eLife assessment

The study used slice physiology and modeling to investigate neurotransmitter release at the cerebellar parallel fiber-to-molecular layer interneuron synapse, revealing that each docking site can accommodate up to two synaptic vesicles simultaneously. The authors have provided convincing evidence addressing how many vesicles can be released by a single release site in a short time. These findings are important for the validation of a two-step docking model and shed light on the mechanisms underlying short-term synaptic plasticity and strategies for achieving synaptic reliability, which plays a critical role in information processing in the brain.

eLife assessment

Pak et al. examined the relationship between the most common spatial patterns of neurodegeneration and the density of different cell types in the cerebral cortex. The study uses innovative methods but the main claims are incompletely supported due to some limitations. While the results might be considered preliminary, this work provides valuable findings and takes a step in the right direction by highlighting the contribution of non-neuronal cell type to the pathobiology of neurodegeneration.

eLife assessment

This fundamental study substantially advances our understanding of the role of zinc in metabolism, specifically a newly established clinical link between mutations in the zinc transporter SLC39A5, elevated serum zinc levels, and a reduction in the risk of Type 2 Diabetes. The provided evidence is solid with state-of-the-art genetic analysis of large human cohorts followed by a comprehensive analysis of a mouse SLC39A5 knockout mutant, establishing that SLC39A5 plays a role in hepatic lipid handling through AMPK signaling, although the limited analysis of a pancreatic phenotype that has previously been described constitutes a weakness. This study will be of relevance to researchers interested in metabolism, fatty liver disease, and the biology of trace elements.

eLife assessment

This valuable study provides a new perspective on preparatory activity occurring before the onset of movement. The authors report that, for a wide variety of recurrent networks, the optimal inputs should start before the desired network output. The authors present convincing evidence by combining mathematically tractable analyses in linear networks and numerical simulation in nonlinear networks. One limitation is that the only cost function considered for the input is that of magnitude. While this constraint is reasonable, it is suspected that other cost functions could lead to greater realism of model responses.

eLife assessment

This valuable study advances our knowledge of the effects of anxiety/depression treatment on metacognition, demonstrating that treatment increases metacognitive confidence alongside improving symptoms. The authors provide convincing evidence for the state-dependency of metacognitive confidence, based on a large longitudinal treatment dataset. However, it is unclear to what extent this effect is truly specific to treatment, as changes in metacognitive confidence in the group receiving online CBT were not statistically different from those in the control group.

eLife assessment

In this fundamental study, the authors propose analytical methods for inferring evolutionary parameters of interest from sequencing data in healthy tissue relevant to hematopoiesis. By combining analyses of single cell and bulk sequencing data, the authors can use a stochastic process to inform different aspects of genetic heterogeneity. The strength of evidence in support of the authors' claim is thus compelling. The work will be of broad interest to cell biologists and theoretical biologists.

eLife assessment

This important study identifies a spatial pattern of neural activity that corresponds to trust in an investment game. It provides a compelling assessment of the validity of this pattern by assessing its expression, or lack thereof, in a variety of datasets. This work, and the "neurometrics" approach it proposes, will be of broad interest to psychology researchers more generally.

eLife assessment

This important study advances our understanding of how listeners understand speech when there are multiple talkers by showing that the content of the speech affects acoustic processing. The evidence is generally solid, although additional details on the methods to allow replication would strengthen the study. The work will be of use to researchers interested in the neuroscience of speech and language processing.

eLife assessment

This is an important contribution that extends earlier single-unit work on orientation-specific center-surround interactions to the domain of population responses measured with Voltage Sensitive Dye (VSD) imaging and the first to relate these interactions to orientation-specific perceptual effects of masking. The authors provide convincing evidence of a pattern of results in which the initial effect of the mask seems to run counter to the behavioral effects of the mask, a pattern that reversed in the latter phase of the response. It seems likely that the physiological effects of masking reported here can be attributed to previously described signals from the receptive field surround.

eLife assessment

The primary goal of this paper is to examine microtubule detyrosination as a potential therapeutic target for axon regeneration. The valuable findings of this study provide convincing evidence for mechanistic links between microtubule detyrosination and neurite outgrowth in vitro and some evidence for axon regeneration in vivo.

eLife assessment

This important work presents an interesting perspective for the generation and interpretation of phase precession in the hippocampal formation. Through numerical simulations and comparison to experiments, the study provides a convincing theoretical framework explaining the segregation of sequences reflecting navigation and sequences reflecting internal dynamics in the DG-CA3 loop. This study will be of interest for researchers in the spatial navigation and computational neuroscience fields.

eLife assessment

This important study uses calcium imaging in mice to advance our understanding of the effect of antipsychotic drugs on neural functioning. The evidence supporting the conclusions is convincing, though some improvements could be made to the statistical testing of the data. This work will be of interest to neuroscientists working on visual processing and psychosis researchers.

eLife assessment

This is an important study that improves gene models for the ferret genome and identifies neural progenitors that are comparable to those found in developing human brains. The data are convincing and clearly presented. Of particular interest to the field, the work identifies enriched expression of FOXJ1 in late truncated radial glia, strongly indicating that towards the end of neurogenesis, these cells likely give rise to ependymal cells. The work is of interest to anyone studying the development of the nervous system, especially colleagues studying the evolution of development.

eLife assessment

This manuscript will provide a valuable method to evaluate the safety of MR in patients with orthopaedic implants, which is required in clinics. A strength of the work is that the in-silicon testbed is solid, based on the widely available human project, and validated. In addition, the toolbox will be open for clinical practice.

eLife assessment

This is important work that examines hepatic acetate production via ACOT12/18 in starvation and diabetes. The investigators use solid loss of function strategies in cells, including mouse primary hepatocytes, and in vivo mouse experiments to show that ACOTs are necessary for normal acetate production in the context of fasting and type 1 diabetes. Given that acetate is commonly thought to primarily represent a fermentation product, this study is of interest as it describes hepatic pathways converting fatty acids to acetate.

