1,356 Matching Annotations
  1. Oct 2022
    1. eLife assessment

      This is an exciting and important study that constitutes a major advance in the molecular understanding of resurgent Na current. Reproducing resurgent current by expression of two proteins has never been done. Here, the authors have for the first time molecularly reconstituted Na channels that produce resurgent Na current. Not only do these experiments satisfactorily and convincingly address a long-standing question in the field, but they also open the door to molecular manipulation of this current, potentially of significant practical use given the proposed role of the current in several disorders and disease states, including pain. The work will be of interest to many neuroscientists.

  2. Jun 2022
    1. 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.)

    1. Evaluation Summary:

      This paper presents an integrated algorithm, based on several standard techniques in infectious disease epidemiology, to estimate the real-time reproductive number and show how it has evolved in different countries during COVID-19. However, the analyses should be modelled in a more integrated fashion. Uncertainty estimation requires more work. And additional data streams should be incorporated to more reliably capture infection 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. The reviewers remained anonymous to the authors.)

    1. 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.)

  3. May 2022
    1. Evaluation Summary:

      Overall this study confirms that TNF-α is increased in peripheral blood B cells from PCOS and metformin decreased production. The study demonstrates the potential mechanism for the increase in TNF-α and reduction due to metformin. This is demonstrated in humans as well as in a mouse model of PCOS. Overall this is a well designed study demonstrating the impact of Metformin on immune function in PCOS.

      (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.)

    1. Evaluation Summary:

      This study uses a combination of conditional knockout mouse embryos with targeted deletion of Elp1 in neural crest cells and neuron-specific antibodies to identify the onset of neural defects associated with the trigeminal ganglion. This manuscript is of potential interest to developmental biologists studying neurodevelopment disorders and, with additional quantification and experimentation, is likely to provide important insights into the mechanisms underlying Familial Dysautonomia in the cranial sensory ganglia.

      (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.)

    1. Evaluation Summary:

      This paper is of broad interest to cellular biologists and immunologists. It offers new insights into how T cell compartments are regulated in vivo defining a new perspective on how the T cell compartment is regulated to maintain immune homeostasis and afford long-term immune protection. By assessing data from a range of mouse model systems, the key deduction is that a simple hypothesis, one which notably does not have complex feedback regulation of cell numbers, provides a remarkably good explanation 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. Reviewer #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      The chemical sensing mechanisms of plants, which are largely unknown, are a topic of broad interest. The authors hypothesise that plant chemical receptors may be transporter proteins or odorant binding proteins analogous to those found in animals. The authors have identified a list of plant proteins with possible odorant binding activity and they predict binding constants for relevant odorants. The calculated binding constants are generally very weak in comparison to known animal odorant binding proteins (i.e., would require much higher concentrations of odor for detection). The in silico investigation, while inspiring, leaves many open questions, for example whether or not there is evidence for functional analogy between plant and animal odorant binding proteins.

      (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.)

    1. Evaluation Summary:

      This paper will be of interest to scientists within community ecology. The authors present a mathematically solid analysis of how nonlinear constraints influence resource-competition models with trade-offs, with the conclusions being similar to those of previous studies in which trade-offs are not exact.

      (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.)

    1. Evaluation Summary:

      The chromatin mark, H3K27me, is deposited by the Polycomb complex PRC2 and is associated with repressed genes. There are two important findings in this paper: 1) that the promoters of some H3K27me-repressed genes are regulated by nucleosome positioning and 2) the H3K27me repressed genes are a diverse group that can be derepressed by different 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 #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This manuscript will be of interest to scientists working on learning and memory and synaptic plasticity. It provides a useful overview of different forms of plasticity taking place in the learning and memory center of the fly, the mushroom body. The study mostly uses an acetylcholine sensor to image activity, which is novel and helps to tie together previous studies reporting memory-induced changes in calcium transients. In particular, the study highlights the compartmentalised plasticity along Kenyon cell axon terminals, the main cell type of the mushroom body. The current version of the manuscript could be improved by including some key issues: (1) behavioral experiments for the Cac knock-down experiments, (2) specific controls for some of the imaging experiments, (3) consideration of the role of dopaminergic neurons and (4) acknowledgment of the complexity of the mushroom body circuit and the literature that has addressed this previously.

      (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.)

    1. Evaluation Summary:

      This study examined how mixture odors are represented in the mouse olfactory bulb. The authors found that compared to the responses in anesthetized mice, mixture responses are more linear in awake mice regardless whether the mice were engaged in a behavioral task or not. The results are potentially important as the results differ from previous studies which were done mostly in anesthetized animals, but the reviewers raised concerns for the validity and the strength of 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 #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      The study proposes that confined migration renders breast cancer cells resistant to apoptosis via NFkappaB-dependent mechanisms. The technical aspects of the study are impressive and experiments are very well performed and demonstrate the value of mimetic bioengineering approaches, but the postulated central premise would require more rigorous support.

      (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.)

    1. Evaluation Summary:

      Catsburg et al. provide a new descriptive characterization of clathrin structures in spines vs dendrites using an excellent knock-in approach they recently developed. These results carefully validate earlier findings using the CRISPR approach and constitute useful baseline information, which would be useful in examining changes in the zone induced by neuronal activity or synaptic plasticity.

      (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.)

    1. Evaluation Summary:

      Presented here is a study on the role of cation chloride cotransporter CCC1 as a key regulator of the plant Trans-Golgi/Early Endosome trafficking network. While the work is well controlled and presented overall, the reviewers judged the data supporting localization of CCC1 to TGN/EE as not being sufficiently clear, as was the role of CCC1 in endocytosis, which is one of the main conclusions. These points can be clarified with future careful 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.)

    1. Evaluation Summary:

      This manuscript will be of interest to readers in the field of anatomy and hippocampal physiology. The authors provide characterization of a novel projection pathway from layer 5a neurons in the MEC to CA1 of the hippocampus. They utilize cell specific viral labelling techniques, RNA-sequencing based projection mapping, and optogenetic aided in vitro physiology. The anatomical conclusions are well supported by the data. Future functional experiments will be necessary to establish the functional role of the projection.

      (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.)

    1. Evaluation Summary:

      The study provides evidence that PEN1 and SYP122 regulate defense structures against filamentous pathogen infection including papillae formation and encasement of haustoria; this appears to be an ancient defense mechanism in land plants. If the findings that PEN1 and its close homolog SYP122 play an overlapping role in pre- and post-invasive immunity against cell-wall penetrating filamentous pathogens could be further validated, this would advance our understanding of callosic papilla/encasement-based nonhost defense 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 #1 agreed to share their name with the authors.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. Evaluation Summary:

      Damaged chromatin displays an increase in nuclear mobility, but the importance of this response in homologous recombination (HR) repair is under debate. This study shows tight temporal coordination between HR repair events in budding yeast, where the increase in the mobility of repair sites follows resection and precedes chromosome pairing and gene conversion. With several elegant assays, the authors demonstrate that this temporal correlation remains intact in conditions that either delay resection or promote resection. This is consistent with the role of increased mobility in promoting chromosome pairing and HR progression, downstream from resection.

      (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.)

    1. Evaluation Summary:

      In this paper, the authors study distal tuft cells that are induced by influenza and bleomycinthe and find that Tuft cells originate from p63+ distal cells in virally-induced dysplastic regions of the lung as evidenced by lineage tracing. Interestingly, single cell sequencing reveals heterogeneity of tuft cells reminiscence of the murine tracheal tuft cells and supports a p63+ cell origin. They also found that the tuft cell induction is independent of the IL-25 and IL-4Ra pathway and since type 2 inflammation has been associated with tuft cell induction in the intestine, this suggests a different biology for the distal pulmonary tuft cells, although the inflammation-associated biology of the corresponding tracheal tuft cells has not been established. Somewhat surprisingly, tuft cell deficient mice do not develop abnormalities of alveolar regeneration following influenza and similarly, mucous metaplasia, which is associated with type 2 inflammation, was unchanged in the tuft cell deficient mice. Although the major findings of the study are negative, it provides important new information on these enigmatic cells.

      (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. This manuscript was co-submitted with: https://www.biorxiv.org/content/10.1101/2022.03.11.483948v1)

    1. Evaluation Summary:

      This study compares the roles of two interconnected dorsal pathway visual cortical areas, CIP and V3A, during perceptual decisions based on judging the tilt of 3D visual patterns. The potential impact of the paper stems from the novelty of directly comparing these two interconnected brain areas in perceptual decisions, and gives insight into their relative roles.

      (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.)

    1. Evaluation Summary:

      Punishment is key form of learning and behavior change, yet its core behavioral and brain mechanisms remain poorly understood and certainly less understood relative to reward learning. This manuscript uses dual fiber photometry to make an important advance in understanding how punishment is learned by studying how punishment changes action and punisher coding in the medial prefrontal cortex and ventral tegmental area of rats. The authors interpret the results as supporting a role for both areas in foraging in the face of risky outcomes. This work follows nicely on prior work and presents a straightforward and interesting experiment, using a validated anxiolytic to test what components of the neural response are related to this emotional component.

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

    1. Evaluation Summary:

      In this manuscript, the authors describe an inhibitory pathway from Purkinje cells in the cerebellum to a subset of molecular layer interneurons. The authors use in-vivo recordings to characterize these synaptic connections and probe their function during a delay conditioning task in vivo and using computer simulations. This is informative and an advance, but some claims regarding the function of this pathway need stronger substantiation. This is relevant to experimentalists and modelers interested in the cerebellum.

      (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.)

