestions in the general comments.

The raw data needed to obtain the GLMM parameter estimates has been provided.
Experimental design: The manuscript presents a novel metric for evaluating centrality in multiplex networks (consensus ranking). This metric successfully captures known features of rhesus macaque social structure, as well as reveals novel aspects missed by single-layer approaches. As consensus ranking can be used in situations where network layers differ in topology and function, it may prove a valuable addition to network analysts’ toolbox.

Data collection protocols and statistical analysis are sound and appropriate ethical approval was obtained. Network randomizations are now integrated with the GLMMs in order to evaluate statistical significance, correcting a major weakness of the initial manuscript.

The methods are generally explained well. I appreciate the additional information the authors now provide for certain methodological decisions (e.g. treating grooming interactions as undirected, summing in- and out-degree in the policing layer).
Validity of the findings: The adjustments made to the Discussion are welcome. The paper flows very nicely, with conclusions logically stemming from the results.
Additional comments: L38: I suggest avoiding abbreviations in the abstract (even a common one such as this).

L61: Include scientific name at first mention.

L127: Delete “in”

L157: Consider describing what betweenness captures without using network jargon such as ‘shortest path’ (as was done nicely for the other metrics here). Perhaps something along the lines of: “the tendency to link together otherwise weakly connected individuals/groups”?

L330-333: As it is brought up earlier (L293-296), I suggest clarifying here that information on aggression intensity was not included in the aggression layer.

L344: In the authors’ response letter, more justification is provided for the use of betweenness. I think it would be helpful to include this information in the text itself; many readers may primarily think of betweenness as a means to evaluate importance for flow/transmission processes, rather than as a measure of social cohesion.

L346-349: I appreciate the additional explanation provided for how the policing layer is treated. I wonder if L325-327 might even be better placed here. Otherwise I fear readers may miss the fact that the policing layer is trying to capture information on valued social relationships (including victims that need defending) rather than simply describing power differences.

L399: “explained by the tiered”

L429: Define the abbreviation ‘GLMM’ here prior to its use later.

L444-448: Consider breaking this sentence up to improve readability.

L525-527: I suspect the authors are correct that the difference in consensus ranks between females from medium and large families is statistically significant, given there is essentially no difference between females from small and large matrilines. However, would it not be relatively simple to change the baseline level and obtain the corresponding p-value?

Figure 1 caption: Thank you for including more information here; the figure now stands on its own. While it is discussed in the text, I suggest including here what the y-axis in 1c represents (i.e. that r^2 is the correlation between the original and tiered centralities, and that the horizontal line indicates where 99% of the variance is explained).

Figure 5 (and similar figures): It would be helpful to include “Sex (male)” here and elsewhere.

Figure 7: Consider re-drawing this figure to match the visual style of your other figures (e.g. Figure 4).

Table 3: The caption says three models are presented. I also suggest defining MSC beneath the table.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A MULTIPLEX CENTRALITY METRIC FOR COMPLEX SOCIAL NETWORKS: SEX, SOCIAL STATUS, AND FAMILY STRUCTURE PREDICT MULTIPLEX CENTRALITY IN RHESUS MACAQUES
Review round: 2
Reviewer: 2

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: After going over the rebuttal and the revised paper, I consider most of my concerns were properly addressed by the authors. Along with the changes made in response to the comments from the other reviewers, I consider the paper was nicely improved and presents very interesting and useful methodological information. The paper is well structured and presented with clear language which makes the study easy to follow. I only have very few observations to the text which I list below. Otherwise, I think the paper is basically ready for publication and I’ll be excited to read the final version.

L64. Edit to: “interact in a variety of contexts…”

L66. Edit to: “…to study…” or “…for the study…”

L127. Edit to: “…heterogeneous…”

Figure captions:

Figure 3: for the dominance and Borda ranks shown in the red-yellow scale, please indicate which color indicates higher and lower ranks.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A MULTIPLEX CENTRALITY METRIC FOR COMPLEX SOCIAL NETWORKS: SEX, SOCIAL STATUS, AND FAMILY STRUCTURE PREDICT MULTIPLEX CENTRALITY IN RHESUS MACAQUES
Review round: 2
Reviewer: 3

Output:
Basic reporting: The revised article is well written and structured. Figures are generally good (although some room for improvement - see my general comments to the authors)
Experimental design: The research question and hypotheses are clear and the methods are largely excellent. Some additional details required in some places to improve clarity further (see my general comments to the authors)
Validity of the findings: I have one new concern related to the analysis that arises from it not being clear how dominance ranks are calculated (apologies for missing this before). If the same data are used to calculate dominance rank (an explanatory variable in several analyses) and the agonistic network/multiplex network and position of individuals within it (the response variable) this could be problematic in terms of model assumptions (although I lack sufficient knowledge to know if it problematic in a practical perspective). I suspect it is potentially a bigger issue in the analysis of the agonistic network IF the same data are used (it may well be that they aren't). This is also outlined in my comments to the authors.

The results seem robust and the discussion/conclusion well-written and clearly stated.
Additional comments: The authors have done an excellent job revising the paper. I have a few remaining concerns and some very minor suggestions highlighted here.

One potential concern that it seems was not picked up on previously (I have tried my best to search for it in the response/original comments and not found it) is how the dominance ranks were calculated. I am assuming they were calculated from a separate dataset than that used to construct the agonistic network used in the study? Currently there is insufficient detail to know this for sure. Otherwise there are potential issues caused by an explanatory variable and response variable not being measured independently from each other (i.e. the dominance ranks that are being used as an explanatory variable are calculated from the same). I know this violates statistical assumptions if it is the case but am not knowledgeable enough to comment on how problematic it is from a practical point of view. It would be a particular issue in the analysis of the aggression layer (although arguably still exists in the full multiplex analysis) and only if the same data was used to construct the networks and calculate ranks. I am hoping/anticipating this is purely a problem of not knowing for sure how dominance ranks were calculated.

Another interesting conundrum is the use of AICc for model simplification prior to the use to randomisations for statistical inference. There might be some situations where this is problematic, but I suspect this isn’t the case for the node-label swaps conducted here (more likely when there is structure/bias in how network data is collected and swaps are to the raw data instead). While I tend to fit randomisations to a full model, I think what the authors have at the moment is a sensible/practical solution to using randomisations alongside a complex model. However, I lack statistical and study system knowledge to be confident that its definitely without caveats. No need to address this comment per se, but potentially worth the authors thinking how removing potential variables using AIC before formal analysis using randomisations might have an impact given their knowledge of the system.

For Figs. 4, 6 and 7 I still think it is important to illustrate something beyond just the model predictions – showing the raw data or group means might be helpful here? While, I think Fig. 4 and 7 are likely fine as they are as they show enough information to be helpful, Fig. 1 as it stands would be better removed and the numbers provided in the main text (as this would be an easier and more accurate comparison). However, Fig. 4 seems like the easiest figure to include some aspect of raw data (group means perhaps?). Apologies for my contradictory suggestions on the previous draft that made this point hard to address.

In L330-338 it is important to say whether weighted or unweighted networks were used and if the former then clarify how weights were calculated. Then when talking about measures be clear whether they are weighted/unweighted measures.

In L464-481 you need to make sure that is clear that randomisations are conducted separately for each top model identified. Which models are used for randomisations is only clear once you have got to the results section currently.

Minor suggestions:
L51-52: This sentence is a little unclear and I feel could be improved by expanding on the point made a little (and perhaps with citations)
L87: This risks confusion as not all layers need necessarily include all of the actors. Deleting “all layers have the same node set” and editing “and this” to “which” would provide an identical definition without this confusion
L116: Suggest “like MANY network measures” as some measures do only account for direct connections (e.g. degree)
L154: Might be too fussy but would suggest “extent” rather the “degree” as it prevents potential confusion with the use of degree as a specific measure
L156: Make sure the definition of degree includes the idea that is the number of or summed weight of all connections of an individual
L157: “eigenvector CENTRALITY”
L175: Suggest changing “the airline transportation network” to “AN airline transportation network”
L184-187: I am not a huge fan of this section as it implies the choice of measure should depend predominantly on network structure. While, this is undoubtedly important the primary/over-riding factor needs to be the biological question being addressed. Would suggest at least mentioning this here.
L297: Suggest changing “macaque monkeys” to simply read “macaques”
L410&428: Is this computer code available anywhere that could be linked to after these statements (supplementary, GitHub etc)?
L537-542: I feel these few sentences could do with some careful revision as they are rather confusing at the moment. In part this is because rank might refer both to dominance rank and centrality rank – so finding a way to avoid this confusion would help a lot. In L540 would suggest “…but THIS was NOT STATISTICALLY significant according…”
L575: Suggest “only reached STATISTICAL significance”
L587-588: Little bit unclear and would suggest being more explicit and saying most central or one of the most central rather than simply high social centrality to make it as clear as possible you are talking about the top one (or few) individual(s)
Fig. 1 legend: Would it help to say “…is the FIRST one which falls below the threshold…”
Fig. 3 legend: Would be helpful to describe what the branching at the top depicts
Would be good to make the figures suitable for printing in B&W given the simple colour schemes (currently they are not!) – obviously this is not essential though
For Tables 3-6 my preference is to report the quantiles themselves as it is these that are important for comparisons to the observed parameters – I can understand if they don’t fit in the main text table but might good to provide in Supplementary if possible?