eLife assessment

The authors develop a cell culture system for studies of muscle tissue development and homeostasis. They convincingly validate a novel 3D cell model. Their thorough molecular and functional characterization will make this useful for future workers in the field.

eLife assessment

This fundamental study advances our understanding of the cell specific treatment of cone photoreceptor degeneration by Txnip. The evidence supporting the conclusions is convincing with rigorous genetic manipulation of Txnip mutations, however, there are a few areas in which the article may be improved through further analysis and application of the data. The work will be of broad interest to vision researchers, cell biologists and biochemists.

eLife assessment

This useful study presents convincing evidence that blood meal source and season affect Culex quinquefasciatus mosquito reproduction. Its unique focus on the interactive effects of both factors on mosquito fitness is of considerable relevance for the field, but the work suffers from inadequate experimental design - no replication, a population mismatch with the hypothesis region, and small sample sizes, limitations that were not sufficiently acknowledged in the discussion. The work will be of interest to those studying malaria and vector-borne diseases.

eLife assessment

This important study introduces a new therapeutic cell targeting system, where an active molecule is divided into inactive or less active parts that are subsequently linked via a bridging receptor on a target cell. Solid experimental proof of concept involving the activation of Wnt signaling in hepatocytes is presented, which could be further strengthened by demonstrating the specificity of the effect when applied to a mix of different cell types. This study may be of substantial interest to medical biologists focused on targeted therapeutics or seeking to utilize cell type-specific pathway modulation in their research.

eLife assessment

This study provides an important demonstration of how the false-positive rate of high-resolution 2D template matching to find particles of a given target structure in 2D cryo-EM images (2DTM) relates to overfitting the data towards the template. The authors present new methods to measure the amount of model bias that gets introduced in high-resolution features of such maps, with compelling evidence that high-resolution features that are not present in the template can still be reconstructed in 3D from images obtained by 2DTM. The paper could be strengthened by the inclusion of a more elaborate discussion (and possibly additional experiments) to describe the limitations of 2DTM for smaller target structures.

eLife assessment

This study presents valuable findings on the role of the small GTPase Rab3A in homeostatic plasticity. While the study demonstrates that Rab3A is required for homeostatic scaling, the evidence supporting the model put forward by the authors is incomplete. The work will be of interest to researchers in the field of synaptic transmission and plasticity.

eLife assessment

This is an important study that addresses a significant question in microbiome research. The authors provide convincing evidence that certain bacterial groups within the fly microbiome have critical functions for host development. Additionally, dietary aspects such as microbial community progression in a natural food source are integrated into their host-microbe interaction analyses.

eLife assessment

This manuscript analyzes large-scale Neuropixels recordings from visual areas and hippocampus of mice passively viewing repeated clips of a movie and reports that neurons respond with elevated firing activities to specific, continuous sequences of movie frames. The important results support a role of rodent hippocampal neurons in general episode encoding and advance understanding of visual information processing across different brain regions. The strength of evidence for the primary conclusion was found to be convincing.

eLife assessment

This is an important study that tests the effects of using neurofeedback, in the form of reward delivery when large sharp wave-ripples (SWRs) are detected, on neurophysiological and behavioral measures. The authors provide convincing evidence that the rate of SWRs increased prior to reward delivery and decreased in the period after reward delivery, with no significant effect on memory performance. The ability to manipulate SWR rate in a naturalistic way is a potentially exciting new tool for studies that seek to understand the function of SWRs.

eLife assessment

This manuscript represents a cleanly designed experiment for assessing biological motion processing in children (mean age = 9) with and without ADHD. The group differences concerning accuracy in global and local motion processing abilities are solid, but the analyses suggesting dissociable relationships between global and local processing and social skills, age, and IQ need further interrogation. The results are useful in terms of understanding ADHD and the ontogenesis of different components of the processing of biological motion.

eLife assessment

In this important study, the authors develop a promising experimental approach to a central question in ecology: What are the contributions of resource use and interactions in the shaping of an ecosystem? For this, they develop a synthetic ecosystem set-up, a variant of SELEX that allows very detailed control over ecological variables. The evidence is convincing, and the work should be of broad interest to the ecology community, leading to further quantitative studies.

eLife assessment

This important paper reports on the redistribution of Pol V and DNA methylation from euchromatic to heterochromatic regions in H1 mutants. While some of the evidence is solid, other parts of the genome-level model proposed to explain the molecular phenotype of H1 mutants (which includes a reduction of DNA methylation at some euchromatic sites) would benefit from additional experimental support. The work will be of broad interest to individuals interested in the mechanisms that have evolved to partition eukaryotic genomes into euchromatic and heterochromatic regions.

eLife assessment

This important study combines experiments and theory to develop a sex-based in silico model of arterial myocytes. The ionic currents of the model and its sex difference based on experimental data and comparisons of model properties with experimental data at the single cell and tissue scale are convincing. If the rigor used to assess the model (specifically the simplicity of the 1D vessel model) was improved, and there was an addition of quantitative analysis of the data examining similarity between male/female experimental/simulation, the paper would be improved.

eLife assessment

The study by Deichsel et al. reports valuable findings that suggest a new, possibly conserved, mechanism by which post-translational modification of a Notch regulator mediates the cellular immune response. However, the claims are only partially supported as the data and analysis are incomplete. The work will be of interest to biologists working on immune cell development or regulation of Notch.

eLife assessment

In this valuable study, patients homozygous for both minor frequency alleles of the APOL1 gene are shown to be at significant risk for progression into sepsis after infection. The study has enrolled a significant number of subjects and provides solid results. The study addresses to infectious diseases and critical care experts and one major weakness is the lack of inclusion of non-Black patients.