    1. Evaluation Summary:

      This paper seeks to expand our understanding of how spinally-projecting serotonergic neurons either inhibit or facilitate nociception depending on physiological context. Capitalizing on differential susceptibility to AAVretro transduction, the authors suggest identification of functional serotonergic subunits within the medullary raphe - one that includes innervation of the superficial dorsal horn and may modulate sensitivity to peripheral thermal stimuli, and another that includes innervation of a deeper lamina of the dorsal horn and may modulate sensitivity to mechanical von Frey stimulation. As well, the viral techniques and findings may inform the design and interpretation of work in 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.)

    1. Evaluation Summary:

      Sphingomyelin synthase 2 (SMS2) is a Golgi-localized enzyme that synthesizes sphingomyelin, a critical lipid in the plasma membrane, and mutations in SMS2 underly a rare genetic disorder of bone formation. This study shows that the disease mutations cause retention of SMS2 in the ER, which leads to sphingomyelin being produced in the wrong place and thus to a disrupted sphingomyelin and cholesterol gradient in the membranes of the secretory pathway. Additional experiments would improve the impact of this study in explaining the underlying reasons for some bone development disorders and providing cell biologists with new tools to manipulate lipids in cells.

      (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.)

    1. Evaluation Summary:

      The work is relevant to colleagues who study non-alcoholic fatty liver disease, the most common chronic disease in the world. It starts with steatosis (fat deposition) in the liver and progresses to very devastating stages of liver fibrosis. This study provides novel insight into mechanisms that result in liver inflammation and fibrosis and identifies a novel disease pathway, which is an attractive target for the treatment of liver fibrosis. The study can be improved, especially by refining the quality of microscopic images and techniques of protein chemistry.

      (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.)

    1. Evaluation Summary

      This work aims to fill an important theoretical gap regarding the role of potential threats to the self in altruistic/prosocial helping. Much of the prevailing knowledge about the motivations for prosocial behavior focuses on the distress of the conspecific-in-need. Leveraging animal research, the authors hypothesize that defensive neural circuitry may aid prosocial helping under threat. Further building on prior work detailing responses along the threat imminence continuum, the authors hypothesize that cognitive fear circuits would respond to more distal threats whereas reactive fear circuits would respond to imminent threats. In addition to examining helping behavior under conditions of threat to self, the authors included representational similarity analyses (RSA) to examine how overlapping representations of self and other distress related to helping behavior. The potential to challenge existing empathy accounts of prosocial helping is intriguing and worthy of interrogation.

      (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.)

    1. Evaluation Summary:

      This work presents in-depth epidemiologic and phylogenetic analyses of tuberculosis cases across Valencia, Spain and comparator low-burden (Oxfordshire, UK) and high-burden (Karonga, Malawi) regions. Findings reveal that the "low burden" observed in Valencia is not in fact reflective of low transmission in this setting, with detected lineages likely to have circulated locally over the course of decades and to have been transmitted in the 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 #1 and Reviewer #2 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This manuscript describes a specific role for CFAP61 - a known component of axonemal radial spokes - in formation and function of sperm flagella in the mouse, and identifies CFAP61 as a disease gene linked to male infertility in a human patient. Furthermore, the authors show that CFAP61 interacts with several radial spoke components, including head and stalk regions, as well as with intraflagellar transport proteins. Overall, the quality of the data is high and the mouse work is consistent with a previously published report. The study underscores the physiological importance of CFAP61 in male fertility and will be of interest to cell and structural biologist studying flagella and motile cilia function, as well as to clinicians involved in fertility genetics. The study can serve a starting point to revealing the precise mechanism by which CFAP61 regulates sperm flagella formation and function and for further analysis human patient 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. Reviewer #3 agreed to share their name with the authors.)

    1. Evaluation Summary:

      In this work, Petrov and Alexeyenko present a novel network-based method, NEADriver, aimed at the identification of mutational (point mutations and copy number variants) driver genes across tumors. The authors evaluate ten large cancer cohorts and assess the overlap of their results with established cancer genes or datasets that are enriched for cancer genes. This manuscript addresses a topic of high interest in the cancer genomics 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 #2 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This manuscript , which focuses on Streptococcus pyogenes M proteins and the antimicrobial peptide LL-37, will be of broad interest to individuals interested in host-pathogen interactions as well as protein-protein interactions.The manuscript provides both structural and functional insight in these areas, including new understanding of how coiled coil proteins can participate in protein-protein interactions and potentially inspiring protein designers and synthetic biologists to design mimetic systems that exploit the principles described here.

      (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.)

    1. Evaluation Summary:

      This study is of relevance to the field of DNA replication, describing how an ATPase known as a 'clamp loader' opens a ring-shaped clamp protein and binds DNA to promote the deposition of the clamp around a nucleic acid duplex to support chromosomal replication. The findings on how different regions of the clamp loader bind to and open a clamp, and how the enzyme engages single-stranded and double-stranded regions of target DNAs provide new insights that further our understanding of the clamp loading reaction. It is intriguing that the clamp loader melts the end of the DNA duplex, an activity that had not been observed before or predicted.

      (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.)

    1. Evaluation Summary: 

      LabNet is a C++ package for low-level networked control of hardware on the Raspberry Pi with two main goals: time-critical operations and ease of extensibility, both topics of great interest to experimental neurobiologists. While the authors do present some interesting benchmarks supporting the real-time performance of LabNet, there are important confounding factors that should be addressed in the interpretation of the results. There is surprisingly little mention on how easy the platform is to extend, but with future improvements in documentation, more examples, and hardware support, LabNet is likely to become a very useful tool for experimentalists who need low-latency control for behavioral experiments over the network. 

      (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.)

    1. Evaluation Summary: 

      Drug resistance in a problem in the control of many infections, including Mycobacterium tuberculosis. In mycobacteria, an error prone DNA polymerase facilitates DNA damage induced mutagenesis to increase the rate of generation of drug resistant strains. The previously identified mutasome components ImuA', ImuB, and DnaE2 and essential for DNA-damage induced mutagenesis. In this manuscript, the authors test their previously proposed model that ImuB interacts with the DnaN DNA polymerase III β clamp to recruit DnaE2. This is of interest to a broad audience interested in microbiology, antibiotic resistance, and genome stability. 

      (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.)

    1. Evaluation Summary: 

      The key contribution of this paper is to measure frailty longitudinally in mice and humans to model 'robustness' (the ability to resist damage) and 'resilience' (the ability to recover from damage). To model these concepts, a frailty index (FI) composed of multiple binary parameters is calculated, but with the novel contribution that newly detected changes represent damage and that the parameters that have previously been detected but are not detected currently represent damage repair. Statistical steps then derive resilience and robustness and their changes over time. The sophisticated attempts to effectively model longitudinal data and rigorous analytic approach are strengths, as is the use of both human and animal species and intervention studies. A few overarching concerns were raised, primarily pertaining to the potential risk of over-conceptualized links between deficit index and biologic constructs of 'damage' and 'repair', but it nonetheless advances a growing field interested in measuring the longitudinal change in biologic age. 

      (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.)

    1. Evaluation Summary: 

      The manuscript identified m6A RNA methylation (via increased m6A writer, Mettl3 expression) as a critical regulator of cardiomyocyte proliferation during the initial regenerative window that was proposed earlier in the mouse heart. The authors have comprehensively profiled Mettl3 expression and Mettl3-dependent m6A regulation during cardiac regeneration using a variety of in vivo models as well as using in vitro primary cardiomyocytes to identify Fgf16 as a key downstream mRNA transcript for m6A RNA modification by Mettl3. Furthermore, they show that m6A-dependent cytoplasmic decay of Fgf16 mRNA in a Ythdf2-dependent pathway is the key underlying mechanism regulating cardiac regeneration in these models. In sum, a well-designed study with new data that shows suppression of a developmentally induced phenomenon as a therapeutic option for inducing cardiac proliferation. 

      (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.)

    1. Evaluation Summary: 

      The authors report that discoidin domain receptor 2 (DDR2), a non-integrin collagen receptor, is required in Gli1+ cells for the development of the craniofacial skeleton. It is known that mutations in DDR2 are associated with craniofacial abnormalities, such as midface hypoplasia and open fontanels. This paper is of potential interest to craniofacial skeletal developmental researchers. While the data quality is high, the paper helps to confirm what has been recently published by the same authors. 

      (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.)

    1. Evaluation Summary:

      This manuscript reports the first full-length structure of membrane-bound adenylyl cyclase from the pathogen Mycobacterium tuberculosis. The structure provides insights into its potential mechanism of action and reveals similarities to its mammalian counterpart. Thus, this paper is of potential interest to a broad audience including the fields of infectious diseases, signaling, and evolutionary biologists.

      (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.)

    1. Evaluation Summary:

      This randomized clinical trial is based on 8,998 participants from the U.S. and the U.K. to examine the association between risk-framing nudges and the willingness to get a Covid vaccine. This manuscript would be of interest to behavioral scientists, particularly behavioral economists. Findings from this work reveal that (1) nudging can substantially increase the likelihood of Covid vaccination; (2) using different nudging frames matters and may produce different 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. Reviewer #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This study identifies two distinct nuclear export elements and a strong cytoplasmic anchoring sequence that restrict transcription factor GDOWN1 to the cytoplasm in normal conditions. The authors identify stress conditions that override this normal control to promote GDOWN1 nuclear localization as part of a protective response. This study will be of interest to the transcriptional regulation 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. The reviewers remained anonymous to the authors.)

