eLife assessment

This is an important study that characterized the activity of optogenetically identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) in mice performing a memory-guided T-maze task. The authors show that subpopulations of dopaminergic and GABAergic neurons exhibited choice-related activity during the delay period, which was enhanced when the task requires short-term memory. The reviewers found that the results are surprising, novel, and convincing, while some relatively minor issues were pointed out regarding the data presentation and analysis.

eLife assessment

This study proposes a deep learning-based segmentation pipeline of fetal brain MRI, with parcellation based on a newly implemented atlas. This represents an important contribution to the field of developmental neuroscience and pediatric neuroimaging, especially as the pipeline and atlas are publicly available. The evidence for the pipeline robustness and atlas relevance is convincing given the extensive validations provided and the very high-quality ground truth dataset. Although beyond the state of the art, the study would benefit from further comparisons with existing methods and additional evaluations of the framework generalizability according to image quality, subject age or brain abnormalities.

eLife assessment

The authors provide a valuable analysis of what neural circuit mechanisms enable varying the speed of retrieval of sequences, as needed for say reproducing motor patterns. Their use of heterogeneous plasticity rules to allow external currents to control speed of sequence recall is a novel alternative to other mechanisms proposed in the literature. They perform a solid characterization of relevant properties of recall via simulations and theory, which would benefit from a better mapping to biologically plausible mechanisms.

eLife assessment

This important study addresses the fundamentally unresolved question of why many thousands of small-effect loci contribute more to the heritability of a trait than the large-effect lead variants. The authors explore resource competition within the transcriptional machinery as one possible explanation with a simple theoretical model, concluding that the effects of resource competition would be too small to explain the heritability effects. The topic and approximation of the problem are very timely and offer an intuitive way to think about polygenic variation, but the analysis of the simple model appears to be incomplete, leaving the main claims only partially supported.

eLife assessment

This is a useful study of the connection between the ubiquitin ligase protein deltex and the wingless signaling pathway. Two different links are inferred from genetic interactions in vivo between loss-of-function mutations and overexpression. While providing useful in vivo physiological context, the approach is necessarily incomplete in so far as it cannot distinguish between direct and indirect mechanisms.

eLife assessment

This study provides an important cell atlas of the gill of the mussel Gigantidas platifrons using a single nucleus RNA-seq dataset, a resource for the community of scientists studying deep sea physiology and metabolism and intracellular host-symbiont relationships. The work, which offers solid insights into cellular responses to starvation stress and molecular mechanisms behind deep-sea chemosymbiosis, is of relevance to scientists interested in host-symbiont relationships across ecosystems.

eLife assessment

The authors provide a fundamental resource, detailing genetic variation of nutrient-responsive islet calcium regulation in mice through the lens of proteomics. The evidence for the mechanisms identified using this resource is compelling and strongly supported by integration with results from genome-wide association studies in humans. The construction of a streamlined and searchable web interface for the data will maximize their accessibility and utilization by the community.

eLife assessment

This study presents a valuable dataset and tool that can aid in arthropathies' assessment, potentially enabling such evaluation to be done outside the lab. There is solid evidence supporting the comparison between the force plate and insole data, which can be strengthened by improvements in cross-validation, but the evidence for distinguishing disease signatures and elimination of walking speed as a factor is inconclusive and would need further analysis. This work will be of interest to physical therapists, clinicians, and researchers in the field of ankle/knee/hip osteoporosis and other lower limb joint diseases.

eLife assessment

This study makes important contributions to our understanding of spinal locomotor circuits by manipulating the function of excitatory and inhibitory V2 interneurons and revelaing their role in locomotor control. The data collected and the methods used by the authors are solid and the authors suggest that V2 excitatory and inhibitory neurons have antagonistic functions in intralimb coordination. This work will be of broad interest for neuroscientists studying development and function of motor circuits.

eLife assessment

This study seeks to determine how synaptic relationships between principal cell types in the olfactory system vary with glomerulus selectivity and is therefore valuable to the sub-field. The methodology is solid, but technical limitations require that claims regarding local interneurons be tempered as they were grouped with other neuron types for analyses, and with only one sample from each glomerulus, it is difficult to assess the import of differences between glomeruli without measures of inter-animal variability.

eLife assessment

This is an important study about the mechanisms underlying our capacity to represent and hold recent events in our memory and how they are influenced by past experiences. A key aspect of the model put forward here is the presence of discrete jumps in neural activity with the posterior parietal region of the cortex. The strength of evidence is largely solid, with some weaknesses noted in the methodology. Both reviewers suggested ways in which this aspect of the model can to be tested further and resolve conflicts with previously published experimental results, in particular the study by Papadimitriou et al 2014 in Journal of Neurophysiology.

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 important study utilizes the nematode C. elegans and mammalian cell culture to investigate the role of MML-1/Mondo in conserved regulation of metabolism and aging. The evidence supporting the conclusions is compelling in some areas, such as localization, upstream pathways, and conservation. It is still incomplete in other areas, such as longevity pathway analysis and the link between Mondo and the key downstream mitochondrial metabolic pathways identified. The paper will be of interest to a broad range of biologists studying aging, metabolism, and transcriptional regulation.

eLife assessment

This is an important follow-up study to a previous paper in which the authors reconstituted CO2 metabolism in Escherichia coli (autotrophy). Here, the authors define a set of three mutations that promote autotrophy, highlighting the malleability of E. coli metabolism. The authors make a convincing case that mutations in pgi are loss-of-function mutations that prevent metabolic efflux from the reductive pentose phosphate autocatalytic cycle, but claims about the role of mutations in two other genes - crp and rpoB - are currently incomplete. This research will be particularly interesting to synthetic biologists, systems biologists, and metabolic engineers aiming to develop synthetic autotrophic microorganisms.