I hope my comments are useful in improving the paper,
Matthew Silk


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: CIRCPARSER: A NOVEL STREAMLINED PIPELINE FOR CIRCULAR RNA STRUCTURE AND HOST GENE PREDICTION IN NON-MODEL ORGANISMS
Review round: 1
Reviewer: 1

Output:
Basic reporting: The article was written in comprehensive English, was well structured, and was easy to understand. The references were appropriate but the authors should have a look at DOI:10.1038/ncomms12060 describing alternative splicing in circRNAs and DOI:10.1093/bioinformatics/btv656 describing a more accurate circRNA detection tool than CIRI.

This is a methods paper with a proof of principal application so it is lacking any major findings. Furthermore, the authors fail to show the information gained by using their program. I suggest two control experiments:
1. of the dataset the used, please show how many circRNAs were annotated with host-genes by the individual circRNA prediction tool, i.e. how many circRNAs were assigned to genes if circRNA detection was run with a reference gtf. How many more circRNAs can be assigned to genes using their program CircParser.
2. To show the overall accuracy, I suggest to use a dataset of a well annotated organism such as human or mouse. Show how many circRNAs are correctly associated with their host-gene.

Minor Remarks.
There were some formatting issues in line 51.
There was a spelling mistake of a program in line 93 it should be "bedtools multiinter"
The resolution of the figures is too small.
Figure legend 1b is not informative.
The raw data is only accessible after August 1st 2020.
Experimental design: The article would fit in the scope of PeerJ.
The research statement was well defined.
The authors should consider running the in silico experiments described above to really show the advantage of their program and make the paper strong and convincing. Currently I am not convinced that I would gain anything by running their program. I would also appreciate it, if the authors showed results for using only one circRNA prediction tool at a time as this would be the more used case.
As this is a methods paper, the authors need to describe the methods in more detail. Especially how they select the appropriate blastn result and assign it to the respective circRNA.
The provided git repository should include a use-case with input, command line and output.
Validity of the findings: In Line150 the authors conclude that their program "represents a fast and reproducible workflow", however they show neither any run-time analyis, nor any results showing reproducibility.
Additional comments: The paper provides a very nice idea and implementation on how to predict circRNA host genes in non-model organisms, however I would highly appreciate if the authors could include the suggestions mentioned above in order to show the validity and information gain of their program.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: CIRCPARSER: A NOVEL STREAMLINED PIPELINE FOR CIRCULAR RNA STRUCTURE AND HOST GENE PREDICTION IN NON-MODEL ORGANISMS
Review round: 1
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Dear authors, it was nice article to read and learn about, however I have some minor remarks that should improve your article.
1. As I understood, the main benefit of CircParser among other tools is that it uses converted to fasta sequences and blast to search for host genes. So I think that you should add more about this benefit in article, because now it's not so clear.
2. Pipeline works only in Unix environment, why don't to put it inside Docker image, as well as other tools and provide single docker-compose file that will do all the analyses in any OS (Linux, Windows, MacOS).


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: CIRCPARSER: A NOVEL STREAMLINED PIPELINE FOR CIRCULAR RNA STRUCTURE AND HOST GENE PREDICTION IN NON-MODEL ORGANISMS
Review round: 2
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Thank you for addressing my main concerns.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: CIRCPARSER: A NOVEL STREAMLINED PIPELINE FOR CIRCULAR RNA STRUCTURE AND HOST GENE PREDICTION IN NON-MODEL ORGANISMS
Review round: 2
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Text was improved and now it's easier to follow general idea of article. Hope to see dockerized version of this software in near future.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SELF-CONCEPT IN POOR READERS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Review round: 1
Reviewer: 1

Output:
Basic reporting: The report is well written. It refers to literature appropriately and uses a professional article structure. It has relevant results to the hypotheses.
Experimental design: The research question is well defined, relevant and meaningful. The investigation is rigorous and well conducted. The methods are described with sufficient detail.
Validity of the findings: As this is a meta-analysis, underlying data are provided in other publications. Analysis is on means and standard deviations from each sample, which are provided within the paper.
Additional comments: The authors state that there is inconsistent research about the relationship between poor reading and self concept and provide three possible explanations for this: the null hypothesis that there is no relationship; that the relationship depends upon what type of reading difficulty is measured; or that the relationship depends on which type of self-concept is measured. While these are three possible explanations, it seems to me that the authors ignore the highly likely explanation that the relationship between the two variables depends on multiple contextual factors which vary across studies, including the age of participants, the environment in which the participants are placed, and the type of reading tuition received. The authors are not in a position to assess these contextual factors, for the most part. However, I feel that the role of additional contextual factors should be acknowledged in the introduction and discussion.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SELF-CONCEPT IN POOR READERS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Review round: 1
Reviewer: 2

Output:
Basic reporting: .
Experimental design: .
Validity of the findings: .
Additional comments: I liked this paper a lot. It was beautifully written, clear and concise. There are a lot of meta-analysis details that requires knowledge on this type of an analysis but the authors give references for meta-analysis guidelines etc.

In my mind there is only one bigger issue; the small amount of studies included in the analysis. Because of that some interesting subgroup analyses were not possible. On one hand this weakens the paper but on the other hand it also brings forth the need for more studies on this topic.  I'm not sure if the choice to omit papers with non-validated or -standardized papers is the best one in this case. I can understand why the authors did this but I wonder if some of the omitted papers would have been of high quality despite this flaw. Self-concept is, in the end, assessed with few questions only and some papers may have used almost equal items to the validated scales? It would be interesting to see if the results would change after entering the studies with non-standardized measures in the analysis. However, I do understand the importance of reliability and validity of measures used and the authors choice in this matter.

More minor issues;
-Line 98: "proffer" should be offer
-Beginning of methods; here it would be helpful to be clearer about what is "subgroup" as you also compare poor readers to others. It is little difficult to follow what exactly are the subgroup analyses here.
-Beginning of method, line 134, sentence starting "First,": This was a difficult sentence to follow.
-line 301: "knew" misplaced?
-Line 311-312: what intervention effects? I guess hat is not the topic of this paper..?
- Authors call self-concept questionnaire items "a test". It seems a little pompous?
  - Please note in the limitations that only English-speaking samples were analyzed.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SELF-CONCEPT IN POOR READERS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Review round: 2
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Wonderful work. Thanks for writing this paper.  I hope this will inspire many new studies in this important area!

(please note that on the second para in Methods it says "see XXX", which likely needs to be re-phrased...)


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE COMPLETE MITOCHONDRIAL GENOME OF DYSGONIA STUPOSA (LEPIDOPTERA: EREBIDAE) AND PHYLOGENETIC RELATIONSHIPS WITHIN NOCTUOIDEA
Review round: 1
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: In this study, Sun et al., sequenced and analyzed a mitogenome of Dysgonia stuposa (Lepidoptera: Erebidae). Further, they compared the mitogenome features with other species and constructed the phylogenetic relationships among 29 species of Noctuoidea. Since the classification between Noctuidae and Erebidae under the superfamily Noctuoidea is still controversial and unclear, the precise classfication of this species will be very helpful in phylogenetic relationship analysis of Noctuoidea. However, there are still some things the authors can do to improve their manuscript.
1. Line 84, ‘Fauna Sinica’ should be italicized.
2. The sentence in line 231, ‘since, ……sharing apomorphies’ has grammatical errors, please revised.
3. Line 246, 247, the color of the period should be black, not red.
4. The key point of this study is the phylogenetic analyses, however, the author only used one species in Catocalinae subfamily. Till now, is there only one species whole mitogenomes has been published in this subfamily?
5. All the references need to unified in the same format, and the authors list need ‘et al’ when the authors number more than six. In addition, the journal’s name should be unified abbreviation or not.
6. Figure 5 need to label the stem and loop structure to make readers can understand the tRNA structure easily.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE COMPLETE MITOCHONDRIAL GENOME OF DYSGONIA STUPOSA (LEPIDOPTERA: EREBIDAE) AND PHYLOGENETIC RELATIONSHIPS WITHIN NOCTUOIDEA
Review round: 1
Reviewer: 2