    1. Evaluation Summary:

      This paper will be of interest to neuroscientists who study navigation and multisensory integration. In it, the authors use several manipulations to convincingly show that hawkmoths use mechanosensory feedback from their antennae to stabilize their head when their body rotates quickly or when they have little visual input. The results are consistent with the hypothesis that control of head angle in insects that lack halteres results from a multimodal feedback loop that integrates visual and antennal mechanosensory feedback. This advances our understanding of how such stabilizing reflexes work beyond Dipteran flies, where much prior work has focused.

      (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.)

    1. Evaluation Summary:

      This paper contributes to the growing body of literature that investigates foraging in complex landscapes. It is therefore of interest to neuroscientists and ecologists. The paper effectively combines behavioral experiments with phenomenological modeling to investigate which navigational strategies are responsive to the type and distribution of food patches. The main experimental results pertaining to food strategy are well supported, with secondary results limited by the low sample sizes.

      (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.)

    1. Evaluation Summary:

      This study reveals the importance of sphingolipids in endothelial cell biology. The authors have examined the role of the Sptlc1 gene in retinal injury as well as in the production of sphingolipid metabolites. These studies provide key insight into how endothelial cell production of sphingolipids alters vascular repair and systemic 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. Reviewer #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This paper will be of interest to the pharmacology community with interest in available drug treatments for osteoporosis and how to optimize these. The key findings of the paper are based on in silico results and indicate that combined drug treatments may be more efficient in treatment of osteoporosis. This could have a significant impact on clinical management of osteoporosis patients.

      (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.)

    1. Evaluation Summary

      The authors comprehensively assess the measurement properties of behavioral (skin conductance and ratings) and fMRI measures of fear conditioning (acquisition and extinction) in a sample of 107 participants, with 71 providing retest measures at 6 months. Retest reliability was generally low, whereas internal-consistency reliability was generally high. At the group level, reliability and criterion validity were generally good. Most measurements proved sensitive to modality, processing, or statistical decisions. Results are framed within a larger discussion of the role of measurement properties in individual difference research and clinical translation and will serve as an important building block towards improvement in both these areas.

      (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.)

    1. Evaluation Summary:

      The paper presents evidence that a genetic variant in the BIRC6 gene increases the risk of invasive bacterial infection. This paper will be of interest to researchers working in areas relating to invasive bacterial infections, malaria, sepsis, and immunogenetics. While this paper presents a hypothesis for the mechanism through which the risk variant acts, larger samples carrying the variant that increases risk, only present in African populations, are needed to further investigate potential 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 #1 and Reviewer #3 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This is a comprehensive, in vivo study of motile cilia dynamics, organisation and coordination in the larval zebrafish nose. The authors used a combination of highly quantitative imaging methods and transgenics to visualise the properties of multiciliated cells in this model organism - with particular emphasis on measuring the spatiotemporal coherence and organisation of cilia across the organ, and on the discovery of large-scale metachronal waves. With the aid of a computational model, the authors also explored the implications of metachronal ciliary action for fluid pumping.

      (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.)

    1. Evaluation Summary:

      Staphylococcus epidermidis is a commensal that colonizes corneocytes of humans and other mammals. Colonization is crucial for many aspects of health including the development of our immune system and protection against invading pathogens. Embp is a long protein encoded by S. epidermidis on the cell surface that coats implanted foreign devices and host fibronectin, but this study shows that Embp does not bind to fibronectin in its soluble form, instead requiring surface binding to expose other epitopes to bind host fibronectin. This study uses atomic force microscopy to demonstrate these specific molecular interactions and their likely relevance to host-microbe interactions with prospects for pharmaceutical interventions.

      (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.)

    1. Evaluation Summary:

      Hoedjes et al. examine how a single nucleotide variant in a regulatory region upstream of the Eip75B gene influences key aspects of life history in Drosophila, using RNAi knockdowns, inbred lines and CRISPR/Cas9 allele replacement at the endogenous locus. This study represents one of the very few examples in animals where the effect of a naturally segregating single nucleotide variant on a complex trait is carefully quantified.

      (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.)

    1. Evaluation Summary:

      This study applies a new novel method of single cell detection to biologically relevant systems to try to understand whether glycans on the surface of CD4+T cells impact HIV susceptibility. They find that cells expressing higher levels of fucose and sialic acid are more likely to be infected with to HIV than those with low levels. The findings point to glycans as a biomarker and potential determinant for HIV cells susceptibility and open the door to new avenues for studies the interplay between cell surface glycans and viral infections.

      (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.)

    1. Evaluation Summary:

      This project has substantial potential for better explaining the physiological basis of how to best use electrical stimulation on the cortical surface to modulate the hippocampal memory system. This would be an important task translationally and practically because it could lead to methods for modulating activity in deep brain structures noninvasively. However, in its current form the paper has weaknesses that make the results hard to trust and interpret. In its current form, it is not clear if the data clearly support the paper's strong 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 and Reviewer #3 agreed to share their name with the authors.)

    1. Evaluation Summary:

      The authors made an important extension of the canonical Hippo pathway by showing that nuclear phosphorylation of the pathway components YAP/TAZ contributes to the shuttling between different cellular compartments. The conclusions are well supported by the experimental evidence under both physiological and tissue-damaging conditions. Given the importance and developmental conserveness of the Hippo pathway, the work is of broad interest to the field of developmental and regenerative biology.

      (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.)

    1. Evaluation Summary:

      This paper will be of interest to neuroscientists, learning theorists and clinicians concerned with factors influencing threat-related response selection relevant to fear vs. panic. The manuscript describes a group of well designed experiments that investigate whether flight-like behaviors reported by other investigators require associative learning in order to occur. The authors demonstrate that non-associative influences can produce strong flight behaviors, but the dataset presented does not eliminate the possibility that associative influences can drive these responses, as well.

      (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.)

    1. Evaluation Summary:

      Zhang et al use evolution-guided mathematical models to guide the timing and dosing of arbiterone treatment in castrate-resistant prostate cancer. While the sample size is limited, the implications of the study outcome are broad and compelling, and the paper importantly highlights the transformative potential of deeply interdisciplinary research.

      (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.)

    1. Evaluation Summary:

      This study addresses the effect of brassinosteroid hormones on acidification of the apoplast. The authors characterize a novel ionic channel involved in this process as well as a gradient of H+-ATPase activity, providing evidence for a fast brassinosteroid response that has so far received little attention. A combination of computational modeling and quantitative cell physiology is used to explain the regulation of proton pumping into Arabidopsis root cell walls. The authors show that regulation of AHA proton pump activity by the activated brassinosteroid receptor complex could potentially explain the experimentally determined zonation of root cell wall pH and growth. The work will be of interest to plant biologists as well as cell biologists in general.

      (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.)

    1. Evaluation Summary:

      This paper describes an approach in which a non-replicating influenza virus expressing a cancer testis antigen is used to induce a systemic and mucosal antigen specific T cell responses. The authors find that this immune response is sufficient to reduce tumor burden following intravenous or subcutaneous tumor challenge. This paper is potentially interesting to tumor-immunity researchers.

      (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.)

    1. Evaluation Summary:

      The work presented herein presents a novel method to characterize hippocampal-cortical anatomical network connectivity. These important results have the potential to generate new hypotheses and influence future queries into the hippocampal-cortical system.

      (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.)

    1. Evaluation Summary:

      This paper identifies a new adaptation phenomenon in the cortical representation of sound that could explain invariance of auditory perception to reverberations of sounds in the environment.

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

    1. Evaluation Summary: 

      This study investigates on how weight loss by bariatric surgery or weight-matched dietary intervention impairs breast cancer growth as well as immunotherapy. This study can potentially provide some therapeutic intervention strategies on combining vertical sleeve gastrectomy and immunotherapy in treating breast cancer. 

      (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.)

    1. Evaluation Summary:

      This paper will be of interest to researchers in the autophagy field. It provides a useful tool to accurately measure autophagy flux, providing a useful alternative to the existing assay. The key claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous.

      (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.)

    1. Evaluation Summary:

      The authors reconstructed the axons of gustatory receptor neurons from the labellum in an EM volume of a whole adult Drosophila brain. The authors were able to correlate the EM data with light microscopic data in terms of the identity of neurons reconstructed, thus enabling the use of published functional data already available in terms of different taste modalities. This revealed that extensive synaptic connections are found between neurons of the same modality. This paper will be of interest to neuroscientists working in the field of circuits and behavior, especially feeding behavior.

      (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.)

    1. Evaluation Summary

      This paper is of interest to neuroscientists studying sleep, memory, and neurodegeneration. The authors found that an altered pattern of brain wave during NREM sleep, changes in the coupling of spindles and slow waves, correlates with amyloid burden and predicts memory decline over time in healthy older individuals. The results suggest that sleep brain waves may be a useful tool in identifying older adults at risk for future cognitive impairment in the earliest stage.

      (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.)

    1. Evaluation Summary:

      The authors shed light on the role that non-cancer stem cell exerts in promoting cancer progression, revealing that non-cancer stem cell-secreted fibromodulin is crucial in mediating angiogenesis in glioma via integrin-dependent Notch signaling. The logic is smooth and clear and the results are solid, and the findings should be interesting for those who are expertized in the field of cancer biology and cancer stem cell.

      (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.)

    1. Evaluation Summary:

      This manuscript is of interest for researchers in the field of mitochondrial genome stability and mitochondrial genetic diseases. The authors show that endonuclease G preferentially binds to mitochondrial genome regions which have a potential for forming G4 tetraplexes, inducing DNA breaks that may lead to a common 9 bp deletion in the mitochondrial genome by microhomology-mediated endjoining.

