eLife assessment

This valuable study reports the induction of supernumerary inner hair cells in the mouse cochlea upon reducing the expression level of a tight-junction protein (claudin-9). However, the evidence supporting the claims is incomplete and the work would be strengthened by adding several control experiments, resolving inconsistencies and imprecisions in the presentation of the results, and providing more mechanistic insight. The work will be of interest to scientists working in the development and regeneration of hair cells in the inner ear.

eLife assessment

This important study used a new double knockout mouse model to investigate the role of two neuropeptides, substance P and CGRPa, in pain signaling. There is convincing evidence that double knockout of these two molecules, both of which have historically been associated with pain, does not affect nociception or acute pain behaviors in males and females. The conclusions would further benefit from additional validation of the approach, consideration of potential outliers and statistical approach in cases with smaller sample sizes, and consideration of the potential for opposing effects across region or peptide. This paper will be of interest to those interested in the neurobiology of pain and/or neuropeptide function.

eLife assessment

Yang et al. investigate whether distinct sources of conflict are represented in a common cognitive space. The study uses an interesting task that mixes different sources of difficulty and reports that the brain appears to represent these sources as a mixture on a continuum in prefrontal areas. While the findings could be valuable to theory in this area, there are concerns with the analysis, design and results, that raise uncertainty regarding the main conclusion of a shared cognitive space. Thus, the evidence reported here ranges from solid to incomplete.

eLife assessment

This work is of fundamental significance to the field of nervous system development as it advances our mechanistic understanding of axon guidance. The rigorous biochemical and genetic approaches are compelling, experiments are well-controlled, and the major claims are supported by convincing data. The study should be of general interest to the developmental neurobiology community.

eLife assessment

These ingenious and thoughtful studies present important findings concerning how people represent and generalise abstract patterns of sensory data. The issue of generalisation is a core topic in neuroscience and psychology, relevant across a wide range of areas, and the findings will be of interest to researchers across areas in perception, learning, and cognitive science. The findings have the potential to provide compelling support for the outlined account, but there appear other possible explanations, too, that may affect the scope of the findings but could be considered in a revision.

eLife assessment

This valuable study links the "taste" of botanicals to their application as medicines used by the ancient Greco-Roman society. The authors used phylogenetic linear mixed models in a Bayesian framework to test the relationships between taste qualities, intensities, complexities, and therapeutic use. The evidence supporting the conclusions is solid, although there is a minor weakness concerning the somewhat inconsistent method of botanical preparation and presentation to the taster panelists; subjective bias and robustness of the participants' responses might have been overlooked. The study may be of broad interest to pharmacologists and scientists working on drug discovery, particularly those interested in natural products.

eLife assessment

This fundamental study provides compelling evidence to explain how chemical variations within a set of kinase inhibitors drive the selection of specific Erk2 conformations. Conformational selection plays a critical role in targeting medically relevant kinases such as Erk2 and the findings reported here open new avenues for designing small molecule inhibitors that block the active site while also steering the population of the enzyme into active or inactive conformations. Since protein dynamics and conformational ensembles are essential for enzyme function, this work will be of broad interest to those working in drug development, signal transduction, and enzymology.

eLife assessment

This valuable study reports on a new tool that allows for light-controlled protein degradation in Escherichia coli. With the improved light-responsive protein tag, endogenous protein levels can be reduced severalfold. The methodology is convincing and will be of interest to the fields of gene expression regulation in bacteria and, more generally to synthetic biologists.

eLife assessment

This work shows for the first time that the balance of mTOR (mTORC1 and mTORC2) in Sertoli cells regulates the rate of sperm epigenetic aging. The manuscript presents valuable findings that have some theoretical and practical implications. The strength of the evidence is however incomplete: they are limited in some places and the aims are not always fully supported by the results.

eLife assessment

The main idea tested in this work is that host galectin-9 inhibits Mycobacterium tuberculosis (Mtb) growth by recognizing the Mtb cell wall component arabinogalactan (AG) and, as a result, disrupting mycobacterial cell wall structure. Moreover, a similar effect is achieved by anti-AG antibodies. While the hypothesis is intriguing and the work has the potential to make a valuable contribution to Mtb therapy, the evidence presented is incomplete and does not explain several critical points including the dose-independent effect of galectin-9 on Mtb growth and how anti-AG antibodies and galectin-9 access the AG layer of intact Mtb.

eLife assessment

This study offers a useful advance by introducing a cord blood DNA methylation score for maternal smoking effects, with the inclusion of diverse cohorts. However, the overall strength of evidence is deemed incomplete, due to concerns regarding low exposure levels, low statistical power, potential overfitting, and the need for clearer descriptions of statistical methods. Building more directly from the existing evidence base, exploring differences between ancestries, and considering additional health outcomes would help to enhance the study.

eLife assessment

This study presents a valuable finding on the impact of metformin-induced shifts in gut microbial community structure and metabolite levels for drug efficacy in a mouse model of liver injury. The current evidence supporting the claims of the authors is incomplete, although inclusion of additional controls and a revision to clarify the reviewer's methodological concerns could strengthen the study. With revision, this paper could be of broad interest to researchers across multiple disciplines, including the microbiome, liver disease, and pharmacology.

eLife assessment

In this important manuscript, the authors used unbiased approaches to identify somatic mutations in publicly available databases that would disrupt clinically approved antibodies targeting HER2. Using a solid combination of both computational and experimental approaches they identify mutations that could restore therapeutic antibody sensitivity in a series of disease-relevant model systems. Additional cell-based and in vivo assays would strengthen the work and increase the translational and potential clinical relevance of the proposed work.

