Interacting with Professional Biomedical Journal Editors

1. Interacting with Professional Biomedical Journal Editors Vivian Siegel, Ph.D. Director, Center for Science Communication, Dept of Medicine, VUMC

2. The Plan • Describe who professional editors are and what they do, and offer advice on presenting your research that helps them become your advocates rather than your administrators • How many of you have published papers? Interacted in the past with professional journal editors?

3. Who are professional editors? • Editors are • Trained in Research (most have PhDs or MDs and postdoctoral experience) • Oriented towards the research community, rather than the publishing community • Generalists (like to think broadly, and don’t know your work as well as you do) • Try to make each decision consistent with journal policy and with other decisions being made by the journal

4. What does this mean for you? • You can treat professional editors as your colleagues • You need to help editors appreciate the significance of your work • You need to appreciate that sometimes “larger forces” are at play than confidentiality allows an editor to explain

5. The Job of an Editor • Determine whether a paper might “in principle” be appropriate for a journal (evaluate) • Identify appropriate reviewers to help then decide whether to publish a paper (oversee peer review) • Explain that decision to you in as constructive and transparent a manner possible (communicate with authors) • Respond to comments from you that might lead them to reconsider that decision (re-evaluate) • Identify important new areas of research (imagine the future)

6. The Evaluation Stage • Assume that all the data are correct, and the interpretations are valid – is this paper appropriate for the journal? (scope, significance) • Placing the paper in the context of what is already known, how significant is the advance? • could the result have been predicted based on what was already known? • does the result change the way you think? answer a longstanding question? open a new line of research? • does the result belong in a textbook? Should the speaker be invited to give a seminar? • If yes, is the paper logically sound?

7. What Do Editors Need to Know to Evaluate a Paper? What’s New and Why Should I Care?

8. What’s New and Why Should I Care? • Abstract • Introduction • Discussion • Cover Letter • Own Knowledge/Literature Search The editor will read your Introduction and Cover Letter but will also do a literature search. Don’t avoid relevant related information that impacts (negatively) on the significance and novelty of your work.

9. Don’t hide what’s important about your work • First and last paragraphs • Overstating or understating what’s already known • Presubmission Inquiries/Cover Letters

10. Presubmission Inquiries • Enable you to get an editorial perspective on your work prior to submission • Are the only time you can query several journals at the same time

11. What Should a Presubmission Inquiry Contain? All the information needed to make an editorial judgment on the paper (1-2 pages). • The important question being answered by your paper, and why it’s important • The significance of your results to and beyond your field • Why you think the scope and significance might make the paper appropriate for the journal • A structured abstract • Any special needs, such as quick review, if you have them

12. The Tone of a Presubmission Inquiry • Pretend you’re writing to a senior colleague (perhaps a mentor), experienced but not necessarily knowledgeable about your particular research project • Respectful to the editor, enthusiastic about your work; may (with appropriate qualifications) claim novelty even if you won’t do it in the text

13. Example of a presubmission inquiry “I would like to submit a presubmission inquiry regarding suitability of our manuscript, "Subversion of cellular autophagy pathway by RNA viruses" by William T. Jackson, Thomas H. Giddings Jr., Sara Mulinyawe, Ron Kopito and Karla Kirkegaard for publication in PLoS Biology. Cellular autophagy is a field that is just entering a period of rapid discovery, because the mammalian homologs for the many yeast genes that affect autophagy have very recently been identified. Some of these have generated new markers for this previously difficult-to-diagnose process. I recently attended the first Gordon Conference on autophagy, and the list of its roles in development, cancer and host responses to pathogens was impressive. It reminded me of 10-15 years ago, when the genes that affect apoptosis were first available as a result of nematode genetics…”

14. “We have been able to use some of these newly available reagents to show that the biochemical constituents of cellular autophagy are used to form the membrane components of the RNA replication complexes of both poliovirus and rhinovirus. This is of especial interest because, as yet, the process of autophagy has been reported to be antiviral, and numerous reports are in preparation that document the role of autophagy in host innate immune responses. Therefore, the ability of a virus to subvert this process, and not just evade it by, for example, inhibiting PKR, provides a new example of host-pathogen interaction. Furthermore, the ability of pathogens to provide molecular inducers of autophagy, such as poliovirus proteins described in the present manuscript, will be extremely helpful in its dissection…”

15. “PLoS Biology would be an outstanding forum for this paper due to its intention of featuring interdisciplinary research publications; we believe that this paper will be of interest to cell biologists, due to the identification of viral inducers of autophagy, and to microbiologists and virologists, because it is being recently appreciated that several bacterial, including Legionella pneumophila and Brucillus abortus may also subvert the cellular autophagy pathway. Furthermore, other RNA viruses, including murine hepatitis virus, a close relative of the human SARS virus, have been shown to replicate on double-membraned vesicles that resemble those found in poliovirus-infected cells. “I have attached a summary of the manuscript. Thank you in advance for considering this pre-submission inquiry.”