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

    1. Evaluation Summary:

      This study used valuable materials from five osteichthyan vertebrate species and investigated their lung morphology in them. The comparison of the observations suggest an origin of the lung as an unpaired organ, with the present-day paired forms in amniotes being a result of secondary modification. The sound morphological comparison presented provides valuable insight into the evolution of the lung. The work will be of interest to colleagues studying vertebrate 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 and Reviewer #3 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This study offers a comprehensive examination of Staphylococcus aureus evolution during infection. This manuscript will be of broad interest to readers in the field of microbiology and infectious disease. It provides a useful analysis of a comprehensive set of genetic signatures of bacterial adaptation. A combination of multiple layers of genome annotation and point mutation variant detection compellingly supports the correlation of infection outcomes with adaptation signatures in S. aureus.

      (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.)

    1. Evaluation Summary:

      This study investigates hippocampal dynamics over the course of early postnatal development with respect to spontaneous movements. Pioneering in vivo imaging in the hippocampus of neonatal mice, the authors find evidence for an abrupt developmental transition in this neural activity at the end of the first postnatal week in rodents and contribute to the understanding of how cognitive functions could emerge from the immature 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 #3 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This work builds on rapidly accumulating evidence for the importance of measuring and accounting for behavior in neural data, and will be of interest to a broad neuroscience audience. Analyses of Allen Brain Atlas datasets show that sensory representations change and match up reliably with behavioral state. The manuscript's main conclusions are supported by the data and analyses and the work raises important questions about previous accounts of the sources of representational drift in sensory areas of 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 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This study addresses an interesting question in lung regeneration following viral injury. The authors describe the ectopic differentiation of tuft cells that were derived from lineage-tagged p63+ cells post influenza virus infection. These tuft cells do not appear to proliferate or give rise to other lineages. Importantly, they demonstrate that depletion of tuft cells caused by genetic deletion of Pou2f3 in p63+ cells has no effect on the expansion or resolution of Krt5+ pods after infection, implying that tuft cells play no functional role in this process.

      (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.)

    1. Evaluation Summary:

      The premise behind this manuscript is timely and of interest to a broad scientific community working in the field of microbial recycling of cellulosic biomass. It provides a useful link between the occurrence and molecular aspects of the bacterial 'machinery' named cellulosome, and physiological traits of the same bacteria when grown on micro-crystalline cellulose. The key claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous.

      (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.)

    1. Evaluation Summary:

      This excellent paper presents the highly interesting finding of a compound that inhibits two targets in lysine synthesis. Further, the mechanisms for the first enzyme is allosteric inhibition, while for the second enzyme the compound is a competitive inhibitor. The authors nicely explain why this is of significant interest for herbicide resistance management with a new compound. The authors convincingly demonstrate that the compound is not a pro-herbicide, and instead that the higher in vivo relative to in vitro activity is due to the additional inhibition of the second step in lysine synthesis. The work is of interest to those studying enzymology, herbicide action and evolution of herbicide resistance.

      (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.)

    1. Evaluation Summary:

      This work extends our understanding of the ATAD1 family of AAA proteins responsible for extracting tail-anchored (TA) proteins mistargeted to the mitochondria. The conclusions of this work are largely consistent to prior structural studies from the same group, but provide clarifications of specific details that will be of interest to those working on these important proteins.

      (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.)

    1. Evaluation Summary:

      This manuscript describing GENESPACE was found to be of high interest for the genomics community across many different fields. GENESPACE is a new and straightforward computational tool to include synteny information in the calculation of genome-wide sets of orthologs. This is very timely as more and more chromosome-scale assembled genomes are becoming available.

      (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.)

    1. Evaluation Summary:

      The paper will be of great interest to scientists looking for new approaches to understanding group behavior, especially within the fields of human cognition, neurosciences, and musicology. Taking joint drumming as a model of collective dynamics, and combining several quantitative methods, the authors characterize how human behavior changes, at the individual- and group-level, as a function of group numerosity. An important take home message of this work is that not everything we know from studies involving dyads should be necessarily generalized to larger groups.

      (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.)

    1. Evaluation Summary:

      The study provides evidence that specific transcriptional responses may underpin the observation that metabolic rates often scale inversely with body mass. The conclusions are supported by direct measurement of metabolic fluxes in mouse and rat livers, although generalizations to other settings remain to be rigorously tested. The study has broad implications for researching and studying animal metabolism and physiology.

      (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.)

    1. Evaluation Summary:

      This manuscript describes an extensive molecular and cellular analysis of spermatogenesis in male mice in the absence of splicing factor Srsf10; a factor known to be involved in alternative splicing. Loss of Srf10 did not prevent formation of spermatogonia in testes, but did inhibit spermatogonia from entering meiosis and producing meiotic spermatocytes. These results should be of interest to molecular, developmental, and reproductive biologists. However, the conclusions require additional experimental support and the molecular basis of the observations need to be more clearly defined.

      (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.)

    1. Evaluation Summary:

      This manuscript is of interest to cognitive neuroscientists working on topics broadly related to memory, event segmentation and mental context. It presents an interesting set of new analyses related to internally versus externally driven changes in mental context. The idea is innovative and the analyses and methods are thoughtful and rigorous. There are some concerns about the degree to which the interpretations are supported by the data, but they could potentially be resolved with additional control analyses.

      (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.)

    1. Evaluation Summary:

      The DISCO-interacting protein 2 (DIP2) family consists of poorly characterized proteins linked to lipid metabolism, with a previously unclear role in cell physiology. DIP2 proteins contain putative fatty acyl-AMP ligase domains (FAALs), which are thought to influence fatty acid activation and attachment to various metabolites. Here, the authors analyze the role of budding yeast ScDIP2, and propose that it regulates a specific sub-pool of diacylglycerol (DAG) lipids and their conversion into storage triglycerides. While the exact molecular mechanism is not clear yet, this study will be of interest to cell biologists interested in lipids, metabolism, and ER stress.

      (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.)

    1. Evaluation Summary:

      Mitra et al. developed an analysis framework using large-scale pan-cancer omics datasets to discover the roles of 30 long non-coding RNAs (lncRNAs) in cancer proliferation and growth. Direct function-testing experiments were also performed to validate the biological mechanisms of two lncRNAs. The analysis framework developed here can serve as a resource to study the functions of lncRNA in cancer, and the computational framework can also be further extended to study cancer-relevant transcriptional and post-transcriptional regulation.

      (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.)

    1. Evaluation Summary:

      This study explores autolysis regulation in the gram positive pathogen Streptococcus Pneumoniae and finds that the turnover of wall teichoic acids at the septum controls cell elongation. Specifically, a possible new enzyme WhyD regulates the level of wall teichoic acids (WTA) at the bacterial septum, limiting the number of WTA-associated autolysins such as LytA at division sites. The study provides new insights into the molecular interactions between enzymes that regulate PG-associated polymers and enzymes that hydrolyze to regulate cell morphogenesis. In principle, such regulation will also apply to other monoderm bacteria. This article will be of interest to microbiologists who are studying bacterial cell envelope dynamics. The experimental data support the conclusions drawn and the work provides tools, concepts and remaining questions to address that will be instrumental to understand the mechanism underpinning autolytic 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 #2 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This is a paper that will be of broad interest to cognitive scientists, cognitive neuroscientists and speech pathologists who study language disorders. They apply a new structural neuro-imaging technique - multi-parameter mapping (MPM) to a very large sample of children with and without developmental language disorders. MPM allows them to identify localized structural differences (particularly myelin) that cannot be observed with other techniques. It offers convincing evidence that differences in a range of neural structures--including theoretically motivated left hemisphere language areas, and procedural learning--can be linked to variation in language ability.

      (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.)

    1. Evaluation Summary:

      The wrinkling of growing biofilms is considered in this paper experimentally in a clever set of experiments in a microfluidic setup that reveals aspects of the onset of the wrinkling instability and the formation of hollow channels within which bacteria move. Variations in the adhesive properties of the underlying surface are shown to affect the instability. While the results will surely be of interest to researchers in a range of areas, the connection with theoretical results needs further development.

      (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.)

    1. Evaluation Summary:

      In this paper, the authors presented the joint efforts from nine modeling teams to provide six-month projection of the COVID-19 pandemic across the US, in view of the circulation of the more transmissible Delta variant. All of the nine models projected substantial Fall resurgences based on data as of 3 July 2021, but the actual resurgence scale as of 31 July 2021 had exceeded the projections of all of the nine models. This suggests that transmission may be even higher than expected given model assumptions, and that forecasts beyond more than a few weeks are likely to be highly uncertain. This paper will be of high interest to public health specialists, forecast modelers, and members of the general public interested in the evolution of the COVID-19 pandemic and the impact of public health interventions in the USA.

      (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.)

    1. Evaluation Summary:

      In this manuscript, the authors use zebrafish histological staining, lineage tracing, enhancer transgenes, and mutants to find evidence for the gill origin of the vertebrate jaws hypothesis. This study nicely integrates into the literature on the origins of the mandibular jaw including discussion of fossil evidence and work in chondrichthyans and tests the hypotheses that the pseudobranch is derived from the mandibular arch, and that the pseudobranch is a segmental homolog of the gills. This paper will be impactful to the field of developmental biology both because the fate mapping methods used are generally applicable to a range of other lineage questions and because evidence for a gill arch origin of the jaw is an important contribution to vertebrate evolutionary biology.

      (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.)