eLife assessment

This important study presents the validation of an oral delta9-tetrahydrocannabinol (THC) consumption mouse model utilizing highly palatable e-capsule gelatin. The results convincingly demonstrate that oral consumption produced THC behavioral and physiological effects, as well as measurable brain levels. The utility of the model for chronic consumption remains to be determined. The authors have clearly acknowledged limitations of their model and areas for future study and development. As the field of cannabinoid research moves toward application of routes of administration that mimic human use, these model systems will be pivotal in assessing the effects of cannabinoid-based drugs.

eLife assessment

Focusing mainly on var genes, the investigators performed comprehensive computational analyses of gene expression in malaria parasites isolated from patients and assessed changes that occur as these parasites adapt to in vitro culture conditions. The study provides an improved computational pipeline for monitoring var gene expression, and importantly, the study documents changes in expression of the core genome and thus provides insights into metabolic adaptations that parasites undergo while transitioning to culture conditions. The findings are important for their technical advances that are more rigorous than the current state-of-the-art. The solid data analyses, broadly support the claims with only minor weaknesses, tell us to be cautious when interpreting results obtained only from cultured parasites.

eLife assessment

This valuable study highlights how the diversity of the malaria parasite population diminishes following the initiation of effective control interventions but quickly rebounds as control wanes. The data presented is solid and the work shows how genetic studies could be used to monitor changes in disease transmission.

eLife assessment

The work by Han and collaborators describes valuable findings on the role of Akkermansia muciniphila during ETEC infection. If confirmed, these findings will add to a growing list of beneficial properties of this organism. However, as it stands, the strength of the evidence used to justify the conclusions in the manuscript is incomplete.

eLife assessment

This valuable study introduces a new simulation model to explain the wide-spread occurrence of genetic inversions in fruit-fly genomes, based on sexually antagonistic alleles and a trade-off between male reproduction and survival. The evidence supporting the conclusions is currently incomplete, but it might be possible to address this with additional simulations and experiments as well as more rigorous analysis of the model and the data. The work will be of interest to population geneticists beyond the fruit-fly system.

eLife assessment

The manuscript presents an analysis of different factors that are required for release of the lipid-linked morphogen Shh from cellular membranes., which will be useful in the field. The evidence is still incomplete as experiments rely on over-expression of Shh in a single cell line and are sometimes of a correlative nature. The study confirms and extends previous findings and will be of interest to developmental biologists who work on Hedgehog signaling.

eLife assessment

This study represents a valuable addition to the understanding of the DNA replication origin selection process in the budding yeast. The authors provide convincing evidence that the number of possible origins of replication is much higher than previously appreciated, although many of the newly identified origins are likely to only direct replication initiation rarely. This work will be of interest to those studying DNA replication and investigating protein-DNA interactions across the genome.

eLife assessment

This investigation of the changes in gene expression and some of the physiological consequences of sublethal exposures to the neonicotinoid insecticide imidacloprid in honeybee larvae is useful, although numerous experiments were not considered based on technical issues. The methodological design leads to concerns and it is therefore not obvious that all conclusions are justified. The study adds to our understanding of how this insecticide impacts development and growth of honeybees, but the evidence supporting the major claims is incomplete.

eLife assessment

This important study furthers our understanding of the antimicrobial properties of siderophores, and their potential use to battle opportunistic pathogens. The evidence supporting the conclusion is solid, based on rigorous biochemical, growth, and virulence assays. The work would benefit from a more in-depth discussion of the consequences and efficacy of 'siderophore therapy' in more complex communities/environments. The work will be of broad interest to colleagues in the fields of evolutionary ecology, microbiology, and medical sciences.

eLife assessment

This important study uses an innovative set of reporter assays to probe the role of the TnpB protein in IS608 transposition. The work provides independent support for the recently reported homing activity of TnpB, where the transposon is restored following excision, and suggests an additional function for TnpB in enhancing the transposase activity of the TnpA transposase. The overall approach is solid, but the authors should consider how the activity of the TnpB protein used, or the levels of ωRNA, impact their model.

eLife assessment

The manuscript offers useful descriptive insights into the potential influence of whole-brain lactate and pH levels on the manifestation of behavioral phenotypes seen in diverse animal models of neuropsychiatric disorders. However, reviewers have raised concerns about the potential loss of specificity in capturing regional and cell-type-specific effects when relying solely on whole-brain analysis methods. While the evidence supporting the conclusions is largely solid, the robustness of these conclusions could be enhanced by the inclusion of additional data and further analysis.

Editors Assessment: Antimicrobial resistance (AMR) is a global public health threat, and environmental microbial communities can act as reservoirs for resistance genes. There is a need for genomic surveillance could provide insights into how these reservoirs change and impact public health. With that goal in mind this study tested the ability of nanopore sequencing and adaptive sampling to enrich for AMR genes in a mock community of environmental origin. On average adaptive sampling resulting in a target composition 4x higher than without adaptive sampling, and increased target yield in most replicates. The methods and scripts for this approach were reviewed and curated together, although the scope of this study was limited in terms of communities tested and AMR genes targeted. And the authors improved their analysis by conducting an additional analysis of a diverse microbial community. Demonstrating the method is reusable and its results are promising for developing a flexible, portable, and cost-effective AMR surveillance tool.

*This evaluation refers to version 1 of the preprint *

eLife assessment

This is a compelling study on pro-inflammatory and anti-inflammatory lipids in relation to skeletal muscle injury. It convincingly identifies pro-inflammatory lipids during recovery predisposing to fibrosis, and maresin 1 as an anti-inflammatory lipid reducing fibrosis, improved muscle regeneration, partially restoring contractile function, of fundamental potential clinical application.

eLife assessment

George et al. present a convincing new Python toolbox ("RatInABox") that allows researchers to generate synthetic behavior and neural data specifically focusing on hippocampal functional cell types (place cells, grid cells, boundary vector cells, head direction cells).