Output:
Basic reporting: Unprofessional and ambiguous English has been used mostly. There are still many suggestions for improving language usage to clarify in introduction, results and discussion.
The raw sequencing data should be deposited at the NCBI (GenBank) and the accession numbers should be provided in the manuscript.
More details in methods section are needed. eg. Partition set, or model parameter  set. I did not support the one mitochondrial genome of D. stuposa can give a convincing result in discussion of the relationship of Noctuidae and Erebidae. If the authors want to discuss the phylogenetic relationship between Noctuidae and Erebidae, they should sequence more samples of Families Noctuidae and Erebidae. But they only sequenced one mt genomes from Erebidae. So I did not think this question should be discussed in the paper. If the authors really want to discuss this relationship, they need sequence more mt genomes from Noctuidae and Erebidae. And they should introduce the detail views from all researchers using the different analyses methods and different molecular markers, and so in the section of introduction.
I also found the authors did not use all mt genomes from GenBank, eg. Amata formosae  KC513737, Cyana sp. MT-2014 KM244679 , Hydrillodes lentalis MH013484,   Spilarctia subcarnea KT258909, Spilarctia alba  KX753670. Why did the authors delete those mt genomes in their analyses methods? They should give an explanation. The figure of BI tree should be consist with the figure ML tree in colour. In a word, the authors should reanalyze the data and rewrite the results and discussion.
Experimental design: Methods have not been described in sufficient detail. It is not clearly specified how was the long PCR fragments sequenced. Used specific primers? Or NGS? Especially in AT-rich region, how can they obtain the high TTTTTTT…. Region? How can the author identify the sequenced high TTT..region right? I failed to find the method of sequencing in the fragment sequencing.
It is not clear how did the authors separate the mitochondria genome from the nuclear genome. Were the mitochondria physically isolated / purified before DNA extraction, or was the complete picture of nuclear and mtDNA sequenced together. How were the mitochondrial reads separated from those from nuclear genome ? These are essential details required in the methods and results section
The listed primers can not obtained the whole mt genomes! Please check the primers.
Validity of the findings: The conclusions that the authors draw from the assembled and annotated genome are valid. However, as discussed above, more details on methods used for sequencing of the assembled genome are essential to evaluate the quality of the assembled genome sequence
Additional comments: The authors have sequenced, assembled and annotated the mitochondrial genome of D. stuposa. The authors have then generated a phylogenetic tree based on 13 protein coding genes from mitochondria, covering some additional lepidopteran genomes. The results are mostly descriptive and have been are supported by their analysis. However, a few key details are missing from the methods section, and these must be included for a proper evaluation of the complete analysis.

Major comments:
1. The raw data must be submitted to the NCBI or an equivalent public database.
2. More details in methods section are needed. eg. Partition set, or model parameter set. I did not support the one mitochondrial genome of D. stuposa can give a convincing result in discussion of the relationship of Noctuidae and Erebidae. If the authors want to discuss the phylogenetic relationship between Noctuidae and Erebidae, they should sequence more samples of Families Noctuidae and Erebidae. But they only sequenced one mt genomes from Erebidae. So I did not think this question should be discussed in the paper. If the authors really want to discuss this relationship, they need sequence more mt genomes from Noctuidae and Erebidae. And they should introduce the detail views from all researchers using the different analyses methods and different molecular markers, and so in the section of introduction.
I suggest the authors added more mt genomes from GenBank and reanalyze the BI and ML trees to discuss the relationship within subfamilies of Erebidae not relationship between Noctuidae and Erebidae. So some background of the relationship of within subfamilies of Erebidae should be added in the introduction.
Unprofessional and ambiguous English has been used mostly. There are still a few suggestions for improving language usage to clarify in introduction, results and discussion.
The raw sequencing data should be deposited at the NCBI (GenBank) and the accession numbers should be provided in the manuscript.
More details in methods section are needed. eg. Partition set, or model parameter  set. I did not support the one mitochondrial genome of D. stuposa can give a convincing result in discussion of the relationship of Noctuidae and Erebidae. If the authors want to discuss the phylogenetic relationship between Noctuidae and Erebidae, they should sequence more samples of Families Noctuidae and Erebidae. But they only sequenced one mt genomes from Erebidae. So I did not think this question should be discussed in the paper. If the authors really want to discuss this relationship, they need sequence more mt genomes from Noctuidae and Erebidae. And they should introduce the detail views from all researchers using the different analyses methods and different molecular markers, and so in the section of introduction.
I also found the authors did not use all mt genomes from GenBank, eg. Amata formosae  KC513737, Cyana sp. MT-2014 KM244679 , Hydrillodes lentalis MH013484,   Spilarctia subcarnea KT258909, Spilarctia alba  KX753670. Why did the authors delete those mt genomes in their analyses methods? They should give an explanation. The figure of BI tree should be consist with the figure ML tree in colour. In a word, the authors should reanalyze the data and rewrite the results and discussion.
3. The correct citation for the analysis softwares in the text should be added. Eg. DNAMAN, Blast, ClustalX, Mega 5.0, MrBayes3.2, and FigTree…
The references should be correctly cited in any places. Eg.
4. I failed to find the annotated mt mitochondrial genome, so I can not check the gene structure. Please submit the sequence in supplement to further check.
5. Line 116-119: Did all RNA can be identified by tRNAscsan-SE?
6. There are many blank in the text. Please check.
7. The English writing should be checked by English native.
8. The sentences are belonging to discussion should be moved from the section of results.
9. The gene writing should be consist in text, figure and table.
10. In reference, the species name should be italic. The journal name should be full name listed.
11. The listed primers can not obtain the whole mt genome.
12. Ten authors did one mt genomes. I suggest the paper should list really contribution authors not ten authors!

Minor revisions are marked yellow in PDF.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE COMPLETE MITOCHONDRIAL GENOME OF DYSGONIA STUPOSA (LEPIDOPTERA: EREBIDAE) AND PHYLOGENETIC RELATIONSHIPS WITHIN NOCTUOIDEA
Review round: 2
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: The authors addressed all the questions and comments and significantly improved the manuscripts with appropriate corrections.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE COMPLETE MITOCHONDRIAL GENOME OF DYSGONIA STUPOSA (LEPIDOPTERA: EREBIDAE) AND PHYLOGENETIC RELATIONSHIPS WITHIN NOCTUOIDEA
Review round: 2
Reviewer: 2

Output:
Basic reporting: Although the paper is improved in some sections, the result, discussion and conclusion should be rewritten again. I did not think the result and discussion are good structure. There are many sentences of results existed in discussion. If the authors did not know how to deal with discussion, I suggest they can put results and discussion together.
Many English grammars should be improved. The native English people need to read the paper.
Experimental design: OK
Validity of the findings: As the first review.
Additional comments: Although the paper is improved in some sections, the result, discussion and conclusion should be rewritten again. I did not think the result and discussion are good structure. There are many sentences of results existed in discussion. If the authors did not know how to deal with discussion, I suggest they can put results and discussion together.
Many English grammars should be improved. The native English people need to read the paper.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE COMPLETE MITOCHONDRIAL GENOME OF DYSGONIA STUPOSA (LEPIDOPTERA: EREBIDAE) AND PHYLOGENETIC RELATIONSHIPS WITHIN NOCTUOIDEA
Review round: 2
Reviewer: 3

Output:
Basic reporting: The written English is not very good, I've attached an edited version of the manuscript with suggested changes to improve clarity.

Referencing is not up to standard for current publications unfortunately.  In some instances very general statements are supported by very supported by citation of papers which made similar statements but weren't the first to propose such a hypothesis or to observe such an aspect of mitochondrial genomics.  For example, you cite Junqueira for skew statistics, but they simply used skew as a statistic in their paper much like you do here.  Perna & Kocher 1995 proposed this statistic, they are the ones who should be cited.  Use of review papers or the original literature is needed for these instances.  In other instances papers do not support the statements for which they are cited, either because the paper has been miscited or because the statement being made is not supported by any literature in this field.  Most such instances I flagged in the edited manuscript, but I would encourage the authors to think hard about whether the best reference is being cited each time.

In a related vein, the text too often includes vague and/or general statements to the effect that variation or similarity exists, but without detailing how or in what way.  Again I've flagged the more obvious ones in the edited copy, but I would strongly discourage the authors from making statements like "and other morphological characteristics are used for classification" (line 60).  Either elaborate on these details or don't comment on them, not every aspect of the paper needs to be mentioned, but that which is mentioned needs to be developed into a detailed text such that the reader can learn about this system, species or genome from the paper, not just that features exist.

Structure has some positive aspects but most of the Discussion is just repeating the results, while the Conclusion section is repeating them for a third time. Discussion sections are about the importance and context of the results found.  They are a separate section because they have a quite different purpose from the Results.  The amount of repetition is marked on the manuscript - not much Discussion is left.  I don't know if this journal allows the combined "Results and Discussion" section that many journals do, but many authors find this conceptually easier to write for than separate sections.  Your editor can advise but I would explore restructuring the paper in this way.