eLife assessment

This study presents a valuable deep learning-based model for predicting fracture within the next five years from just a standard distal radius and ulna scan obtained using high-resolution computed tomography images. The evidence supporting the conclusion that the model-predicted fracture prediction score can be used clinically to identify women at risk of fracture more effectively than with the current standard clinical approach is convincing. This work will be of interest to biomechanists and biomedical engineers working on osteoporosis.

eLife assessment

This study provides important findings on the distinct functions of resident and recruited macrophages during cardiac healing after myocardial ischemia. Using state-of-the-art fate-mapping models and genetic and pharmacological targeting approaches, the authors provide solid evidence that the absence of resident macrophages do not influence infarct size but instead alter the immune cell crosstalk in response to injury. However, the functional evaluation of resident macrophages is limited by potential off target effects in ∆FIRE mice. This study should be of interest to the fields of Development, Immunology and Cardiology.

eLife assessment

This manuscript provides novel and important findings regarding the impact of noradrenergic signaling from the locus coeruleus on hippocampal gene expression. The locus coeruleus is the sole source of noradrenaline to the hippocampus and many rapid molecular changes induced by stress are regulated by noradrenaline. This manuscript provides a rigorous investigation into hippocampal genes uniquely regulated by noradrenaline in the presence or absence of stress. Data were collected and analyses were performed using solid methodology, and the results mostly convincingly support the conclusion made with few weaknesses. The study would benefit from a more comprehensive analyses of sex differences.

eLife assessment

This useful study presents data regarding the presence of synaptic proteins in the extracellular vesicle present in the blood of Parkinson's patients and healthy people, trying to correlate changes in such levels with the progression of Parkinson´s symptoms. The results are preliminary, suggesting that these biomarkers might be useful for this purpose. The evidence is incomplete, and more adequate methods to isolate the extracellular vesicles and quantify the proteins are recommended. Also, a better presentation of the results will help the reader to understand the significance of the report, and in addition, more focused Introduction and Discussion sections are recommended.

eLife assessment

This study presents a valuable new behavioral apparatus aimed at differentiating the strategies animals use to orient themselves in an environment. The evidence supporting the claims is solid, with statistical modeling of animal behavior. Overall, this study will attract the interest of researchers exploring spatial learning and memory.

eLife assessment

By combining electrophysiological analysis of mutant channels and molecular dynamics simulations, this important study identifies a common binding site for two structurally distinct activators of KCNQ1-KCNE1 channels. The findings represent an important advance for the field, with convincing functional and computational data to support the claims. The work will be of interest to those studying the binding of small molecule drugs to membrane protein complexes.

eLife assessment

This valuable study describes an interesting synergism between macropinocytosis and Wnt signaling in multiple biological systems. The main claims are at least partially supported with solid evidence. The pharmacological manipulations comes with a number of caveats, and the mechanistic basis of the described synergism remains unclear. The study will be of interest to cell biologists and biomedical researchers, particularly in the Wnt field and in tumor biology.

eLife assessment

This important study uses near full-length HIV-1 sequencing to examine proviral persistence in various tissues derived from three individuals who received antiretroviral therapy until time of death. Intact as well as defective HIV-1 proviruses are found at various anatomical sites including the central nervous system, results that are convincing and relevant for our understanding of latent viral reservoirs, especially in the brain.

eLife assessment

Alpha-synuclein is a synaptic vesicle associated protein that is linked to a number of neurodegenerative disorders. In this manuscript, the authors provide compelling evidence of alpha-synuclein's interaction with E-domain synapsins as the main culprit mediating the suppression of neurotransmitter release and synaptic vesicle recycling by alpha-synuclein. This important work provides molecular mechanisms underlying the pathophysiological functions of alpha-synuclein.

eLife assessment

This useful study presents a genetically encoded barcoding system that could not only advance transcriptomic studies but that also has potential further applications, such as in high-throughput population-scale behavioral measurements. The evidence supporting the claims of the authors are currently inadequate to demonstrate that the method is indeed greatly superior to existing approaches in behavioural and transcriptomic studies.

eLife assessment

The manuscript looks at how dysregulated purine metabolism impacts the behavior, neural circuits and survival of the fruit fly with the possibility of generating a model for Lesch-Nyhan Disease. The study is valuable but the strength of evidence is currently incomplete regarding the use of this model for LND.

eLife assessment

This study presents a valuable analysis of the effects of covariates, such as age, sex, socio-economic status, or biomarker levels, on the predictive accuracy of polygenic scores for body mass index; it also presents approaches for improving prediction accuracy by accounting for such covariates. While the analyses are solid, the study falls short of providing a cogent interpretation of key findings, which could be of great interest and utility. The work will be of interest to people using and developing methods for phenotypic prediction based on polygenic scores.

eLife assessment

Zhao et al describe a novel function for RAPSYN in bcr-abl fusion associated leukemia. They show that RAPSYN stabilizes the oncogenic BCR-ABL fusion protein. Their findings are important and the strength of findings is convincing. The reviewers have made suggestions about further strengthening the rigor by use of more primary samples.

eLife assessment

This study, based on a large-scale data set and established behavioural tasks, has the potential to provide a valuable contribution to the literature if the authors could combine and correlate their behavioural evaluations with neural data and/or clinical assessments. As a standalone dataset, however, the current study appears incomplete because it does not go beyond merely replicating existing findings in a large cohort of children. In order to elevate their study, the authors are encouraged to publish their full dataset and explore the relationship between behavioural and neural or clinical data.

