Evaluated articles

Evaluation Summary:

The manuscript describes a metadynamics simulation-based characterization of the binding and unbinding dynamics of a buried phosphorylated residue in the inhibitory module to the functional domain of Vav1, in an effort to shed lights on the autoinhibition mechanism. The work led to a conformation-selection scenario of the event. The authors discussed the inconsistency between the computational findings and the NMR data, in terms of the free energy differences between the bound and unbound states. Further justification is required for the somewhat ad hoc choice of three collective variables for the metadynamics simulations, including two that are highly correlated.

(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 present here an analysis of the gene expression patterns of lesions as found in patients wet age-related macular degeneration, known as choroidal neovascularization. This gene expression analysis is compared to an experimental mouse model. Using this analysis, the authors have identified a candidate target, FN14, as a potential target for the treatment of choroidal neovascularization. Identifying an alternative treatment modality is important for the treatment of these lesions beyond the current standard of care.

(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 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of broad interest to readers in the field of motion perception. The authors use concurrent psychophysics and single unit recordings, along with modeling, to investigate how primate cortical area MT uses specific visual signals to make inferences that distinguish between visual motion induced by self-motion and the motion of other objects in the world. The experiments and stimuli are expertly designed and the analyses are careful.

(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 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper is of interest for cell biologists, developmental biologists and tissue engineers. The authors identify a combination of natural extracellular matrix and growth factors that enables to grow cholangiocytes as branched three-dimensional ducts in culture. The work is physiologically relevant and represents an interesting step forward in the study of bile duct formation and disease, although the cultured ducts could be characterized more in depth.

(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 manuscript describes a method of evaluating the steady state levels and kinetics of protein-protein interactions at the plasma membrane of living cells. This approach builds on previous work in this area, and with stronger validation and demonstration of biological applications, it may be complementary to other biochemical or imaging-based approaches to address important questions related to mechanisms of cell signaling.

(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:

Here, Taguchi et al. study a member of the kinesin-4 family of motors, which is important in controlling microtubule length during normal development and maintenance. The authors aim to determine how a member of the kinesin-4 family is able to stabilize the tips of microtubules to suppress both their growth and shrinkage. This paper provides compelling data on KLP-12 by combining in vivo C. elegans work with in vitro single-molecule analysis and structural studies of the motor domain. The structure shows that KLP-12 bends tubulin heterodimers to a level that lies in between the extremes of bending by KIF5B (lattice stabilizer) and KIF2C (lattice destabilizer). This study will be of interest to those in the fields of neuronal development and cytoskeletal dynamics.

(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:

In this paper, Bostock and Fernandes show that photoreceptor axons provide a graded Hedgehog signal to their target region, the lamina, that is highest in the distal and lowest in the proximal lamina. High levels of Hh favor specification of the distally located lamina neurons L2 and L3, while low levels favor specification of the proximal L5 neurons. This graded response raises interesting parallels with the patterning of the vertebrate spinal cord. The paper will be of special interest to those who study optic lobe development, but will also be of more general interest to developmental neurobiology.

This manuscript was co-submitted with: https://www.biorxiv.org/content/10.1101/2021.12.13.472383v2

(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:

Using biophysical measurements, this work establishes that the SWR1 chromatin remodeling complex, which directs incorporation of the histone variant H2A.Z adjacent to nucleosome depleted regions, preferentially associates with longer DNA fragments. It is proposed that larger stretches of free DNA determine the specificity of the complex in vivo. These findings will be of general interest to researchers interested in understanding how chromatin remodelling enzymes act to influence the localisation of histone variants.

(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:

The role of Replication Factor C (RFC) in DNA replication and repair has been known for many years. RFC/PCNA binds to a double strand-single strand DNA junction with a 3'-recessed end, with the DNA passing through a central chamber in the five-subunit protein. The current paper reports structures of RFC/PCNA with two separate DNA molecules, one containing the well characterized 3'-recessed DNA and surprisingly, a second 5'-recessed DNA outside the central chamber.The paper is an important addition to understanding RFC function, particularly in DNA repair, but it could be improved with some clarifications. The work is of interest to all studying DNA replication.

(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 name with the authors.)

Evaluation Summary:

Exocytosis of synaptic vesicles is mediated by synaptic SNARE proteins that overcome the energy barrier for membrane fusion by assembling into a helical bundle, thus pulling the membranes together. Here the authors have introduced mutations into the membrane-proximal region and transmembrane domain of one of the SNAREs (syntaxin 1a) showing that not only charge reversal but also palmitoylation of the transmembrane domain influence both spontaneous and evoked neurotransmitter release. The results add important details to our understanding of the late steps in SNARE-mediated exocytosis.