Hypothetical scope of the paper is OK.
Experimental design: Research question is kind of loose but common across these types of papers.

There are two main problems with how the analyses are chosen for the study.

1).  Genome analysis features.
I know that it is common to report statistics about mitogenomes in papers such as this - nucleotide composition, skew, RSCU etc.  But what is often missing, and is the case here is why these features are being analysed?  Particularly if the genome is kind of average - as is the case here - with statistics that fall within previously reported ranges or genomes.  It is one thing if a genome is extreme - the most or least biased or skewed or whatever, as outlier species are useful to identify and to look at why they might be so biased.  But reporting that 'its pretty well like everything else' is kind of pointless.  All of these statistics can be used to inform other analyses - biases of these types affect phylogenetic analyses in some instances.  But why did you do these analyses?  What is actually being tested?  What do you want to know that an RSCU statistic will tell you?
In contrast the case for doing the phylogenetic analyses is clearer - you want to know if this species is classified in the right family, what it is related to etc.  No such justification for doing the statistics is offered, and just because a lot of other papers don't justify doing these statistics doesn't make it right (I routinely make this point in reviews, but clearly can only review so many papers per year).  Please think about why you do the analyses which you do?

2).  Phylogenetic analyses
Even though the questions are justified, the methods aren't of current high standard for a number of reasons.
First, analysing the amino-acid sequence rather than DNA is not best practice.  Each time this has been examined in detail it has been shown that the amino-acid dataset has less resolving power than the DNA one.  The issue with third codon positions is readily accounted for by excluding third codons from the analysis, or by using partitioning to accommodate the different mutational dynamics on third positions.
Secondly, the methods are somewhat confusing.  No input partitions are listed for PartitionFinder (it groups between predetermined starting partitions, you need to list what they are) and the output partitions are not reported.  "Performed in IQ-Tree" also doesn't make sense - they are separate pieces of software.  IQ-Tree includes a partition and model finding algorithm (ModelFinder) but it isn't a shell for implementing PartitionFinder, so which software did you actually use for models/partitions? Why is RAxML used for ML tree inference if you are using IQ-Tree for partition/model inference - IQ-Tree is a perfectly good ML inference software, it seems inefficient to switch programs. One best-fit model is listed (mtMET+F+R5) but how is that if you did partitioning?  Multiple models are more likely, or in the unlikely event that the same general model was preferred for all partitions, say so and also state whether you used those models as linked or unlinked in the analysis.  For BI a 'mixed model' is listed (line 145) but that just means different partitions can have different models - which ones were actually used and what is the partitioning system?  The number of generations in the BI run was far, far too few - 10 million would be a minimum for an analysis of this size.
Accordingly, the phylogenetic analyses needs to be completely repeated.  Use DNA, use partitioning to compensate for third codon effects, get your software use sorted out so it is clear what is being used and why, report on partitioning choices and model outcomes, run the BI for much much longer.
Validity of the findings: 1) Phylogenetic results suspect due to poor methods choice as outlined above, will need to be fixed before final judgement.

2) Annotation of the genome includes at least two obvious errors.  rrnS and rrnL are on the N strand in most insects and all Lepidoptera sequenced to date.  Either they are on N in this species and this was misreported on line 193, or this is the most divergent moth mitogenome yet sequenced in which case you can't state that it is comparable to other species.  Secondly, an overlap of 65bp between trnH and nad4 is not going to be accurate.  Insect mitogenomes do not overlap by these margins, but MITOS is not always accurate in reporting annotations.  With respect, I don't believe that you have accurately compared the start codon for nad4 against other Noctuoid mitogenomes as stated in lines 122-123.  If the 20 amino acids that make up this overlap align well to the first 20 amino acids of nad4 in other species please provide a figure illustrating the alignment?  But I strongly suspect that this is an error.

3) The interpretation of some relationship between how 'advanced' an insect is (itself a very flawed concept - see Crisp & Cook 2005) and nucleotide composition is very flawed.  Parafronus may have the lowest A+T% of any pterygote, but this ignores results from the other 20+ mayfly mitogenomes which are available.  Parafronurus is not representative of mayflies, and so this primitive = low A+T argument is demonstrably wrong.  Conversely, Gotsek (2010) never claim that Solenopsis (an ant) is the most advanced insect, or that there is any relationship between that and A+T%.  No published study makes the claim made by the authors in line 243 and the data presented in this study doesn't support making it here.  Remove all of this.
Additional comments: This paper has some potential but it needs to be extensively reanalysed and rewritten.  There are major flaws in the use of citations and in the interpretation of previous publications, I would encourage the authors to deeply read in this field to correct these problems.  Finally, the authors should focus on why this species was studied and what is unique findings of this study, not repeating analyses found in other similar papers that lack a purpose in the current one.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE COMPLETE MITOCHONDRIAL GENOME OF DYSGONIA STUPOSA (LEPIDOPTERA: EREBIDAE) AND PHYLOGENETIC RELATIONSHIPS WITHIN NOCTUOIDEA
Review round: 3
Reviewer: 1

Output:
Basic reporting: The paper improved greatly. I still suggestion the paper should be read by a English native person or organization.
Experimental design: The paper improved greatly.
Validity of the findings: All the data are good.
Additional comments: I still suggestion the paper should be read by a English native person or organization.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE COMPLETE MITOCHONDRIAL GENOME OF DYSGONIA STUPOSA (LEPIDOPTERA: EREBIDAE) AND PHYLOGENETIC RELATIONSHIPS WITHIN NOCTUOIDEA
Review round: 3
Reviewer: 2

Output:
Basic reporting: Greatly improved from the previous version, I've made more editorial suggestions to improve the written expression on a scanned-copy of the manuscript.
Experimental design: Again greatly improved.  The phylogenetic portion now conforms to current standards and is repeatable based on the methods described.  It is sufficiently rigorous for the questions posed and the discussion of the results.

One thing to note though in terms of interpreting the phylogenies so produced.  Nodal support values are statistical measures of support for the hypothesis summarised by the tree.  So a branch can be present such as the one for Catocalinae (mentioned in line 227) but have statistically significant support - as was the case for the node supports quoted.  For Bootstrapping any values <70% are not significant, whereas posterior probabilities are more like p-values, anything below 0.9 is not significant.  I've rewritten the sentence to reflect that, but for the future consider the significance of a nodal support, not just whether a branch is present or not.
Validity of the findings: Concerns expressed in the former review have been accounted for.  The data presented is sufficient for the conclusions drawn.
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: NKCC1 INVOLVEMENT IN THE EPITHELIAL-TO-MESENCHYMAL TRANSITION IS A PROGNOSTIC BIOMARKER IN GLIOMAS
Review round: 1
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Comments to the Author
The manuscript entitled “NKCC1 is involved in the epithelial-to-mesenchymal transition as a prognostic biomarker in glioma” suggests that NKCC1 plays important roles in regulating EMT in gliomas. This is an interesting article which can provide a novel strategy in treating glioma invasiveness. However, there are several concerns should be considered:
Major concerns:
1. The author showed the results in U251 cells. However, there is no any information about the source of U251 cell. Please provide the detailed information.
2. How about the effects of NKCC1 on the crucial factors of EMT, such as E-cadherin, N-cadherin, vimentin, ZEB1, etc?
3. The author should also provide the crucial signal pathway involved in glioma invasiveness to further reveal the mechanism of NKCC1.
Minor concerns:
1.	There are some grammar and format mistakes in this manuscript. For example:
Line 41, “plays” should be “played”.
Line 47, there is an extra space behind the word “function”.
Therefore, the author should polish the language of this manuscript by a native English speaker.
2. Please provide the histogram figures for the detection of migration and invasion.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: NKCC1 INVOLVEMENT IN THE EPITHELIAL-TO-MESENCHYMAL TRANSITION IS A PROGNOSTIC BIOMARKER IN GLIOMAS
Review round: 1
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: 1. The effect of NKCC1 was only detected in one cell line U251 which made the conclusions not stringent.
2. Migration and invasion effects of NKCC1 was detected by transwell assay and western blot. I suggest author could add RT-qPCR assay for a better supporting of their conclusion.
3. The information of patients should be provided in the ‘Materials and Methods’ section, including gender, ages, stages, etc. The exclusion and inclusion criteria of the patients should be indicated as well.
Validity of the findings: 1. Authors should explain why “we did not determine a definite and specific regulatory relationship or potential mechanism between NKCC1 and transforming growth factor beta (TGF-β) induced EMT in vivo or vitro experimental conditions.”. The depth of “Discussion” section is not enough.
2. Authors should discuss is there any target genes involved in the underlying mechanism of NKCC1. The further research should be discussed, otherwise only one pathway will lead to insufficient research depth.
3. P value is statistical result so it should be presented in ‘Result’ part.
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: NKCC1 INVOLVEMENT IN THE EPITHELIAL-TO-MESENCHYMAL TRANSITION IS A PROGNOSTIC BIOMARKER IN GLIOMAS
Review round: 2
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Comments to the author:
Within this manuscript entitled “NKCC1 is involved in the epithelial-to-mesenchymal transition as a prognostic biomarker in glioma”, authors explored the function and mechanism of NKCC1 in glioma cells. The results shown that high expression of NKCC1 could regulate the EMT in glioma. And NKCC1 overexpression were correlated with glioma grade. This is explored the novel insight of NKCC1. However, there are several minor issues that need clarification and correction.
Materials and Methods
- How long the transfection last?
- How did you quantify the protein concentration in Western blot part? Did you use a kit? In addition, the catalog and dilution of antibodies should be provided.
Results:
-The error bar was missing in Figure7.
- Since author said all data were expressed as mean ± SD, however, in Figures, it was presented as mean + SD.
Discussion:
Author introduced too many experimental results in this part, the depth of discussion should be improved, I suggest author increase the cited references size to combine with previous studies for a in-depth discussion.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: FEATURE SELECTION BASED ON DIFFERENTIALLY CORRELATED GENE PAIRS REVEALS THE MECHANISM OF IFN-Β THERAPY FOR MULTIPLE SCLEROSIS
Review round: 1
Reviewer: 1