    1. Evaluation Summary:

      This is an interesting study addressing an overlooked feature of morphogen gradient interpretation. By studying transcriptional activation of early zygotic genes during early Drosophila development the authors' findings suggest that morphogens, which are known to pattern tissues in distinct domain of gene expression, can also induce a graded transcriptional response within these domains.

      (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.)

    1. Evaluation Summary:

      By theoretically analysing the energy of a confluent epithelial tissue, the authors unveil the reason for nearly universal shape fluctuations that have been reported earlier. With a better justification of some of the underlying approximations used by the authors, the manuscript would be relevant for all people with an interest in tissue structure and 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 #2 agreed to share their name with the authors.)

    1. Evaluation Summary:

      The authors leverage theory, simulations, and empirical population genomics to evaluate what are the consequences of differences in substitution rates in hybridizing species. This is a largely overlooked phenomenon. This study highlights the issue and demonstrates that two hybridizing species of Papilio have differences in their substitution rates. The work will be of interest to a large group of evolutionary biologists, especially those studying evolution at the whole-genome level.

      (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.)

    1. Evaluation Summary:

      The importance of extracellular matrix (ECM) in multicellular organization has been studied in many different contexts. This study investigates the role of the ECM in the formation of the very first cell types to form in a mammalian embryo. The authors find that it may help stabilize the cell fate of early inside cells and play a role in promoting the epithelial organization of the next cell type to form within the inner cell mass. With appropriate extended experimental analysis, this study could be of interest to the specialist mammalian development 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. The reviewers remained anonymous to the authors.)

    1. Evaluation Summary:

      The authors present an impressive view of introgression across the Drosophila clade. There is strong support for signals of introgression along numerous branches of the phylogeny. However, the placement of these introgression events on the phylogeny and their impact on genome-wide patterns of relatedness are less clear.

      (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.)

    1. Evaluation Summary:

      This manuscript is of interest to neuroscientists conducting reward learning and basal ganglia research. It combines optogenetics and dopamine recordings to demonstrate that dopamine release in the dorsal striatum is smaller following self-stimulation than unpredicted stimulation of dopamine neurons. These results build on similar findings recently shown for the ventral striatum. Further development of the underlying mechanism or the behavioral significance would broaden the scope of the paper.

      (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.)

    1. Evaluation Summary:

      Basic epidemiological parameters such as the force of infection (rate at which susceptible individuals acquire the infection) remain undetermined for human infection with the neglected food-borne zoonotic cestode Taenia solium, which may cause taeniasis and cysticercosis. Dixon and colleagues address this major gap by fitting simple mathematical models to datasets that describe the prevalence of taeniasis and cysticercosis in several countries. Importantly, they found that infection acquisition rates per year vary widely (up to two orders of magnitude) across endemic settings and provide an approach for mapping the global public health impact of taeniasis and cysticercosis.

      (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.)

    1. Evaluation Summary:

      The paper presents a Bayesian model framework for estimating individual perceptual uncertainty from continuous tracking data, taking into account motor variability, action cost, and possible misestimation of the generative dynamics. While the contribution is mostly technical, the analyses are well done and clearly explained. The paper provides therefore a didactic resource for students wishing to implement similar models on continuous action 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. Reviewer #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      The authors demonstrate that isoform-specific Dystonin-b (Dst-b) mutant mice show significant myopathy in skeletal and cardiac muscle at older ages without the peripheral neuropathy or post-natal lethality that are commonly observed by loss of function of the DST gene. The study provides novel information about the role of the Dst-b isoform in maintaining skeletal and cardiac muscle health. In addition, the study suggests that isoform-specific mutations in Dst-b gene may cause some hereditary skeletal and cardiac myopathies.

      (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.)

    1. Evaluation Summary: 

      This manuscript is of broad interest to geneticists and bone biologists because it describes a method to filter candidate genes, identified from GWAS, and pinpoint the gene that affects bone biology. This method identified a gene with a previously unknown role in bone biology and the authors showed that its loss reduces bone mineral density, supporting the key claims in the paper. 

      (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.)

    1. Evaluation Summary: 

      Glioblastoma is a challenging disease with a high level of heterogeneity. Here the authors use global methylation profiling of tumor-initiating cells and matched iNSCs and identify a subgroup of hypomethylated tumors with an astrocytic phenotype. Understanding heterogeneity in glioblastoma is a major challenge, and the identification of alterations of functional and clinical impact is of importance 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. The reviewers remained anonymous to the authors.)

    1. Evaluation Summary: 

      This manuscript is of interest to developmental and cell biologists exploring cilia dynamics and ciliopathies. The authors address the molecular mechanisms by which INPP5E, a phosphoinositide phosphatase essential for regulating cilia function, is targeted to the primary cilium of cultured mammalian cells. Using immunoprecipitation, ciliary localization, phosphatase activity assays in combination with structural modelling, the authors identify four motifs important for ciliary localization of INPP5E, and uncover several novel and important interactions with other ciliary proteins providing a likely mechanism for ciliary targeting. The claims are generally well supported by the data, but some additional data acquisition and analysis are required to fully support the authors' conclusions and provide a conceptual advance in 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 #1 and Reviewer #3 agreed to share their names with the authors.)

    1. Evaluation Summary:

      Hair cell activity has been postulated to underlie their vulnerability to environmental insult including toxin exposure. Previous work has been confounded by the fact that reducing mechanotransduction also reduces entry of toxic chemicals. Here Lukasz and colleagues test these ideas by examining the vulnerability of zebrafish mutants with impaired synaptic activity, thought to be a major driver of neuronal metabolic load.

      (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.)

    1. Evaluation Summary:

      The manuscript presents data that high expression of Protein Phosphatase 1 (PP1) inhibitor in triple-negative breast cancer contributes to poor outcomes by downregulation of an important kinase, GSK3β. The study clearly demonstrates that changes in PPP1R14C expression alter the behaviour of the studied cancer cells and mouse models and proposes a mechanism linking PP1 inhibitor to GSK3β. If this mechanism were substantiated, this would enhance our understanding of the pathophysiology of this important disease and might suggest new treatment options.

      (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.)

    1. Evaluation Summary:

      Caner/cancer metastasis-induced bone loss-mediated fracture is a serious clinical problem. In this regard the authors have done an interesting study to show how miR155 exhibits a catabolic effect on osteogenesis and bone mass phenotype via interaction with the Sphingosine 1-phosphate receptor-1 (S1PR1) gene. The study suggests that inhibition of miR155 could be a potential strategy for bone regeneration and bone defect healing.

      (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.)

    1. Evaluation Summary:

      This manuscript presents DATES, a method to infer the timing of admixture events using genetic data from present-day or ancient individuals. This is a robust method that is useful in the field of paleogenomics and outperforms existing methods. In this manuscript, DATES is applied to >1000 ancient human genomes to characterize major admixture events during the European Holocene. This work will be of interest to scholars in the fields of population genetics, paleogenomics, archeology, biological anthropology, and history.

      (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.)

    1. Evaluation Summary:

      This study explores the utility of cell free DNA analysis in non-malignant disease using epigenomic methods. By using brain specific methylation loci the authors identify higher levels of brain-related DNA in the plasma of patients with acute psychotic illness compared with non-disease controls. This paper will be of interest to readers in the field of liquid biopsy.

      (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.)

    1. Evaluation Summary:

      Lu et al. provide a new method that looks at whether disorders tend to share excess de novo mutations in genes across the genome. The authors apply the method to nine disorders including a developmental disorder, autism spectrum disorder, congenital heart disease, schizophrenia, and intellectual disability, finding statistically significant overlap between 12 pairs of disorders in de novo mutations that cause a loss of gene function. This method will be of interest to researchers working on disorders caused by de novo mutations, but further clarification of its strengths and weaknesses compared to alternative approaches (mTADA in particular) would strengthen the paper.

      (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.)

    1. Evaluation Summary:

      Transcriptional memory is a phenomenon via which certain genes are activated more robustly in response to repeated stimulation and in this manner, are able to "remember" previous experiences. This report dissects the molecular mechanism of inositol-driven transcriptional memory and highlights the key role of the histone mark H3K4 di-methylation, which is deposited independently from RNA Polymerase II activity. This memory-specific H3K4 di-methylation is found to be inherited over multiple cell divisions and to require specific transcription factors and chromatin machinery components to be established and maintained. The work will be of interest to those studying transcriptional regulation and epigenetics.

      (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.)

    1. Evaluation Summary:

      This important and exciting paper demonstrates that the blind cavefish, known for its lack of eyes and increased number of lateral line hair cells, also exhibit physiological adaptations to increase lateral line sensitivity. The authors demonstrate that these adaptations have convergently evolved in multiple populations that have independently colonized cave environments. By leveraging the numerous strengths of the cavefish model, the authors are able to show precisely how neural circuits can be affected by adaptation to the environment.

      (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.)

    1. Evaluation Summary:

      The process of secretory vesicle formation, transport, and fusion in yeast has mainly been characterized through biochemical and genetic means. Only limited information was available about the detailed timeline and order of events. This study fills the gap with a high-resolution temporal analysis, which provides new insights into when key components arrive and depart and how they promote vesicle tethering and fusion. The work is experimentally strong, and improvements to the presentation will ensure that the findings are communicated effectively.

      (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.)

    1. Evaluation Summary:

      This paper describes a microfluidic approach to determine the viscoelastic properties of living cells from their deformation in a fluid flow. Its implementation seems accessible and the method offers the possibility to perform measurements on a large number of cells. This technique could eventually be used in many laboratories, including those not specialized in cell mechanics.

      (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.)