This is valuable for theory-driven research where synthetic benchmarks should be used. Beyond just navigation, it can be highly useful for novel tool development that requires jointly modeling behavior and neural data. The authors provide convincing evidence of its utility with well documented and easy to use code and the corresponding manuscript.

eLife assessment

The authors introduce a potentially valuable novel method that provides trial-by-trial probabilistic estimates of learning and decision-making strategies inferred from choice behavior across species. This approach could prove more useful over traditional techniques for arbitrating between strategies and detecting when learning happens, and because it is computationally lightweight. Reviewers identified several concerns that limit the strength of the evidence provided, rendering the findings incomplete.

eLife assessment

This important study combines disparate results from both psychophysics and neural silencing experiments to suggest a new interpretation of how animals and humans represent and interpret recent events in our memory. A key aspect of the model put forward here is the presence of discrete jumps in neural activity within the posterior parietal region of the cortex. The model is distinct from other models, and the authors provide convincing evidence to support it both from existing results as well as from novel experiments.

eLife assessment

This study reports valuable behavioral and computational observations regarding how passive exposure to auditory stimuli can facilitate auditory categorization. The combination of behavioral results in mice with a study of artificial neural network models provides solid evidence for the authors' conclusions. This paper will likely be of broad interest to the general neuroscience community.

eLife assessment

This paper reports valuable results regarding the potential role and time course of the prefrontal cortex in conscious perception. Although the sample size is small, the results are convincing, and strengths include the use of several complementary analysis methods. The behavioral test includes subject report such that the study does not allow for distinguishing between (phenomenal) awareness and conscious access; nevertheless, results do advance our understanding of the contribution of prefrontal cortex to conscious perception.

eLife assessment

This is a valuable study of Eph-Ephrin signaling mechanisms generating pathological changes in amyotropic lateral sclerosis. There are exciting findings bearing on the role of glial cells in this pathology. The study emerges with solid evidence for a novel astrocyte-mediated mechanism for disease propagation. It may help identify potential therapeutic targets.

eLife assessment

This important manuscript investigates the roles of DKK3 in AD synapse integrity. Although previous work has identified the involvement of Wnt and DKK1 in synaptic physiology, this study provides compelling evidence that suppression of DKK3 rescues the changes in excitatory synapse numbers, as well as memory deficits in an established AD model mice. The authors provide both gain and loss of function data that support the main conclusion and advance our understanding of the mechanisms by which Wnt pathway mediates early synaptic dysfunction in AD models.

eLife assessment

This study provides an important starting point for unraveling the molecular basis of the pathological phenotypes of the repeat expansion in the gene associated with open reading frame 72 in human chromosome 9. The coarse-grained simulation method used by the authors goes beyond the state of the art, investigating a compelling number of binding partners. The evidence supporting the claims of the authors is solid, although experimental validation of the results would strengthen the major conclusions of the work. The work will be of broad interest to biophysicists and biochemists.

eLife assessment

In this important study, Guma and colleagues describe the use of structural neuroimaging to assess the cross-species convergence of sex differences in global and regional brain volumes in humans and mice. The goal of the work is to inform to what extent mouse studies of these aforementioned sex differences have relevance to humans. The authors suggest which aspects of brain anatomy (as measured by volume) are conserved or not, across species, which has theoretical and practical implications beyond a single sub-field. The evidence to support the findings is solid, it uses methods and data analysis that are appropriate and validated.

eLife assessment

This important work advances our understanding of how brains flexibly gate actions in different contexts, based on dynamically reconfiguring neural dynamics in motor circuits. The findings, using analyses of many neurons recorded simultaneously during mouse behavior, as well as causal perturbations, are clear and compelling. This work will be of interest to systems neuroscientists and to researchers studying context-dependent computation generally.

eLife assessment

This manuscript reveals important insights into the role of ipsilateral descending pathways in locomotion, especially following unilateral spinal cord injury. The study provides solid evidence that this method improves the injured side's ability to support weight, and as such the findings may lead to new treatments for stroke, spinal cord injuries, or unilateral cerebral injuries. However, the methods and results need to be better detailed, and some of the statistical analysis enhanced.

eLife assessment

This is an important study that investigates BMP signaling mechanisms in the developing chick cerebellum to better understand germinal layer formation, cellular amplification and neuronal differentiation. The data from human tissue is compelling and lends support to the possible links of these processes to medulloblastoma, although these specific statements could be toned down and presented only as part of the discussion. Overall, this is a solid piece of work with beautifully presented findings.

eLife assessment

The manuscript aims to better understand the mechanisms underlying the behavioral responses of C. elegans to hydrogen sulfide, a toxin known to exert remarkable effects on animal physiology in a range of contexts. To this end, the authors provide a series of useful findings regarding the mechanisms by which hydrogen sulfide may be sensed, their relationships to other gas-sensing pathways, and the role of a variety of physiological pathways in responding to hydrogen sulfide exposure. While some of the findings are solid, other aspects of the paper are incomplete, such that some claims are incompletely supported, and an integrated understanding of the authors' observations does not clearly emerge.

eLife assessment

This potentially valuable study provides some evidence that upregulation of sodium-activated potassium channels contributes to neuronal hyperexcitability and seizures following traumatic brain injury. However, the evidence supporting a direct link is incomplete. This work will be of interest to epilepsy and ion channel researchers.

eLife assessment

This important work provides insight into the activity and spatial organization of synapses during early postnatal development in the mouse visual cortex, using state-of-the-art tools to show that synapses are distributed in co-active clusters well before eye opening. The evidence supporting the claims is convincing, although additional methodological details are needed to fully assess the rigor of the analysis. This work is of particular interest to the field of developmental neuroscience and can also be used by computational neuroscientists studying dendritic integration.

