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.

eLife assessment

This important study provides a substantial advance with a method by which a protein target resistant to therapeutic approaches can be uniquely modulated by a cellular protein kinase ferried by nanobodies to a precise molecular site of recruitment. Evidence for this major claim is compelling, but evidence for some of the minor claims seems incomplete. The work will be of broad interest to cell biologists, cardiovascular researchers, and drug developers.

eLife assessment

This important study provides a state-of-the-art framework to explore the coupling of complementary cerebral measures (neural, hemodynamic, and metabolic) during development by providing an interesting roadmap for multimodal neuroimaging in infants. The methodological contribution is compelling with an original setup for simultaneous EEG and NIRS recording and solid data analyses. However, the claims about functional specialization and the role of the temporal-parietal junction in social processing are only partially supported by the results. This work will be of interest to a broad audience of scientists interested in multimodal neuroimaging and cognitive development.

eLife assessment

Overall, this is an important study that characterizes human oral lichen planus via single-cell analysis. Although the work is descriptive, it can represent an important resource for future studies and highlights potentially relevant biology. However, the claims are a bit overstated and some of the analyses that lead to interpretations remain incomplete.

eLife assessment

This study is a valuable contribution to our understanding of vocal variation in acoustic displays of male baleen whales, part of a developing story about cultural change in songs in species other than the relatively well studied humpback whales. The authors present solid evidence of changes at various timescales in 20-Hz song note intervals and call center frequency over decadal time scales and large spatial scales.

eLife assessment

This is an important study demonstrating distinct roles for the nuclear receptor genes COUP-TFI and COUP-TFII in hippocampal development. The strength of evidence is compelling, using rigorous state-of-the-art methods to demonstrate functional redundancy of these genes in regulating the Lhx2/Lhx5 axis. The major strengths of the study are the dramatic morphogenic phenotypes, and the resultant altered gene networks. These findings have theoretical or practical implications beyond a single field, and will be of interest to geneticists, developmental neurobiologists and chromatin biologists among others.

eLife assessment:

This study offers new fundamental information on a role for the sodium/potassium pump in sleep regulation. Elegant methods were used to provide compelling evidence supporting the claim. The work will be of interest to sleep researchers in zebrafish as well as in other species for future investigation.

eLife assessment

This important study provides a framework bearing on the role of Eph-Ephrin signaling mechanisms in the clinically condition of amyotropic lateral sclerosis. It provides compelling evidence for the roles of glial cells in this condition. This novel astrocyte-mediated mechanism may help identify future therapeutic targets.

eLife assessment

This is an important study that revealed a new noncoding RNA regulatory circuit involved in T cell function. The authors provide compelling evidence, that is more rigorous than the state-of-the-art, using genetically engineered mice and cell-based experiments. The interpretation of the results should be tempered due to the small effect size observed.

eLife assessment

This important study aims to discover the mechanisms governing the switch between conventional DNA replication and the specialized mechanism of telomere end replication. Solid genetic and biochemical assays suggest an interplay between sumoylated PCNA and chromosome terminal capping proteins. The questions addressed have implications for several fields, such as genome stability.

eLife assessment

This valuable Tools and Resources paper presents new tools for investigating GLP-1 signaling: a genetically-encoded sensor constructed from a mutated GLP1R receptor as well as a caged agonist peptide. The evidence for these tools working as advertised is largely convincing and they may be helpful for screening compounds that bind to GLP1R. On the other hand, their overall utility is limited by their very weak apparent affinity relative to the likely biological concentration and response. Incomplete characterization of the properties of the tools makes it difficult to anticipate which applications are most likely to succeed.

eLife assessment

This valuable Tools and Resources paper presents new tools for investigating GLP-1 signaling: a genetically-encoded sensor constructed from a mutated GLP1R receptor as well as a caged agonist peptide. The evidence for these tools working as advertised is solid and they may be helpful for screening compounds that bind to GLP1R.

eLife assessment

This study examines the role of the locus coeruleus in the extinction of instrumental behaviors. The work is valuable to highlight the function of this part of the brain. Evidence is incomplete as spontaneous recovery is not demonstrated in control subjects. Further analyses on the effect of the manipulations on baseline lever pressing, magazine entries, and the coupling of lever-presses and magazine entries help capture the function of the locus coeruleus.

eLife assessment

This study aggregates across five fMRI datasets and reports that a network of brain areas previously associated with response inhibition processes, including several in the basal ganglia, are more active on failed stop than successful stop trials. This study is valuable as a well-powered investigation of fMRI measures of stopping. However, evidence for the authors' conclusions regarding the role of subcortical nodes in stopping is incomplete, due to the limitations of fMRI and a lack of theoretical synthesis.