    1. Evaluation Summary:

      The premise behind this manuscripts is that concepts from thermodynamics and statistical mechanics can be used to understand brain states and the transitions between such states, just like it is done with transitions between solid and liquid states in well define thermodynamic systems. While this is an interesting attempt to use thermodynamic concepts and equations to analyze fMRI signals, the legwork needed to meaningfully translate those concepts to understand their actual physiological meaning and their relationship to brain function has not yet been achieved.

      (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.)

    1. Evaluation Summary:

      The paper describes a re-analysis of a public fMRI data set which includes measures of resting state connectivity and separate task-based scans of memory encoding and memory retrieval tasks. The paper proposes an analysis method termed "information transfer" that reveals functional interactions between various brain networks during encoding and retrieval as well as differences in these interactions during encoding vs. retrieval. While the methods are potentially interesting, the payoff-or new insight afforded by these methods compared to existing methods-is not fully 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. The reviewers remained anonymous to the authors.”)

    1. Evaluation Summary:

      This paper provides a comprehensive co-mutation analysis of over 30 thousand cancer patients and 1700+ cancer cell lines to identify associations with prognosis and drug resistance that could have translational value for clinical practice. Once validated, it would provide a useful framework for precision oncology.

      “(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.”.)

    1. Evaluation Summary:

      This work provides an insightful analysis of how animals can use different types of sniffing to quickly find the sources of odorants in natural, often turbulent, environments. As it turns out, the air near the ground is less turbulent but does not provide high precision information about the location of sources that are far away. To get that kind of information, animals have to pause and sniff in the air. Authors show that the relative balance between sniffing near the ground and in the air shifts as the animals approach the source and that this shift matches optimal strategies that can be pursued based on partially observable statistical models of the environment. The paper also includes a very useful set of simulations of odorant flow in the presence of obstacles that will be made publicly available.

      (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.)

    1. Evaluation Summary:

      The manuscript studies the heterogeneity of megakaryocytes using single cell RNA-seq and identifies a subpopulation of CXCR4-high megakaryocytes with immune modulatory roles. The authors also perform functional studies which show that this subpopulation of megakaryocytes promotes bacterial phagocytosis by macrophages and neutrophils. This work would be of significant interest to researchers in the fields of immunology and host defense as well as researchers studying hematopoiesis and megakaryocyte biology because it provides new perspectives on megakaryocyte heterogeneity as well as the role of megakaryocytes in host defense and immune 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 agreed to share their name with the authors.)

    1. Evaluation Summary:

      The manuscript by Ferguson and Huguenard examined the mechanism underlying attentional deficits in the haploinsufficient Scn8a mouse model of absence epilepsy. Using a detection behavior paradigm where detection of the cue was dependent on the attention level, they show that Scn8a+/- mice perform worse than controls when cues are of intermediate duration. In the medial prefrontal cortex (mPFC), high gamma-band power, which is presumed to be mediated by activity in parvalbumin-positive (PV+) interneurons, was reduced in Scn8a+/- mice, but optogenetic stimulation of these neurons at low gamma-frequency normalized performance on the cue-based attention task. The results of this study identify mPFC PV dysfunction, rather than seizure activity, as a potentially important cellular substrate, for attention during cue-presentation.

      (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.)

    1. Evaluation Summary:

      This ms examines changes in brain region size in several groups of weakly electric fishes, the Mormyroidea, and the Gymnotiformes and weakly electric catfishes (Synodontis spp.), which evolved electroreception independently of mormyrids. These are an interesting group for examination of mosaic growth. Many analyses are thoughtful and well executed, but there is some concern about whether the observed volumetric decreases are a consequence of the method.

      (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.)

    1. Evaluation Summary:

      This paper is a cross-sectional assessment of the association between COVID-19 related stress and mental wellbeing and whether certain behaviors mediate this association. This work would be of interest to researchers, psychologists, and clinicians involved in the psychological impact of COVID-19. The strength of this work is two folds. First, this is an important and timely topic. The collection of primary data at four time points during the pandemic was innovative. Second, examining the mediatory effects of certain behaviors could shed light on ways to reduce pandemic-related stresses. Future work should address a few limitations, including the inherent biases of using social media as a recruitment strategy and the lack of generalizability.

      (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.)

    1. Evaluation Summary:

      This manuscript will be of strong interest to scientists studying the development of early jawed vertebrates, in particular the extent and structure of their dermal skeleton, but it will also interest a broader audience, given how it connects modern-day morphological techniques to paleobiology. The authors provide the most complete account to date of the body scales of an antiarch stem-group gnathostome; this is the first work to model in 3-D the entire scale cover of such a fossil fish. The authors show that the body scales are varied in form, regionalized and that they comprise two main tissue layers. Based on this they argue that these conditions are plesiomorphic for antiarchs and the gnathostome crown group.

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

    1. Evaluation Summary:

      The hypoxia inducible factor (Hif) pathway was defined based on its role in cellular adaptation to hypoxia. In this paper, the authors examine the function of the pathway under 'physiological' normoxia in highly aerobic locust flight muscle. They find that a muscle-specific variant, Hif-1alpha2, is induced extensively by flying. By integrating bioinformatic analyses, measurements of gene expression and regulation, metabolites as well as redox regulation and flight assays, it is shown that Hif-1alpha2 plays an important role in sustaining prolonged flight by promoting glucose oxidation and upregulating a reactive oxygen species quencher (DJ-1). This study demonstrates the physiological requirement for two Hif-1a variants in a highly aerobic tissue in migratory locusts, a species that is both physiologically fascinating and a major agricultural pest. The work will be of interest to colleagues studying the physiology of muscles and flight.

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

    1. Evaluation Summary:

      This is an interesting study describing the role of Samd14-capping protein (CP) complex in stress erythroid signaling. Using orthogonal cellular, biochemical and genetic complementation approaches, the authors provide evidence to establish a previously unrecognized mechanism for Samd14-CP interaction in regulating Kit signaling in erythroid regeneration in response to acute anemia. Findings of this work will be of broad interest to the study of erythropoiesis and cellular 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 #3 agreed to share their name with the authors.)

    1. Evaluation Summary

      This manuscript demonstrates that male mice lacking androglobin, a poorly understood heme-containing protein, are infertile and have defects in late stage spermatogenesis. A variety of molecular techniques were used to delineate the mechanism of spermatogenesis defect. A strength of the data is the identification of the androglobin interacting partner septin 10. With some clearer data on the mechanism underlying the connection between androglobin and septin, the paper will be of interest to researchers studying spermatogenesis.

      (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.)

    1. Evaluation Summary:

      This manuscript describes a female mosquito's behavior after a brief exposure to CO2, which has long been known to trigger host-seeking behaviour in female mosquitoes. The authors develop optogenetic tools in Aedes aegypti that enable the controlled delivery of 'fictive' CO2 to them. They show that a brief pulse of fictive CO2 alters the behavioral state of female mosquitoes, which lasts about 15 minutes. It provides new insights into how activation of CO2-sensing olfactory neurons alters the behavioral state of a mosquito towards sensory cues to increase host-seeking behaviors. The study will be of great value to the vector biology community, as well as to neurobiologists in general.

      (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.)

    1. Evaluation Summary:

      This manuscript explores the role of the central amygdala (CeA) on the mechanisms underlying chronic pain. An acid-induced muscle pain (AIMP) mouse model was used. The authors report a key pro-nociception role of CeA Somatostatin (SST) expressing neurons. The central sensitization of CeA-SST neurons was blocked by pregabalin. This work also further highlights the opposing view of the roles of CeA-SST neurons compared to CeA-PKCd neurons in modulating pain-related behaviors. This work will likely have a significant impact in the field and reconciles different previous 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. Reviewer #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      This manuscript provides new knowledge of one of the major molecules, claudin5, expected to maintain the integrity of the cell-cell contacts of the blood vessel wall. The results highlight organ and vessel-type specific significance of this mechanism in the regulation of vascular permeability, partially challenging the current view. A combination of in vivo microscopy and genetic mouse models is used to support the key claims in the paper. This manuscript will be of interest to scientists across vascular biology, and especially in the field of vascular permeability regulation.

      (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.)

    1. Evaluation Summary:

      This paper will be of interest to urban foresters, ecologists, and planners. It provides an urban tree dataset across US cities that can be used to address questions on urban biodiversity and ecosystem services. It contains clear descriptions about the data processing and structures in general, but would need further clarifications about the sample completeness and representativeness 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.)

    1. Evaluation Summary:

      The authors explored the relationship between amyloid-beta and tau deposition and neural oscillations in Alzheimer's disease (AD) by using a computational neural mass model that can generate neurophysiological power spectra comparable to EEG- or MEG-like, macroscopic brain activity assessments. This analysis demonstrates the different, frequency-specific effects of amyloid-beta and tau proteins on excitation and inhibition, providing an integrated, multimodal explanation of the AD pathogenesis.

      (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.)

    1. Evaluation Summary:

      This study is of interest to animal geneticists studying molecular breeding for infection resistance. The authors provide substantial new insight into the generation of a goat expressing domain fusion receptor TLR2-4, and clarify the mechanism to effectively eliminate S. aureus in macrophages from the gene-edited goat. Taken together, their findings suggest that TLR2-4 knock-in goats can serve as a good animal model for disease resistance breeding.

      (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.)