eLife assessment

This valuable study poses a provocative mechanism of channel activation of the mechanically activated ion channel TREK-1. The data provide evidence that the application of shear to cells causes a redistribution of both TREK-1 and an associated enzyme, PhospholipaseD2 in the membrane that increases the enzyme activity. The work offers a new mechanism; however, evidence is incomplete and restricted to the over-expression system used.

eLife assessment

The aim of this valuable study is to identify novel genes involved in sleep regulation and memory consolidation. It combines transcriptomic approaches following memory induction with measurements of sleep and memory to discover molecular pathways underlying these interlinked behaviors. The authors explore transcriptional changes in specific mushroom body neurons and suggest roles for two genes involved in RNA processing, Polr1F, and Regnase-1, in the regulation of sleep and memory. At present, the strength of the evidence is incomplete to support the main claim that these two genes establish a definitive link between sleep and memory consolidation.

eLife assessment

This paper demonstrates that subjective treatment effects are an important and under appreciated element in randomized controlled neurostimulation trials. The authors present compelling evidence that has significance in the context of other modalities of treatment, treatment for other diseases, and plans for future randomized controlled trials. This is an important examination and will help guide the theoretical framework for future inquiry with lessons learned for neurostimulation and other emerging areas of psychiatric research.

eLife assessment

This paper provides a fundamental expansion of our understanding of vestibular compensation into transient and partial dysfunction, as well as insights into the adaptation of visual reflexes in this process. The conclusions are convincingly supported with paired histological and behavioral measurements, which are additionally modeled for further interpretation. This work would be of interest to neuroscientists working in multisensory integration and recovery mechanisms.

eLife assessment

This paper provides useful information regarding visuospatial working memory performance in patients with MS compared to healthy controls using a relatively novel continuous measure of visual working memory. The strength of evidence provided, however, is incomplete reflecting the need for better clarification of inclusion/exclusion criteria and underlying pathophysiology. The paper will be of interest to those working in the field of clinical neuroscience.

eLife assessment

This article describes a useful python-based image-analysis tool for bacteria growing in the 'mother-machine' microfluidic device. This new method for image segmentation and tracking offers a user-friendly graphical interface based on the previously developed, promising environment for image analysis 'Napari'. The authors demonstrate the usefulness of their software and its robust performance by comparing it to other methods used for the same purpose. The comparison provides solid support for the new method, although it would have been even stronger if tested using data sets from other groups. This article will be of interest for scientists who utilize the 'mother machine', not least because it also provides a short overview of how to set up this widely used device.

eLife assessment

This manuscript presents valuable findings about how sphingolipids and membrane contact sites are involved in promoting vacuole fission in S. cerevisiae. While a connection between the levels of sphingolipids and vacuole homeostasis is interesting, the data pertaining to this issue are incomplete and do not fully support the claim for causality between altered lipid composition and organelle dynamics. The work will be of interest to cell biologists working on organelle biogenesis and lipid metabolism.

eLife assessment

In this important study, the rabbit was used as a non-rodent mammalian model to show that DMRT1 has a testicular promoting function as it does in humans. The experiments are meticulous and compelling, and the arguments are clear and convincing. These results may explain the gonadal dysgenesis associated with mutations in the DMRT1 locus in humans and highlight the need for mammalian models other than mice to better understand the process of gonadal sex determination in humans.

eLife assessment

In this valuable manuscript, the authors attempt to examine the role of long non-coding RNAs (lncRNAs) in human evolution, through a set of population genetics and functional genomics analyses that leverage existing datasets and tools. Although the methods are at times inadequate - for example, suitable methods and/or relevant controls are lacking at many points, and selection is inferred sometimes too quickly - the results nonetheless point towards a possible contribution of long non-coding RNAs to the evolution of human biology and they suggest clear directions for future, more rigorous study.

eLife assessment

This paper reports important findings on a potent activator of the YAP pathway, demonstrating its mechanism through alternative splicing changes. The authors provide convincing evidence to support their claims, although more consistent inhibitor concentrations would have strengthened the study. This research is of interest to biologists studying alternative splicing or the Hippo pathway, with significant implications for medical research.

eLife assessment

This important study helps to elucidate the mechanism by which the agr quorum-sensing system in Staphylococcus aureus contributes to virulence. The results are supported by solid evidence using state-of-the-art methods. The linkage of metabolism and virulence in this pathogen will be of interest to the areas of microbiology, infectious diseases and immunology.

eLife assessment

This study adds a valuable new perspective to a long-standing question: What controls the repair of photosystem II (PSII), a key process in maintaining and optimizing photosynthesis? The work supports a role for chemical modification in the recognition and subsequent degradation of a key protein subunit of PSII by a bacterial-type protease, suggesting that tryptophan oxidation of components of the photosynthetic apparatus after high light stress plays a critical role in initiating the PSII repair system. The evidence supporting the authors' conclusions is solid, although their arguments would be strengthened by additional experiments.

eLife assessment

This study provides valuable insights into the dynamic interplay between the starvation and hyper-osmotic stress responses in budding yeast, where the presence of one stress can impact the concurrent effects of another perturbation. Using microfluidic devices and extensive quantitative analyses of time-series responses, the authors applied concurrent (in-phase) or alternate (anti-phase) stresses. Their compelling analyses reveal some unexpected behaviors that could not have been guessed from simpler experimental designs, revealing that investigating complex environmental inputs can reveal new biological insights, even for well-studied systems.

eLife assessment

Cryo-EM has become the dominant method in structural biochemistry, and making more efficient use of expensive microscope time is therefore of broad interest to academic and industrial users. The authors identify a bottleneck in cryoEM data collection, namely path optimization, and provide a valuable machine-learning model to overcome this bottleneck. The solid data presented suggests their model can replace a human operator to automate efficient data collection.

