Evaluated articles

Evaluation Summary:

This study, which will be of interest to neuroscientists in the fields of learning and memory, somatosensation, and motor behavior, uses systems neuroscience tools to expand our view how the postero-medial (POm) nucleus of the thalamus contributes to goal-directed behavior. The reviewers suggested additional ontogenetic experiments to clarify the nature and specificity of those roles. They also indicated that certain alternative explanations to the experimental observations could be addressed for a more balanced presentation and interpretation of the results.

(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:

Vinbert et al. provide a conceptual replication on individual differences in conditioned skin conductance response during fear acquisition training and BOLD fMRI in a large sample (N=285) of healthy individuals (mono- and dizygotic twins). The authors report results that are in line with previous work and new results from a whole-brain analysis and suggest unique and shared contributions of individual brain regions. This is a timely and well-conducted replication study, the sample size is large for this area, and there are robustness (multiverse) analyses in place to ensure that findings are not driven by particular analysis choices.

(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 paper will be of interest both to marine biologists and to biophysicists studying voltage-gated proton channels. It describes cloning and full biophysical characterization of the first ion channel ever identified in reef-building coral species, and develops a mechanistic model for understanding regulation of voltage-gated proton channels.

(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 is a well-performed study that defines the role of purported host cell receptors in the entry of hantaviruses into human endothelial cells. This is an important study as it applies CRISPR-mediated deletion studies for candidate receptors in the same endothelial cell line (TIME).

(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 article is of general interest to scientists who perform two-photon calcium imaging in vivo and explore the link between function and structure in real neural networks. The development of efficient approaches to estimate true correlations between large sets of noisy individual neurons based on realistic and thus limited observation time is a key to better understand functional local circuits. The effectiveness of the proposed method is illustrated by simulations and applied on real data, but several steps in its procedure remain to be clarified in the current form of the manuscript to be usable by a wide range of users.

(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:

In this work, Holz and colleagues develop a computational stochastic model of lamellipodial actin network growth and turnover to address an unresolved important question: how do these networks remain wide enough, maintain angular order, and actually increase the filament length behind the leading edge? They compare the filament organization and rate of incorporation/detachment of actin subunits with experimental data published in the literature. A main result from this study is that frequent filament fragmentation and annealing are key events in the reorganization of branched actin networks. The paper is well written, contains very thorough and fair literature review, is accurate, well documented. The result is novel and significant.

(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:

Cell movement is essential for development and tissue homeostasis. While the cellular machineries involved in movement have been well studied, how cells maintain a persistent direction of motion is less well understood. Here, Coppey's team shows that movement persistence emerges from the coupling of two cellular systems: protrusions at the leading edge and polarity of secretion. This coupling is controlled by the small GTPase Cdc42. The authors propose a physical model that recapitulates the coupling, defines two key parameters and explains persistent cell migration.

(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 is of broad interest to scientists in the field of reproduction and has clinical relevance. It builds on innovative studies interrogating the impact of cell senescence on stromal cell differentiation and embryo implantation. It presents the development of a novel co-culture system taking advantage of organoid technology to study cell-specific interactions and outcomes.

(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. Reviewers #1, #2, and #3 agreed to share their names with the authors.)

Evaluation Summary:

This study examined the neural mechanism underlying stimulus-outcome associations. Using a series of sophisticated experiments with otpogenetics and pharmacogenetics, the authors show that interactions between the basolateral amygdala (BLA) and the lateral part of the orbitofrontal cortex (lOFC) play critical role in learning to predict the identity of outcome predicted by a cue, but not in learning to predict reward generally. These results extend our understanding of how BLA and lOFC regulate the formation of associative learning and subsequent decision-making.

(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 will be of interest to neuroscientists studying the effects of cholinergic modulation throughout the brain. It provides strong support for the view that activity in the basal forebrain cholinergic system is not monolithic, but varies across the rostrocaudal axis, consistent with previous reports of differential connectivity of these areas. Strong evidence for regional differences in cholinergic responses collected simultaneously under multiple behavioral conditions provides valuable context for interpreting variability in existing and future studies.

