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All critiques were adequately addressed and I am please to accept your revised manuscript.
[# PeerJ Staff Note - this decision was reviewed and approved by Pedro Silva, a PeerJ Section Editor covering this Section #]
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The authors have modified their manuscript to address all my previous concerns.
no comment.
no comment.
no comment.
no extra comment. The author has answered my questions quite well. The work is good.
Please address all the critiques of the reviewers and revise your manuscript accordingly.
[# PeerJ Staff Note: Please ensure that all review comments are addressed in a rebuttal letter and any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate. It is a common mistake to address reviewer questions in the rebuttal letter but not in the revised manuscript. If a reviewer raised a question then your readers will probably have the same question so you should ensure that the manuscript can stand alone without the rebuttal letter. Directions on how to prepare a rebuttal letter can be found at: https://peerj.com/benefits/academic-rebuttal-letters/ #]
The manuscript ''Comprehensive analysis of circRNA expression profiles and circRNA associated competing endogenous RNA networks in IgA nephropathy'' is interesting, well-structured (conforms to PeerJ standards), and professional English language is used throughout. However, the whole manuscript could use some editing to make it more clear and unambiguous. Some specific changes are suggested below:
Line 85 suggest -> suggesting
Line 98 have providing evidence -> provide evidence
Line 102 procession -> processing
Line 104 remove: therefore the circRNAs been produced
Line 104 are -> is
Line 107 regulating -> regulate
Line 108 please check: thus been discrible involed
Line 109 have -> has
Line 110 remove: ''many''
Line 112/116 please check: ''; novel_circ-113 0004153/rno-miR-1443p/Gpnmb ceRNA relationship have been reported involved in acute kidney injury of rat model (Cheng et al., 2019); in another way, human antiviral circRNAs are activated for responding to Kaposi's sarcoma herpesvirus infection, which been proved work as an antiviral mechanism by suppressing crucial viral genes''
Line 122 the change of -> changes in
Line 123 please check: ''Because PBMCs are full of lymphocytes (with 70-90% T cells, B cells, and NK cells) could partially represent the change of the immune system, it had been broadly investigated in IgAN''
Line 127 remove: ''underlying''
Line 135/136 patients were excluded from any other systemic diseases or secondary IgAN -> patients with any other systemic diseases or secondary IgAN were excluded
Line 141 of -> using
Line 143 ugs -> g
Line 144 left -> remaining
Line 146 synthesis -> synthesized
Line 164 denovo -> de novo
Line 165 ''; '' -> ''. ''
Line 166 remove: ''were''
Line 187 are -> were
Line 188/189 please check: ''Normalize Between Arrays in the Limma package was used to normalize''
Line 190 Significantly differential -> Significance of differential
Line 201 which expressed -> which are expressed
Line 207 found -> find
Line 211 screened -> screen
Line 226 have -> that
Line 227 validation the expression -> validation of the expression
Line 229 with the following: -> with the following conditions
Line 232 and listed -> and are listed
Line 239 differential -> differentially
Line 241 is listed -> are listed
Line 250 remove: ''briefly''
Line 256 Fc gamma R- -> Fc gamma Receptor-
Line 258 upregulate -> upregulated
Line 262 function -> functions
Line 265 ''; '' -> ''. ''
Line 265 upregulate -> upregulated
Line 274 remove: ''have''
Line 275 overlapping -> overlapped
Line 278 identified -> identify
Line 285 and 286 remove: '', ''
Line 287 most -> mostly
Line 296 remove: ''And''
Line 299 was -> were
Line 368 transformer -> differentiation?
Line 369 prepossessing -> preprocessing
Line 381 remove: ''using''
Line 382 has -> have
Line 383 please check: ''adaptions''
Line 401 These Vivo and Vitro phenotypes -> These in vivo and in vitro phenotypes
Line 432 remove: ''of''
The authors explain the context of their study and support their data with well referenced and relevant literature.
The figures are relevant and high quality. However, there are some errors in some of the titles:
Table 1- Title: Most -> most
Table 1- Column 2: please check ''CricBase ID'', is it CircBase?
Table 1- Columns are too close to each other. A suggestion is to reduce the unnecessary decimals in the last two columns (log2(FC) and p-value).