eLife assessment

This study is of fundamental significance, providing compelling data on the mechanism by which ULK4 regulates the transcription factor GLI2 and on the ULK4/STK36 interaction promoting GLI2 phosphorylation and activation of the sonic hedgehog (SSH) pathway. The work will be of interest to cell biologists and the signaling community in general.

eLife assessment

This study presents valuable findings showing the contrasting responses of two bacteria to the phytoplankton-derived compound azelaic acid. Metabolomic and transcriptomic data provide convincing evidence for activation of the assimilation pathway in one marine bacterial species and a stress response in another species. There is also solid evidence for azelaic acid altering marine microbial community structure in mesocosm experiments, but the underlying community-level mechanisms are not investigated in this study.

eLife assessment

In this important paper, the authors report a link between brumation and tissue size in frogs, summarizing convincing evidence that extended brumation is associated with smaller brain size and increased investment in reproduction-related tissues. The research will be of broad interest to ecologists, evolutionary biologists, and those interested in global change biology. While the dataset involves significant field work and advanced statistical analyses, the manuscript would benefit from more explanation of the models, including why frogs are a good model in which to address these questions, and from general improvement in the structure and conciseness.

eLife assessment

This valuable study presents findings on the mode of action of MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c), and its impact on monocyte-derived macrophages. The authors present solid evidence for its increased expression in stimulated monocytes/macrophages, its direct bactericidal functions, as well as its role in the modulation of monocyte differentiation into macrophages. Since most of the data were generated from a cell line (THP1), future work is required to validate observations in primary cells and to further support the claims of this work.

eLife assessment

In this intriguing study, the authors offer a new metric, Codon Adaptation Index of Species (CAIS), which allows one to determine the strength of selection and effective population sizes using data on GC content and amino acid composition. This could be of broad use in molecular evolution, as it could be applied across species. The study offers important findings that may aid in our ability to compute key population genomic parameters from genomic data, and the conclusions are based on solid evidence.

eLife assessment

This important study addresses both the native role of the Plasmodium falciparum protein PfFKBP35 and whether this protein is the target of FK506, an immunosuppressant with antiplasmodial activity. The demonstration of the essentiality of FKBP35 in parasite growth relies on compelling genetic evidence. However, it remains unclear whether FK506 exerts its antimalarial activity through an FKBP35-independent mechanism.

eLife assessment

The adaptation of organs including the heart to chronic stress has interested biologists for a long time. Using an elegant model of overexpression of adenyly cyclase, the authors demonstrate posttranslational modification of the protein by phosphorylation, making an important contribution to approaches for the protection of heart performance in these transgenic mice. The convincing results open a new paradigm in understanding the biological effects of stress.

eLife assessment

This important study shows that a splice variant of the kainate receptor Glu1-1a that inserts 15 amino acids in the extracellular N-terminal region substantially changes the channel's desensitization properties, the sensitivity to glutamate and kainate, and the effects of modulatory Neto proteins. The functional data supporting the role of the 15 amino acid insert are solid, although some clarifications and more data are needed to determine the molecular mechanism by which the insert changes the functional profile of the channel. Even so, these findings substantially advance our understanding of splice variants among glutamate receptors and will be of interest to neuro- and cell-biologists and biophysicists in the field.

eLife assessment

This valuable study provides a comparative interactome analysis of α-arrestin in human and Drosophila. Using convincing methodology that includes affinity purification/mass spectrometry, bioinformatic tools and experimental data in human cells, the authors identify biological roles of protein-protein interactions (PPI) involving α-arrestin in the two species. This study will serve as a broadly relevant resource for understanding the PPI network of human and Drosophila α-arrestins.

eLife assessment

Using a newly developed C. elegans model of Alzheimer's disease that expresses Abeta aggregates extracellularly, the authors provide convincing evidence of a disintegrin and an ortholog of human ADAM9 that participate in removing these extracellular aggregates. The worm model presented in this important paper may be very useful to the Alzheimer Disease field.

eLife assessment

This important paper reveals distinct dynamics of two meiosis-specific cohesin complexes containing either REC-8 or CHO-3/4 in C. elegans: REC-8-cohesin is essential for sister chromatid cohesion in meiosis I and DNA double-strand break repair, while COH-3/4-cohesin, whose binding to meiotic chromosomes is stabilized by the cohesin accessory protein SCC-2, is necessary for loop-axis formation. The experimental evidence in the paper is solid based on cytological analysis using a conditional depletion of the gene. The work will be of interest to researchers working on meiosis and chromosome dynamics.

eLife assessment

This important manuscript, which describes the largest genetic association study to date, uses broadly compelling methods to address the genetic susceptibility to tuberculosis infection. A strength of the paper is that this multi-ancestry meta-analysis of genetic association studies than is more powerful than what has been done before. A weakness is that its main result is difficult to interpret due to the complexity of the genetic association signal.

eLife assessment

This is an important study on learning strategy differences in autism vs typically developing controls. The study identifies similar learning rates but different learning strategies. The evidence provided by the authors is convincing, relying on well-done tasks and fMRI analyses.

eLife assessment

This important work provides evidence regarding the impact of the COVID-19 pandemic on cervical cancer screening and precancer treatments in the USA. As there are few screening registries, the study provides solid evidence using a survey of health providers' impressions to assess whether cervical cancer screening services declined during the pandemic. The work will be of interest to public health professionals working in cancer prevention.

eLife assessment

Salmonella invades and survives in host cells via SPI-1 and SPI-2 type III secretion system mechanisms, with the SPI-2 system allowing for intracellular survival in Salmonella-containing vacuoles, which have a low-pH environment. Transcription of SPI-2 genes at low pH is activated by the DNA-binding SsrB protein, which sits at the top of the SPI-2 regulatory hierarchy. This study provides important insights as to how SsrB is allosterically affected by pH resulting in acid-dependent DNA binding. However, there are concerns about some experiments, and the evidence presented is not fully conclusive.