    1. Evaluation Summary:

      This manuscript is of interest to colleagues in immunity and signal transduction. Cytokines are small protein signaling molecules with a diverse range of activities in inflammation and immune system function. This manuscript reports the cryo-EM structure of the cytokine interleukin-27 (IL-27) bound to soluble domains of two receptor subunits, IL-27Rα and gp130. IL-27 is a composite cytokine consisting of the protein p28 bound to EBI3, which resembles soluble cytokine receptors such as the receptors for IL-6, IL-11 or CNTF. IL-27 signals predominantly via STAT1 and plays an important role in immune homeostasis. The data provide a detailed molecular view of how IL-27 binds to its receptor.

      (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.)

    1. Evaluation Summary:

      This paper presents a method to identify membrane proteins in native cell membranes based on a combination of single molecule AFM and an unsupervised clustering procedure to identify clusters of single-protein curves. This original approach represents a definitive step forward for AFM technology and methodology, which can generally only be used to characterize purified biomolecules of known identity. The work will be of interest to all students of membrane biology and especially membrane proteins.

      (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.)

    1. Evaluation Summary:

      This study measures the strength, timing, feature specificity and for the first time - spatial extent - of pre-saccadic processing of peripheral target information at the fovea, when fixation is not constrained. The authors conclude that saccade preparation causes feature-specific pre-saccadic visual enhancement restricted largely to the center of gaze. The manuscript is based on a rigorously curated dataset, it is well written and illustrated, and will be of potential interest to a broad readership of vision scientists, neuroscientists, and modelers. However, some key weaknesses in the interpretation of data were identified, which call into question the conclusion that the foveal enhancement observed can only be explained in terms of saccade preparation, thus weakening our ability to infer its mechanistic substrates.

      (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.)

    1. Evaluation Summary:

      The author present a large amount of sequencing data of EBV present in a variety of individuals, including a few with the interesting and unusual disease manifestation known as Chronic Active EBV (CAEV). The data show that there is a great deal of heterogeneity in the EBV genomes among people and overtime in some individuals, but the data do not reveal any particular mechanistic insights about the importance of this heterogeneity and the sample size is too small to warrant use of these deletions as therapeutic biomarkers.

      (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.)

    1. Evaluation Summary:

      Activation of NMDA receptors requires two co-agonists: Glutamate which binds to the GluN2 subunit and glycine/D-serine which binds to the GluN1 subunit. In the present manuscript, the authors address the interaction of D-serine, which is a less studied co-agonist than glycine, with the GluN1 and GluN2A subunits using molecular simulations as well as electrophysiology experiments. Surprisingly they find that D-serine interacts with the GluN2 subunit, further expanding our molecular understanding of NMDA receptor structure-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 names with the authors.)

    1. Evaluation Summary:

      The soluble membrane attack complex (sMAC) is generated from complement activation and contains the complement proteins C5b, C6, C7, C8, C9 together with the regulatory proteins clusterin and vitronectin. Despite intense interest in sMAC, the mechanisms regulating its formation remain poorly understood. In this manuscript the authors demonstrate that sMAC is formed when complement is activated on bacteria that are resistant to killing by MAC pores.

      (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.)

    1. Evaluation Summary:

      Lupkin and McGinty studied gaze patterns in monkeys during value-based decision-making to determine whether relationships between gaze and choices that have been described in humans are also present in monkeys. Although previous literature has interpreted the effects of gaze on choice behavior to mean that attention to an option influences the decision that is made, a full understanding of the mechanisms underlying these biases will ultimately require data from non-human primates, making this an important and timely study. The authors use a clever task design to show that, as in humans, value-based choices are related to the amount of time spent viewing each option. The study is well-designed and the topic is significant to the field, but reviewers raised concerns about potential confounds and limitations not addressed by the current analyses.

      (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.)

    1. Evaluation Summary:

      This work advances our understanding of the nuclear pore complex (NPC) biogenesis pathway by providing much needed additional insight into the function of one of the few NPC assembly factors, Brl1. It thus addresses a long-standing and fundamental question relevant to individuals interested in nuclear transport, nuclear cell biology, and membrane-protein interactions more generally.

      (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.)

    1. Evaluation Summary:

      This is a remarkably ambitious study that has been skilfully executed on a strong number of control participants, amputees, and one-handers. The complementarity of state-of-the-art uni- and multi-variate analyses are in the service of the research question, and the paper is clearly written. The main contribution of this paper, relative to previous studies, resides in the mapping of multiple face-part all at once in the three groups. The study suggests that the deprived hand cortical territory is not invaded by the facial cortical neighbor, the forehead, but instead by the lips that are more distant but functionally related to the hand as it can be used to compensate hand loss for manipulating objects.

      (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.)

    1. 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.)

    1. Evaluation Summary:

      The pathophysiology of Zika virus infection remains an area of high research interest. In this study, the authors use diverse experimental models to examine the potential role of Gas6 in Zika virus infection and associated neurological sequelae.

      (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.)

    1. Evaluation Summary: 

      This manuscript reveals the contribution of intrinsic excitability to the formation of cortical neuronal ensembles. By combining optogenetic and electrophysiological approaches in vitro, the authors provide new insight regarding the role that plasticity of membrane excitability (intrinsic plasticity) plays in synaptic plasticity and the formation of memories. 

      (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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

  4. Apr 2022
    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. 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.)

    1. Evaluation Summary:

      This study investigates oculomotor behavior of cortically-blind patients (with lesions in area V1) performing a saccade and ocular following response toward a cued moving target placed either in their intact or in their blind visual field. Whereas perceptual training led to a good recovery of perceptual performance in the blind field, the ocular following response did not appear to benefit from this training. The authors conclude that V1 lesions result in impaired transmission of signals selectively driving the ocular following response. The manuscript is based on a valuable patient dataset, well written and illustrated, and will be of potential interest to a broad readership of vision scientists, neuroscientists, and clinical neurologists. However, some major weaknesses in the analysis and interpretation of data call into question the conclusion that the selective eye movement deficit reveals a true perception-action dissociation.

      (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.)

    1. Evaluation Summary:

      This paper is of potential interest to psychologists and cognitive neuroscientists studying learning, decision-making, belief formation and metacognition. The authors use a clever, elegant task in which people make decisions with or without control over the information they sample, and link the cognitive processes at play to MEG and pupillometry signatures. The key finding is that when participants have control over information sampling (i.e. are seeking information), they need more contradictory evidence in order to switch their choices, and such switches are made with lower confidence. Anticipatory suppression of alpha-band activity in occipital and frontal regions occurred prior to decision switches, while pupil dilation increased post-switch. The authors propose a computational model to account for behavioral differences between conditions. However, some of the conclusions may not be fully supported by the data and alternative interpretations are possible; therefore further analyses are required to bolster the authors' claims.

      (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.)

    1. Evaluation Summary:

      In this study, Phillips et al. report the ancient role of Hippo signaling nuclear effector YAP/TAZ/Yorkie ortholog (coYki) in a unicellular organism Capsaspora owczarzaki. Two major advances of this work include development of genome editing in Capsaspora owczarzaki and characterization of a key gene coYki. The authors found that different from Yki's role in multicellular organisms, the coYki does not contribute to cell proliferation. Instead, it affects cell adhesion to extracellular matrix to ensure the spherical shape of the aggregates. Overall, the presentation of this manuscript is clear with a nice logical flow, and this study should be of interest to the evolutionary cell biology 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 #1 agreed to share their name with the authors.)

    1. Evaluation Summary:

      The mechanisms of TGF-beta signaling have been intensively investigated. In this study, the authors reveal a novel mechanism of TGF-beta regulation, which suggests a higher order of signaling complexity. With some stronger experimental support, the paper will be of interest to those studying signal transduction.

      (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.)

    1. Evaluation Summary:

      The results in this report are intriguing in providing evidence that differences in codon optimality in mRNAs can underlie tissue-specific differences in expression and that this phenomenon operates in restricting expression of an evolutionarily young endogenous genes to the testis versus ovaries in a manner important for female fertility in the fruit fly. The scientific quality of the work would be further enhanced by additional experiments to determine whether the differences in expression arise primarily at the translational level or also/rather involve altered mRNA turnover or transcription in response to poor codon usage outside of testis and 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 agreed to share their name with the authors.)

    1. Evaluation Summary: 

      This paper is of interest to readers in the fields of DNA repair, DNA-protein interactions and those employing single-molecule techniques. Using single-molecule methods, the authors discovered that RecX exerts its regulatory effect on the RecA filament through two modes of action: i) by promoting RecA dissociation from ssDNA, and ii) by causing a reversible conformational change of the filament. The latter mode of RecX action is novel and of particular interest. The authors present a plausible model of the RecX-RecA-ATP-ssDNA system that could be further validated in future experiments. 

      (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.)

    1. Evaluation Summary:

      This study is of great interest to a broad group of neuroscientists including those studying plasticity in the nervous system and in neurodevelopmental disorders such as autism. The current work illustrates the importance of protein phosphorylation in regulating a form of homeostatic plasticity known as synaptic scaling, which has been associated with different neurodevelopmental disorders. In particular, the authors provide compelling evidence that the phosphorylation state of one synaptic scaffolding protein, Shank 3, is a necessary part of a complex signaling pathway mediating synaptic scaling and thus could be therapeutically useful for certain associated disorders.

      (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.)

    1. Evaluation Summary:

      This study contributes to our understanding of how a diverse and increasing number of activating adaptors allow the dynein motor protein to move a wide range of intracellular cargoes. Here the authors identify a transmembrane protein called KASH5 as the activating adaptor required for dynein to move meiotic chromosomes, a process that facilitates homolog pairing. Overall, the work is well done and will be of interest to the cell biology, cytoskeletal, and meiosis research communities.

      (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.)