eLife assessment

This study presents a rather valuable finding that IQGAP1 interacts with TNFAIP2, which activates Rac1 to promote drug resistance in TNBC. The evidence supporting the claims of the authors is quite solid. The work will be of interest to scientists working on breast cancer.

eLife assessment

This study presents a valuable finding for the treatment of PCCs by sequencing 16 tumor specimens from five patients with pheochromocytomas by single-cell transcriptomics and proposing a new molecular classification criterion based on the sequencing results and characterization of tumor microenvironmental features. The evidence supporting the claims of the authors is solid, although the inclusion of more patient samples would strengthen the study's conclusions. The work will be of interest to clinicians or medical biologists working on rare pheochromocytomas (PCCs).

eLife assessment

The authors present a potentially useful model involving Ca2+ signaling in inflammasome activation. As it stands, it was felt that the data were not sufficient to support the model and the claims of the study are inadequately presented.

eLife assessment

This important study describes the discovery and further engineering of a red light-activated, chloride-conducting Channelrhodopsin (ACR) that could be used to inhibit neuronal activity. The authors were able to demonstrate some inhibition of neuronal activities in vitro and in vivo with 635 nm light, however the study was incomplete. Adequate controls and direct comparisons to the performance of already-established variants were missing, making it difficult to confirm the future utility of MsACR1 and raACR1.

eLife assessment

This paper describes a new complexity estimator for time series based on state-space modeling, which can directly decompose signal entropy in both time and frequency. The authors compare their estimator to Lempel-Ziv (LZ) complexity using a variety of time series neurophysiological data from humans and non-human primates. This represents a potentially valuable methodological contribution for existing studies using LZ complexity in their analyses, although the paper currently ignores much of the existing literature which has already developed related solutions to the same issues. The strength of the evidence supporting the superiority of the new complexity metric is currently incomplete, and should be backed by additional analyses.

eLife assessment

This paper presents an important contribution to the field of hippocampal registration by introducing a novel surface-based approach that utilizes the topological and morphological features of the hippocampus for anatomical registration across individuals, rather than volumetric-based methods commonly used in the literature. The study provides compelling evidence for the efficacy of this approach using histological samples from three different datasets and offers validation of the method through comparison with traditional volumetric registration. This is important work given the large number of studies that examine hippocampal shape, thickness, and function in large cohorts, providing strong support for the use of hippocampal unfolding methods in future studies.

eLife assessment

This important and compelling study investigates the problem of intracellular acidification induced by commonly-used optogenetic stimulating opsins. The low proton permeability of two high-performance opsins is shown to reduce photostimulated acidification. The findings may be of broad interest in the fields of neuroscience research and optogenetic therapies.

eLife assessment

This study presents important findings indicating that gradients of functional connectivity are present in the human foetal brain, and that these gradients develop further during gestation, particularly in multisensory brain regions. The study uses state-of-the-art connectomic mapping techniques. However, recent findings suggest that such gradients may reflect confounds within the analysis technique more than underlying brain functions. The evidence for the authors' claims therefore currently appears inadequate as it does not account for these potential confounds.

eLife assessment

This important study uses a combination of computational modeling and glutamate imaging to show how a particular synaptic organization referred to as space-time wiring has a limited contribution to a dendritic computation that occurs in the retina. The evidence supporting the claims of the authors is convincing, although the findings are largely confirmatory of previous modeling and experimental results. The work will be of interest to retinal neurobiologists and neurophysiologists interested in dendritic computations.

eLife assessment

The finding that Fusicoccin promotes locomotor recovery after spinal cord injury is useful, and the idea of harnessing small molecules that may affect protein-protein interactions to promote axon regeneration is interesting and worthy of study. However, the main methods, data, and analyses are inadequate to support the primary claim of the manuscript that a 14-3-3-Spastin complex is necessary for the observed Fusicoccin effects.

eLife assessment

Franke et al. explore and characterize the color response properties in the mouse primary visual cortex, revealing specific color opponent encoding strategies across the visual field. The data is solid; however, the evidence supporting some conclusions and details about some procedures are incomplete. In its current form, the paper makes a useful contribution to how color is coded in mouse V1. Significance would be enhanced with some additional analyses and resolution of some technical issues.

eLife assessment

This study presents valuable findings on the roles of the axon growth regulator Sema7a in the formation of peripheral sensory circuits in the lateral line system of zebrafish. The evidence supporting the claims of the authors is solid, although further work directly testing the roles of different sema7a isoforms would strengthen the analysis. The work will be of interest to developmental neuroscientists studying circuit formation.

eLife assessment

This valuable study has the potential to shed mechanistic light on how attention mechanisms that influence competition between multiple visual stimuli are modulated by the relative neural similarity of these stimuli. The study implements an interesting experimental design that provides relevant data, especially for future modeling efforts. However, the presented evidence is considered incomplete due to some features of the design and model, as well as certain analysis choices.

eLife assessment

This study provides a valuable 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 validation of the results is needed to further strengthen the major conclusions of the work. The work will be of broad interest to biophysicists and biochemists.

eLife assessment

This paper presents data suggesting the novel finding that stimulating the senses can open the normal barrier to the brain and lead to changes in the brain. However, the paper was unclear in methods and data, which made the strength of evidence for the conclusions seem incomplete. However, the reviewers considered the potential significance of the study to be important.

eLife assessment

This study suggests that PAK3 may play a critical role in cognitive function after cranial irradiation, highlighting a potential therapeutic target to mitigate the adverse effects of radiotherapy. The main finding is of significance, and the evidence is compelling to support their major conclusion. This is an important discovery providing novel insight into the molecular mechanism of how PAK3/LIMK/Cofilin signaling modulates synaptic spine morphology in response to irradiation.

