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.

Evaluation Summary:

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

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

Evaluation Summary:

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.)

Evaluation Summary:

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

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

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

Evaluation Summary:

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

This study was designed to examine the orphan ligand ActivinC. The authors show that ActivinC signals through ALK7. The data presented are strong and convincing. Indeed, the use of purified proteins for the interaction assays and in vivo analysis of adipocytes provide considerable rigor to the analysis. The work will be of interest to the areas of signal transduction and drug design.

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

Johnson and Desai previously reported "increasing cost epistasis", where mutations tended to have more deleterious effects in higher fitness backgrounds. Here they use the same system as before to investigate adapting populations by introducing a set of 91 mutations at multiple time points. As expected, the mean fitness effect of the mutations does decline in most (but not all) populations as they adapt but the effect is weaker than in the previous work, and in another condition, mean fitness effects of mutations do not change as the populations adapt. They suggest an intriguing interpretation (among others) that the "control coefficient" of selection on growth shifts between different genetic modules over time.

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

Evaluation Summary:

This manuscript will be of interest to the broad class of biologists and especially mouse geneticists who study the function of protein-coding genes. The authors confirm the utility of the auxin-inducible degron tool to rapidly degrade the target protein of interest by developing genetically modified mouse models. This expands the set of tools to study gene function in a cell/tissue type, in adults (bypassing embryonic lethality) and also to more finely dissect the different functions of pleiotropic genes.

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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

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

Evaluation Summary:

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.)

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.)

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)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)