eLife assessment

This fundamental study advances substantially our understanding of sound encoding at synapses between single inner hair cells of the mouse cochlea and spiral ganglion neurons. Dual patch-clamp recordings-a technical tour-de force-and careful data analysis provide compelling evidence that the functional heterogeneity of these synapses contributes to the diversity of spontaneous and sound-evoked firing by the neurons. The work will be of broad interest to scientists in the field of auditory neuroscience.

eLife assessment

This valuable study on the molecular and cellular mechanisms of ingestion avoidance of high salt in insects is focused in scope, but the authors present convincing evidence that a specific subset of gustatory receptors in a pair of pharyngeal taste neurons are necessary and sufficient for avoiding ingestion of high salt during feeding. This work will be of interest to Drosophila neuroscientists interested in taste coding and feeding behavior.

eLife assessment

This work presents an important technological advance, in the form of a high throughput platform for Single Particle Tracking allowing us to measure millions of cells and thousands of compounds per day. Analysis of the diffusional behaviour of fluorescently-tagged targets permits the identification of, and differentiation between, small molecules that bind directly or affect the target indirectly. The evidence provided is compelling, although some methodological information is undisclosed.

eLife assessment

This study presents a valuable finding on the distinct subpopulation of adipocytes during brown-to-white conversion in perirenal adipose tissue (PRAT) at different ages. The evidence supporting the claims of the authors is convincing, although specific lineage tracing of this subpopulation of cells and mechanistic studies would expand the work. The work will be of interest to scientists working on adipose and kidney biology.

eLife assessment

The authors have identified a media condition that maintains iPSCs in suspension cultures by inhibiting the PKCβ and Wnt signaling pathways. The manuscript is valuable for the pluripotent stem cell field. This is a solid study with substantial data to support the conclusions in the manuscript.

eLife assessment

This is an important study that develops a method to fluorescently label peptide MHC complexes on live dendritic cells to enable detection of antigen specific T cells in polyclonal populations. Solid evidence that this can be used to effectively identify antigen specific T cells in vitro and in vivo is provided for one model antigen systems (Ova-OTII). The approach has exciting potential as prior single step methods with directly conjugated single peptides have generally failed due to high background. Thus, this approach potentially moves the state of the art forward, but further work is needed to realise and determine the limits and ultimate utility of the approach.

eLife assessment

The study presents a valuable finding on sexually-dimorphic patterns of osteocyte transcriptomics and low calcium diet-induce bone loss. The evidence supporting the claims of the authors regarding the protective role of Irisin/FNDC5-deficiency in lactation and low-calcium diet in female mice is incomplete, due to the relatively modest phenotypes observed and the insufficient link between Irisin/FNDC5 and calcium homeostasis or milk production.

eLife assessment

This important study provides novel strategies to overcome certain limitations when investigating the metabolism of hematopoietic stem cells, mainly due to their low abundance. The study provides compelling evidence suggesting that proliferative hematopoietic stem cells mainly use glycolysis (rather than mitochondrial OXPHOS or TCA cycle) as their primary energy source during emergency hematopoiesis. The article provides direct links between metabolic features and cell proliferation and explores alternative energy sources, and is of great interest to stem cell biologists.

eLife assessment

This is a useful study that shows changes in the chromatin landscape of GABAergic neurons in induced pluripotent stem cells (iPSCs) derived from both Dravet Syndrome (DS) patients and healthy donors. The strength of the evidence is currently incomplete because the authors compared iPSCs from different individuals, rather than isogenic controls, and they did not examine the expression of the gene and encoded protein (SCN1A or Nav1.1) that are thought to be responsible for the majority of DS cases in these iPSCs. The work would be of interest to scientists who study development, developmental disorders, and epigenetic contributions to disease.

eLife assessment

The delineation of MBOAT function is important with theoretical and practical implications in MAFLD, alcohol-induced hepatic steatosis, and lysosomal diseases. The strength of evidence is convincing using methodology in line with current state-of-the-art, with good support for the claims.

eLife assessment

The significance of this work is important in that the authors propose a novel method to therapeutically harness myeloid cells which can be otherwise immunosuppressive and hamper T cell and immunotherapy responses. The strength of evidence is convincing but requires critical pieces of in vivo work to validate the therapeutic efficacy of this approach.

eLife assessment

This important work presents data showing that all non-proneural phenotypes of the Inhibitor of DNA binding (Id) protein emc are mediated through inappropriate non-apoptotic caspase activity. Using the developing Drosophila retina as a model the authors convincingly show that emc acts by transcriptionally regulating the Death-Associated Inhibitor of Apoptosis 1 (diap1) gene, which impacts on Notch signaling by caspase-dependent increase of Delta protein. These findings are interesting for the caspase/apoptosis field as they add more non-apoptotic functions of caspases to the list, as well as for the Id field, which examines how Id proteins inhibit cell differentiation.

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eLife assessment

Through a theoretical approach, this study makes important contributions to our understanding of the evolutionary causes of the ageing process. Using a simple individual-based model and computational simulations, the authors provide convincing evidence that ageing can be a trait under natural selection, opening the door for further discussion in the context of lifespan extension research.

eLife assessment

The fundamental study presents a two-domain thermodynamic model for TetR which accurately predicts in vivo phenotype changes brought about as a result of various mutations. The evidence provided is solid and features the first innovative observations with a computational model that captures the structural behavior, much more than the current single-domain models.

eLife assessment

The work is a valuable contribution to understanding the mechanism of nuclear export of tRNA in budding yeast. The authors present solid evidence that Dbp5 functions in parallel with Los1 and Msn5 in tRNA export, in a manner dependent on Gle1 for activation of its ATPase activity but independently of Mex67, Dbp5's partner in mRNA export. It further presents biochemical evidence that Dbp5 can bind tRNA but that Gle1 and InsP6 are required for activating ATP hydrolysis by the Dbp5-tRNA complex, suggesting a possible mechanism for tRNA export by Dbp5.