eLife assessment

This paper presents a valuable pipeline based on state-of-the-art analytical software that was used to study genetic pleiotropy between neuropsychiatric disorders. The presented evidence supporting the claims is solid, although the paper is lacking an appropriate comparison to previously published methods as well as a more detailed exploration of some of the findings. The created pipeline is made publicly available and can thus be used by researchers from diverse fields to study different combinations of diseases and traits.

eLife assessment

Chang et al. provide glutamate co-expression profiles in the central noradrenergic system and test the requirement of Vglut2-based glutamatergic release in respiratory and metabolic activity under physiologically relevant gas challenges. Their experiments provide compelling evidence that conditional deletion of Vglut2 in noradrenergic neurons does not impact steady-state breathing or metabolic activity in room air, hypercapnia, or hypoxia. This study provides an important contribution to our understanding of how noradrenergic neurons regulate respiratory homeostasis in conscious adult mice.

eLife assessment

Multimodal experiences that for example contain both visual and tactile components are encoded as associative memories. This manuscript is a valuable contribution supporting structural and functional brain plasticity following associative training protocols that pair together different types of sensory stimuli. The results provide solid support for this plasticity being a basis for cross-modal associative memories.

eLife assessment

This fundamental study provides a unique tool for assessing the range of phosphorylation in insulin reactions due to genetic variation and dietary influence through the utilization of genetically distinct mouse strains. The discoveries of this study hold substantial importance, as they shed light on the interplay between genetic attributes and environmental conditions in shaping the insulin-signaling network within skeletal muscle, a crucial regulator of metabolism. The supporting evidence presented is compelling, and the work is anticipated to captivate a wide audience within the metabolism discipline due to its extensive appeal and by providing inspiration for further hypothesis-driven research.

eLife assessment

This important study presents convincing evidence for the utility of orangutan teeth as terrestrial proxies to reconstruct rainfall regimes, while exploring the potentially conflicting impact of breastfeeding signals. The findings have ramifications for the methods and tools used by the field in the reconstruction of environmental conditions in the historical and archeological past.

eLife assessment

This fundamental work uses computational network models to suggest a possible origin of the wide range of time scales observed in cortical activity. This claim is supported by convincing evidence based on comparisons between mathematical theory, simulations of spiking network models, and analysis of recordings from the orbitofrontal cortex. This manuscript will be of interest to the broad community of systems and computational neuroscience.

eLife assessment

This valuable work explores how transcription factors regulate transcription through cooperative binding to enhancers. Through experiments and modeling, the authors show convincingly that the cooperativity of transcription factor binding regulates transcriptional bursting and the extent of the amount of time that the target promoter remains in an active state.

eLife assessment

This manuscript reports important new results, but it provides incomplete support for its claims. Recent data has shown that schizophrenia-related synaptic alterations induce changes in neural network synchrony, and this manuscript provides the first theoretical understanding of the underlying network mechanisms. Proper support for this result, however, requires a tighter link between the computational model and the experimental data and a more in-depth understanding of the model mechanisms.

eLife assessment

In this important study, Esmaily and colleagues investigate the "confidence matching" between two agents and present a useful exploration of its computational and physiological correlates. Further analyses would be helpful to provide a tighter link between fluctuations of confidence, pupil size, EEG response, and computational variables, to delineate the causal relations between these quantities, which are nevertheless incompletely documented at present.

eLife assessment

This study reveals a novel mechanism of Acetylcholine- Acetylylcholine receptor signaling in regulating gut barrier function in Drosophila, which provides important implications on the pathway played in human diseases, such as Chronic Obstructive Pulmonary DiseaseCOPD. The evidence supporting the claims of the authors is solid.

eLife assessment

The present study provides a valuable new perspective on the optomotor response based on an inversion of the behavior under specific (non-natural) conditions that may help elucidate the principles of this specific behavior. The evidence provided is convincing.

eLife assessment

Using a novel micropipette-based, minimally invasive approach in combination with theoretical and computational analysis, this important work probes tissue mechanics in the Drosophila embryo. The authors provide compelling evidence for the applicability of their method, which reveals important differences between the mechanical properties on the apical and basal tissue sides. This work should be of broad interest to scientists studying tissue mechanics, membranes, and developmental processes.

eLife assessment

This elegantly performed and rigorous study generates new and conceptually important insights into the interaction between an essential malaria parasite invasion ligand (and vaccine candidate) called PfRH5, and its erythrocyte surface integral membrane receptor basigin. The authors provide compelling evidence based on rigorous biochemical assays that erythrocyte basigin is predominantly expressed in a complex with one of two distinct erythrocyte membrane proteins called PMCA and MCT1 and that PfRH5 binds to these complexes better than to isolated basigin. Certain invasion-inhibitory antibodies, that do not prevent binding of PfRH5 to isolated basigin, do in contrast prevent binding to the basigin complexes, explaining the mode of action of these previously enigmatic antibodies and providing valuable data towards the improved design of vaccines based on PfRH5.

eLife assessment

This study provides a potentially useful assessment of the effect of testing contacts of cases in school classes when identified, rather than at the end of quarantine, on both the number of secondary infections and other outcomes including tracing delay and identification of the possible source of infection. The authors find that the intervention likely led to a decrease in tracing delay and an increase in the number of possible sources of infection, though were unable to determine whether secondary transmission decreased, due in part to unmeasured confounding. While the surveillance system described provides a solid dataset appropriate for this analysis, the description of methods, study outcomes, and consideration of potential confounding factors is incomplete.

eLife assessment

The manuscript describes a set of detailed modeling and experimental studies to disentangle the respective roles of gap junctional electrical vs. metabolic coupling mechanisms in the synchronization of islet activity. This is of interest due to the importance of islet synchronization and generally islet network properties in the regulation of insulin secretion from the pancreas. The significance of the findings was judged to be mostly important and the strength of evidence provided was judged to be mostly solid overall.