eLife assessment

Based on a technological advance which couples onboard calcium imaging with in vivo electrophysiology in freely behaving mice, this work presents important insights about the brain circuits through which the cerebellum could participate to social interactions. In particular, correlative measurements provide interesting but incomplete evidence that connections between cerebellum and cingulate cortex connections specifically contribute to the complex sensory-motor computations underlying social contacts. This study is of interest for a broad range of neurophysiologists.

eLife assessment

This important study reveals the use of an allocentric spatial reference frame in how the perception of the location of a dimly lit target is updated during locomotion. The evidence supporting this claim is convincing, based on a series of cleverly and carefully designed behavioral experiments. The results will be of interest not only to scientists who study perception, action and cognition, but also to engineers who work on developing visually guided robots and self-driving vehicles.

eLife assessment

This important work advances our understanding of the differences in locomotion-induced modulation in primate and rodent visual cortexes. The evidence in support of these differences across species is convincing, although greater use of the primate dataset with some additional analyses would have strengthened the claims. This work will be of broad interest to neuroscientists.

eLife assessment

The study provides valuable insights into allosteric regulation of BTK, a non-receptor protein kinase, challenging previous models. Using a variety of biophysical and functional techniques, the paper presents evidence that the N-terminal PH-TH domain of BTK exists in a conformational ensemble surrounding a compact SH3-SH2-kinase core, that the BTK kinase domain can form partially active dimers, and that the PH domain can form a novel inhibitory interface after SH2/SH3 disengagement. Overall the presented evidence is solid, but the EM results may be over-interpreted and the work would benefit from additional functional validation.

eLife assessment

The manuscript describes a valuable theoretical calculation focusing on the structural changes in the photosynthetic reaction center postulated by others based on time-resolved crystallography using X-ray free-electron laser (XFEL) (Dods et al., Nature, 2021). The authors argue that calculated changes in redox potential Em and deformations using the XEFL structures may reflect experimental errors rather than real structural changes. The study is still incomplete in the sense that it focuses on explaining why the proposed structural changes do not match the theoretical calculations, but it does not yet provide an alternative model.

eLife assessment

This is a valuable study of the molecular basis of summer-to-winter transition in Cacopsylla chinensis. Despite the convincing molecular and organism-level experiments, evidence of cold sensitivity in the protein of interest is incomplete, with a lack of methodological detail. The results of this study will be of interest to entomologists.

eLife assessment

This study and associated data is compelling, novel, important, and well-carried out. The study demonstrates a novel finding that different chemotherapeutic agents can induce nucleolar stress, which manifests with varying cellular and molecular characteristics. The study also proposes a mechanism for how a novel type of nucleolar stress driven by CDK inhibitors may be regulated. The study sheds light on the importance of nucleolar stress in defining the on-target and off-target effects of chemotherapy in normal and cancer cells.

eLife assessment

This interesting study describes the development of a three-dimensional cell culture system to investigate muscle tissue development and homeostasis. It is a solid study that could be valuable in the study of human as opposed to animal cells in studying muscular disorders.

eLife assessment

This study presents useful findings regarding the impact of forest cover and fragmentation on the prevalence of malaria in non-human primates. The evidence supporting the claims of the authors is, however, incomplete, as the sampling design cannot adequately address the geospatial issues that this study focuses on.

eLife assessment

This study by Verdikt et al. provided solid evidence demonstrating the potential impacts of Δ9-tetrahydrocannabinol (Δ9-THC) on early embryonic development using mouse embryonic stem cells (mESCs) and in vitro differentiation. Their results revealed that Δ9-THC enhanced mESCs proliferation and metabolic adaptation, possibly persisting through differentiation to Primordial Germ Cell-Like Cells (PGCLCs), though the evidence supporting this persistence was incomplete. Although the study is important, it was limited by being conducted solely in vitro and lacking parallel human model experiments.

eLife assessment

This manuscript describes useful information on in vitro binding and hydrogen exchange (HDX) mass spectrometry experiments using various bacterial-expressed BRAF N-terminal fragments, to tease out domain-specific interactions with RAS proteins or wildtype and oncogenic mutant BRAF kinase fragments. The characterization of the auto-inhibitory mechanism of the regulation of BRAF is solid but several concerns remain. The data will be of interest for researchers in the RAS/RAF and general kinase regulation fields.