Table 2- Title: deferentially -> differentially
Table 2- Column 4- Title: Different -> Differential
Additionally, there is a lack of cohesion throughout the manuscript when referencing Figures. Sometimes the full word appears. Other times they are named as ''Fig.''. I suggest homogenizing.
The authors supplied raw data for circRNA (available at GEO accession number GSE154046) and RT-PCR (Excel file).
The original primary research of this manuscript is within the scope of the journal.
IgA nephropathy remains a significant cause of renal failure that results from the formation of IgA1-containing immune complexes. Our current understanding of its pathogenesis is mostly based on the abnormal increase of circulating O-galactosylated IgA1 and the production of O-glycan-specific antibodies. However, it has become evident that other genetic, epigenetic, and immunological mechanisms are responsible for mesangial IgA1 deposition and renal injury. Hence, the authors´ research question is relevant and meaningful in furthering our understanding of IgA nephropathy's pathogenesis. The authors state that their research fills an identified knowledge gap (understanding the molecular pathogenesis of IgA nephropathy) that could lead to improved targeted therapies to ameliorate disease progression.
Rigorous investigation is performed to a high technical and ethical standard. Overall,
the methods are described with sufficient detail and information to replicate. Some minor comments:
Methods section- A description of RT-PCR data normalization and analysis is missing. Looking at the Excel file containing the raw data it is evident that they used actin as the house-keeping gene for normalization. However, this is not stated in the manuscript and the primers used for actin amplification are also missing in Table S1. Also, the full names of ASB16, HLA-B, TRIM21, and SEC24C are not provided.
All underlying data have been provided, they are robust and statistically sound. I found the results to be supported by the data presented.
Conclusions are well stated. However, I was left wondering how their findings compare to other studies of non-coding RNAs in PMBCs from patients diagnosed with glomerular diseases other than IgA nephropathy. Could any of their circRNAs, miRNAs, and mRNAs have the potential to be used as diagnostic or prognostic markers? Additionally, I found the number of patients in which they performed the validation of their findings through RT-PCR rather small (IgA nephropathy n=4 and healthy controls n=4). I suggest elaborating on this issue as a limitation of their study.
The GEO accession number of the circRNA data is not written in the manuscript. Is this intentional?
1. The title of this manuscript is “Comprehensive analysis of circRNA expression profiles and circRNA associated competing endogenous RNA networks in IgA nephropathy”. It should be better using “circRNA-associated” instead of “circRNA associated”.
2. The English language should be improved to ensure that an international audience can clearly understand your text. Some examples where the language and grammar could be corrected or improved include lines 48, 75, 85, 90, 107, 108, 122, 358 and so on – the current phrasing makes comprehension difficult.
3. The introduction needs to be more concise, and highlights the background of circRNA-mediated ceRNA networks in IgA nephropathy. Therefore, line 88 – line 99 elucidating that miRNA has universal role in the pathophysiology of IgAN could be redundant.
4. Line 124, the last sentence of the introduction described that “PBMCs from IgAN and healthy controls were collected and sequenced with next-generation technology”. It’s necessary to indicate clearly PBMCs were collected from IgA nephropathy patients instead of animal model.
5. Figure 2A: The spelling of “cricRNA” was wrong. Please correct it.
no comment.
6. The author didn’t use qRT-PCR to confirm the differential expressed circRNAs identified in the circRNA-sequencing data. It will improve the accuracy of this manuscript if the qRT-PCR confirmation experiment could be supplemented.
7. In Conclusions (line 439), the manuscript elucidated that “4 circRNAs competed with miR765 to regulate the expression of GALNT2 in IgAN”. However, the experiment design of this article didn’t validate this point. Therefore, the author couldn’t draw this definite conclusion. Suggest the author could modify the content of “Conclusions”.
8. In the Discussion, line 338 – line 343 described that “the hsa_circ_007056、hsa_circ_006671、hsa_circ_0073237 and circRNA3302 were significantly upregulated in our study, and all of them may play roles as ceRNAs of miR765, therefore participating in the manipulation the expression of target GALNT2. However, all the 3 circRNAs were up-regulated, therefore didn’t follow the classic circRNA(down in IgAN)-miRNA(up in IgAN)-mRNA(down in IgAN) interaction regulation”. This finding was interesting, but the explanation of this part was not sufficient. Hope the author could discuss deeply about this finding.
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