Evaluated articles

Evaluation Summary:

The authors have used two transgenic mouse models expressing dominant negative Cx43 mutants to evaluate the role of Cx43 hemichannels in mechanical loading response in bone. While understanding the molecular mechanisms by which osteocytes respond to mechanical strain is of interest in the skeletal biology arena, the conclusions of this study are not fully supported by experimental data and are of only incremental in nature.

(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 suggests that the neuronal circuit from the basal amygdala (BA) to the ventral hippocampus (VH) consists of both excitatory and inhibitory projections to specific targeted areas. The main message is that excitatory input specifically targets VH neurons that in turn project to the BA and nucleus accumbens (NA). In contrast, BA inhibitory input preferentially targets VH neurons that project to the BA to gate place-value associations. The reviewers agree that the manuscript reports potentially interesting data. However, they all agree that the claim made is preliminary and only partially sustained by the submitted experimental evidence.

(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 study of cortical regulation of behavior under conflict is novel, timely, and important. It is of broad interest to neuroscientists studying the neural substrates of fear and reward and offers a novel behavioural perspective showing how these opposing motivational states interact to influence behaviour differentially across individuals and how this is regulated by glutamatergic and GABAergic neurons in the prefrontal cortex. The paper uses a variety of cutting-edge tools to dissect the microcircuits of the prefrontal cortex. The claims are generally supported by the data, but some claims comparing individual differences require additional statistical analyses and consideration of potential alternative interpretations for the behavioral phenotypes observed.

(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 present MS describes an effort to create a general mathematical model of synaptic neurotransmission. The authors invested great efforts to create a complex model of the presynaptic mechanisms. This is an exceptionally challenging task and it falls short of a true general theory. Nonetheless, the model will be an important addition to an emerging field attempting to generate predictive models of complex neuronal biophysical processes, including synaptic transmission.

(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 work will be of interest to readers in the fields of cell biology, evolutionary biology, and biophysics. The collected data are of good quality and are properly analysed. The work thus convincingly demonstrates that energetic considerations (building costs versus potential benefit) must be taken into account to understand flagellar evolution.

(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 main protease of SARS-CoV-2 (Mpro) is a leading target for drug design due to its conserved and indispensable role in the life cycle. This study used cutting-edge molecular and statistical methods to generate a detailed genotype-phenotype map of this protein, also called a "fitness landscape." This fitness landscape is impressive in its detail and resolution and offers new insight that can be used to potentially generate new anti-viral drugs. This study was original in conception, precise in execution, and impressive in design. In sum, this constitutes a very meaningful addition to scientific literature.

(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 study was designed to examine the orphan ligand ActivinC. The authors show that ActivinC signals through ALK7. The data presented are strong and convincing. Indeed, the use of purified proteins for the interaction assays and in vivo analysis of adipocytes provide considerable rigor to the analysis. The work will be of interest to the areas of signal transduction and 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

Wayne Mitchell et al. report the study aimed to determine the structural features of cationic hydrophobic tetrapeptides in their cytoprotective efficacy. Detailed structural characterization of the peptides "free" in solution and bound to membranes is followed by their comparison in protecting cells from starvation-induced stress and the loss of viability. Overall, there are important and detailed observations regarding the peptide-membrane interactions, while their relevance to cytoprotection mechanisms in not demonstrated.

(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 study of previously unexplored roles of a cytoskeleton protein termed Septin-7 in muscle could be a significant contribution to understand muscle development and regeneration. The majority of the data support the importance of Septin-7 protein in muscle physiology. With some additional experiments and data analysis to strengthen the mechanistic characterization of Septin-7 in muscle physiology, this manuscript will be of broad interest to readers in the skeletal muscle research field.

(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 effective approach for targeting select subsets of enteroendocrine cells described here will be important for neuroscientists, endocrinologists, microbiologists, and other scientists studying nutritional biology. The study reveals new detail of how enteroendocrine cells signal through spinal and vagal sensory neurons to control immediate behavior and to guide learning about potential food sources. Overall, the approach is well thought out and the results are interesting and unexpected.