Output:
Basic reporting: The manuscript is interesting, well written and relevant. But a few points should be addressed.

Under the introduction it´s stated that MS is a immune-mediated disorder. There are known genotypes for subsets of MS this ought to be mentioned.

Under the section of Biological implications Genecards are extensible used. If considering the involvment of AKT1 in MS the association i based on one GWAS study with a single SNP showing association to AKT1 but additionally nummerous other genes f.x. IGHA1. What is the argument for especially focusing on AKT1?
In the litterature AKT1 is mainly associated to different cancer phenotypes; Cowden, Proteus, Gastric cancer and others please consider these aspects.
Concerning Genecards and MPO and C3, respectively, here I don´t see these genes mentioned. whereas MPO and C3 are mentioned as associated to MS in pubmed searches. But then again a multitude of genes have been correlated to MS. Both MPO and C3 has been associated to a multitude of immunological related phenotypes - is the association seen here a MS association or an association to inflammation/immunological disease?
The study is using correlation coefficients hence both p-values and values corrected for multiple testing should be presented and addressed in the discussion.
Experimental design: The experimental design is performed fully sufficient.
Validity of the findings: As mentioned under basic reporting I miss further arguments and considerations under the biological implications and discussion on the statistically significans of the findings..
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: FEATURE SELECTION BASED ON DIFFERENTIALLY CORRELATED GENE PAIRS REVEALS THE MECHANISM OF IFN-Β THERAPY FOR MULTIPLE SCLEROSIS
Review round: 1
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: The authors proposed a bioinformatics method to identify gene pairs differentially correlated over time by replacing the difference in mean gene expression with that in correlation coefficients. The method was applied to a longitudinal microarray dataset which evaluates the effect of INF-β on multiple sclerosis (MS) patients. The aim is to study the underlying therapeutic mechanisms of IFN-β and to predict which MS patients will respond to IFN-β therapy based on the identified molecular signature. The idea is well described but the too small sample size reduces the power of the study and increases the margin of error. The authors have to investigate if in GEO repository are present more gene expression data sets to be analyzed with their procedure concerning MS patients treated with Interferon. See Nickles D., Chen H., Li M., Khankhanian P., Madireddy L., Caillier S., Santaniello A., Cree B., Pelletier D., Hauser S., et al. Blood RNA profiling in a large cohort of multiple sclerosis patients and healthy controls. Hum. Mol. Genet. 2013;22:4194–4205.
Validity of the findings: I commend the authors because the manuscript is clearly written in professional and unambiguous english language but there are major problems concerning the statistical analysis of data which should be improved upon before Acceptance.
1.	It is not clear how the authors choose to adopt a threshold of 0.8 for differential correlation. The selection of differentially correlated genes is the result of the application of a statistical hypothesis test. It is necessary to estimate a null distribution for the difference in correlation between 2 genes (for example by permutation of labels) and by exploiting the null distribution, it is possible to compute the p-value. If the p-value indicates strong evidence against the null hypothesis, you reject the null hypothesis. It is necessary to introduce a threshold on the p-value. Typically,  a p-value ≤ 0.05 indicates a strong evidence to reject the null hypothesis (see Anglani R, Creanza TM, Liuzzi VC, et al.  Loss of connectivity in cancer co-expression networks. PLoS One 2014;9:e87075).
2.	Why the authors choose to use Pearson’s correlation coefficients instead of Spearman correlation that it is considered more appropriate for these analysis. Moreover, we can read in conclusions: “so one may argue that Spearman’s correlation coefficients between gene pairs may be more suitable”.
3.	What is the meaning of  p=0.2 for differential expression? Is p the p-value? if it is so, this theshold is not appropriate. The authors have to clarify the meaning of p and eventually repeat the analysis with a more suitable threshold.
4.	The predictive accuracy at line 197 is not clear: is 63 the size of the set of both responders and non responders? At lines 132-133, the authors declare that 21 patients are in the testing set.
5.	The results are not clear mostly in their interpretation at lines 249-255. The authors write:” if  the correlation directions are positive for the first three gene pairs and negative for the last time point”. Do they mean that the correlations directions are positive in the first time points? More important, at line 255 they write “for a patient without such correlation”, but how is possible to measure a correlation for a single patient? For a specific time point we have a value for each gene, we can not evaluate a value of correlation. I can not understand these considerations that represent the meaning and the value of their work.
6.	Are the genes found by the authors known IFN-responsive genes as recorded in the Interferome database (http://www.interferome.org/?
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: FEATURE SELECTION BASED ON DIFFERENTIALLY CORRELATED GENE PAIRS REVEALS THE MECHANISM OF IFN-Β THERAPY FOR MULTIPLE SCLEROSIS
Review round: 2
Reviewer: 1

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: No comment


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: FEATURE SELECTION BASED ON DIFFERENTIALLY CORRELATED GENE PAIRS REVEALS THE MECHANISM OF IFN-Β THERAPY FOR MULTIPLE SCLEROSIS
Review round: 2
Reviewer: 2

Output:
Basic reporting: The paper is well written but the authors have to correct these little errors.

•	It is not correct the legend of Figure 2 just above the picture: “Venn-diagram showing the overlapped genes between differentially expressed genes over time and genes involved in the consistently differentially correlated edges.” This is to be substituted by “Venn-diagram showing 41 genes involved in the statistically significant DCEs. “ that is the correct legend that you can read in the list at 448 row.

•	In the table 1, the negative sign cannot be on the top of the number, try to put the sign before the number on the same line.

•	At the 225-226 rows, it is not correct to write that negative correlation means that “one is overexpressed/under-expressed, then the other tends to be overexpressed/under-expressed as well.” This the case of positive correlations.

•	In the legend of figure 3, it is to be correct 6-gene list with 7-gene list.
Experimental design: no comment
Validity of the findings: I noted that the discussion is not properly supported by the results section: some conclusions are not limited to supporting results.
•	In details, the rows from 203 to 220 describe the differences in expression mean values  between the two groups such as the following text in capitol letters: “From Figure 3, it is observed that at the first time point (the measure before IFN-β treatment was given) the expression levels of CXCL9, CSF2, IL2RB and GCA were BASICALLY THE SAME between the two groups; IL2RA and CXCR3 had a LOWER EXPRESSION value in the non-responder group; and AKT1 had a lower expression value in the responder group. At the last time point (the measures at year two when all non-responders had experienced the first relapse and the responders were at least three years away from their first relapses), CXCL9 and CSF2 had a lower mean expression value in the responder group; AKT1, IL2RA and CXCR3 had a HIGHER expression value in the responder group; and the mean expression values of IL2RB and GCA remained approximately identical.” These conclusions refer to the differential expression of genes between the two conditions and have a scientific meaning only if they follow a statistical analysis of differential expression that turns out a statistical significance of results but I do not understand why the authors chose to eliminate the analysis of differential expression in this second version of the paper.

•	In the result section, at 186-189 rows we found the value of the performance of a support vector machine model trained by using the 41 genes as predictors to compute the probability of a MS patient being a responder at each time point (accuracy=80%). At 213-214 rows, we read that the “7 genes may bore no or low prognostic values for the response status of IFN-β treatment”. But in the Results section we do not find the performance of a machine learning model trained by using only these 7 genes so how can we comment about the prognostic value of these subset of 7 genes? This sentence in the discussion section is not supported by the results of the statistical analysis.