eLife assessment

The study by Gu et al. presents direct evidence on the role of microglia morphological dynamics during sleep/wake cycles and the modulatory effect of sleep deprivation, making it a valuable contribution to the ongoing investigation of microglial function. The use of a novel miniature two-photon microscope technique adds strength to the evidence supporting the conclusions. However, concerns remain about certain methodological and experimental aspects of the study, indicating that further validation is necessary and that the evidence presented is currently incomplete.

eLife assessment

The discovery of Homo naledi-associated evidence for intentional burial and engravings would undoubtedly have important implications for our understanding of the evolution of complex cognition and behavior. Based on claims made in two related preprints by Berger et al., this study discusses the potential implications of the purported mortuary practice and symbolic behaviors claimed to be associated with the small-brained H. naledi remains. Unfortunately, the evidence presented in the two related submissions that the current paper entirely relies on is incomplete at this stage.

eLife assessment

This paper presents important information about potentially Homo naledi-associated markings discovered on the walls of the Hill Antechamber of the Rising Star Cave system, South Africa. If confirmed, the antiquity, intentionality, and authorship of the reported markings will have profound archaeological implications, as such behaviors are otherwise widely considered to be unique to our species, Homo sapiens. As it stands, the study is incomplete, and the evidence presented does not support the claims about the anthropogenic nature, age, and author of the engravings. While it is appreciated that this report concerns preliminary findings, all reviewers agree that: a) the initial nature of the reported results must be more clearly indicated, b) the anthropogenic nature of the engravings must be adequately demonstrated, c) ideally the chronology of the claimed engravings has to be established for any age estimate to be reliable, and d) the claim about H. naledi being the author of the reported engravings requires robust association.

eLife assessment

The authors study the context of the skeletal remains of three individuals and associated sediment samples to conclude that the hominin species Homo naledi intentionally buried their dead. Demonstration of the earliest known instance of intentional funerary practice – with a relatively small-brained hominin engaging in a highly complex behavior that has otherwise been observed from Homo sapiens and Homo neanderthalensis – would be a landmark finding. However, the evidence for these claims is considered inadequate in the current version of the study. The four reviewers were in strong consensus that the methods, data, and analyses do not support the primary conclusions. Without full excavations, the study is missing crucial geoarchaeology (especially micromorphology) and taphonomic components, among other limitations, that make premature the conclusion that H. naledi intentionally buried their dead. The null hypothesis must be that these skeletons accumulated naturally and the research must then reject the null hypothesis and robustly exclude equifinality in order to justifiably draw the remarkable conclusions made in the present version of the paper.

eLife assessment

Brain inflammation is a hallmark of multiple sclerosis. Using novel spatial transcriptomics methods, the authors provide convincing evidence for a gradient of immune genes and inflammatory markers from the meninges toward the adjacent brain parenchyma in a mouse model. This important study advances our understanding of the mechanisms of brain damage in this autoimmune disease.

eLife assessment

This research advance article describes a valuable image analysis method to identify individual cells (neurons) within a ‎population of fluorescently labeled cells in the nematode C. elegans. The findings are solid and the method succeeds to identify cells with high precision. The method will be valuable to the C. elegans research community.

eLife assessment

This important study characterises the involvement of condensin complexes in the segregation of telomeres in fission yeast. The authors present solid evidence in support of their claims, employing a diverse range of complementary techniques. This research will be of interest for cell biologists working on chromosome biology and cell division.

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. The evidence supporting the major claims is solid, although experiments to distinguish the impact on antibody binding versus 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 article provides insights into the neural centres in the Japanese quail brain that are associated with photoperiod-induced life-history states. The physiological and transcriptomic analyses of the mediobasal hypothalamus and pituitary gland offer evidence for a coincidence timing mechanism for measuring day length, which is relevant for the field of circannual biology. Despite some shortcomings in data analysis, the study's convincing experiments and findings have the potential to captivate the attention of molecular and organismal endocrinologists.

eLife assessment:

This important study describes spatial RNA processing events by combining methods for single-cell transcriptomics data with spatial transcriptomics data. The evidence supporting the claims of the authors is solid, although the analysis could be further strengthened by including a broader range of samples as well as orthogonal validation either by experimental methods or simulated data. The work will be of general interest to researchers in the spatial transcriptomics field as well as researchers investigating alternative pre-mRNA processing across diverse tissues.

eLife assessment:

Trypanosoma brucei evades mammalian humoral immunity through the expression of different variant surface glycoprotein genes. In this fundamental paper, the authors extend previous observations that TbRAP1 both interacts with PIP5Pase and binds PI(3,4,5)P3, indicating a role for PI(3,4,5)P3 binding and suggesting that antigen switching is signal dependent. While much of the evidence is compelling, one reviewer suggested that the work would benefit from further controls.