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 compelling, the electrophysiological data is high quality and the experimental design is rigorous.

eLife assessment

In this useful study, the authors explore regulatory cascades governing mammalian cochlear hair cell development and survival. They confirm previous studies that the transcription factors Pou4f3 and Gfi1 are necessary for hair cell survival, and use compelling evidence to demonstrate that the RNA binding protein gene RBM24 is regulated by Pou4f3, but not Gfi1. These findings will be of interest to those working on hearing loss, and hold significance for viral gene delivery methods aiming to manipulate gene expression.

eLife assessment

In zebrafish, primary motor neurons (PMNs) control escape movements, and a more heterogeneous population of secondary motor neurons (SMNs) regulate the speed of rhythmic swimming. Using single cell RNA sequencing (scRNAseq), the authors have obtained convincing evidence that PMNs, and two types of interneurons innervating them, express a set of three genes encoding voltage-gated ion channels enabling rapid firing. The PMNs also express high transcript levels of proteins involved in exocytosis, which would be expected to support rapid neurotransmitter release. These results will be important for those working on spinal cord function and zebrafish genomics/transcriptomics.

eLife assessment

This study provides valuable insights into how the brain parses the syntactic structure of a spoken sentence. A unique contribution of the work is to use a large language model to quantify how the mental representation of syntactic structure updates as a sentence unfolds in time. Solid evidence is provided that distributive cortical networks are engaged for incremental parsing of a sentence, although the contribution could be further strengthened if the authors would further highlight the main results and clarify the benefit of using a large language model.

eLife assessment

This paper describes important advances from the results of studies on atypical language lateralisation and how this might impact language behaviour, as well as its associations with reading skills and the prevalence of schizotypy and autistic traits. Despite most of the conclusions of this paper being supported by evidence, several aspects including the characteristics of participants tested, hypotheses/predictions, and data analysis, are incomplete and/or need some clarification. The work has implications for evolutionary hypotheses and our understanding of the effects of brain damage on distinct cognitive functions.

eLife assessment

This fundamental work substantially advances our understanding of retinol transport through the blood-brain barrier. The evidence supporting the conclusions is compelling, with rigorous biochemical assays. In general, the work is of broad interest to cell biologists, biochemists and neuroscientists.

eLife assessment

This valuable study provides a comprehensive assessment of cell-free DNA methylation to explore the ability of a newly-developed so-called "multimodal" predictive model in detecting malignancies and discriminating tumor of origin. The strength of evidence is solid and the logic beneath this study is well-organized. The study sheds insights into the early detection of malignancies with noninvasive methods using a large sample size with external validation cohort. This study will be of interest to cancer geneticists and oncologists for early diagnosis of cancer.

eLife assessment

This important study advances our understanding of the ways in which different types of communication signals differentially affect mouse behaviors and amygdala cholinergic/dopaminergic neuromodulation. Researchers interested in the complex interaction between prior experience, sex, behavior, hormonal status, and neuromodulation should benefit from this study. Nevertheless, the data analysis is incomplete at this stage, requiring additional analysis and description, justification, and - potentially - power to support the conclusions fully. With the analytical part strengthened, this paper will be of interest to neuroscientists and ethologists.

eLife assessment

This study provides a valuable tool for predicting binding between immune cells receptors and antigens based on protein sequence data. Its improvement over existing methods is supported by solid analysis, though more details on data, architectures and benchmarking are needed to fully justify this claim. This study will be of interest to immunologists and computational biologists.

eLife assessment

In Drosophila melanogater, the Store-operated Ca2+ entry (SOCE) channel, Orai, is required for the development of flight-promoting dopaminergic neurons. Here, Mitra et al. determine that expression of a loss-of-function Orai1 mutant during the 72-96 hour window of pupal development impairs gene expression in dopaminergic flight neurons in part through the expression of Set2, a histone methyltransferase. The authors identify a large number of genes that are controlled by Set2, and show that Set2 is controlled by the trl transcription factor. Although the findings reported here are important, the evidence supporting some of the claims is incomplete.

eLife assessment

This manuscript supports the intriguing idea that some aspects of novel learning can occur during sleep and outside of awareness. The authors provide solid evidence that presenting participants with novel words and their translations during sleep, especially during slow oscillation troughs, leads to the ability to categorize the semantic meaning of those words during awake testing 36 hours later. These findings represent a valuable contribution to the literature on unconscious processing and learning during sleep, although the claim that the results reflect episodic memory formation, in particular, deviates from typical use of this term in the literature.

eLife assessment

In this manuscript, Chakraborty et al address the role of IP3R1 in regulating store-operated calcium entry in neurons and neural progenitors. Long-standing observations in non-neuronal cells have shown that IP3Rs are not required for SOCE. In contrast to those findings, this manuscript determines that in neuronal cells, knockdown of IP3R1 suppresses SOCE by disrupting ER-plasma membrane contact sites. The paper supports a novel role for IP3R1 as a tether in promoting membrane contact sites which would have broad implications for a range of physiological processes including SOCE and lipid metabolism.