eLife assessment

This study presents valuable findings on the contrasting responses of two bacteria to the phytoplankton-derived compound azelaic acid. Metabolomics and transcriptomics evidence convincingly shows the assimilation pathway in one marine bacterium and a stress response in a second bacterium. The study provides evidence that azelaic acid can alter marine microbial community structure in mesocosm experiments, though the mechanisms underlying this shift in community structure remain to be explored in future studies.

eLife assessment

This valuable study considers empirical macroecological patterns in microbiome data across multiple taxonomic scales. The work convincingly shows that the Stochastic Logistic Growth model is a more appropriate choice of null model than the neutral theory of biodiversity. The work will be of particular interest to microbial ecologists.

eLife assessment

The findings of this study are valuable as they provide new insights into the role of acetylcholine in modulating sensory processing in the auditory cortex. This paper reports a systematic measurement of cell activity in the auditory cortex before and after the microiontophoretic application of Ach during an oddball and cascade sequence of auditory stimuli. The evidence presented is convincing, as the study used a rigorous experimental design and statistical analysis. The manuscript will interest researchers in auditory neuroscience and neuromodulation, as well as clinicians and individuals with auditory processing disorders.

eLife assessment

This is an important and interesting account of the ability of Ym1 crystals to promote type 2 immunity in vivo, in mice. The data presented are compelling, building on and significantly advancing evidence this group has previously published on the type 2 immunogenicity of other protein crystals. The work will be of relevant interest to immunologists and researchers working on type 2 inflammatory disease, in the lung and in others tissues.

eLife assessment

The paper represents a novel application of recursion theory to the long call vocalisations of orangutans to demonstrate repetitive, rhythmic sub-structuring. The authors use detailed acoustic analyses to show compelling evidence for self-embedded and nested isochronic motifs. These fundamental results have the potential to significantly advance current approaches used to compare nonhuman communication systems with human language.

eLife assessment

This study presents useful observations about how the human brain uses long-term priors (acquired during our lifetime of listening) to make predictions about expected sounds - an open question in the field of predictive processing. However, the evidence as currently presented is incomplete. Both the theoretical background and analysis approach should be strengthened.

eLife assessment

Overall, this is a significant study, and it is able to highlight mast cells in amphibians and their putative capability to respond to and combat fungal infections. Therefore, this study is important for the field. However, the manuscript is incomplete from the standpoint that there is functional data lacking on how these mast cells are activated and their precise functional properties. Such experiments would add substantial impact and rigor and fully support the conclusions.

eLife assessment

This valuable study applies voltage clamp fluorometry to provide new information about the function of serotonin-gated ion channels 5-HT3AR. The authors convincingly investigate structural changes inside and outside the orthosteric site elicited by agonists, partial agonists, and antagonists, helping to annotate existing cryo-EM structures. This work confirms that the activation of 5-HT3 receptors is similar to other members of this well-studied receptor superfamily. The work will be of interest to scientists working on channel biophysics but also drug development targeting ligand-gated ion channels.

eLife assessment

The authors present a comprehensive set of tools to compactly characterize the time-frequency interactions across a network. The utility of the toolbox is compelling and demonstrated through a series of exemplar brain imaging datasets. This fundamental work adds to the repertoire of techniques that can be used to study high-dimensional data.

eLife assessment

This work uses an interdisciplinary approach combining microfluidics, structural biology, and genetic analyses to provide valuable findings that show that pathogenic enteric bacteria exhibit taxis toward human serum. The data are solid and show that the behavior utilizes the bacterial chemotaxis system and the chemoreceptor Tsr, which senses the amino acid L-serine. The work provides an ecological context for the role of serine as a bacterial chemoattractant and could have clinical implications for bacterial bloodstream invasion during episodes of gastrointestinal bleeding.

eLife assessment

This important study contributes insights into the regulatory mechanisms of a protein governing cell migration at the membrane. The integration of approaches revealing protein structure and dynamics provides convincing data for a model of regulation and suggests a new allosteric role for a solubilized phospholipid headgroup. The work will be interesting to researchers focusing on signaling mechanisms, cell motility, and cancer metathesis.

eLife assessment

In this valuable manuscript, Yao et al. describe new methods for assessing the intracellular itinerary of Botulinum neurotoxin A (BoNT/A), a potent toxin used in clinical and cosmetic applications. The current manuscript challenges previously held views on how the catalytic portion of the toxin makes its way from the endocytic compartment to the cytosol, to meet its substrates. The approach taken is deemed innovative and the experiments are carefully performed, however, they are somewhat incomplete with respect to the drawn conclusions, as it is possible that the scope of their findings could be restricted to the specific neuron model and molecular tools that were used. This paper could be of interest to both cell biologists and physicians.

eLife assessment

In this study, camera trapping and species distribution models are used to show that human disturbance in mountain forests in the eastern Himalayas pushes medium-sized and large mammal species into narrower habitat space, thus increasing their co-occurrence. While the collected data provide a useful basis for further work, the study presents incomplete evidence to support the claim that increased co-occurrence may indicate positive interactions between species.

eLife assessment

This fundamental study addresses a long-standing mystery in splicing regulation: does splicing occur co- or post-transcriptionally? The authors provide compelling evidence demonstrating that splicing can occur post-transcriptionally at a transcription site proximal zone, changing the way we think about splicing.

eLife assessment

This is an important study using 3D mapping of neuronal activation throughout the brain after pair-bonding in the monogamous vole, which can be broadly applied to other species and behaviors. The authors provide compelling evidence that there is some synchrony between male and female partners that have formed a pair bond, the strength of which is based on the number of ejaculations received by the female. Same-sex pairs also form a pair bond and were found to have activation in the same brain regions as mixed sex couples. An overall low level of sex differences in the degree and location of brain activation was observed, which was unexpected. This work will be of interest to those interested in social behavior and its neural mechanisms, or brain systems or behavior more broadly.