eLife assessment

This paper describes an important, well-organized study into an under-exploited area of spatial transcriptomics. The limitations of the approach are generally made clear, but there is insufficient orthogonal validation to demonstrate the biological significance of the results, which leads to the evidence for the claims being currently incomplete. Nevertheless, the tools presented will provide a resource to researchers wishing to characterise spatial patterning of mRNAs, and the paper will be of interest to researchers studying cell biology, RNA biology, and method development for spatial transcriptomics/proteomics.

eLife assessment

This important paper reports a novel, compelling method, based on barcoding viral genes and next-generation sequencing, to quantify both viral transcription levels and progeny virus production in influenza virus-infected cells at the single-cell level. The authors show that viral transcription and progeny virus production are unexpectedly poorly correlated, and that cells in which viral RNAs are transcribed at high levels are not necessarily those producing the most progeny virions. Because of its novelty, the study will be of interest to the broader virology community.

eLife assessment

This is an important study that reports the discovery of a new pathway of miRNA sorting to exosomes, involving a mitochondrially-localized protein. The evidence provided by some of the biochemical data is convincing. However, the major body of evidence is still incomplete.

eLife assessment

Overall, this is an interesting topic of study, and the conclusions could be of relevance more broadly. However, mechanistic support, limited TTF frequencies/timing, and visual support of the quantitative data would be critical in order to provide convincing and rigorous support for this interesting concept.

eLife assessment

This study explores the regulatory function of O-GlcNAcylation on DNA methyltransferase 1 and identifies serine 878 as the main target. This study is of interest to those in epigenetics and metabolism. The significance is important and the strength of the evidence is convincing.

eLife assessment

This US study presents findings from an online survey and in-person interviews of healthcare providers in areas associated with cervical screening provision during the post-acute phase of the pandemic. The findings are valuable as they provide insights into a range of areas, from healthcare characteristics to screening barriers and HPV self-sampling. The evidence supporting the claims of the authors is solid, although the inclusion of a nationally-representative sample of healthcare providers and a greater gender/ethnicity/racial mix of interviewees would have strengthened the study. The work will be of interest to public health scientists and a cancer prevention and control audience.

eLife assessment

This manuscript suggests a novel mechanism of purifying selection by which programmed cell death contributes to the selective removal of mtDNA deletion mutations in C. elegans. The evidence for this mechanism of removal is strong although questions remain regarding the underlying mechanism and the role of canonical ageing pathways. Because of the likely central role of mtDNA deletions in ageing and age-dependent diseases, this work will be of interest to scientists in the field of mitochondrial biology as well as ageing.

eLife assessment

This work provides a valuable structural and functional characterization of the neurotransmitter's spatial distribution heterogeneity in cortical and subcortical regions. The authors report a systematic description and annotation of a new "layer" of brain organization that has been relatively poorly integrated with the wider neuroimaging literature to date. In sum, this paper has the potential to be of great interest to a wide audience in neurosciences.

eLife assessment

This important paper describes a valuable systematic review and meta-analysis of mental health problems in polycystic ovary syndrome (PCOS) that drive the excess economic burden associated with this common endocrine disorder. Interestingly, the cost of the diagnostic evaluation is only a relatively minor part of the total costs, but mental health disorders were identified as a significant component of the economic burden. These solid findings could not have been anticipated intuitively and are of considerable value for public health prioritization of PCOS.

eLife assessment

This study presents a valuable and elegant kinetic analysis of the GSKbeta activity as a function of phosphorylation and Axin binding - providing insights into critical steps of Wnt pathway signaling. The results will be of big use to the broader signaling community, however, the incomplete dissection of the mechanism by which Axin binding inhibits GSKbeta inhibitory phosphorylation remains a weakness of this study. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This important study used high-resolution brain imaging methods to visualize and index non-invasively auditory and language pathways of young children born with inner ear malformations or cochlear nerve dysfunction resulting in profound hearing loss. Nerve fiber impairments were compellingly demonstrated in subcortical auditory and cortical language pathways relative to typically-hearing controls. The results suggested novel approaches for clinical assessment of central auditory and language pathways that may influence different intervention strategies, pending further evidence linking these structural findings with functional outcomes.

eLife assessment

Rodberg et al. show systemic β adrenergic antagonism reduces engagement in decision-making, particularly in female rats, and reduces task-related encoding in neural activity. This is a valuable finding that addresses a gap in the field, however, the understanding of the direct contribution of β adrenergic receptors to the observed effects is incomplete. Further, the theoretical grounds, data analyses, and results could be improved in several ways.

