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Both I and the reviewers are happy with your modifications and I am therefore happy to proceed to recommend this for publication.
[# PeerJ Staff Note - this decision was reviewed and approved by Vladimir Uversky, a PeerJ Section Editor covering this Section #]
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I'm afraid that neither reviewer-2 nor I are terribly compelled by your revisions. I am then returning this to you for another attempt.
In particular, please address:
- what makes a fresh review necessary now?
- discuss the contexts more clearly and use these to illustrate the importance of your review
- the therapeutic sections needs a considerable work - please refrain from simply listing studies and rather review their importance
- please pay particular attention to the final paragraph of reviewer-2.
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After going through the manuscript, my overall impression is that it’s a very ambitious and comprehensive attempt to cover almost every known physiological and pathological aspect of AIMP1, with emphasis on its interactions with TGF-β signalling, immune regulation, neurological processes, and cancer biology. The breadth of literature is impressive, but the way the information is presented makes the review feel more like a catalogue of studies rather than a critical synthesis. Right now, it reads in a fairly linear “study-by-study” fashion, which makes it harder for a reader to grasp overarching concepts, mechanistic links, and areas of controversy or uncertainty. The language is generally understandable, but there are a lot of grammatical slips, awkward constructions, and overuse of jargon, which slows the flow and will need a careful language edit. Figures are present but feel under-utilised for summarising complex pathways; some are essentially text-heavy diagrams that could be redesigned to highlight conceptual frameworks rather than re-state results.
In terms of scientific framing, the introduction sets up AIMP1 as a multifunctional player, but doesn’t convincingly articulate what makes a fresh review necessary now. The paper would be stronger if the authors justified why AIMP1 is at a particularly interesting crossroads in research: e.g., emerging as a therapeutic target, being re-evaluated in light of recent structural biology, or its role in immune–neuro–tumour crosstalk. In the body, while the disease-specific sections are packed with findings, there’s minimal comparison between contexts (e.g., why AIMP1 suppresses tumour progression in some cancers but promotes it in others). This kind of contrast is exactly where a review can add value beyond a literature list. The therapeutic implications section is promising in concept, but it suffers from being too much of a re-summary of earlier sections without offering a critical roadmap,what are the most druggable aspects of AIMP1 biology, what preclinical evidence is robust, and where do translational hurdles lie? Better to mention the AIMP1 biomarker role, cite recent paper “Clinical powers of Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1) for head-neck squamous cell carcinoma, 2022”I think you should expand the discussion on how cancer biomarker discovery can be applied to drug development. In this context, please cite and discuss “Fast, tracking drug development with biomarkers and companion diagnostics.” Liquid biopsy is been applied in cancer, cite ““Updates on liquid biopsies in neuroblastoma for treatment response, relapse and recurrence assessment, 2024” and discuss if the target/biomarker reported in this study can be applied for Liquid biopsy. Given that AIMP1 has important function , if it is detectable in circulating fractions, incorporating it into a liquid biopsy panel could enable longitudinal tracking of pathway activation, early detection of cancer, thereby translating our mechanistic insights into a clinically actionable assay for dynamic patient
There are also several areas where citations are thin for some claims or skewed toward older literature. Recent high-impact studies on AIMP1’s structural dynamics, context-dependent signalling, and interactions with extracellular vesicles in the tumour microenvironment are not covered, and the immuno-oncology discussion could benefit from integrating up-to-date checkpoint blockade or CAR-T perspectives. The review would also gain from including more integrative schematic models,showing, for instance, how AIMP1-mediated TGF-β modulation could simultaneously influence angiogenesis, immune cell polarisation, and neuronal survival. Right now, the figures and text feel siloed by disease type.
As you will, the reviewers are largely positive about this review and believe it will make an important contribution. However, they have highlighted some concerns which are a combination of writing clarity, some areas of omission and a need to synthesize facts more fluently. Hence, I am returning this to you with a clear expectation that a revision is both shorter and more focused, and as noted by reviewer-2 a more obvious 'why this is important' and 'what is missing' in our knowledge gaps. As this reviewer notes: 'A tighter focus, clearer linkage between sections and more critical discussion of conflicting data would take it from a catalog of findings to a compelling story.' I completely agree!
**PeerJ Staff Note:** Please ensure that all review and editorial comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
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This manuscript provides a comprehensive overview of AIMP1 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 1), discussing its biological roles and its involvement in various pathological conditions.
The inclusion of a “Survey Methodology” section is appropriate, and the manuscript is generally well-structured with coherent subsections. The authors offer an insightful perspective on the relevance of AIMP1, extending beyond the tRNA synthetase field to its potential implications in disease contexts.
There is extensive literature references, although some missing regarding AIMP1-associated neurological diseases.
The language is clear overall, but there are issues with tense consistency. Statements referring to well-established facts should be in the present tense, rather than past tense.
As a review, the manuscript successfully compiles findings from the literature; however, certain sections could benefit from improved integration of facts and interpretation.
1. In some sections, there is excessive factual listing with limited interpretation or synthesis. For example, in Lines 74–86 (AIMP1 in immune response), the section could be improved by integrating conclusions or highlighting the broader implications of the facts presented.
2. Some segments are overly detailed in areas that are outside the main topic. While providing context is important, parts like in Lines 247–257 (TGFβ) and in Lines 312–331 (microglia) could be shortened or more directly tied back to AIMP1 to maintain focus.