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 is an important study on the role of the Ras/MEK/Erk signaling cascade in brain development, with both theoretical and practical implications in multiple fields. The authors reveal functional redundancy and shared function for Erk1 and Erk2 in determining medial ganglionic eminence derived glial number, and exclude a role for Erk1 and Erk2 in the regulation of GABAergic neuron number or initial specification of GABAergic identity. They combine multiple methods including Ribotags, electrophysiology, and chemogenetic stimulation using DREADDs towards comprehensive conclusions. Reviewers expressed concerns about the coherence of the findings, and about the selection of controls mouse lines. Heterozygous ERK1/2 mice are used as 'het controls' throughout the manuscript, however, reviewers felt that there was not sufficient evidence that ERK levels in heterozygous mice are similar to wildtype mice. Nevertheless, these compelling findings will be of interest to a broad readership, and especially readers interested in kinase function and neurodevelopmental syndromes.

eLife assessment

The work examines the effect of transcranial alternating current stimulation on the perception of specific features in sound: gaps in a frequency modulated noise. Several theories link the phase of brain oscillations to perception: the work is important in suggesting direct support for the link. The work is technically well executed on a good size cohort. Still one reviewer raised concerns that the effect seen might be an artifact of the analysis used, so the strength of evidence is incomplete at this stage . We encourage the authors to respond to this issue.

eLife assessment

fMRI was used to address an important aspect of human cognition - the capacity for structured representations and symbolic processing - in a cross-species comparison with non-human primates (macaques); the experimental design probed implicit symbolic processing through reversal of learned stimulus pairs. The authors present solid evidence in humans that helps elucidate the role of brain networks in symbolic processing, however the evidence from macaques was incomplete (e.g., sample size constraints, potential and hard-to-quantify differences in attention allocation, motivation, and lived experience between species).

eLife assessment

The manuscript by Bull et al provides valuable information on the relationship between metabolic features, in particular different lipoproteins and fatty acids, and colorectal cancer. They use solid methods and combine different data sources to analyze forward and reverse Mendelian Randomizations that support their claims.

eLife assessment

This paper provides a useful set of data examining the role of PTPMT1, a mitochondria-based phosphatase, in mitochondrial fuel selection. The data were collected and analyzed using solid methodology and can be used as a starting point for further studies that build on the findings here.

eLife assessment

This valuable study provides solid evidence that the stability and function of the Eph-B2 receptor (EPHB2) are affected by interactions with the multifunctional MYCBP2 and Fbxo45 proteins, extending our knowledge of how members of this key family of receptors are regulated, in particular in regard to their forward signaling. The biochemical binding evidence is generally convincing, but the evidence from the C. elegans experiments is still incomplete.

eLife assessment

This study presents the valuable finding that a cleaved form of METTL3 (termed METTL3a) has an essential role in regulating the assembly of the METTL3-METTL14-WTAP complex. The evidence supporting the claims of the authors is solid, and the work will be of interest to medical biologists working on breast cancer.

eLife assessment

This valuable study provides the community with a set of clearly interpretable computational methods to identify new pioneer transcription factors (PTFs) from which thirty two putative PTFs were predicted. The authors used multiple approaches to validate their predictions, and the evidence to support their claims is solid. This work will be of interest to computational and molecular biologists working on transcription factors.

eLife assessment

This valuable study combines in vitro experiments with simulations to identify the mechanisms governing modulation of microtubule dynamics by GTP hydrolysis. The authors introduce a solid new approach by using a mixed GDP/GMPCPP lattice and varying GDP concentration to reveal that the nucleotide at the interface of two tubulin dimers determines the strength of the interaction between two dimers. Overall, the findings will be of interest to biophysicists and cell biologists, especially in the field of microtubule biology.

eLife assessment

The study presents patterns of cancer care disruption in southern Illinois and eastern Missouri in the summer of 2020. Survey results show factors that impact cancer care during the COVID-19 pandemic, including group differences by race. The important findings provide solid evidence about variation in cancer care disruptions and opportunities to improve return to care.

eLife assessment

This valuable work presents new results to characterize the relationship between electrical excitation and torque generation in stick insect joints. The evidence supporting this work is a series of torque-voltage measurements across individuals. The strength of evidence is solid in supporting the outcomes, but some details of the methodology, which could potentially shed light on the sources of this variation, are missing.

eLife assessment

This important study reports selective CDKL5 inhibitors that may be of high interest to investigate the role of this kinase in disease (particularly, in CDKL5 deficiency disorder) and to address unsolved issues of inconsistency in the phenotypic characterization of CDKL5-deficient knockout mice. The evidence supporting the conclusions is convincing, with rigorous biochemical, in vitro and ex vivo assays. The work will be of interest to cell and medical biologists and epileptologists working in the fields of epilepsy and neural excitation.

eLife assessment

This study presents a valuable finding on the combination treatment of ONC201/TIC10 with everolimus for metastatic ER+ breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer.

eLife assessment

This study demonstrates an important method that drastically improves the precision of ultrasound localization in interacting mice. The authors present convincing evidence of the usefulness of the method for quantifying vocal behavior in various situations and demonstrate an interesting vocal dominance phenomenon between males. This tool will be of great interest to all scientists interested in vocal behavior in small animals.

eLife assessment

This important study reports selective CDKL5 inhibitors that may be of high interest to investigate the role of this kinase in disease (particularly, in CDKL5 deficiency disorder) and to address unsolved issues of inconsistency in the phenotypic characterization of CDKL5-deficient knockout mice. The evidence supporting the conclusions is convincing, with rigorous biochemical, in vitro and ex vivo assays. The work will be of interest to cell and medical biologists and epileptologists working in the fields of epilepsy and neural excitation.

eLife assessment

This study presents a valuable finding on the optimal prioritization in different malaria transmission settings for the distribution of insecticide-treated nets to reduce the malaria burden. The evidence supporting the claims of the authors is solid, although the authors have made various simplifications to enable the identification of optimal strategies. The work will be of interest from a global funder perspective, though somewhat less relevant for individual countries.