eLife assessment

This important study reports on an improved deep-learning-based method for predicting TCR specificity. The evidence supporting the overall method is compelling, although the inclusion of real-world applications and clear comparisons with the previous version would have further strengthened the study. This work will be of broad interest to immunologists and computational biologists.

eLife assessment

Studies of synaptic development and plasticity in the nematode C. elegans have been limited by the difficulty of rapid, accurate assessments of synaptic structure. Here, with a series of convincing studies, the authors introduce and validate a valuable computational pipeline, "WormPsyQi," that allows rapid, reproducible quantitation of fluorescent synaptic puncta while minimizing human error and bias. The authors also describe a new set of strains carrying synaptic markers. Together, these tools should provide groups studying this model system with the ability to quantitatively characterize chemical and electrical synapses, even in densely packed regions in 3D space such as the nerve ring.

eLife assessment

The study is of importance for the cardiac modeling field by developing a novel mathematical model with sex difference. The data are compelling, and the model is helpful for mechanistic understanding, and thus is also important for experimental physiology. The model is based on experimental data and validated against some experimental data.

eLife assessment

The important work by Aballay et al. significantly advances our understanding of how G protein-coupled receptors (GPCRs) regulate immunity and pathogen avoidance. The authors provide convincing evidence for the GPCR NPR-15 to mediate immunity by altering the activity of several key transcription factors. This work will be of broad interest to immunologists.

eLife assessment

BMP signaling plays a vital role in skeletal tissues, and the importance of its role in microtia prevention is novel and promising. This important study will shed light on the role of BMP signaling in preventing microtia in the ear. Solid data broadly support the claims with only minor weaknesses.

eLife assessment

The study has added value to what we have already known in the potential pharmacological immunomodulatory therapies in LPS-induced sepsis, and especially the use of oral leucine might be of great interest to the readers engaged in this field. We believe this study is important and provides solid evidence on the potential use of leucine in sepsis.

eLife assessment

This useful study presents a novel method to analyze the correlation between the degree of pigmentation, and the gene expression profile of human-induced pluripotent stem cell-derived Retinal Pigmented Epithelial (iPSC-RPE) cells at the single cell level, trying to establish if this parameter might be of use as a guide for transplantation. The presented evidence is incomplete: pigmentation was not an indicator of functionality or maturity and the data, although obtained from a pertinent approach, is limited to in vitro conditions; further, this approach is not complete since no attempts were made to graft iPSC-RPE.

eLife assessment

This useful study introduces a simple mechanical model of C. elegans locomotion that captures aspects of the worm's behavioral repertoire beyond forward crawling. While the kinetic model (ElegansBot) provides a useful compromise and starting point to help understand the mechanical components of C. elegans behavior, the claim that this work improves on extant mechanical models is incomplete. In addition, the results of the application of the model to previously unstudied behaviors are primarily qualitative and do not produce new predictions.

eLife assessment

This study presents a valuable finding on developing a state-of-the-art generative model of brain electrophysiological signals to explain temporal decoding matrices widely used in cognitive neuroscience. The evidence supporting the authors' claims is convincing. The results will be strengthened by providing more clear mappings between neurobiological mechanisms and signal generators in the model. The work will be of interest to cognitive neuroscientists using electrophysiological recordings.

eLife assessment

In this important paper, Blin and colleagues develop a high-throughput behavioral assay to test spontaneous swimming and olfactory preference in individual Mexican cavefish larvae. The authors present compelling evidence that the surface and cave morphs of the fish show different olfactory preferences and odor sensitivities and that individual fish show substantial variability in their spontaneous activity that is relevant for olfactory behaviour. The paper will be of interest to neurobiologists working on the evolution of behaviour, olfaction, and the individuality of behaviour.

eLife assessment

This study by Chiu and colleagues is a valuable contribution to the study of the circuitry of aggressive behaviours and of mechanisms that generate persistent behavioural states. The authors find that activation of two interconnected sets of neurons results in an increase in female aggression. The data ruling out recurrent connectivity between these clusters underlying this persistent state are convincing.

eLife assessment

This important study reports on a new method for the fabrication and the analysis of the transport through nuclear pore complexes mimic. Methods, data and analyses are convincing and show a clear correlation between the size of the nuclear pore complex mimic and its transport selectivity. This work will be of high interest to biologists and biophysicists working on the mechanosensitivity of nucleocytoplasmic transport.

eLife assessment

This valuable study analyzes a large cohort of Adolescent Idiopathic Scoliosis (AIS) patients, identifying an association with a variant in COL11A1 (Pro1335Leu). Experimental testing of this potentially pathogenic variant in vitro suggests a connection between Pax1, Col11a1, Mmp3, and estrogen signaling, thus providing solid support for the proposed link between hormonal and matrix components in the development of AIS.

eLife assessment

This useful study applies solid and previously validated methodology to identify archaically introgressed genes involved in high altitude adaptation. However, to test the robustness of the approach, this study would benefit from using at least one other method to detect adaptive introgression, and clarification on how the authors scored the networks in the signet analysis. With these parts strengthened, this paper would be of interest to population geneticists, anthropologists, and scientists interested in the genetic basis underlying high-altitude adaptation in Tibet.

eLife assessment

This valuable study reports on the genome evolution of a poorly studied fungal group. By combining long-read sequencing and various bioinformatics approaches, the authors show that the giant genome of Entomophthora muscae expanded due to extensive transposable element activity. The strength of evidence is largely solid, but some analyses are only partially supported due to different methodologies used to analyze the genomes that are being compared. This paper will be of relevance to fungal biologists as well as to evolutionary biologists interested in the study of genome size dynamics.