3. This section is promising but requires restructuring. The therapeutic potential of AIMP1 is not thoroughly analyzed. Additionally, some subsections repeat content already discussed in the disease context. A more concise and focused discussion emphasizing the translational relevance and future therapeutic directions of AIMP1 would enhance this part of the manuscript.
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The review offers valuable insights into AIMP1’s roles, particularly in disease contexts. However, the section discussing genetic variants requires substantial revision for clarity and scientific accuracy. Specifically:
1. The authors should standardize the nomenclature of AIMP1 variants—choose either cDNA, protein-level, or genomic notation and apply it consistently;
2. Please larify and standardize terms like “recessive,” “biallelic,” and “two variants,” as they are used interchangeably;
3. Please note that Pelizaeus-Merzbacher-like disease (PMLD) can be X-linked, but this inheritance pattern is not relevant to the AIMP1;
4. Consider adding a comprehensive table or schematic summarizing all known phenotypes associated with AIMP1 variants. Figure 3B, in its current form, is incomplete and should be revised accordingly
The full name of AIMP1 should be consistently written as aminoacyl tRNA synthetase complex-interacting multifunctional protein 1. Note that the gene name AIMP1 should be italicized throughout the manuscript.
This manuscript tackles an important topic by pulling together what we know about AIMP1’s roles in normal physiology and various diseases.The authors compile a huge number of studies, from its basic function in the multisynthetase complex to its emerging roles in cancer, immunity and neurobiology, and even outline therapeutic angles. That breadth is impressive and the tables of mutations, animal models and signaling pathways are useful. Yet at nearly 6,000 words it often reads like a list of facts rather than a narrative that guides the reader through “why this matters” or “where the real gaps are.” A tighter focus, clearer linkage between sections and more critical discussion of conflicting data would take it from a catalog of findings to a compelling story.
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In the Abstract, you introduce AIMP1 clearly but then jump straight into “accumulating evidence” without giving a hint of the scale or sources of that evidence. It might help to say “over 100 papers” or “work from labs X, Y and Z” to ground the reader in why this protein suddenly deserves its own review. In the Survey methodology subtitle, the description of search terms is fine but the criteria (“mechanistic or therapeutic focus”) could be backed by a reference to established review–writing standards (e.g., PRISMA guidelines). A sentence like “We followed PRISMA recommendations for literature selection” and a citation would strengthen your rigor claim.
Under “AIMP1 in physiological conditions,” the first sentence in the “immune response” section starts “Generally speaking, immune response was marked with…” which is awkward. One paper suggested to cite is “Clinical powers of Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1) for head-neck squamous cell carcinoma, 2022” as an example for AIMP1 in cancer immunity. You might rephrase it as “Immune responses are characterized by activation of immune cells and inflammation.” Also, I noticed you refer to EMAPII sometimes as “EMAP a” (line 74)—that looks like a typo. In the CNS section, the subtitle is “AIMP1 in central nervous system (CNS),” but later you say “As described above, AIMP1 regulated TGF³ signaling,” even though TGF-β wasn’t introduced in that subsection. It would flow better to remind the reader that you first discussed AIMP1–TGF-β links in the immune section.
Throughout the Results-like subsections you often list one study after another without noting where the data conflict or how strong the evidence is. For instance, you cite multiple papers on AIMP1’s anti-tumor versus pro-tumor roles in different cancers, but you don’t discuss why it seems to suppress breast cancer growth yet promote myeloma progression A comparative table or a paragraph weighing these opposing roles, and suggesting reasons like tumor microenvironment or dosage, would add depth.
I also spotted a few missing or sparse citations. In the opening of the angiogenesis section you state “Angiogenesis generally referred to the formation of new blood vessels,” but don’t cite any classic reviews (e.g. Carmeliet & Jain 2011). Likewise, when you describe TGF-β’s complex signaling, you list only two recent reviews; a landmark reference on SMAD versus non-SMAD pathways would help readers unfamiliar with the pathway. And when asserting that AIMP1 modulates NF-κB in macrophages, a direct citation right after that clause would avoid any ambiguity.
Grammar and style could use a light copy-edit. Sentences like “Previous studies have shown that AIMP1 was present in the conditioned medium…” (in the cancer section) could be tightened to active voice—“Smith et al. detected AIMP1 in conditioned medium from GH-secreting adenomas.” I’d also watch for consistency in gene/protein nomenclature (sometimes you write “TGF³,” other times “TGF-β”) and correct small mistakes like “AIMP1 might played a role” (should be “might play a role”) in line 99.
Finally, the Discussion/Conclusions read like another Results paragraph rather than a place to highlight unanswered questions. What are the top three critical gaps? Where should future mechanistic work focus—on cleavage to EMAPII, on receptor identification, on cell-type specificity? More forward-looking commentary and fewer summary sentences would make the ending more memorable. I recommend opening your report with a cohesive paragraph that introduces cancer biology and treatment modalities, cite review by Chief of US National Cancer Institute D. Sonkin, A. Thomas “Cancer Treatments: Past, Present, and Future (2024)” . and discuss how AIMP1 can be apply for cancer therapy.
In short, this is a solid compendium of AIMP1 literature, but it needs more narrative drive, critical synthesis of conflicting findings, a few extra foundational citations and some light polishing of language. Once those issues are addressed, this could be a go-to reference for anyone entering the AIMP1 field.
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