•	Finally and more important, the work finds a significant difference in correlation between IL2RB and IL2RA and CXCR3 and CSF2. The authors conclude at 222-230 rows that “to determine which patients might respond to IFN-β treatment, instead investigating the expression values of these genes, the correlation directions between IL2RA and IL2RB, and CXCR3 and CSF2 should be focused. If the correlation directions are negative for the two gene pairs (meaning one is overexpressed / under-expressed, then the other tends to be overexpressed / under-expressed as well. For a single sample, the overexpression or under-expression may be determined by comparing with mean expression values of a reference population), the patient tends to respond to IFN-β treatment fairly well. For a patient without such negative correlation patterns among these two gene pairs, maybe an alternative regimen should be pursued.”

The authors suggest to use for a single patient this value (“ the correlation direction”) to predict the status of responder. This value is the contribution of the patient to the calculus of the correlation that can be computed as the average value of these contributions on the data set. The prediction of the response of the patient based on this value is in general an improperly posed question. In details, we can have significant difference of correlation also in the case of small correlation in a class and large value of correlation in the other class. The correlation is small when the values on single patients are small or large but with a mean value near zero. In the latter case, in the class with small correlation all patients have different values that will be also different in sign: how can you use the value on a patient to predict the response to the treatment?
In the case of large negative correlation between two genes in a class and large positive correlation in the other class, the question could be well posed and we can suppose that for a patient the direction of correlation  (or better of its contribution to correlation) can help to predict the response of the patients but in this work the authors did not perform a statistical analysis to test the prognostic value of this variable.  The result section refer to a machine learning model based on the value of the 41 genes and not on this “correlation direction” between pairs of genes. The result section is not useful to support this idea described in the discussion section.
Additional comments: I have a question about SNPs in IL2RA (254 row). Can your study suggest that SNPs related to MS but present only in one class (responder or not responder) can alterate the regulation of the expression of a gene in the DCE and produce the difference in the correlation with the other gene in the DCE?


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 1
Reviewer: 1

Output:
Basic reporting: 1.The title should be more specific and more concise, because the genetic resources are solely from Guizhou province. So, Guizhou province, China must add to the title. The below title is suggested for the authors:
Development of the core collection for Guizhou tea genetic resources and GWAS of leaf size using SNP developed by genotyping-by-sequencing

2. Several important references about tea core collection in China, worldwide are missed.
Wang XC, Chen L, Yang YJ. Establishment of core collection for Chinese tea germplasm based on cultivated region grouping and phenotypic data. Front. Agric. China 2011, 5(3): 344–350
Taniguchi F, Kimura K, Saba T. Worldwide core collections of tea (Camellia sinensis) based on SSR markers. Tree Genetics & Genomes 2014, 10, 1555-1565
Experimental design: no comment
Validity of the findings: 3.Line 45-46.
The Guizhou Plateau is the center of origin of tea plants (Wei et al., 2018; Jin et al., 2016). This is not a correct statement, and Jin et al.(2016) did not have this result. So, this sentence should be deleted.

4.Line 103-104,
From the second to the fourth, Camellia should be abbreviated form C.

5.Check all the original references carefully
Line 538-539
Chen, L., Apostolides, Z., and Chen, Z.M. (2013). Global Tea Breeding: Achievements, Challenges and Perspectives. Advanced Topics in Science & Technology in China.

Should be:
Chen, L., Apostolides, Z., and Chen, Z.M. (2012). Global Tea Breeding: Achievements, Challenges and Perspectives. Springer-Zhejiang University Press

Line681
Yao, M.-Z., Ma, C.-L., Qiao, T.-T., Jin, J.-Q., and Chen, L. (2011) should be (2012)
Additional comments: The construction of core collection for  Guizhou tea genetic resources is very important for the conservation and utilization of tea germplasm.
Anyway, the title should be re-written to be more specific and concise. The references should also to be checked carefully.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 1
Reviewer: 2

Output:
Basic reporting: This manuscript describes a population level study using collected tea plants. Authors displayed the diversity of their collected samples to some extent, and a diverse collection of samples will be useful for the community. The study is potentially meaningful, however, many accession are not pure enough. The data generated in this study will be difficult to be reused and should be discussed or mentioned. I have several suggestions for this manuscript.

1.	Please considering to shorten the title to be more concise.
2.	Many places of English/scientific writing are weird and need to be improved, for example, L44, “Tea has,” there is no need to add comma after has; L59, “Compared with other means”, means is a weird word used in here; L60, “Finding yielded”? I can not understand this; L101, “five” should be replaced by 5. Places like these need to be caught carefully and fixed.
3.	Figure 1, other than labelled the number for each color, please also label the name of your defined collection.
4.	For figure 3, it is less informative to show this as a main figure, since all collections for any of allele or allele ratio are almost the same.
5.	For table 5, please mention clearly what the highlighted red text means?
6.	What is the SNP naming rule in your analysis? If I find one SNP such as PG_1:32346865, how could I refer it to the genotyping data you provide?
7.	L290, you mentioned Niu et al.2019 as one of citations, but I can not find it anywhere.
8.	L322-L323, please give a citation for the low self-pollination rate.
Experimental design: 1.	Based on the geographical map provided, I worried there are strongly closed relationship among individuals, please providing a PCA plot with each group labeled.
2.	In the supplemental figure, it seems more than half of collected samples have heterozygosity > 0.2, those accessions should not be considered as “accessions”, since they will be hard to propagated. Tea genome is 3.2GB, that means >640MB genome are heterozygous. Many loci will be segregated in progeny. Genotype and phenotype from one of these accessions will could not be maintained consistently through generations.
Validity of the findings: 1.	I am not able to trace any potential biological meaning for each classified group. Why not use the STRUCTURE suggested subpopulations? If you just list numbers, people will definitely get confused. For some groups, like group 8, 9, 13, 14, there are only a very few accessions, how meaningful they are? Please provide more solid evidence to support this classification.
2.	For table 5, you should write clearly how MAF was calculated. Since in this current table, for example, PG_10:98891957, mentioned MAF is 0.06, but 1/306=0.003, which is much lower. How many heterozygous are there? But overall, most of significant SNPs are rare alleles, very weird. Please clearly report how many accessions carrying homozygous majors alleles, how many carrying homozygous minor alleles, and how many carrying heterozygous alleles.
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 1
Reviewer: 3

Output:
Basic reporting: Under the frame of the work entitled „Development of the core collection and genome-wide association analysis (GWAS) of leaf size in tea plant using genome-wide single-nucleotide polymorphism (SNP) developed by genotyping-by-sequencing“ written by Niu et al., tea accessions were mostly collected from the Guizhou region in China. These accessions were phenotypically characterized for breeding relevant traits related to leaf size as well as genotypically profiled by using genotyping-by-sequencing. In addition, core-collections were developed using this data and were subsequently evaluated according to different criteria like, for instance, the amount of retained diversity as compared with the original population, their reduction in size, among other quality criteria for core-collections. Domestication and plant breeding have produced selection bottle necks in most cultivated species, with tea plants not being an exception. For this reason and more than never, studies characterizing genetic resources are highly valuable and could be interesting for a broad audience of readers. The results are in general good presented and further discussed. Unfortunately, I cannot recommend the manuscript for direct publication at its current state, since there are some issues that I found while reading the submitted documents. The most important one refers to the often mentioned statement “These core-collections are suitable for future GWAS studies” which was not directly assessed by the authors in the experimental work. In the following paragraphs I make some suggestions on how to deal with this issue and included additional important minor points. For instance, although the manuscript is relatively well written, there are several sections that need revision. Since the manuscript has no page number, I base the positioning of manuscript sections, that should be assessed by the authors before manuscript acceptance, by using the page numbering of the pdf file that was automatically created by the Journal Managing System of PeerJ.

Most important issue:

The statement “These core-collections are suitable for future GWAS studies” was several times mentioned in the manuscript (see for instance page 18, lines 335-338, or page 19, lines 358-361). In this respect, authors should support this statement by at least reporting the number of marker-trait associations that were identified in the whole population and afterwards retained in core-collections. This will give readers better insights about the power of GWAS using these core-collections.

Minor issues:

Introduction

Page 8, lines 76-79: Please cite the original works of Frankel (1984) and Brown (1989) in this section:
-	Brown   AHD   (1989)   Core   collections—a   practical   approach   togenetic-resources management. Genome 31(2):818–824.
-	Frankel OH (1984) Genetic perspectives of germplasm conservation.In: Arber WK et al (eds) Genetic manipulation: impact on manand society. Cambridge University Press, Cambridge,  England,pp 161–170.

Materials and Methods

Page 9, line 110 to page 10, line 117: From what you mentioned in the introduction, tea is a highly heterozygous species, which should be quite similar to that case observed in maze. In maize, this situation leads to a high diversity within accessions, which means that some of them should be interpreted as a sample from a larger populations instead of considering them as defined genotypes. For this reason, it is very typical that several individuals of a same maize accession are characterized and thus represent the diversity pool existent in that particular accession. I know that this is not an easy task and obviously not cheap to assess, but can you at least make a comparison (maybe in the discussion section?) between what is being performed for species like maize and the state-of-the-art in tea? And also mention that this point should be assessed in the future?