(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 uses the parlance and framing of the fitness landscape to articulate a co-evolution story between host and parasite. It utilizes a tractable system, bacteriophage λ and E. coli, to ask questions that unite different pillars of evolutionary theory - evolutionary genetics (via the fitness landscape analogy), co-evolution, and host-parasite interactions. The findings will be relevant to a number of audiences, and will likely spawn downstream studies that further interrogate the molecular specifics that underlie host-parasite co-evolution.

(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 develop a new technique allowing simultaneous imaging of hippocampal subfields in behaving mice. This paper will be of interest to the large number of neuroscientists who study the hippocampal circuit, and more broadly to those interested in methods to enable high-resolution in vivo imaging across depths in the brain.

(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:

Johnson and Desai previously reported "increasing cost epistasis", where mutations tended to have more deleterious effects in higher fitness backgrounds. Here they use the same system as before to investigate adapting populations by introducing a set of 91 mutations at multiple time points. As expected, the mean fitness effect of the mutations does decline in most (but not all) populations as they adapt but the effect is weaker than in the previous work, and in another condition, mean fitness effects of mutations do not change as the populations adapt. They suggest an intriguing interpretation (among others) that the "control coefficient" of selection on growth shifts between different genetic modules over 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 manuscript will be of interest to the broad class of biologists and especially mouse geneticists who study the function of protein-coding genes. The authors confirm the utility of the auxin-inducible degron tool to rapidly degrade the target protein of interest by developing genetically modified mouse models. This expands the set of tools to study gene function in a cell/tissue type, in adults (bypassing embryonic lethality) and also to more finely dissect the different functions of pleiotropic genes.

(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:

This study is of broad interest to neuroscientists interested in membrane excitability and translational biologists and physicians eager for robust animal models for disorders involving mutations in the KCNMA gene, such as paroxysmal nonkinesigenic dyskinesia PNKD3. Here, phenotypes of mouse models of three of the more common patient disease-related mutations in KCNMA are evaluated for similarities to patient phenotypes. This work establishes that BK channel mutations linked to human neurological disease can, on their own, cause similar pathology in mice, and it also begins to provide neurological bases for the associated behavioral deficits. Importantly, one of the mutant alleles expressed in mice most closely phenocopies the patient phenotype and will serve as an important animal model for studies seeking therapeutic treatments for the resulting debilitating disease moving forward.

(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 issue of general fitness effects in organisms expressing Cas9 enzymes as part of gene drive genetic control strategies is important, particularly in the emerging field of vector control. This manuscript reports experiments aimed at teasing apart such effects in a Drosophila model system, providing evidence that off-target effects predominate, which may be ameliorated by utilising high-fidelity nucleases, but a more detailed analysis of data and justification for some of the assumptions, especially some direct evidence of off-target cleavage, are still needed to support the authors' inferences. It is currently also not entirely clear how the lines were generated and tested. Finally, additional modelling to include scenarios where the initial frequency of the drive allele is very low (as would be the case for an actual release) would help to strengthen the conclusions.

(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 paper bears on cardiac pro-arrhythmic findings reported on Duchenne Muscular Dystrophy. iPSC-CMs reprogrammed from cardiomyopathic DMD patients showed a dysfunctional NaV1.5-Kir2.1 channelosome relatable to reduced cardiac excitability and conduction. These findings suggests a possible clinical rescue of this phenotype by introducing the scaffolding protein α1-syntrophin.

(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 observation that CHI3L1 has the potential to modulate SARS-CoV-2 variants is timely and of potentially great significance. This is a novel approach to treatment and if sufficient additional data can be provided regarding in vivo efficacy this would be of great interest.

(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 undertake a detailed investigation focused on how the abundance of the sole Cav2 Ca2+ channel Cac in Drosophila is regulated at active zones (AZs) using the larval neuromuscular junction (NMJ) as a model system. The larval NMJ is a particularly powerful system to address this question, and the authors have taken full advantage of the unique approaches available. This work makes important advances in our understanding of AZ Ca2+ channel regulation during development and will be of significant interest to the field.

(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 manuscript considers whether genetic information can improve the clinical utility of population norms derived from brain imaging data. The authors propose to incorporate polygenic scores into normative models of hippocampal volume to improve predictions of neurodegenerative disease. This approach is elegantly demonstrated in this manuscript and may be useful for clinical translation of population neuroimaging.

(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.)