eLife assessment

In this study, Sparta et al., generated and employed a battery of fluorescent reporters that allowed them to perform time-resolved monitoring of mechanistic target of rapamycin complex 1 (mTORC1) responses to stimuli including glucose, amino acids, and insulin at the single cell resolution. The results of this elegant approach support a model of graded mTORC1 activation in response to the aforementioned stimuli when applied individually or in combination. This model is consistent with continuous adjustment of mTORC1 signaling to changes in cellular environment and opposed to the "on/off" model of mTORC1 function. Considering the pivotal role of mTORC1 in integrating signals such as nutrients, hormones, growth factors, oxygen, and energy status with a plethora of outputs that affect cell fate and organismal physiology, it was thought that this study will be of interests across a variety of biomedical disciplines. Overall, the elegance and robustness of the approach was highly appreciated, though the paper would be strengthened by addressing some technical issues and concerns regarding the positioning of the proposed model of mTORC1 regulation in the field.

eLife assessment

This important study describes a high performance computational approach to interrogate how microscopic epistasis and clonal interference affect evolutionary dynamics in a spin glass model of microbial evolution. The study offers several insights that can aid in our understanding of the forces that operate in adaptive evolution. The evidence provided is compelling, with its rigorous use of models and analytical descriptions of how these forces manifest in evolution.

eLife assessment

This important study reports how swallowtail butterflies pattern structures composed of chitin at the nanometer scale to produce structural colors. The work uses state-of-the-art microscopy techniques to convincingly show that F-actin is utilized in these butterflies in a novel way to produce structure, paving the way for further studies on growth regulation leading to precise ultrastructures and structural colors.

eLife assessment

This important manuscript reveals signatures of co-evolution of two nucleosome remodeling factors, Lsh/HELLS and CDCA7, which are involved in the regulation of eukaryotic DNA methylation. The results suggest that the roles for the two factors in DNA methylation maintenance pathways can be traced back to the last eukaryotic common ancestor and that the CDC7A-HELLS-DNMT axis shaped the evolutionary retention of DNA methylation in eukaryotes. The solid evolutionary analyses form an interesting basis for experimental follow-up studies. The work should be of interest to colleagues in the fields of evolutionary biology, chromatin biology and genome biology.

eLife assessment

Large scale cell movements occur during gastrulation in vertebrate embryos but their role in this major morphogenetic transition in formation of the body plan is poorly understood. Using the chick embryo model system, this study makes important advances using elegant methods to show that extension of the primitive streak during gastrulation, occurring through cell proliferation, polarisation and intercalation, and large-scale polonaise cell movements, can be uncoupled. Although the driving mechanism and precise role of these movements remains a mystery, the study provides convincing evidence for the uncoupling through independent approaches, the most creative of which are the effects shown after induction of a supernumerary primitive streak.

eLife assessment

This valuable study uses phylogenetic linear mixed models in a Bayesian framework to explore the relationships between taste qualities and the therapeutic use of botanicals from the ancient Graeco-Roman vademecum. The evidence supporting the authors' conclusions is, however, incomplete, and the paper would benefit from a more exhaustive methodological description. The work is nevertheless of broad relevance to ethnobotanists, pharmacologists, and scientists working on drug discovery, particularly those interested in natural products.

eLife assessment

This important study uncovers a surprising link between two self-cleaving RNAs that belong to the same structural family. The evidence supporting the main conclusions is convincing and based on extensive biochemical and bioinformatic analysis. This research will be of broad interest to RNA molecular biologists and biochemists.

eLife assessment

This valuable study presents a solid transcriptomic analysis of enterochromaffin cells, but there are weaknesses in the functional and physiological data describing the role of enterochromaffin cell mechanosensory receptors (Piezo2 channels) in regulating colonic motility.

eLife assessment

This important study reconstructs the evolutionary history of Heliconius butterflies, a well-established model system for understanding speciation in the presence of gene flow between species. Using a convincing statistical phylogenetic approach that relies on the multispecies coalescent, the authors reconstruct the evolution of the lineage, including the timing of speciation events and the history of gene flow. The new phylogeny will be of interest to all researchers working on Heliconius butterflies, and the phylogenetic approach to investigators aiming to understand the history of lineages that have experienced extensive gene flow.

eLife assessment

This important study reports a new mutant mouse with compromised function of one of the BRCT repeats of TOPBP1, a DNA damage response protein. Mutant mice are viable but males are sterile, owing to the lack of spermatocytes beyond the late pachynema stage of the first meiotic prophase. Using immunofluorescence, phospho-proteomics and single-cell sequencing of cells in the testis, the authors provide solid evidence that the animals are defective in the maintenance (but not the initiation) of sex chromosome inactivation in pachynema. The report is of interest to researchers in the fields of meiosis as well as gene silencing/sex chromosome inactivation.

eLife assessment

The manuscript by Kahraman et al. describes the use of a fluorescent dye for purifying and analyzing human islet alpha cells. The study provides solid evidence that the alpha cells can be purified using this method and the cells remained viable and functional after culturing for several days. The significance of the study is access to a new tool that will be useful for islet biologists and researchers studying diabetes mechanisms.

eLife assessment

This study presents valuable findings that could be utilized for the identification of women at risk for preeclampsia prior to the onset of the disease. The novel aspect of this study lies in the utilization of exosomes with two different sizes. However, the data is incomplete: the patient population has not been well-defined, and the study only measured the proteins at a single time point.

eLife assessment

This important study describes how the composition and stabilization of nanodomains in the plasma membrane are an integral part of plant defence against viruses, with a focus on the calcium-dependent kinase CPK3 and its apparent interaction with a plasma-membrane nano domain scaffold protein from the remorin family. While the evidence for a specific role of CPK3 in limiting viral spread is convincing, the claims regarding the CPK3-remorin interaction would be strengthened by additional experimental support. The work, which will be of interest to plant cell biologists and plant virology, opens new avenues for understanding the role of plasma membrane nanodomains in limiting viral spread.