eLife assessment

This work provides fundamental new insight into fine axonal morphologies based solely on extracellular action potential recordings. They provide compelling evidence of fine resolution in mapping functional connections between neurons. The work may have broad use in neurobiology, bioengineering, stem cell biology, as well as tissue engineering in functional characterization.

eLife assessment

The tool developed and implemented in this study has valuable significance for the combined analysis of large, diverse omics datasets, but some of the methodology is incomplete. Regarding the strength of evidence, there are some more significant concerns regarding potentially inadequate controls for false discovery and multiple testing corrections.

eLife assessment

The manuscript represents a valuable contribution to an ongoing discussion about the substrate binding site and mechanism of the Bile Acid Sodium Symporter (BASS) family of transporters. Structural and biochemical analysis of a bacterial homolog, ASTBnm, in complex with its native substrate (not bile acids, but a vitamin A precursor, pantoate) show a new binding site that is consistent with classical proposals for elevator-type transport mechanisms. Molecular simulations highlight the improved stability for the substrate in the active site when ions are present, suggesting a binding order during the transport cycle. The structural studies, binding assays, and MD simulations are convincing, although support for the transport mechanism is incomplete without a pantoate transport assay.

eLife assessment

This important study advances our knowledge of how parasites evade the host complement immune system. The new cryo-EM structure of the the trypanosome receptor ISG65 bound to complement component C3b is highly compelling and well-supported by biochemical experiments. This work will be of broad interest to parasitologists, immunologist, and structural biologists.

eLife assessment

This important study identifies two new transporters of the apicoplast, a non-photosynthetic organelle of apicomplexan parasites. In its current state, evidence is incomplete, as it only partially reveals how important those transporters are and as it does not address the metabolic function for the parasite. The results should be of interest to parasitologists and eukaryotic cell biologists.

eLife assessment

This study includes important findings on protein evolution, namely that changes in function are largely attributable to pairwise rather than higher-order interactions, and that epistasis potentiates rather than constrains evolutionary paths. Compelling evidence supporting the conclusions is provided by applying a new model to a previously generated experimental dataset on deep mutational scanning of the DNA-binding domain (DBD) of steroid hormone receptor. The implications of this work are of considerable interest to protein biochemistry, evolutionary biology, and numerous other fields.

eLife assessment

This fundamental study identifies the components of the N6-methyladenosine methyltransferase complexes in yeasts, with major differences with the same complexes in mammals and flies. The evidence supporting the conclusions is convincing, with rigorous high-throughput sequencing approaches and detailed functional analysis. This work will be of broad interest to colleagues in the RNA modification and meiosis fields.

eLife assessment

This valuable study examined the use of dantrolene, a Ryanodine Receptor stabilizer, in slowing pathological progression of pressure-overload heart failure in a guinea pig model and reducing arrhythmias. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for future studies of dantrolene in Ca2+ handling in ROS production and further deterioration of cardiac function in chronic heart failure.

eLife assessment

The paper provides a useful and novel application of recursion theory to the long call vocalisations of orangutans to demonstrate repetitive, rhythmic sub-structuring. However the evidence provided to support the major claims of the paper is currently incomplete. Specifically, it is not yet clear how the rhythmic structuring found in these long calls is more similar to human language recursion per se rather than isochrony as a broader, more common phenomenon.

eLife assessment

This important study describes a combination of in vitro and in vivo results implicating Dyrk1a in the regulation of mTOR. Strengths include the combination of cell and whole-animal (Drosophila) based studies. However, the evidence supporting the conclusions is incomplete and additional experimentation (which could include IPs, more confirmation of the T1462 phosphorylation, and more information about Akt) would strengthen the main conclusions.

eLife assessment

This study reports important findings about new locomotory dynamics of crawling Drosophila larva based on imaging the reaction forces during larval crawling. The new high-resolution microscopy method is compelling, as it significantly improves the spatial, temporal, and force resolution compared to previous methods for studying Drosophila larva and could be applied to other crawling organisms. The manuscript would nevertheless benefit from more details explaining the new technology, limitations, and justifications for the choice of technology and certain experimental details. The work will be of interest to the broad neuroscience community interested in the mechanisms of locomotion in a highly tractable model.

eLife assessment

This study reports the important finding that there appears to be a timer that monitors the repair of DNA after damage and regulates whether cells are subsequently able to enter mitosis. The authors identify proteins important for this decision and propose a mechanism supported by solid but not conclusive data. This study will be of interest to researchers in the fields of DNA damage repair and cell cycle control.