16. Editing and follow up • If you are writing to several journals at once, check that you have inserted the appropriate journal name into the letter… • If you don’t hear back within 72 hr, feel free to follow up with a second email or a phone call • If you have queried several journals and received several positive responses, it is good form to let the journal editor know you have chosen to submit the paper elsewhere (at least before it comes out in the other journal)

17. The Cover Letter • Sometimes you will find it easier to convey why the work is interesting and important in a cover letter than you were able to do in the paper itself. The contents are very similar to a presubmission inquiry, including • The important question being answered by your paper, and why it’s important • The significance of your results to and beyond your field • Why you think the scope and significance might make the paper appropriate for the journal • Any special needs, such as quick review, if you have them, but also recommendations for reviewers or reviewer exclusions, nontraditional peer review, etc., if you want to provide them. • Any related work that is in preparation or under consideration at another journal

18. “Dear Molecular Biology of the Cell Editor, “Thank you for considering our manuscript “Identification of Histoplasma capsulatum Transcripts Induced in Response to Reactive Nitrogen Species” for publication in Molecular Biology of the Cell. Reactive nitrogen species (RNS) such as nitric oxide are potent anti-microbial effectors used by the immune system to destroy microbes.The ability of persistent organisms such as H. capsulatum to resist killing by RNS and establish latent infections in the host is thought to be important for pathogenesis. However, the molecular response of H. capsulatum to RNS has not been previously elucidated. Here we use a combination of two different microarray technologies to identify 153 transcripts that are induced in response to treatment with RNS. These genes are candidate virulence factors that might affect the ability of H. capsulatum to survive in the host. We show that expression of one of these genes is sufficient to increase resistance to RNS in culture.”

19. “The primary significance of this work is four-fold. First, this is the only large-scale analysis of the transcriptional response of the fungus H. capsulatum, a major pathogen of humans, to reactive nitrogen species (RNS). (The only other example of transcriptional profiling in H. capsulatum was performed by our laboratory and published in Molecular Biology of the Cell (Hwang et al., 2003. Mol Biol Cell 14, 2314-2326).) Because molecular genetic tools in H. capsulatum are limited, and because the genome sequence is not yet available, the identification of a large set of genes that contribute to the nitrosative stress response is a highly significant step forward for the field. Second, we have identified the first candidate nitric oxide reductase in H. capsulatum, which will allow future analysis of the role of nitric oxide detoxification in H. capsulatum pathogenesis. Third, we used high density oligonucleotide tiling arrays generated by CombiMatrix Corporation to precisely determine the boundaries of RNS-induced transcripts. This technology is under-utilized, financially accessible to small academic labs, and relevant to a variety of applications—and thus of great interest to a number of researchers. Fourth, this work is being co-submitted with two other papers that elucidate the global transcriptional response to RNS in two other fungi: the model eukaryote Saccharomyces cerevisiae (Sarver et al.) and the fungal pathogen Candida albicans (Hromatka et al.). We observed interesting similarities and differences between the transcriptional responses to RNS for these three fungi, each of which inhabits a unique environmental niche. As a whole, these three papers greatly enhance our understanding of how eukaryotic microbes respond to nitrosative stress..”

20. What did this cover letter have • The important question being answered by the paper, and why it’s important • Understanding how persistent organisms resist killing by nitrosative stress and thereby establish latent infections is important for our understanding of pathogenesis (and in potential treatment). • The significance of the results to and beyond the field • candidate virulence factors • Utility of approach • Increase our understanding of how eukaryotic microbes respond to nitrosative stress • Special need • cosubmission with other papers

21. Choices at the evaluation stage • Reject without review (expect a letter outlining the reasons for the decision) • Review, but with a strong editorial perspective that will influence the ultimate decision • Review, without a strong editorial perspective; reviewers will determine the outcome of the decision making process • (At some journals, such as JBC, editors can decide to accept papers without further review)

22. Rejection without review • The journal form letter • “The field has advanced to the point where the work is no longer appropriate for Cell…” • “We have come to the view that papers describing new components of signal transduction pathways are no longer appropriate, and that for us to consider such a paper, there would need to be some mechanistic insight…”

23. “Custom” letters • “Previous work has shown…Your paper extends this work by demonstrating…given the results that have already been published, such a finding, while of some interest to the field, is not unanticipated…” • Hopefully constructive

24. If there is a strong editorial opinion at the outset… • Some editors will tell you before review, and you can encourage this level of communication during the presubmission inquiry or as part of the cover letter • The editors may send a special letter to the reviewers asking that particular attention be paid to a particular aspect of the work.