eLife assessment

The manuscript describes important findings supported by convincing data. The authors present persuasive genetic and biochemical evidence that supports the biological mechanism for optimal nodulation in soybean presented in this study. The results are of relevance to understanding the signaling pathway underpinning beneficial rhizobia symbiosis, while repressing the immune response. With the discussion part strengthened this paper would be of broad interest to plant biologists working on cell signaling and plant-microbe interactions.

eLife assessment

This manuscript investigates how chloroplasts are broken down during light-limiting conditions as plants reorganize their energy-producing organelles during carbon limitation. The authors provide convincing live-cell imaging data of plastids, documenting that buds form on the surface of chloroplasts and pinch away, then associate with the vacuole via a mechanism that depends on autophagy machinery, but not plastid division machinery. However, the absence of quantitative analyses makes the work incomplete at the current stage. The manuscript nevertheless provides important groundwork for other scientists studying the regulation and breakdown of energy-producing organelles, including chloroplasts and mitochondria.

eLife assessment

This study provides useful information by identifying the cell type (macrophages) in synovial tissues involved in the pathogenesis of post-traumatic osteoarthritis (OA) and clarifying distinct transcriptomic signatures that may be a good therapeutic target for OA. However, the analysis performed so far is incomplete, with a main weakness being the lack of data to confirm the authors' speculation about the underlying mechanisms.

eLife assessment

This important study presents a new way to selectively activate a cell signaling pathway in a specific cell type by designer ligands that link signaling co-receptors to a marker specific to the target cells. Convincing experimental results demonstrate that the agonist molecules activate Wnt signaling in target cells expressing the marker as intended. More broadly, this concept could be used to induce Wnt signaling or another pathway initiated by co-receptor association in a cell type-specific manner. In vitro results in this study could be further strengthened by assessing the biological consequences of Wnt activation in target cells.

eLife assessment

This important study reports the generation of genetic tools for manipulating several tissues at the same time in Drosophila. The authors provide convincing evidence that this allows the generation of LexA and QF2 driver lines, which will be of great utility for understanding inter-organ communication. Making the tools available through the Drosophila stock center and plasmid depository will ensure that they are easily accessed by many researchers.

eLife assessment

This study represents a valuable mechanistic contribution towards understanding how ribosomal RNA is processed during ribosome biogenesis. The biochemical evidence supporting the major conclusions is convincing. This work will be of interest to cell biologists and biochemists working on ribosome biogenesis.

eLife assessment

This study presents valuable findings on the potential of short-movie viewing fMRI protocol to explore the functional and topographical organization of the visual system in awake infants and toddlers. Although the data are compelling given the difficulty of studying this population, the evidence presented is incomplete and would be strengthened by additional analyses to support the authors' claims. This study will be of interest to cognitive neuroscientists and developmental psychologists, especially those interested in using fMRI to investigate brain organisation in pediatric and clinical populations with limited fMRI tolerance.

eLife assessment

This valuable study draws attention to the importance of a previously overlooked structural motif in kinase regulation. While the data presented are intriguing and mostly solid, further analysis and additional experiments will be needed in the future to support the authors' hypothesis. The work will be of interest to protein biochemists and enzymologists with an interest in kinases and allostery.

eLife assessment

The reviewers were generally enthusiastic about this study, noting that it reports new tools that could be valuable to the community. However, the results in follow-up experiments testing specific tools are often inconsistent with those in the literature, and some conclusions are overstated. More details are needed for both sections, the tool generation and the testing of the CNMa peptide. While the evidence for the tool development was solid, evidence demonstrating the validity of the tools was deemed incomplete.

eLife assessment

This important study combines disease-associated genetic variation with a massively parallel reporter assay and different cellular perturbations to identify context-specific genetic regulatory effects. The methods and analyses are solid and the proposed functional variants will be helpful for experimental and quantitative geneticists studying a wide range of complex traits.

eLife assessment

In this manuscript, the authors investigate whether the effects of the BCG vaccine on immunity to Mtb infection could be improved by inhibiting amidation of the peptidoglycan sidechains to allow for recognition by NOD-1. This is a very important area and an interesting new approach to improve vaccination for TB. The authors find that CRISPRi knockdown of murT-gatD causes rather dramatic cell wall defects, more accessible cell wall labeling, and results in attenuated growth in macrophages and mice. This forms a foundation for further study of whether an approach like that which is presented herein would improve vaccination responses in TB.

eLife assessment

In this study, deep learning methods are deployed in the context of a group hunting scenario wherein two predators pursue a single prey. Through deep learning, the two predators achieve higher predation success than occurs with single predators. Much of the evidence in this important study is solid, with implications for future work on the ethology and simulation of cooperative behaviors.

eLife assessment

This study provides a valuable investigation into whether phenotypic variance due to interactions between genetic variants can be measured using genome-wide association summary statistics. The authors present a method, i-LDSC, that uses statistics on the correlations between genotypes at different loci (linkage disequilibrium) to estimate the phenotypic variance explained by both additive genetic effects and pairwise interactions. While the authors present extensive simulations on the performance of their method and empirical results indicating the presence of epistasis (as they define epistasis) it is unclear how their method and results relate to the traditional definitions of additive and non-additive genetic effects, which are different from the authors' definitions.

eLife assessment

This study presents valuable findings regarding inter-individual variability in the neural and behavioral effects of ketamine. The methodological approach used to characterize this variability is compelling, but the evidence to support the specificity of the changes and their genetic correlates is incomplete. The study would benefit from a more thorough examination of the specificity of the pharmacological and genetic results.