eLife assessment

This is important work analyzing the trial-by-trial progression of learning, and how the outcome of one trial influences cortex-wide neural responses on the next trial. However, the evidence for the central claims is incomplete because the potential confounds of slow hemodynamic effects and behavioral changes induced by the previous trial were not adequately addressed.

eLife assessment

In this paper, the authors demonstrate an interesting link between mitofusin function (MFN2) and PARKIN recruitment and mitophagy, underlying cardiomyopathy. This is a valuable finding with broad implications for understanding the mitochondrial biology as well as mechanisms involved in heart pathologies. However, the analyses are incomplete and the main conclusions are only partially supported and need to be further evidenced.

eLife assessment

This paper presents important findings on the hexametric structure of MCM8/9, which potentially explain its role as a DNA helicase in homologous recombination. This solid work will be of interest to biologists studying DNA transactions.

eLife assessment

This study presents a valuable description of RNA in extracellular vesicles (EV-RNAs) and highlights the potential to develop biomarkers for the early detection of colorectal cancer (CRC) and precancerous adenoma (AA). The data were analysed using solid methodology and would benefit from further validation at each stage of CRC/AA to evaluate the potential application to early detection of CRC and AA.

eLife assessment

This useful manuscript describes the TOR signaling pathway in the human and plant pathogen Aspergillus flavus. While the authors provide a large amount of descriptive and often confirmative data, the evidence for the new claims made here for the TOR pathway in this species is incomplete.

eLife assessment

How the genome is folded three dimensionally is thought to control gene regulatory pathways during critical processes such as cellular differentiation. Using multiple assays, the authors of this important study probe topologically associated domains (TADs) and report involvement of a protein arginine methyltransferase 5 in chromatin organization and transcriptional regulation. The data gathered are generally solid and broadly support the role of this protein in organization of the adipocytic lineage, but additional control experiments would make the inferences stronger.

eLife assessment

This useful study emphasizes some previously ignored aspects of synaptic communication between Purkinje neurons and their targets in the cerebellar nuclei. Reviewers felt that some aspects of the evidence were solid but that others were incomplete.

eLife assessment

This manuscript compiles existing algorithms into an open-source software package that enables real-time motor unit decomposition from muscle activity collected via grids of surface electrodes and indwelling electrode arrays. The software package is valuable given that many motor neuroscience labs are using such algorithms and that there exist a host of potential real-time applications for such data. Validation of the software package is generally solid but incomplete in some significant areas: the primary data is narrow in scope and only from male participants, and there is a lack of ground truth tests on synthetic data. The impact of the software package could be strengthened by making it less tied to specific electrode hardware and by expanding it to easily permit offline analysis.

eLife assessment

This valuable study presents a large experimental study to examine the effects of plant species richness, plant genotypic richness, and soil water availability on herbivory patterns on Piper species in several tropical sites. The authors find that water availability and both intra- and interspecific plant diversity influence herbivory and herbivore diversity, but that the effects differ in significant ways across sites. The major weakness lies in findings that can be better presented in a less complicated fashion. The major claims are currently supported by a combination of solid and incomplete evidence, and the manuscript would benefit from better organization.

eLife assessment

The authors have used a 'digital twin' strategy to recapitulate human pathophysiology of arrhythmia. These important findings have theoretical and practical implications beyond the single subfield of cardiovascular science for personalised medicine. The experimental design relies on state-of-the-art methodologies, with compelling results. The work will be of broad interest to colleagues in the general area of computational biology.

eLife assessment

This study by Chiu and colleagues is an important contribution to the study of the circuitry of aggressive behaviours and of mechanisms that generate persistent states. The data ruling out current ideas in the field are convincing.

eLife assessment

This valuable study considers the relationship between performance in a path-integration-based navigation task and the degree to which medial entorhinal grid cells encode the animal's position. Using a virtual reality environment combined with neural recordings, the work presents solid evidence that the variability in the spatial firing of grid cells correlates with the behavioral performance of the mouse on the navigational task.

eLife assessment

The authors tested the hypothesis that age-dependent factors in human sera affect the core circadian clock or its outputs in cultured fibroblasts. While the paper does not provide molecular mechanistic insight how sera from young versus old donors lead to differences in cyclic gene expression, it does provide fundamental insights and a possible explanation for previous observations showing that circadian gene expression in peripheral tissues tend to dampened or phase-shift with age. As presented, the strength of the evidence is, however, incomplete.

eLife assessment

This study provides important new insights into the structural diversity of effectors - proteins secreted by pathogens and symbionts into host cells - from the plant-associated fungus Fusarium oxysporum f. sp. lycopersici. The study provides a convincing approach to understand how effectors navigate their host environment using both computational and experimental approaches to understand how their structure influences binding partners. The work will be of interest to those studying molecular host-microbe interactions and disease protection.

eLife assessment

This valuable study presents findings on how the hypoxia response pathway senses and responds to changes in the homeostasis of the amino acid cysteine and other sulfur-containing molecules, with compelling and rigorous genetic analyses. The works adds to a growing body of literature showing that prolyl hydroxylation is not the only mechanism by which the hypoxia response pathway can act. Although the paper does not reveal new biochemical insight into the mechanism, it opens up new areas of investigation that will be of interest to cell biologists and biomedical researchers studying the many pathologies involving hypoxia and/or cysteine metabolism.

eLife assessment

By developing a novel method for detecting genetic variants associated with germline mutation spectrum variation, this important study identifies a new "mutator" locus in a population of inbred mouse strains, although the causal gene(s) within this locus remains uncertain. The authors further demonstrate that this new mutator locus interacts epistatically with a previously identified mutator allele on C>A mutation rate, showcasing the complexity of the genetic basis underlying variation in mutation rate and spectrum. Evidence for major findings in this paper is convincing, but the power, statistical properties and limitations of the new method need to be further characterized to support its broader applicability to other systems.