25. The Peer Review Stage If the paper seems appropriate and logically sound, who would be best to assess the technical aspects of a paper? Methodologies Model Systems Big Picture Sense of Journal

26. What can you do to help? • Don’t be afraid to suggest reviewers, along with their expertise (esp. for papers that use unusual methodologies) • If there are conflicts that would lead to a reviewer not being able to offer an objective opinion, don’t be afraid to ask that this person be excluded, but explain why.

27. Do not… • Exclude an entire field from reviewing your paper (editors will generally respect 2 or 3 exclusions, but if you exclude everyone, then they will have a hard time reviewing the paper) • Offer as potential reviewers only people who have collaborated with you in the past

28. Types of Peer Review • Traditional: Authors are known to reviewers, but reviewers are anonymous • Open peer review (reviewers are known to authors, usually policy is set by journal but can be modified on request from reviewer) • Double-blind peer review (can be requested by author)

29. The decision • Depending on the nature and strength of the editorial opinion, and what other papers are being considered by the journal, the role the reviews play in the ultimate decision will vary. • The editor’s letter will hopefully convey (as much as it can given the confidential nature of the review process) any discrepancies between the reviewer and editorial opinions on the paper.

30. Types of Decisions • Accept without revision • Accept with revision (major or minor) • Reject This should be clear from the letter, and don’t let wishful thinking get in the way of figuring out which one it is.

31. Recognizing rejection “I am really sorry that we cannot be more positive on this occasion but hope that you find our referees' comments helpful.” “Our review of your manuscript…is now complete. I regret to say we have decided against publication in Science…We hope you find the referees’ suggestions helpful and we hope you will consider Science for future papers. I’m sorry we couldn’t bring better news this time.”

32. Clear invitation to resubmit “As you will see below, all three reviewers liked your study quite a lot.  Although two of them raise some issues, I suspect that they won't be too difficult to address (though it will require some thought and effort).  Assuming you can address their concerns in a satisfactory manner, I hope to be able to make a final decision on a revised manuscript without re-review.  (That's not a promise, but my expectation.)  Please let me know if any of my comments or the reviewer's comments needs clarification.”

33. Do the editors want it back? “As with all papers submitted to the journal, yours was seen by the PLoS editorial staff as well as by an academic editor with relevant expertise. In this case, your article was also evaluated by two independent reviewers…The reviewers appreciated the attention to an important problem. Based on the reviews, we will not be able to accept this manuscript for publication in the journal, although we would be willing to review again a much-revised version, based on the review comments. We cannot of course promise publication at that time…”

34. “While Reviewer #2 points out that other [related] efforts have been made…, the editors and the academic editor feel that this work is the most definitive to date, and as such, that it in principle merits publication in PLoS Biology. However, several experimental issues remain to be addressed before the manuscript could be considered suitable for publication in the journal. In particular…. “Additionally, the academic editor points out that more work is needed to improve the clarity and presentation of the data; the Results and Discussion could both be significantly shortened (as much as 50%), and modified to remove excessive speculation and overly detailed description of experiments. Please note that we consider it essential that you address both the experimental concerns as well as the issues of presentation in a revised manuscript.

35. “Should you decide to revise the manuscript for further consideration here, your revisions should address the specific points made by each reviewer. You should also send along a cover letter, indicating your response to the review comments and the changes you have made in the manuscript. You should also cite any additional relevant literature that has been published since the original submission and highlight any additional citations in your response. The editors will consider the advance your revised manuscript represents over work published prior to its submission in reaching a final decision regarding publication.”

36. Reviewers always ask for more • Think about what you might be able to include in a revised paper, and whether it might make sense to hold back an experiment from the original submission

37. Split reviews: what is the outcome? • If an Editor hasn’t already formed an opinion, it is likely to be rejected. Publishing is a very visible act. If you accept a paper and it’s widely thought to be rubbish, the whole world knows it. If you reject a paper that turns out to change the world as we know it (or to be published in another journal of comparable stature), the mistake is usually pretty private. • If an Editor is already interested in the paper prior to review, it is more likely to be accepted.

38. You’re much better off if the editors rather than the reviewers control the final decision. Why? • The editor can decide which of the reviewers’ comments are critical and which are not. Otherwise, you might just have to do everything the reviewers say. • The editor is building a relationship with you and an appreciation for the field. At some point, the editor may decide it’s time to “invest” in the area in which you work. • The editor can ensure that decisions are consistent from paper to paper. Reviewers (since they change from paper to paper) cannot.

39. There are two parts to a decision letter • Letter from the Editor • Can you address the major concerns raised by the editor? • Reviewer’s comments • Can you address all or only a subset of concerns raised by the reviewers?

