Peer Review: Highlighting preprints reviewed by eLife during February

Read what peer reviewers thought about three recent preprints on the links between heart disease and breast cancer, proton pumps and malaria, and the response of neurons to mechanical forces.

eLife has changed its peer-review process to emphasize the public review of papers initially published by the authors as preprints. Our aim is to create a system in which publishing is controlled by authors via preprints, and where research is assessed via public peer reviews.

Starting last July, eLife began exclusively reviewing preprints. And, for over a year, our reviewers have been writing ‘public reviews’ that discuss the strengths and limitations of every paper we assess, and our editors synthesize these into a short ‘evaluation summary’ that encapsulates their views on the paper.

The evaluation summary and public reviews are posted alongside the preprint, and the authors can post a response to both if they wish.

Authors are also sent additional detailed feedback on the manuscript, including suggestions for improvement, and this feedback is posted alongside the article if it is accepted for publication in eLife.

Below we highlight some of the evaluation summaries, public reviews and author responses that have been posted alongside preprints on bioRxiv and medRxiv in the past month.

Preprint title: Risk of heart disease following breast cancer: results from a population-based cohort study

In this medRxiv preprint the authors studied the incidence of heart disease in a cohort of more than 8000 women diagnosed with breast cancer in Sweden between 2001 and 2008. They found increased risks of arrhythmia and heart failure in breast cancer patients compared to matched controls; the risk of ischemic heart disease was only elevated in the first year after diagnosis. Trastuzumab and anthracyclines were also associated with increased risk of heart failure.

Here is what the evaluation summary for the preprint said:

This manuscript will be of interest to oncologists, cardiologists, cardio-oncologists, and primary care providers who treat patients with breast cancer and adds to the growing body of literature that identifies the increased risk for cardiotoxicity associated with breast cancer treatment and does so at the general population level. The results of this study are interesting and supported by the data provided, however they must be interpreted with caution as the database utilized includes intended treatment regimens (chemotherapy, radiotherapy) rather than the confirmed treatments patients received.

The three reviewers went into the strengths and weaknesses of the work in more detail in their public reviews, as can be seen in the following paragraphs from Reviewer #1:

The authors should be commended for this large cohort study that achieves its goal of identifying the incidence and hazard ratio of cardiotoxicity associated with breast cancer treatment within a general breast cancer population. Their findings of increased risk of heart failure in patients treated with anthracyclines and trastuzumab is consistent with multiple prior studies in the field of cardio-oncology and adds to the validity of the data. The finding that there is only a slightly increased (and statistically insignificant) risk of ischemic heart disease after left sided radiotherapy is quite interesting, and as noted by the authors, differs from prior understandings about risk of ischemic heart disease associated with breast radiation therapy. Without data on mean heart dose or total radiation administered the results are hypothesis generating, but should not be utilized to guide medical decision making.

One of the major limitations of this study is that the authors' goal is to identify the incidence and risk of cardiotoxicity associated with the various breast cancer treatment regimens and determine these risks over time, and as noted by the authors, the registry utilized only includes planned treatment not whether patients did receive this therapy (and what dose of therapy). This is a key point that should be emphasized when interpreting the results.

The evaluation summary, public reviews and author response were all posted on February 13, 2022.

Preprint title: Malaria parasites utilize pyrophosphate to fuel an essential proton pump in the ring stage and the transition to trophozoite stage

In this bioRxiv preprint the authors study a proton pump called PfVP1 in Plasmodium falciparum, the parasite that causes malaria, and the transition between the ring and trophozoite stages of the parasite.

Here is what the evaluation summary for the preprint said:

This work will be of interest to researchers seeking new ways to target malaria parasites. The work provides insight into the energy requirements of parasites during the first day of their two-day life cycle, a period during which they are significantly resistant to a wide variety of antimalarial drugs, and identifies an essential enzyme that could be targeted in early-stage parasites. The study shows this protein is necessary for normal development and growth of parasites in red blood cells.

The public review from Reviewer #3 goes into more detail:

The conclusions of this paper are firmly supported by data, often from more than one type of experimental approach. The conclusions provide fundamental information about the stage of parasite development that has been hard to target with antimalarial drugs.

The most energy-consuming process in a cell is the maintenance of membrane potential and in malaria parasites, it is known that proton pumps (rather than sodium pumps) are responsible for this process. Although PfVP1 was previously reported to be located internally in an organelle of the parasite, the data presented in this report clearly define its location on the plasma membrane and its essential role in maintaining the membrane potential.

PfVP1 inhibitors could preferentially target early stage malaria parasites and the current results support efforts to find these inhibitors.

Perhaps the most exciting aspect of this work is the potential to act synergistically and enhance the effect of current antimalarial drugs on early stage parasites. In this vein, the authors tested four antimalarial compounds in conjunction with knockdown of PfVP1 to determine whether there was enhanced activity. These experiments were not conducted in a systematic way and this is perhaps the only weakness of the paper.

The evaluation summary and public reviews were posted on February 15, 2022.

Preprint title: Drosophila mechanical nociceptors preferentially sense localized poking

In this bioRxiv preprint the authors study how sensory neurons called nociceptors – neurons that respond to painful and potentially dangerous stimuli – respond to mechanical forces. They focus on the role of two key mechanosensory molecules, Piezo and Ppk1/Ppk26, in c4Da neurons in fly larvae.

Here is what the evaluation summary for the preprint said:

Liu et al present fascinating findings that significantly extend the understanding of molecular and cellular pathways of mechanical nociception in Drosophila larvae. This work is of very high interest to neuroscientists studying sensory function and its molecular underpinnings with implications for our understanding of acute sensation of painful stimuli. The approach and data are of very high quality and provide unprecedented insight into mechanosensory functions in an intact tissue environment.

Reviewer #2 places the work in context, and also raises concerns that the authors need to address, as illustrated by these extracts from their public review:

The authors developed a sophisticated piezo-driven probe to deliver precisely defined mechanical stimuli and combined it with functional imaging of Drosophila larval nociceptors in semi-intact preparations. Their clever setup allowed them to measure mechanical responses of these neurons to mN range stimuli. By using defined probes with different diameters, they showed that c4da neurons display almost uniform responses nearly independent of the stimulation site within their dendritic field. Moreover, the authors convincingly show that c4da neurons preferentially respond to small diameter probes (30 microns) and that their uniform dendritic coverage is also required for detection of distal mechanical stimuli. Stimulation of these neurons results in defensive rolling behavior, which has likely evolved in Drosophila larvae to defend against being stung by parasitoid wasps. The typical ovipositor of such wasps is 5-20um suggesting that c4da neuron responses are indeed optimized for detecting small diameter mechanical stimuli as shown by the authors. Elaborating on the broader biological significance of the authors' findings (and extrapolation to other species/higher organisms) might have been useful for a more general audience.

[The authors show] that two of the expressed mechanosensory channels, ppk26 and piezo, differentially contribute to c4da neuron responses. The authors argue that ppk26 is important for overall and piezo for localized mechanosensitivity, with both participating in sensing lateral tension. The interpretation of the data seems simplified for multiple reasons: a) piezo has been shown to be widely expressed in different tissues (e.g. Kim et al. Nature 2012), thus it might contribute in different ways to c4da mechanosensitivity. b) piezo loss of function does not strongly affect responses to the 30/60 micron probe when applied proximal to the neuron, but does so only in distal regions. c) loss of ppk26 results in disproportionally stronger loss of responses to the 30 micron probe (i.e. more local force), which suggests it could be particularly relevant for perpendicular pressure sensing.

The evaluation summary and public reviews were posted on February 13, 2022.


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