eLife assessment

In this useful study, a solid machine learning approach based on a broad set of systems to predict the R2 relaxation rates of residues in intrinsically disordered proteins (IDPs) is described. The ability to predict the patterns of R2 will be helpful to guide experimental studies of IDPs. A potential weakness is that the predicted R2 values may include both fast and slow motions, thus the predictions provide only limited new physical insights into the nature of the relevant protein dynamics.

eLife assessment

This important study provides insights into the functions of different GNAI subunits, substantially advancing our understanding of their roles in the regulation of hair cell stereociliary bundle development. Convincing evidence is provided to support the findings and overall, the results of this study provide a thorough and careful examination of the roles of different GNAIs in the inner ear, with only minor weaknesses identified in review.

eLife assessment

This work is a valuable exploration of a new stability-guided fine-mapping method, which aims to identify causal genetic variations, by extending the previously proposed PICS method. While the results are empirically validated using functional annotations, their evaluation is incomplete and lacks extensive simulations where true causal variants are known. The approach to improving fine-mapping of causal variants presented will be of interest to geneticists and biomedical researchers using genetic data to guide their investigations.

eLife assessment

This study presents valuable findings on the symptoms and disease trajectories preceding a diagnosis of pancreatic cancer in Denmark. The evidence supporting the claims of the authors is solid, although an error analysis of the text mining evaluation results and a discussion on how the findings can be applied in practice would strengthen the study. The work will be of interest to public health researchers and clinicians working on pancreatic cancer.

eLife assessment

This article is of broad interest to public health researchers and to health policymakers in populations with national screening programs. It provides important knowledge on the impact of the COVID-19 pandemic on participation in mammography screening in Denmark by socio-economic indicators. The study provides convincing evidence for how the pandemic exacerbated disparities in breast cancer screening in Denmark.

eLife assessment

In this valuable report, the authors explore the connection between mTORC signaling and APA regulated by the CFIm complex. Using a combination of genetic and functional genomics approaches, the study reveals that a twin UGUA motif is a potent cis acting regulation of PAS usage that is recognized by CFIm. Overall, the evidence in general is convincing and supports the conclusions and provides the field with additional mechanistic insight of how signaling connects to APA regulatory machinery.

eLife assessment

This is an important study of the dimensionality and synchrony of calcium responses in Purkinje cells measured across a large region of the cerebellar cortex over the course of learning. This work has the potential to inform our understanding of the functional organization of the cerebellum and longstanding hypotheses about the role of cerebellar climbing fibers in the induction of learning and in the timing of movement, but the evidence provided for the many sweeping claims is incomplete. The paper would benefit from additional statistical analyses to more rigorously evaluate the central claims, with consideration of appropriate comparison groups and potential confounds.

eLife assessment

This important study uses mathematical modelling to demonstrate that conformational autoinhibition of the RAF kinase is an important feature of its paradoxical activation by pharmacological inhibitors. This part of the theoretical analysis is highly compelling but its extension to the investigation of how the binding of 14-3-3 adaptors additionally contributes to the paradoxical activation phenomenon is incomplete and would benefit from more rigorous experimental validation. With the experimental part addressing 14-3-3-dependent regulation strengthened or the 14-3-3 part completely removed, this paper would be of considerable interest to cell biologists and cancer biologists, ultimately paving the way for improved RAF therapeutics.

eLife assessment

This is a descriptive paper in the field of metascience, which documents levels of accessibility and reproducible research practices in the field of cardiovascular science. As such, it does not make a theoretical contribution, but it argues, first, that there is a problem for this field, and second, it provides a baseline against which the impact of future initiatives to improve reproducibility can be assessed. The study was pre-registered and the methods and data are clearly documented. This kind of study is extremely labour-intensive and represents a great deal of work.

eLife assessment

This study presents important evidence of the impact of the covid pandemic on breast cancer screening globally but with important variations by healthcare setting. The data analysis is comprehensive, using solid systematic review methods. The results will be of interest to public health policymakers and health care and cancer control practitioners and researchers across the globe.

eLife assessment

TP73 is a member of the p53 family of tumor suppressors. The authors provide compelling evidence that a TAp73-alpha to TAp73-gamma switch could be a frequent phenomenon in human cancers and provide novel evidence that TAp73-gamma has oncogenic functions via Leptin. The authors provide a substantial amount of high-quality data and convincingly demonstrate a novel function of this specific isoform of p73 in lipid metabolism and tumorigenesis.

eLife assessment

This is a valuable contribution to the effort to provide genetic access to and characterization of the major classes of interneurons in the mammalian neocortex. The authors develop an improved strategy for intersectionally targeting a fourth (and final) major category of diverse interneurons in the mouse, including the previously studied neurogliaform cells. They provide a detailed characterization of these cells and show convincingly that their genetic strategy can be used to identify and manipulate these cells, both in vitro and in vivo.

eLife assessment

In this important study, the authors present evidence for the novel involvement of a scavenger receptor in tubular morphogenesis. Using a convincing set of data, the authors propose that the Drosophila scavenger receptor Emp (homologous to human CD36 ) couples endocytosis of luminal molecules and regulates tube length via controlling Crumbs and Src. This work will be of broad interest to cell and development biologists as well as cancer biologists.

eLife assessment

This manuscript is important as it showed an establishment of a method for looking a neuronal activity in embryos which can support the previously reported laterality in chick thalamofugal system. However, the evidence the author provided was incomplete as no actual data was provided.