eLife assessment

This study has uncovered some important initial findings about cellular responses to aneuploidy through analysis of gene expression in a set of donated human embryos. While the study's findings are in general solid, some experiments lack statistical power due to small sample sizes. The authors should try to get much more insight with their data highlighting the novel findings.

eLife assessment

This study has uncovered some interesting findings about the fungal composition and its interaction with bacteria in Caesarean section scar diverticulum (CSD). While the study's findings are valuable and with translation possibilities, the strength of the conclusions obtained is incomplete due to the small sample size and methodological issues indicated by the reviewers such as the lack of controls and the location of samples analyzed.

eLife assessment

This valuable study describes engineered dengue virus variants that can be used to dissect epitope specificities in polyclonal sera, and to design candidate vaccine antigens that dampen antibody responses against undesirable epitopes. While the major claims are supported by solid evidence, experiments to distinguish the impact on antibody binding from neutralizing activities would have strengthened the study. This work will be of interest to virologists and structural biologists working on antibody responses to flaviviruses.

eLife assessment

This important study explores numerous lines of evidence for the surprisingly diverse diets of a group of toothed birds that lived over 100 million years ago. The large amount of data the authors collected forms a solid dataset for their statistical analyses. The methods are, to various extents, extensible to other limbed vertebrates. The conclusions in the article itself will be of interest to anyone who studies ecological evolution in birds or dinosaurs more generally, as well as to anyone who studies the impact of the mass extinction event 66 million years ago on ecology and evolution.

eLife assessment

This study describes an important bioinformatics tool for normalizing gene copy number from metagenomic assemblies. The tool is used in a meta-analysis of data from inflammatory bowel disease (IBD) patients and healthy controls. While some of the evidence for the power of the method is compelling, other evidence seems incomplete. The inclusion of additional computational and/or experimental validation would markedly strengthen the study. This paper will likely be of broad interest to researchers studying the role of complex microbial communities in host health and disease.

eLife assessment

This important work provides a comprehensive study of how different cell types of the lateral and dorsomedial hypothalamus are affected by an Influenza H1N1 infection. The evidence presented here is solid; the methodological approach is state-of-the-art, however, the theoretical analysis can be strengthened by further reanalysis of the datasets. This work is of interest to virologists and neurobiologists as the results are promising and open a new door to understanding the effect of respiratory viruses on the physiology of the central nervous system.

eLife assessment

In this valuable paper, the authors analyze the functions of the five C-terminal repeat sequences in the Dux embryonic transcription factor and their role in recruiting cofactors for gene regulation. The evidence is solid and the work is carefully done, although additional experiments could strengthen the overall conclusions of the manuscript.

eLife assessment

This study provides important imaging evidence for the connectopic mapping of the locus coeruleus (LC) and links a rostro-caudal gradient to heterogeneous functional organisation of this structure. Using a well-established gradient approach applied to large 3T and 7T fMRI datasets, the study demonstrates a change in LC functional gradients with increasing age. Overall, the study provides solid evidence and highlights the importance of using more specific spatial definitions of the LC based on distinct connectivity patterns in future studies.

eLife assessment

The role of CRB3A/B in ciliogenesis was discovered several years ago in epithelial cells and in vivo, but the mechanism by which CRB3A/B regulates ciliogenesis has been unknown. Here, the authors confirm the requirement of CRB3A/B expression for primary ciliogenesis in both mouse and human cells and propose a mechanism by which CRB3A/B promotes ciliogenesis. The results are useful but currently incomplete: further experimentation and data analysis are needed to support some of the authors' central claims.

eLife assessment

This study presents valuable insights into the circuit mechanisms of how the fly nervous system modulates ingestive behaviors in response to metabolic conditions. The authors present convincing findings on how downstream neurons connected to Interoceptive Subesophageal zone Neurons modulate nutrient and/or water ingestion in Drosophila melanogaster.

eLife assessment

There is a tremendous need to increase agricultural productivity with means that are both practical and efficient. Drawing on data from variable field environments, this important study provides a theoretical framework for the identification of new factors with presumed relevance for crop growth. This framework can be applied in the context of both agricultural and ecological studies. There is solid evidence for several of the authors' claims, but the impact of the study is limited due to missing functional validation of candidate species in the field. Plant biologists and ecologists working in agricultural and natural environments will find the work interesting.

eLife assessment

There is a tremendous need to find practical and efficient means in order to increase agricultural productivity. Drawing on data from variable field environments, this study provides a valuable theoretical framework to identify new factors that could increase agricultural production. There is solid evidence to support the authors' claims, though following the fate of candidate species after introduction into rice fields would have strengthened the study. Plant biologists and ecologists working in nature and fields will find the work interesting.

eLife assessment

This fundamental study provides a framework for leveraging systems genetics data to dissect mechanisms of gut physiology. The authors provide compelling analyses to highlight diverse modes of interrogating intestinal inflammation, dietary response, and consequent impacts on IBD. As a resource, it will have great utility for linking genetic variation and diet to gut-related pathophysiologies.

eLife assessment

This valuable study contributes to understanding how retinal activity shapes the response properties of excitatory and inhibitory neurons in a major visual target, the superior colliculus. The evidence supporting the claim is convincing: the work is technically excellent yet the interpretation of these results assumes an unbiased sampling and integration of the RGC axon in the SC, a caveat pointed out by the authors. Overall, this study provides insights into the integration of visual information from the eye to the brain, and this work will be of interest to visual neuroscientists.

eLife assessment

This fundamental study leverages natural genetic diversity in mice to discover candidate genes for insulin sensitivity, followed by experimental identification of compounds that can modulate insulin sensitivity, and finally initial mechanistic investigation of the mode of action. The generalized approach presented here – the integration of systems genetics data with drug discovery – supported by compelling evidence, will be a guide for others who seek to translate insights from mammalian genetics to drug discovery.