(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 manuscript is of particular interest to researchers in the fields of neuroecology of insect olfaction and of insect-plant interactions in general. The authors investigate the olfactory signals that guide the specialist hawkmoth Manduca sexta towards plants that are used for oviposition and for nectar-feeding in a natural setting. How insects distinguish useful information from irrelevant information is an important question. The authors use elegant chemical ecology techniques and recordings of neuronal activity to ask how female moths (Manduca sexta) could discriminate co-occurring behaviorally relevant vs irrelevant plant and floral volatiles.

(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:

The paper presents a tour de force examination of the role of PAG CCK neurons in threat. It is exemplary in the use of a variety of high and low threat tasks along with corresponding behavioural measures, as well as gain and loss of CCK function approaches. The results reported will be of significant benefit for those studying the behavioural and neural mechanisms of learned and unlearned threat, and decision-making in threatening situations.

(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:

The focus of the manuscript is the lysosomal Cl-/H+ transporter CLC-7. The main finding is the direct regulation of CLC-7 by PI(3,5)P2, which keeps CLC-7 inactive. This finding may explain the lysosomal and cellular phenotype of a newly identified gain-of-function mutation in CLC-7 that causes lysosomal hyperacidification and large vacuoles.

(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 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

The authors analyzed a national database to gain insights on deficits in cervical and colorectal cancer screening in the United States. Their work may provide a set of predictors to enhance health promotion messaging to women who are underscreened and thus eliminate disparities in cancer control.

(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 paper is of potential interest to people working at the interface between agronomy, ecology, and evolution. By growing experimental mixtures of crop species, i.e., intercrops, the study aims at testing whether positive interactions between species grown in association strengthen over generations of coexistence. The data are original and of high quality, and the statistical analysis are rigorous. The interpretation of the Results as well as the Discussion and Conclusions currently ignore an important discrepancy in the results for competition versus overall yield.

(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:

The authors describe a comprehensive characterization of a new humanized FSH blocking antibody (MS-Hu6), which they have studied in-depth in terms of its efficacy on bone and fat tissues. They provide compelling data on mouse and monkey species with a complete evaluation of its pharmacokinetics and biodistribution and characterize its effect for the treatment of obesity and bone loss. It is an important contribution and will be useful to a general readership in endocrinology, bone and fat metabolism.

(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 is a very exciting study that presents a novel approach to examining dopamine release with spatial precision that is so far unrivaled. This manuscript is also important and timely in the field of biosensor development and of potential interest to neuroscientists who study neurochemical release. It introduces a synthetic nanofilm with high spatiotemporal resolution and quantal sensitivity to dopamine measurement. By utilizing this technology to visualize sub-cellular dopamine efflux, the work provides new insights into the spatiotemporal dynamics and protein machinery of somatodendritic dopamine release. The authors identify hotspots for DA release and also provide evidence for DA release in the presence of TTX, suggesting the occurrence of quantal release.

(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:

The authors quantitatively characterize binding interactions between all known MIM motifs of ESCRT-III proteins with the MIT motifs of several AAA+ ATPases. In addition to the analysis of these interactions, which will be an important resource to the ESCRT community, the authors also identify new roles of the ATPases SPASTIN, KATNA1 and CAPN7 in cytokinesis. Therefore, the work will be of broad interest to biologists interested in membrane-associated complexes and in cell cycle and cytokinesis.

(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 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

In the present manuscript by Blake et al., the investigators show that myocardial infarction (MI) leads to increased sulfation of CSPGs in the cardiac scar. The investigators subsequently demonstrate that reducing sulfation with a sulfatase, arylsulfatase B (ARSB), promotes sympathetic neurite growth in vitro and ex vivo in a co-culture system. This paper provides interesting results regarding neural remodeling of the heart and has implications for visceral innervation in health and disease. This work is important in highlighting the role of neural-myocardial interactions after MI and offering a potential pathway to target in preventing post-MI sudden cardiac death.

(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 #4 agreed to share their name with the authors.)

Evaluation Summary:

To better understand proteins and pathways regulated by deubiquitinating enzymes (DUBs), this study has assembled a database that integrates existing datasets with additional knock-out experiments. Co-dependent genes as well as protein-protein interactions and co-expression were taken into account. The combined data confirms known functions and highlights potential new functions of DUBs. This will be a useful resource for investigators aiming to elucidate DUB functions, as well as for research efforts to develop therapies for the treatment of different cancer types through targeting DUBs.

(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.)