(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 will be of interest to cell biologists interested in understanding processes that regulate the biogenesis of the primary cilium, and to others interested in ciliopathies (ie disorders of the primary cilium). The authors have identified a novel pathway that controls the generation and length of primary cilia and show that its effects are mediated at least in part through its effects on regulating the cytoskeleton. They suggest that this pathway may also have clinical relevance for autosomal dominant polycystic disease, but the data and rationale underlying this part of the study wold need to be strengthened.

(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 will be of interest to researchers working on a broad range of questions in evolutionary biology, from the evolution of multicellularity to senescence and cancer. With their model, the authors study an often-neglected aspect of cellular differentiation and division of labour. While the model is relatively simple, the premise and the findings are thought-provoking and this study can potentially provide the groundwork for further investigation.

(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 manuscript is of potential interest to experimental haematologists studying initiation and maintenance factors in leukaemia. Overall, the study is well designed and the data is clearly presented. However, in some places the analysis lacks depth and technological sophistication, and the novel insights are limited without additional experimentation.

(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 study by Vanacker et al examines the effect of activating GFAP expressing cells within the POA and ARC on the activity of GnRH and TAC2 neurons as well as LH levels. The authors found that activation of GFAP POA cells activated GnRH neurons and increased circulating LH levels, limited to intact males. Activation of ARC GFAP cells failed to alter TAC2 activity or LH levels. Inhibition of POA GFAP cells or activation of POA GFAP cells in females failed to alter the firing rate of GnRH neurons. The study is largely well done and clearly presented.

(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:

Kasper et al. have analyzed intra-ocular cells in four subjects with HLA-B27-associated acute anterior uveitis, 2 subjects with HLA-B27-negative anterior uveitis, and one subject with bacterial endophthalmitis using several assay techniques including single cell RNA-Seq, fluorescence activated cell sorting, and quantification of multiple cytokines. They discovered a unique pattern in HLA-B27 positive uveitis that exclusively featured plasmacytoid and classical dendritic cells (cDC) infiltrate and plasma cells. These might provide hints for the pathogenesis of this disease.

(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:

Zappia et al investigate the function of E2F transcriptional activity in the development of Drosophila, with the aim of understanding which targets the E2F/Dp transcription factors control to facilitate development. They characterize changes in gene expression by proteomic profiling, and characterize Dp loss phenotypes in muscle, fat body, and the whole body. They document low levels of glycolytic intermediates and circulating trehalose, which is traced to loss of Dp in the fat body. Strikingly, this phenotype and the resulting lethality during the pupal stage (metamorphosis) can be rescued by increasing dietary sugar. Hence the authors provides new insights in the function of E2F/Dp.

(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 will be of interest to structural biologists, enzymologists, and cell biologists. The kinase complex mTORC1, a master regulator of cell growth, can be inhibited by another protein, DEPTOR. This protein is of general interest for several reasons, including the hope that understanding how DEPTOR works will lead to new strategies for therapeutically tuning mTORC1 activity. This study provides insights into the binding and inhibitory effects of DEPTOR on mTORC1. Solving a few technical questions will improve the work.

(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:

The authors have determined the atomic resolution cryo-EM structures of M. tuberculosis cytochrome bcc at 2.7 Å resolution and in complex with anti-tuberculous drugs Q203 at 2.7 Å and TB47 at 2.9 Å resolution. The Q203 compound is a drug candidate otherwise known as Telacebec with promising results in phase 2 clinical trials. The complex structure could pave the way for rational-based drug design.

(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 is an interesting synthesis of iterative model development and experimental work in an influenza model of infection in mice. The work is quite groundbreaking in the field as it is the first to use models to link dynamics of lung viral load, infected cells, inflammation, virus-specific CD8+ T cells, bystander CD8+ T cells, and disease status. The paper suggests that CD8+ T cells are vital for elimination of infected cells but can also contribute directly to lung damage and disease severity.

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 article presents molecular dynamics simulations of the pH-gated pentameric ion channel GLIC, which has been the subject of many structural and functional studies. GLIC can be considered as a model system for pentameric ligand-gated ion channels that are responsible for fast chemical-electrical communication between cells in animals. The findings include the solution of open- and closed-like channel forms, intermediates and a "pre-desensitised" state. The approach reproduces modulation by pH and mutation, surprisingly finding a predominance of closed channels, despite activating conditions, and suggest a role for asymmetry in channel gating. Overall, the sampling of channel dynamics is significant and the description of state interconversions sheds new light on pLGIC mechanisms.

(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.)