eLife assessment

This important study leverages natural genetic diversity in mice to discover candidate genes for insulin sensitivity, followed by experimental identification of compounds that can modulate insulin sensitivity, and finally initial mechanistic investigation of the mode of action. The generalized approach presented here – the integration of systems genetics data with drug discovery – supported by convincing evidence, will be a guide for others who seek to translate insights from mammalian genetics to drug discovery.

eLife assessment

This valuable manuscript attempts to identify the brain regions and cell types involved in habituation to dark flash stimuli in larval zebrafish. Habituation being a form of learning widespread in the animal kingdom, the investigation of neural mechanisms underlying it is a worthwhile endeavor. The authors use a combination of behavioral analysis, neural activity imaging, and pharmacological manipulation to investigate brain-wide mechanisms of habituation. However, the data presented are incomplete and do not show a robust causative link between pharmacological manipulations, neural activity patterns, and behavioral outcomes.

eLife assessment

This study presents fundamental new insight into the regulatory apparatus of PI3Kgamma, a crucial kinase in signaling pathways that control the immune response and cancer. A suite of biophysical and biochemical approaches provide convincing evidence for new sites of allosteric control over enzyme activity. The rigorous findings provide structure and dynamic information that may be exploited in efforts to control PI3Kgamma activity in a therapeutic setting.

eLife assessment

This paper demonstrates valuable evidence for genetic redundancy of the COUPTF transcription factors in hippocampal development by creating conditional compound knockouts in combination. Authors aim to demonstrate specific and complementary roles of the two COUPTF homologues. The paper uses convincing methods that includes both anatomic and behavioral studies for the roles of these factors. However, the strength of evidence was incomplete, due to the use of a Cre line that was not adequately described, and lack of concordance with expression domains of the COUPTF factors with the published literature dampened enthusiasm. This concern is expressed by reviewers in the interpretation of some of the finding that may require additional experiments in the future.

eLife assessment:

This valuable study, of interest for students of the biology of genomes, uses simulations in combination with published data to examine how many TADs remain after cohesin depletion. The authors suggest that a significant subset of chromosome conformations do not require cohesin, and that knowledge of specific epigenetic states can be used to identify regions of the genome that still interact in the absence of cohesin. The theoretical approaches and quantitative analysis are state-of-the-art, and the data quality and strength of the conclusions are solid. However, because "physical boundaries (of domains?)" in the model appear to be a consequence of preserved TADs, rather than the other way around, the functional insights are limited.

eLife assessment

This valuable study presents a novel analysis of a large human intracranial electrophysiological recording dataset. The study challenges the traditional view that neural responses to word lists exhibit smoothly drifting contexts over time, showing that items just after a boundary have a characteristic response that occurs repeatedly. The evidence is incomplete, however, leaving open the possibility for alternative explanations.

eLife assessment

This convincing study, which is based on a survey of researchers, finds that women are less likely than men to submit articles to elite journals. It also finds that there is no relation between gender and reported desk rejection. The study is an important contribution to work on gender bias in the scientific literature.

eLife assessment

This study, of interest to cell biologists, presents valuable findings on the positioning mechanics of microtubule asters in Drosophila embryo explants. While the experimental setting is artificial (centrosomes are detached from nuclei and the cell cycle is arrested in interphase in these explants), it extends the framework of aster positioning from recently published work. The authors reach the conclusion that asters interact via pushing forces, an interesting conclusion supported by solid evidence. The identification of motors and MAPs functioning in the aster positioning mechanism would further strengthen the study.

eLife assessment

This important study identifies a short amino acid sequence that, when fused in multimeric form to the amino termini of luminal ER proteins, initiates proteasomal degradation via the Hrd1 ER quality control ubiquitin ligase complex. The authors provide solid evidence that this sequence functions as a "degron" for ER proteins. Future work is required to get a more detailed view of the properties of this degron, the mechanisms underlying its recognition by ER-resident and cytoplasmic factors, and the in vivo relevance of the findings.

eLife assessment

This study presents a useful inventory of the joint effects of genetic and environmental factors on psychotic-like experiences, and identifies cognitive ability as a potential underlying mediating pathway. The data were analyzed using solid and validated methodology based on a large, multi-center dataset. The claim that these findings are of relevance to psychosis risk and have implications for policy changes are partially supported by the results.

eLife assessment

This valuable study examines the ancestral function of Hippo pathway kinases in contractility and cell density in the ameboid organism Capsaspora owczarzaki, a unicellular animal that is a close relative of multicellular animals. There is solid evidence for Hippo kinases regulating contractility and cell density but not proliferation in C. owczarzaki. The work complements previous work on the Hippo effector Yorkie homolog in this species, although the unavailability of extensive genetic tools in this species precludes informative epistasis experiments. The work would be of interest to evolutionary and developmental biologists.

eLife assessment

This important study combines extensive phenotyping of genome-wide deletion mutants and machine learning-based prediction to generate a large scale resource for understanding the functions of thousands of fission yeast protein-coding genes. This resource is supported by convincing phenotyping data and state-of-the-art bioinformatic analyses and will be of interest to many geneticists.

eLife assessment

This important study advances our understanding of the functions and regulation of the Drosophila transcriptional regulator Bonus, an ortholog of mammalian TIF1 family members. Solid evidence, leveraging both in vivo and in vitro studies, reveals the molecular requirements for Bonus' function as a transcriptional repressor, including a key role for sumoylation.

