Evaluated articles

Evaluation Summary:

This interesting, timely and well-done study focuses on the mechanism underlying nevus growth arrest, which has received renewed attention as a result of recent studies that question the dogma that such arrest is mediated by oncogene-induced senescence. Through experiments involving both cultured primary human melanocytes and cells derived from clinical samples, the authors show that Braf-oncogene-induced nevus cell growth arrest results from microRNA-dependent suppression of the mitotic kinase Aurkb, which influences whether Braf activity is proliferative versus antiproliferative. While the conclusions made within the manuscript are justified, and there is sound acknowledgment of certain pitfalls that could be addressed in future research, more expansive sample sizes and further in vivo work would aid in providing more clinical relevance. This manuscript would appeal to researchers in the melanoma field, especially those studying the underlying mechanisms behind phenotypic plasticity and tumor heterogeneity.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This study provides an experimental and computational method for the identification and reconstruction of full-length circRNAs using nanopore sequencing,. With a better comparison to other existing methods in the field and a clearer demonstration of the advantages of the described methodology, the work would be of great interest to researchers in the circular RNA community.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This study describes reduced antibody cross-reactivity between the SARS-CoV-2 B.1.1.7 variant and the parental strain or the B.1.351 variant. Asymmetric antibody responses and reduced neutralizing antibodies against heterogeneous variants have been demonstrated in multiple studies. The current study reports reduction of B.1.1.7 COVID-19 sera against the SARS-CoV-2 parental strain and B.1.351. This observation is interesting and could be useful for future vaccine development. The work is of interest to virologists and infectious disease specialists.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The authors perform a tour-de-force study of classical conditioning in fly larvae. Experiments are original, findings are exciting, and we expect this paper to have a substantial impact. There is potentially an issue in the assay of larvae preference taking an hour of unrewarded presentation of CO2, while the training and extinction happen on much shorter scales, muddying the ability to interpret the results. A mathematical model of the conditioning process is also missing, which also makes interpretation harder.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This paper is of great interest for researchers working in the filed of cell adhesion and cell migration. The authors show for the first time that alpha5beta1 ligand spacing profoundly influences the collective migration behaviour of keratinocytes. They demonstrate that this parameter can outcompete the well-known and studied influence of substrate stiffness.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This is an interesting study aiming to link the evolutionary effects of dietary mismatch in humans to increased inflammatory responses and risk of chronic diseases. To uncover more insights into the causal links, the study used a non-human primate (macaque) model to show that the dietary switch from a Mediterranean to a modern Western diet leads to the polarisation of monocyte cell populations toward a more pro-inflammatory state, which in addition to increasing the chronic health risk can also impose behavioural changes such as anxiety and social isolation. The results of this study are convincing, interesting, and have fundamental importance in evolutionary biology, immunology and psychology. The extent to which these findings can be extrapolated to human populations remains to be established.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

Although the role of membrane potential in Cell Permeable Peptides (CPP) translocation has been consistently described in artificial systems, this multi scale study, combining cell biology, genetics and in silico approaches, further extends this topic to a live cell context where it shows that internalization stops when the membrane polarization is decreased by the removal of potassium channels. It proposes an original mechanism of CPP translocation based on water pore formation, which should be of interest for biophysicists, cell biologists and for applications such as drug delivery.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation summary:

Glioblastomas, like many tumors, consist of a cohort of actively dividing cells and a substantially larger fraction of non-proliferating cells. The standard of care involves the administration of a chemotherapy drug (temozolomide (TMZ)) whose antitumor activity is thought to be dependent on a toxic intermediate produced during DNA replication. In this report, the authors show how this compound is also processed by the interaction of two DNA repair pathways which produce the same intermediate without the requirement for DNA replication. The paper will be of interest to those scientists concerned with the implications of DNA damage and repair for cancer chemotherapy, particularly for tumors as deadly as glioblastoma.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This study uses the approach of labeling neurons with distinct birthdates so they can be differentiated in experiments performed later in development. The authors then test morphological, functional and circuit inputs/outputs patterns of these neurons by using immunohistochemistry, slice electrophysiology, retrograde labelling, morphological reconstructions and behavioral assays. The manuscript is likely to make a strong impact in the field of developmental neuroscience and a good impact related to more general cellular and molecular neuroscience.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This study in the field of collective behavior addresses how naïve and experienced individuals (i.e., homing pigeons) pool information in order to navigate while flying back home. The authors show that the passage of information is largely democratic, meaning information passes both ways, and that, unexpectedly, exploration of the route is initiated both by naïve and experienced birds. The work provides a new perspective on information sharing during collective learning.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This study reports that calsyntenin-3, a synaptic adhesion molecule, is expressed in cerebellar Purkinje cells and that acute knockout of calsyntenin-3 increases excitatory synapse density and decreases inhibitory synapse density. The manuscript provides compelling evidence that elimination of calsyntenin-3 from cells in the cerebellar cortex alters the E/I balance for Purkinje cells by increasing the strength of excitatory parallel fiber inputs and decreasing the strength of inhibitory inputs. However, it would have been far better to selectively target Purkinje cells, but that was not done. This is the first study showing that a particular synaptic adhesion molecule regulates excitatory and inhibitory synapse in opposite directions.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The work will be of interest to anyone interested in signal transduction, and especially those studying GPCRs and membrane receptors. Dimerization and oligomerization of G protein-coupled membrane receptors (GPCRs) are expected to be critical for receptor function. This intriguing study helps understand the usually underestimated role of GPCR soluble domains. The authors discovered that oligomerization of a GPCR can be mediated by multiple weak interactions between soluble domains that are "tunable" by environmental factors, thus possibly modulating the function of this important class of membrane receptor proteins. What remains to be shown is how oligomerization alters receptor function.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript will be of interest to epidemiologists and population biologists interested in outbreak dynamics in populations with complex social structures, such as emergent viral infections of humans. The study offers a functional, differential-equation (DE)-based framework for capturing the transition from emergence to endemicity without the huge over-compensation cycles typically predicted by DE models but rarely seen in natural populations. The model framework currently offers insights into the drivers of epidemic dynamics and, after further testing and calibration, may be useful for assessing control strategies for emerging infectious diseases.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

Drosophila species have long served as an important model system for genetics and genomics. The authors have developed an important community resource of high standard genomes for many species across the Drosophila clade. This resource will serve to empower the next generation of Drosophila research and provides an important road map for similar efforts in other groups of organisms.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors present the first digital adult zebrafish brain anatomy atlas that includes ten highly informative markers for different brain regions and cell types. The authors utilize new clearing techniques to enable staining of the whole fixed zebrafish adult brains, and light sheet microscopy fluorescent imaging to obtain high resolution three-dimensional data. Several individual dataset for each marker are registered and aligned to an anatomical model using fluorescent cell nuclei and autofluorescence patterns by state of the art volume registration algorithms. The results appear to be of high quality. The authors also provide a detailed and state-of-the-art anatomical annotation of brain regions. Using ten different antibodies to fluorescently label different neuron types, stem cells and glia, proliferation zones, and some specific anatomical regions, the authors demonstrate the utility of their database. This will be a valuable resource for neurobiology research in zebrafish.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript will be of interest to developmental geneticists interested in neuroscience, as it demonstrates how spinal motor neurons maintain their unique identities in adulthood after fate decisions are made in the embryo. The work here suggests that a Hox transcription factor acts as a terminal selector to control motor neuron identity, thus mirroring recent studies in C. elegans, and pointing towards this type of gene regulation as important in building diverse nervous systems.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This submission reports an approach to identify bacterial specific carboxyesterases that can be exploited to activate prodrugs of antibiotics in Staphylococcus aureus. The main premise is that charged functional groups found in some antibiotics prevent entry of these into bacteria, an effect that can be circumvented through esterification of the antibiotic to allow entry. Thereafter, activation of the antibiotic will occur in the bacterial cytoplasm through hydrolysis by bacterial esterases. This could lead to new antibiotic delivery strategies.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in APC and KRAS. The authors identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and differentiation, suggesting that translation elongation can be used as tumour-specific target.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

Tian et al. used a battery of biophysical techniques to compare wild-type SARS-CoV-2 with two variants (B.1.1.7 and B.1.351). The authors obtained evidence consistent with the receptor-binding domain (RBD) of the variants exhibiting higher affinity ACE2, providing a possible explanation for their higher transmission. However, the effects are modest, and further work will be needed to confirm that this difference explains the increased transmission of the variants. Despite the need for follow-up studies, the paper is among the first to show definitively that the N501Y mutation confers enhanced binding to ACE2.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The authors ask why the APOE4 allele has persisted, often at high frequencies, in human populations despite its associations to heart disease and Alzheimer's disease. They consider the hypothesis that APOE4 may be advantageous in a high pathogen and high physical environment settings (as opposed to a low pathogen industrial lifestyle) through an in-depth characterization of the Tsimane in Bolivia. The study is of broad interest with an insightful dataset; the conclusions are somewhat limited by the nature and current description and treatment of the data.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)