Page 11, line 150: After filtering, how did you deal with the remaining missing data? Did you performed all analyses ignoring this issue or did you impute missing values? Please clarify.

Page 11, lines 153-154: What do you mean with 20 groups? Are these linkage groups? Chromosomes? Please clarify

Page 11, line 167: Which kind of measurements did you use to measure skewness and kurtosis? Please specify.

Page 12, line 171: Please explain the equation by describing its different components.

Page 12, line 190: 0.0008 corresponds to an Euclidean distance? Please specify.

Page 13, lines 203-204: I do not understand what do you mean with “the irrelevance among genotypes”. The Kinship matrix accounts for the relatedness between individuals. Please correct this.

Page 13, lines 206-207: How did you calculated the R-squared? Was this base on the mixed model or using a simple linear regression model? Please specify. In addition, R-square is the coefficient of determination, not a correlation coefficient.

Results

Page 13, lines 210-212: I do not think that reporting the size of the datafiles before filtering is so informative. Please mention the average number of read calls per genotype before filtering, or something similar, to give the size of the data a genetic meaning. This also can be applied in the discussion (page 18, line 316).

Page 17, lines 286-287: I do not understand why you wrote “These results suggest that the four traits could be used for association mapping”. Please clarify and justify this idea, otherwise I suggest to eliminate it.

Discussion

Page 19, lines 354-355: “This proportion is significantly higher than those reported in previous studies”. Why do you think this is happening? Could be maybe due to the fact that other populations are too large and have a high level of redundancy, which leads afterwards to a substantial reduction in the number of accessions retained by the core-collection? Please work on this idea and comment in the text.

Page 20, lines 370-371: “Associated traits were characterized under two different environments, suggesting that the significantly associated SNPs were genuine and stable”. I do not agree with this idea. A dataset with two environments is not robust-enough to make such a conclusion. Were the two environments similar or contrasting? How was the correlation of phenotypic values among them? Please clarify and improve.

Page 20, lines 373-375: “Leaf size is associated with local adaptation, and it can actually decrease the false rate by removing accessions with extreme genetic diversity and phenotypic expression”. Please explain in more detail how this decrease in false rate happens.

Page 20, line 376: I do not agree with the idea that the models used offer the resolution that is required for detecting SNPs. Resolution is a property of the population itself and has nothing to do with these models. I suggest to mention here the reduced rate of false positives provided by this model, instead. Please modify.

Page 20, line 381: “assuming an independent relationship between individuals”. This make no sense, please delete.

Page 21, lines 393-394: You already mentioned in page 21 line 386 that Tan et al. (2016) reported one major QTL for leaf size in tea plant. You also found that leaf size is affected by major effect genes, but then say that your findings contradict the ones of Tan et al. (2016). Either you were not clear enough in page 21 line 386, or you are being contradictory. Please be clear and fix this issue.

Page 21, line 397: “This is the first GWAS performed for a tea population”. Please be careful with this kind of statement in the future, because a single search in Google using words “association mapping” and “tea” showed me several studies on GWAS in tea populations. Please modify or eliminate this sentence.

Page 21, line 404: What “linked functional markers” are you talking about? To claim that markers are functional you have to conduct biological validations using complementation or loss-of-function methods. Please modify.

Writing issues or less important issues that could improve legibility of the manuscript if assessed:

Title

Page 5, line 1: I suggest to use “development of core-collections” instead of “development of the core-collection”. Otherwise sounds to me like this is and will be always the one and only tea core-collection developed.

Abstract

Page 6, line 18: Please use “key for” instead of “key to”.

Page 6, lines 19-21: I suggest to present the study in this way “… resources. Genotyping-by-sequencing  was used to characterize 415 tea accessions mostly collected from the Guizhou region in China. A total of 30,282 high-quality SNPs were used to estimate the genetic relationships, develop core collections, and perform genome-wide association analysis (GWAS). We suggest 198 and 148 accessions to represent the core set …”

Page 6, line 24: I suggest to use “very well retained” instead of “were almost showed”.

Introduction

Page 7, line 34: Please replace “beverage” with “beverages”

Page 7, line 34: Are tea, coffee and cocoa also the most produced or consumed beverages worldwide? Please add a sentence on this.

Page 7, line 37: Please replace “in family” with “in the family”.

Page 7, line 44: Please replace “Tea has, been” with “Tea has been”.

Page 8, line 60: Please replace “Finding” with “Findings”.

Page 8, line 66: Please check and correct the character size of “the linkage disequilibrium (LD)”, because it is not matching the rest of the text.

Page 8, line 68: Please replace “; other advantages” with “. Other advantages”.

Page 8, lines 69-70: Please replace “and less time-consuming for developing” with “and providing a less time-consuming approach for developing”.

Page 8, line 81: “Criteria basis on” or “criteria based on”? Please check and correct.

Page 8, line 86: I know the reference population used in the study of Muqadassi et al. (2018) very well. In this respect, I can say that this population DOES NOT correspond to a core-collection as defined by Frankel (1984) and Brown (1989). It is actually a diversity panel of European wheat cultivars. I suggest to use another reference in this section or simply eliminate it.

Page 9, line 89: This is the first time in the introduction that you use the term GBS. Please introduce it first a “Genotyping-by-sequencing (GBS)”.

Page 9, line 97: I suggest to stick to either MAS or MAB, but not both, throughout the manuscript. This will reduce the number of abbreviations and terms that you are using.

Materials and Methods

Page 9, lines 105-109: You used the word “referred” four times in less than . I suggest to use some synonyms.

Page 10, line 128: Please replace “of the 12” with “of 12”.

Page 10, line 137: Please replace “basing” with “based”.

Page 11, line 142: Please replace “perl” with “Perl”.

Page 11, line 157: Please move the description in Page 11, lines 161-163 “We measured the length… in March and September, 2018” to the beginning of this paragraph and eliminate the “as described below” phrase. Afterwards you can describe what is MLSI and MLA, otherwise is too confusing.

Page 12, line 174: Please replace “were using” with “were performed using”.

Page 12, line 190: “synonym accessions”. Do you mean “duplicates”?

Page 13, lines 194-195: You already introduced all those abbreviations in the text. Please use only the abbreviations.

Page 13, line 205: Please try to stick to one single format number. For instance, write “30,282” instead of “30282”. Check the format consistency of numbers greater than 1,000 throughout the whole manuscript, figure captions, supplementary material, etc.

Results

Page 13, line 216: Please write “had an observed” instead of “a observed”.

Page 13, line 217-218: Please write “The pairwise genetic distance between two accessions ranged from” instead of “The genetic distance between two accessions within each pair ranged from”.

Page 14, line 224: Please write “the here-derived” instead of “formed”.

Page 14, line 228: Please write “and” instead of “and the”.

Page 14, line 235: Please write “which were” instead of “they were”.

Page 14, line 240: Please write “population. These” instead of “population; these”.

Page 14, line 247: You use the term “variety” interchangeably to make reference to accessions or to cultivars. This could be confusing and lead to misunderstanding. I suggest to use the term “variety” only to make reference about “cultivars”.

Page 15, line 264: Please replace “sets almost were same as the whole” with “set were almost the same as for the whole”.

Page 15, line 266: Please replace “of the whole tea accessions, separately” with “of those of the whole population, respectively”.

Page 15, line 272: Please replace “1). The proportion of samples number removed from per group” with “1), respectively. The proportion of samples number removed per group”.

Page 16, line 283: Please replace “displayed normal distribution” with “did not differed from those of a normal distribution”.

Page 17, lines 297-298: Please replace “For MLL,” with “In the case of MLL, significant association were detected for SNPs” and delete “were detected with these SNPs”.

Page 17, line 301 to page 18, line 302: Please replace “; a negative effect of major alleles of -1.31 and a positive effect of minor alleles of 0.44 were detected” with “. This SNP has a negative major allele effect of -1.31 and a positive minor allele effect of 0.44”. In addition, please specify the trait you are referring to.

Page 18, line 308: Please replace “the deduced” with “while the deduced”.

Discussion

Page 18, line 315: I presume there was problem when the text file was converted into pdf, the word “cost-efficient” has a square instead of a “ff”. Please verify and correct.

Page 18, line 318: Please replace “high-quality SNPs retained” with “high-quality SNPs were retained”.

Page 18, line 321: Please replace “cross-pollination” with “cross-pollinated”.

Page 19, line 331: Please replace “low observed genetic divergence and genetic variation in the tea collection sustained” with “with the low observed genetic divergence and high genetic variation retained from the original tea population”.