eLife assessment

This important study expands on current knowledge of allosteric diversity in the human kinome by C-terminal splicing variants using as a paradigm DCLK1. The authors provide convincing evolutionary and some mechanistic evidence how C-terminal isoform specific variants generated by alternative splicing can regulate catalytic activity by means of coupling specific phosphorylation sites to dynamical and conformational changes controlling active site and substrate pocket occupancy, as well as protein-protein interactions. The data will be of interest to researchers in the kinase and signal transduction field.

eLife assessment

This important study in the protozoan parasite Toxoplasma gondii significantly advances our understanding of calcium signaling mediated by the kinase CDPK1 in this species. The authors' conclusions are supported by convincing evidence, with rigorous biochemical experiments and microscopy analysis. The work will be of broad interest to researchers in the fields of signal transduction and protozoan biology.

eLife assessment

This work presents important insights regarding the mechanism underlying the assembly, maintenance, and disassembly of a very stable microtubule-based structure, termed quiescent-cell nuclear microtubule (Q-nMT) bundle, formed in quiescent yeast cells to ensure cell survival and viability. Some of the evidence is solid, but some of the major claims are only incompletely supported and require additional analyses using state-of-the-art methodology and more precise descriptions.

eLife assessment

This study provides a clearly presented and thoughtfully analyzed single cell-resolution dataset of gene expression in wildtype and mutant zebrafish skin. These data are used by the authors to develop and test hypotheses about cell lineage relationships and signaling interactions between cell types in the skin, allowing them to identify roles for several signaling pathways and the hypodermis in scale and pigment cell development. These findings constitute a fundamental contribution to the field, and the rigor of the analyses make this manuscript compelling.

eLife assessment

This study presents valuable findings on genetic risk factors for type 1 diabetes and celiac disease using a large cohort from the Environmental Determinants of Diabetes in the Young (TEDDY) study. The evidence supporting the claims of the authors is solid, although the inclusion of the genetic effect of this locus on individuals with different genetic backgrounds would have strengthened the study. The work will be of interest to population geneticists working on diabetes and celiac disease.

eLife assessment

This study presents a valuable set of experiments to test whether Bombus terrestris bumblebees can detect lethal-level doses of a series of pesticides in nectar-mimicking sugary solutions. Behavioural essays were coupled with electrophysiological measurements to show that B. terrestris mouthparts cannot detect high levels of the tested pesticides. If confirmed using pesticide formulas, and other bumblebee species, the study will be of general interest in environmental science research. Most experimental data are compelling, and the conclusions are solid, but the write-up would benefit from being more to the point and less overgeneralizing.

eLife assessment

The findings of this work on the protective role of Leucine in LPS-induced cytokine release syndrome by modulating macrophage polarization are potentially valuable in establishing the link between metabolic regulation of macrophage function and inflammatory responses. The evidence supporting the conclusions that the mTORC1/LXRa axis but not the STAT6 pathway mediates Leucine-promoted M2 polarization are is solid. The manuscript is well written, but the mechanistic studies are incomplete, hence should be improved.

eLife assessment

This convincing study demonstrates a potentially important role for the factor Numb in skeletal muscle excitation-contraction coupling. Numb knockout reduced contractile force. The authors thus demonstrate a novel role for Numb in calcium release in skeletal muscle.

eLife assessment

This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. While of significant interest to those working on the immune biology of urothelial cancer and drug discovery, this work does not provide any mechanistic insights into the role of DUX4 and immune suppression and the assessment on clinical samples forms the discovery part of a biomarker program, requiring further cohorts for validation.

eLife assessment

The authors have made important contributions to our understanding of the pathogenesis of erectile dysfunction (ED) in diabetic patients. They have identified the gene Lbh, expressed in pericytes of the penis and decreased in diabetic animals. Overexpression of Lbh appears to counteract ED in these animals. The authors also confirm Lbh as a potential marker in cavernous tissues in both humans and mice. While solid evidence supports Lbh's functional role as a marker gene, further research is needed to elucidate the specific mechanisms by which it exerts its effects. This work is of interest to those working in the fields of ED and angiogenesis.

eLife assessment

This manuscript presents a useful method for a comprehensive numerical simulation to systematically characterise the effect of heterogeneity in either the initial conditions or the biophysical parameters on the dynamic behaviour of protein signalling networks. Nevertheless, the presentation and detail of their model appear incomplete to fully support the main claims of the manuscript.

eLife assessment

The authors set out to study the development of high altitude polycythemia, which affects mice in a hypoxia chamber and humans staying at a hypoxic atmosphere at high altitude. The findings are useful both for initiating the discussion of the hypothesis that splenic red pulp macrophages, central to red cell survival, are impacted by hypoxia, and for providing some data that partially supports this hypothesis. However, the current data are inadequate to fully support the authors' conclusions that RPM are inefficient during hypoxia, reducing erythrophagocytosis, and new data provides evidence of the opposite conclusion, given that RBC lifespan is decreased (rather than increased) in response to hypoxia, suggesting that RPM are more efficient at erythrophagocytosis.

eLife assessment

The authors generate a new formulation built upon a previous nanoparticle platform to generate a new system termed bicontinuous nanospheres (BCN), allowing for the dual incorporation of lipid and protein antigens. The authors generate mycolic acid (MA)-loaded BCN and perform a series of characterization studies to demonstrate the superior performance of this new formulation relative to the original one in terms of antigen persistence, a quality needed to sustain responses after vaccination. This work provides important new insights relevant to the TB vaccine field and it suggests that alternative antigens to proteins could be used in TB vaccine formulations. The data are convincing and will be of interest to individuals working on tuberculosis, vaccines and basic immunology.

eLife assessment

This work is useful as it highlights the importance of data analysis strategies in influencing outcomes during differential gene expression testing. While the manuscript has the potential to enhance awareness regarding data analysis choices in the community, its value could be further enhanced by providing a more comprehensive comparison of alternative methods and discussing the potential differences in preprocessing, such as scFLOW. The current analysis, although insightful, appears incomplete in addressing these aspects.