eLife assessment

This study presents a useful deep learning-based inter-protein contact prediction method named PLMGraph-Inter which combines protein language models and geometric graphs. The evidence supporting the claims of the authors is solid, although it could have information leakage between training and test sets, and although more emphasis should be given to predictions starting from unbound monomer structures. The authors show that their approach may be useful in some cases where AlphaFold-Multimer performs poorly. This work will be of interest to researchers working on protein complex structure prediction, particularly when accurate experimental structures are available for one or both of the monomers in isolation.

eLife assessment

The bacterial neurotransmitter:sodium symporter homoglogue LeuT is an well-established model system for understanding the fundamental basis for how human monoamine transporters, such as the dopamine and serotonin, couple ions with neurotransmitter uptake. Here the authors provide convincing data to show that K+ binding on the intraceullular side catalyses the return step of the transport cycle in LeuT by binding to one of the two sodium sites. The mechansitic consequences of K+ binding could either facilitate LeuT re-setting and/or prevent the rebinding and possible efflux of Na+ and substrate.

eLife assessment

This paper reports the fundamental discovery of adrenergic modulation of spontaneous firing through the inhibition of the Na+ leak channel NALCN in cartwheel cells in the dorsal cochlear nucleus. This study provides unequivocal evidence that the activation of alpha-2 adrenergic or GABA-B receptors inhibit NALCN currents to reduce neuronal excitability. The evidence supporting the conclusions is exceptional, the electrophysiological data is high quality and the experimental design is rigorous.

eLife assessment

The authors pair single-cell sequencing technology with the LoopSeq synthetic long-read method to examine samples of hepatocellular carcinoma and benign liver, with the goal of identifying mutations and fusion transcripts specific to cancer cells. The authors present a valuable resource and the overall support for the major claims is solid.

eLife assessment

This important study explores infants' attention patterns in real-world settings using advanced protocols and cutting-edge methods. The presented evidence for the role of EEG theta power in infants' attention is currently incomplete. The study will be of interest to researchers working on the development and control of attention.

eLife assessment

In this important study, chromatin is simulated as a polymer at the scale of genes, and the 3D organization of chromatin is analyzed at nucleosome resolution. There is convincing evidence for the emergence of chromatin microdomains due to the action of transcription factors, based on the simulation incorporating well-known biophysical properties of DNA, of nucleosomes, of linker histones, and of the transcription factor pair Myc:Max, as well as considering how the 3D organization of chromatin results from bending and looping of DNA. The work greatly improves our understanding of how the joint action of transcription factors and chromatin features affects chromatin structure and accessibility, which is of interest to anyone studying gene regulation.

eLife assessment

This paper, offering insights into the mechanisms of neuronal cell type diversification, provides important findings that have theoretical or practical implications beyond a single subfield. The data are compelling and provide evidence that features methods, data and analyses that are more rigorous than the current state-of-the-art.

eLife assessment

This paper explores how Notch activity acts together with homeodomain transcription Bsh factors to establish distinct cell fates (L4 vs L5) in the visual system of Drosophila. The findings are important and have theoretical or practical implications beyond a single subfield. The methods, data, and analyses are compelling and support the claims with only minor weaknesses.

eLife assessment

This useful study presents a possible solution for a significant problem - that of draining vein sensitivity in functional MRI, which complicates the interpretability of laminar-fMRI results. The addition of a low diffusion-weighted gradient is presented to remove the draining vein signal and obtain functional responses with higher spatial fidelity. However, the strength of the evidence is inadequate, most tests appear to have been done only in a single subject. Significance thresholds in presented maps are very low and most cortical depth-dependent response profiles do not differ from baseline, even in the BOLD data shown as reference. Curiously, even BOLD group data fails to replicate the well-known pattern of draining towards the cortical surface.

eLife assessment

This important study combines psychophysics, fMRI, and TMS to reveal a causal role of FEF in generating an attention-induced ocular dominance shift, with potential relevance for clinical applications. The evidence supporting the claims of the authors is solid, but the theoretical and mechanistic interpretation of results and experimental approaches need to be strengthened. The work will be of broad interest to perceptual and cognitive neuroscience.

eLife assessment

This important study presents a detailed investigation of the early development of cardiac and respiratory interoceptive sensitivity in infants aged 3, 9, and 18 months. The evidence supporting the conclusions are solid and based on convincing statistical analyses, despite the limited sample size for the younger and older age groups. This study will be of significant interest to developmental psychologists and neuroscientists working on interoception and its influence on socio-cognitive development.

eLife assessment

This study presents a valuable framework and findings for our understanding of the brain as a fractal object, by observing the stability of its shape property within 11 primate species. Although the framework is well-detailed, the evidence presented is incomplete and would be strengthened by additional analyses to support the authors' claims, particularly on the effects of aging and on the interpretation of links between brain shape and the underlying anatomy. This study will be of interest to neuroscientists interested in brain morphology, and to physicists and mathematicians interested in modeling the shapes of complex objects.

eLife assessment

In the last 15 years, large-scale association studies (GWAS) have served to estimate the association between genome-wide common variants and a large number of disparate traits and diseases in humans. This valuable method provides a new way to find correlations between the genetic component of a phenotype of interest, and all this wealth of genetic information. This software adds as a new tool to investigate genetic correlation between traits, and to generate new mechanistic hypotheses and dissect the role of the observed associations in disease heterogeneity. The results of the application of their method are solid and generally agree with what others have seen using similar AD and UKB data.

eLife assessment

This study presents important findings on the different polymorphs of alpha-synuclein filaments that form at various pH's during in vitro assembly reactions with purified recombinant protein. Of particular note is the discovery of two new polymorphs (1M and 5A) that form in PBS buffer at pH 7. The strength of the evidence presented is solid, but the addition of replicate experiments with re-purified proteins at pH 5.8 and pH 7 would further strengthen the conclusions. The work will be of interest to biochemists and biophysicists working on protein aggregation and amyloids.