    1. Evaluation Summary:

      This work provides insight into how phospholipase C gamma (PLCγ1) becomes activated upon binding to phosphorylated receptor tyrosine kinase, with an analysis of PLC γ1 bound to the soluble kinase domain of FGFR1 (FGFR1K) and/or liposomes containing PIP2. The most interesting finding is that regions of the protein far from the FGFR1K binding site increase in exchange upon binding. This is new information for a large protein that is arguably difficult to study, but it conforms to what has been observed in many other autoinhibited systems with similar SH2 and SH3 domains such as kinases. The results will be of interest to structural biologists and cell biologists with interest in the mechanisms leading to the regulation of phospholipase C activity on membranes.

      (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.)

    1. Evaluation Summary:

      This study uses a large dataset on alcohol misuse in adolescents that have been followed up for several years. MRI data are used to test whether the structure and connectivity of the brains of adolescents can predict their alcohol misuse later in their early twenties. The results show that binge drinking can be predicted out of multiple brain phenotypes with a good accuracy, even after control for many confound variables. This study can be impactful as it suggests a reevaluation of studies of the effect of alcohol on the adolescent 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. The reviewers remained anonymous to the authors.)

    1. Evaluation Summary:

      This study uses both humans and rats to demonstrate that the level of glutathione in the nucleus accumbens correlates with effortful behaviors. The authors provide causal evidence for glutathione in rats by manipulating enzymes involved in the synthesis of glutathione. Although how exactly glutathione regulates effort-related behavior remains to be clarified, overall, the study gives convincing evidence for an important role of glutathione in nucleus accumbens in regulating the willingness to invest effort to obtain reward or escape an aversive situation.

      (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.)

    1. Evaluation Summary:

      This work is of broad interest to readers in the fields of cytoskeletal research, muscle biology and heart disease. By utilizing a combination of quantitative biochemical and biophysical experimental approaches, this work provides critical new insights into the molecular mechanisms of understudied mutations in myosin that cause heart disease. The data are rigorously controlled and analyzed and support the claims of 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 #2 and Reviewer #3 agreed to share their name with the authors.)

    1. Evaluation Summary:

      Plant cells can grow to extraordinarily large volumes; Arabidopsis root cells, for example, can expand beyond 50um long. Vacuole expansion is correlated with cell elongation, presumably to "fill up" the volume of the cell without requiring a tremendous volume of cytoplasm. Here, the authors carefully characterize a new small molecule inhibitor of endocytic trafficking to the vacuole. This new tool will be valuable to researchers studying endocytic trafficking and vacuole biogenesis in plants.

      (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.)

    1. Evaluation Summary:

      The authors present an automated system for phenotyping root system architecture based on bioluminescent roots resulting from a constitutively expressed luciferase transgene (GLO-Root). They have developed a robotics-assisted phenotyping platform and an automated image analysis pipeline for high throughput analysis. An impressive array of 93 luciferase expressing Arabidopsis thaliana accessions provides a major resource for understanding the genetic basis for root system architecture variation in response to a range of environmental conditions. The work will be of interest to plant biologists and all those studying genetic variation in plants.

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

    1. Evaluation Summary:

      This paper will be of broad interest to scientists who study collective cell migration and cytoskeletal dynamics. The findings of this paper connect proteins involved in planar polarity to the actin protrusive machinery which establishes an axes for polarized collective cell migration. The data presented largely supports the claims of the authors who take advantage of quantitative imaging techniques and Drosophila genetics to establish this connection.

      (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.)

    1. Evaluation Summary:

      Synaptic connections are crucial for determining neural circuit function and for storing adaptive changes in the brain. This study performs a highly detailed quantitative analysis of certain excitatory connections in mouse neocortex, and finds that the physical size of these connections has a bimodal distribution. This is an important finding that has implications for our understanding of synaptic plasticity and neural circuit 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 #2 and Reviewer #3 agreed to share their names with the authors.)

    1. Evaluation Summary:

      This paper will be of interest to lung biologists, developmental biologists, and neonatologists interested in lung injury. In this manuscript, the authors used gene expression signatures to construct a gene regulatory network to identify genes associated with alveologenesis. While reviewers were impressed with the novelty of the approach, questions were raised about the robustness of the results in mice and the validation in human samples.

      (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.)

    1. Evaluation Summary:

      Neto et al set out to use Two-Photon FLIM and machine learning to classify macrophages that are polarised along the M1/M2 axis and then subjected to different metabolic stresses classically used to distinguish metabolic strategies of different cell states. Additional information is sought regarding the photophysics of the measurements and if there are an adequate number of photons to fairly compare the three conditions. The work will be of interest to immunologists, physiologists interested in metabolism and engineers looking to translate the findings.

      (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.)

    1. Evaluation Summary:

      This manuscript is interesting to a broad audience in the general fields of RNA and structural biology. It provides detailed and important molecular insight into one of the mechanisms by which ATP-fueled RNA helicases can cause the local destabilisation of terminal base-pairs and eventually contribute to RNA structure remodelling and it is a prime example of how crystallographic high-resolution snapshots of conformational intermediates can be combined with sophisticated NMR techniques and assays into a comprehensive model. The manuscript would benefit from a broader and more explicit comparative discussion including the limitations of the proposed model, because DbpA is a rather specialised RNA helicase and because the double-stranded RNA substrates were specifically designed to exclusively investigate unwinding from the side of a short 5'-overhang.

      (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.

    1. Evaluation Summary:

      This paper, of interest to neuroscientists in the field of memory engrams, presents novel insights to understand the complex functional network connected with the prefrontal cortex that shape memory-related neuronal ensembles and modulate memory formation in a time-dependent manner. The large data set due to the systematic approach yielded transparent, well analyzed, and clearly presented data. Still, the conclusions require additional support and extended discussion.

      (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.)

    1. Evaluation Summary:

      This study will be of broad interest to neuroscientists, immunologists, and gastroenterologists, revealing a novel role of complement C1q in intestinal macrophages and the regulation of gut motility. The manuscript is well written and key datasets are convincing, but the lack of mechanistic details that lead to dysmotility require additional supportive datasets at this 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 #3 agreed to share their name with the authors.)

    1. Evaluation Summary:

      Cryo-electron tomography has been successful at uncovering the details of the eukaryotic cilium/flagellum but there remains a limited number of taxa represented in the studies to date. Pinskey et al. fill this gap with a flagellar structure from choanoflagellates: single-celled organisms that are the closest living relatives of animals. The findings yield many new insights of broad interest to the field, such as the similarity of outer dynein arms and radial spokes to metazoan cilia, the observation of a flagellar vanes, and the presence of mysterious barb structures.

      (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.)

    1. Evaluation Summary:

      This study establishes for the first time that selective auditory attention reduces activity in the auditory cortex, similar to effects produced by engagement in a behavioral task. Moreover the study establishes the diversity of cortical modulations generated by attention.

      (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.)

    1. Evaluation Summary:

      This paper by Dr. Abbas and colleagues uses genomic and epidemiological methods to track SARS-CoV-2 spread in a healthcare facility. It demonstrates that genomic data can be used to track the spread of viruses in healthcare environments and documents that inter-ward transmission is important in healthcare settings. Overall, the conclusions are supported by the data and analysis and the paper demonstrates that genomics may be an important adjunct tool for tracking the nosocomial transmission of respiratory viruses.

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

    1. Evaluation Summary:

      This manuscript uses a combination of in vitro and in vivo approaches and uncovers a potential mechanism of autocrine/paracrine signaling in oligodendrocyte maturation, which provides an exciting avenue for future investigation. In particular, the authors examined the role of oligodendroglial exocytosis, and specifically the role of L-type prostaglandin D synthase (LPGDS), in modulating oligodendrocyte differentiation and myelination. This work will be of interest to glial and myelin disease researchers.

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

    1. Evaluation Summary:

      Hoye et al. analyzed conditional inactivation of Ddx3x gene in mouse dorsal forebrain, which leads to decreased brain size and widespread apoptosis in females but not males. Interestingly, the authors showed that Ddx3y was transcriptionally upregulated in cKO males, and suggested that Ddx3y compensated for the loss of Ddx3x. These results are attributed to prolonged cell cycle, impaired cell cycle exit, leading to increased progenitor populations. Ribo-Seq analysis showed differentially translated genes, providing potential new insights into Ddx3x function and pathogenic mechanisms. Overall, this study is of great importance and provides novel insights into the pathogenesis of DDX3X syndrome and the crucial role of DDX3X during cortical development.

      (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.)

    1. Evaluation Summary:

      This study investigates the release machinery of synaptic vesicles prior to SNARE-mediated fusion using atomistically detailed molecular dynamics simulations. While the approach provides an unparalleled perspective on a complex process that has eluded direct experimental access, the physiological relevance of the conclusions is not clear yet because of the short duration and necessary molecular approximations and assumptions underlying the simulations. The work will be of interest to all who study vesicle fusions.

      (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.)

    1. Evaluation Summary:

      This paper puts forward a new approach to generate vascularized brain organoids to copy in vivo structures, which will be of interest to neurobiologists working in both basic and disease-related areas of neuroscience. The novelty of their approach lies in the simultaneous production of vessel-like networks and brain-resident microglia immune cells in a single organoid. The fusion of brain and vessel organoids (fVBOrs) resulted in robust engraftment of vessel-like structures and microglia around ventricular zone (VZ)-like structures, correlating with increased neuronal progenitors. The conclusions are mostly well supported by the data, but a few points need to be clarified and some conclusions would benefit from further experimental support.

      (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.)