Page 19, line 336: Please replace “variety” with “diversity”.

Page 19, lines 345-347: The syntax of the sentence “Compared with … (Odong et al., 2013)“ seems odd and needs to be improved.

Page 19, lines 348-349: Please replace “distance-based methods to propose the first core collection and the mini-core collection from tea origin center, the Guizhou plateau, by GBS, accounting” with “distance-based methods applied on GBS data to propose the first core collection and the mini-core collection from the tea origin center, the Guizhou plateau, and accounting”.

Page 20, line 358: Please replace “appropriate sets considering of the cost of study in the future research” with “appropriate set, considering the costs of future research”

Page 20, line 359: The word “are” is twice in the sentence. Please conserve only one of them.

Page 20, line 365: Please replace “signifies” with “is associated to”.

Page 20, line 369: Please replace “sensitivities to environmental changes” with “influenced by the environment”.

Page 20, line 371: Please replace “genuine and stable” with “environmentally stable”.

Page 20, line 372: Please replace “employ” with “employed”.

Page 20, line 374: Please replace “byremoving” with “by removing”.

Page 21, line 386: Please replace “reported that one” with “reported one”.

Page 21, lines 390-392: I do not understand the text segment “This trend … another (Table 4).”. Please improve the syntax.

Figure and Table legends

General comment: I do not know if this is due to the formatting tool of the Journal, but Figure captions and Table headings appear again several times after page 32. Please double check this issue.

Page 22, lines 412-414: the are several spacing problems with commas and brackets. There must be no space before a comma and there must be a space after the comma. In the case of brackets, there must be a space before an opening bracket “(“ and no space before a closing bracket “)”, whereas there must be no space after an opening bracket and here must be a space after a closing bracket. The only exception is when a closing bracket is followed by a point “.”, because in this case, the closing bracket is directly followed by the point in the way “).”. Please be consistent with this formatting throughout the whole text (manuscript, figure captions, table headings, supplementary files, etc.).

Page 22, line 417: Please replace “entire tea” with “entire collection of tea”.

Page 22, line 417: Please replace “explain” with “conform”.

Page 22, lines 427-428: the term “growth way” is not so clear and can lead to misunderstandings by the readers. I suggest to use instead the term “cultivation status”. Please check this throughout the whole text (manuscript, figure captions, table headings, supplementary files, etc.).

Page 22, line 431: Please replace “plant” with “accessions from”.
Competing interests

Page 24, lines 472-473: “Competing interests” should be in a single line (press enter before the word “Competing”).

Figures and Tables

Page 38, lines 10-11: Please double check that all specific names are written in italics throughout the whole work (manuscript, figure captions, table headings, figures, supplementary files, etc.).

Page 43: In Table 2, the column names are too long and this make the table look odd. Please improve. In addition, in the first column and last row of the table the word “Totle” should be replaced with “Total”.

Page 49: I presume the note “Pre-Group”, Pseudo Group; MAF minor allele frequency” is not complete. Please improve this and include this note as footnote (not in the heading). What is Pse-Group? Pseudo-Group? Again, there are some columns with extremely long names. Please improve.
Experimental design: I included everything in the basic report.
Validity of the findings: I included everything in the basic report.
Additional comments: I included everything in the basic report.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 2
Reviewer: 1

Output:
Basic reporting: good
Experimental design: good
Validity of the findings: good
Additional comments: This manuscript reported the core collection of tea genetic resources in Guizhou province and the  GWAS of leaf size using SNPs by GBS technique. The authors addressed all comment and  suggestion raised by the first circule of review. So, it is acceptable for publication in this version for Peer J after a minor revision.
Line  44, "Tea has been cultivated for more than 5000 years in the Yunnan-Guizhou Plateau" should be deleted or changed into “Tea has a long utlization history in the Yunnan-Guizhou Plateau”. Line 45, "Chen et al, 2013" should be “Chen et al. 2012??”
Through the paper, the "variety" should  be used correctly, for example “breeding varieties" can be changed into "breeding cultivars",  variety can be used with species.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 2
Reviewer: 2

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: Authors addressed most of my concerns. However, for SNPs detected in GWAS result with only 1 or 2 minor allele are really hard to believe they are true. Please drawing violin plot or box plot to show phenotypic difference for individuals carrying these alleles. And authors should also discuss the drawback of these GWAS results in the discussion section.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 2
Reviewer: 3

Output:
Basic reporting: Please read the attached pdf
Experimental design: Please read the attached pdf
Validity of the findings: Please read the attached pdf
Additional comments: Please read the attached pdf


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 3
Reviewer: 1

Output:
Basic reporting: good
Experimental design: good
Validity of the findings: good
Additional comments: Line 106, breeding varieties should be changed into breeding cultivars


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 3
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Authors addressed my concerns properly. This current version of manuscript is acceptable to be published.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: DEVELOPMENT OF CORE-COLLECTIONS FOR GUIZHOU TEA GENETIC RESOURCES AND GWAS OF LEAF SIZE USING SNP DEVELOPED BY GENOTYPING-BY-SEQUENCING
Review round: 3
Reviewer: 3

Output:
Basic reporting: The authors properly assessed all my most important comments and almost all of my remarks regarding syntax and typos. Although I consider that the manuscript can be already accepted for publication, I kindly would like to ask the authors to take into account the following points before publication:

[Original] General comment: There are still some text formatting issues in the manuscript and you must double check them before sending the new version of your manuscript. There are sections with two blank spaces together (for instance in the reference section).
[A Response] We apologize our carelessness and have checked carefully and corrected point-by-point in text.
[R Response] Please revise again. I still found double blank spaces in the reference section.
[Original] 21. Page 9, lines 221 to 222: it should be “to cut down the rate of false positives” instead of “to cut down the false positive among genotypes”.
[A Response] We have revised in the text (Materials and Methods section, line214, page9).
[R Response] Please revise again, the mistake is still there. You cut down the rate of false positive associations, not of false positive genotypes. Or if you prefer it, you can say “to correct for relatedness among genotypes”. But if you are talking about false positives, then you have to refer to markers and their associations.
[Original] 28. Page 12, lines 327 to 328: it should be “phenotypic variation. This SNP has a negative major allele effect of -1.31 and a positive minor allele effect of 0.44 for MLW.”.
[A Response]We have revised in the text (Results section, line316, page12).
[R Response] Please revise again, the mistake is still there.
Experimental design: Please read the basic report.
Validity of the findings: Please read the basic report.
Additional comments: Please read the basic report.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULE MODULATORS OF CDK8/CYCLIN C COMPLEX WITH PHENYLAMINOQUINOLINE SCAFFOLD
Review round: 1
Reviewer: 1

Output:
Basic reporting: The writing is clear and well structured. Contains sufficient revised bibliography regarding the subject of the document. The author has several reports in the area. The support material presents the characterization of the compounds reported in the document.
Experimental design: Due to the structure of the article, first presents the synthesis of the compounds, but reference to scheme 1 until results, so it is difficult to follow the document. I recommend that scheme 1 be referenced in the synthesis.
In line 103 it is recommended to indicate in which articles the compounds 3-4 and 5a-c, i were previously reported.

The way of reporting the characterization of the compounds is not homogenous. It is recommended to follow a single style and completely assign the protons. One suggestion is to enumerate the protons and indicate it. After each value of J, it indicates that they are in Hz. Some have the error of being in this way HZ and must be Hz.

Figure 1, requires a higher resolution.
In Table 1, it is recommended that significant numbers be considered, for example
The values for 5a es correct (83.91 ± 1.83), but the values for 5b its not correct (37.925 ± 1.31), the way of reporting must be homogeneous.
Validity of the findings: The results presented are interesting and of great value for the study area. The conclusions are in accordance with what is presented in the document.
Additional comments: I believe that the document is well structured and of great interest to the area. I believe that it would be improved if it reports in a homogeneous way, since it reports synthesis of new compounds and must completely assign the signals of each compound. It would be interesting to discuss more the structure-response relationship.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULE MODULATORS OF CDK8/CYCLIN C COMPLEX WITH PHENYLAMINOQUINOLINE SCAFFOLD
Review round: 1
Reviewer: 2

Output:
Basic reporting: CDK8/CycC complex has been recognized as a potential target for cancer therapy. This manuscript reported the synthesis and evaluation of a series inhibitor of CDK8/CycC complex. Generally, the manuscript is clear and well written with professional English. However, the literature references are outdated. The figure legend doesn't provide sufficient details.
Experimental design: The experiments are original and well performed.
Validity of the findings: The results can clearly stated, conclusions are well stated which could be supported by their results.
Additional comments: 1.	The authors should be careful about some typo mistakes in the manuscript. For example, in the first paragraph of introduction.
2.	Figure legend is too simple. The authors should include more information.
3.	The references are outdated, they should cite more lately references.
4.	Include more details in the results part.