40. Revising the Paper If you can respond to everything, great. If not, check with your editor first about your plan of action before resubmitting the paper

41. Responding to Rejection • Give yourself time to digest the reason for the rejection. Do not call the editor minutes after you get the decision. • See if the decision make sense. If you feel too emotional, ask a colleague you respect to help you assess this. • Sometimes editors do make mistakes, and, if they do, you may be able to persuade them to change their minds. Don’t be afraid to write an appeal letter or call the editor (it IS part of their job), but you may wish to have a colleague look at it before you send it.

42. If you decide to appeal • Stick to the science. Arguments about the number of postdoc years the paper took or the effect this publication will have on your career will not help. • Treat the editor as your colleague, not your enemy.

43. Responding to criticism • Recognize that there is something to learn from every criticism, and act respectful (even if you don’t feel it). Assume that the editors and reviewers worked hard to reach this decision, so if you want them to be open minded, you should not insult their intelligence or ability to do their job. -For example, a requested experiment might actually be in the paper, but was missed by the reviewer. Simply point out that the experiment has been done (and offer to make it more prominent) without voicing your frustration over the fact it wasn’t noticed.

44. Response to Reviews(Example) “This letter is a point-by-point response to the reviewer's comments. Our responses are in blue. We eagerly await your final decision on our manuscript…”

45. “NOR1 experiments in Figure 8: The most strongly induced NOR1 transcript is the shortest one which initiates within the coding sequence. Can you say anything about whether the part of the protein that would be missing in the short transcript is known to be non functional? The truncation would appear to remove some conserved amino acids as depicted in Figure 8C. So is this highly induced transcript even likely to encode a functional protein?” “We have no way of knowing whether the shortest NOR1 transcript encodes a functional protein. It is possible that it encodes a protein with altered localization when compared to the full-length protein, or that the truncated protein plays some type of regulatory role. The protein that is predicted to be translated from the short transcript is missing 2 amino acids that were shown to be critical for NADH binding in the Fusarium oxysporum P450nor protein. Therefore, it is possible that the short-form is unable to bind NADH and reduce nitric oxide. The function of all of the NOR1 transcripts will be one focus of future studies.”

46. “When they express a NOR1 gene to check for increased resistance to RNS, do they express the short transcript? That would have been the better way to do it. How do the levels of the transcript induced by copper compare to the induction they see of the endogenous transcript? Perhaps they can do a Northern to check. The concern I have is that they are inducing abnormally high levels of the full length gene, and the phenotype of this may not reflect that of the modest induction of the shorter transcript.” “As shown in Fig. 8B, 3 NOR1 transcripts are observed when H. capsulatum cells are exposed to nitric oxide. The largest transcript is constitutive. The medium transcript and the smallest transcript are both induced. Mapping studies indicate that the medium transcript likely encodes the full-length protein as shown in Fig. 8C. We ectopically expressed the medium NOR1 transcript. We chose to express the medium transcript because the transcript is definitely induced during nitrosative stress, and because it encodes a full-length protein that is highly homologous to known nitric oxide reductases in other fungi. The shortest transcript may not be functional, as described in point 1, above. Although it might be interesting to overexpress the shortest transcript to see if it affects RNS resistance, those experiments are beyond the scope of this study…”

47. “We have performed Northern analysis to compare the levels of ectopic expression of the NOR1 transcript with levels of endogenous induction during nitrosative stress (data not shown) and the ectopic expression of NOR1 is clearly at a higher level than the endogenous induced transcripts. Because it can be difficult to overexpress a single gene and observe a phenotype, it is often necessary to overexpress at a high level. Future experiments could address whether lower levels of induction would alter the resistance phenotype, but our feeling is that the key experiments require generation of a gene disruption strain. Though we have already spent a year trying to generate a NOR1 disruption strain, some new technologic developments make us hopeful that another year of effort might successfully yield a disruption of this gene. Therefore, we will focus our efforts in this direction. (See reviewer 3, point 1.)”

48. “The statement on p 9 (Materials and Methods) "we did not analyze clones for which the sum of the ratio of the medians for the 635 nm and 532 nm channels was <= 500 intensity units" does not make sense. What do they mean by sum of the ratio of medians?” “The reviewer is absolutely correct. The sentence has been changed to say ‘the sum of the median intensities’ rather than the ‘sum of the ratio of the medians.’”

49. What do you think happened with this paper? • It was accepted without being sent back for re-review • Because an editor was given the authority to make a decision on the paper

50. Submitting your rejected paper to another journal • Respond to the concerns of the original reviewers either in word or deed • It will improve your paper • You may get them again • The pros and cons of telling a journal you’ve been somewhere else first • No one wants to be seen as taking rejects • You may get a quick decision