eLife assessment

The paper investigates a potential cause of a type of severe epilepsy that develops in early life because of a defect in a gene called KCNQ2. The significance is fundamental because it substantially advances our understanding of a major research question. The strength of the evidence is convincing because appropriate methods are used that are in line with the state-of-the art, although there are some revisions/corrections that would strengthen the evidence further.

eLife assessment

The findings in this manuscript are important and novel, and the genomic analyses are convincing. This study expands upon our understanding of the role of hnRNP proteins in lncRNA function and the evidence is compelling, suggesting shared mechanism(s) in the regulation of ASARs and Xist RNAs by RBPs that bind Cot1 sequences in these lncRNAs. This manuscript should be of interest to the noncoding RNA and chromatin biology communities.

eLife assessment

This valuable study provides insights into how the brain parses the syntactic structure of a spoken sentence. Convincing evidence is provided that distributive cortical networks are engaged for incremental parsing of a sentence, and neural activity recorded by MEG correlates with sentence structure measures extracted by a deep neural network language model, i.e., BERT. A contribution of the work is to use a deep neural network model to quantify how the mental representation of syntactic structure updates as a sentence unfolds in time.

eLife assessment

This study enhances our understanding of the relationship between cortico-hippocampal interactions and behavioral performance. Using an inter-areal coherence metric to gate trial initiation in real time, the authors provide solid evidence that links high hippocampal-prefrontal theta coherence to correct performance on spatial working memory and cue-guided decision-making tasks. Although reviewers agreed that the results do not demonstrate causality between hippocampal-prefrontal synchrony and behavioral performance, the findings are viewed as important given their potential implications for brain-machine interface applications in humans.

eLife assessment

The reprocessing and reanalysis of archived samples can yield further insights from past experiments. Here, a useful procedure to perform tissue clearing and immunolabeling on large-scale formalin-fixed paraffin-embedded brain specimens is convincingly evaluated on a set of archival pathology specimens, and its applicability to further such samples is analyzed. This method will be of interest to both neuroscientists and pathologists.

eLife assessment

This important study presents relevant information about the involvement of TOR pathway in aflatoxin production by Aspergillus flavus. However, some of the presentation is confusing, leaving the study in its current form is incomplete. The strength of the evidence could be augmented with additional experiments and reorganization of the manuscript aiming to fully understand and characterize the involvement of TOR pathway in A. flavus aflatoxin production.

eLife assessment

This useful study, which systematically addresses off-target effects of a commonly used chemotherapy drug on bone and bone marrow cells and which therefore is of potential interest to a broad readership, presents evidence that reducing systemic inflammation induced by doxorubicin limits bone loss to some extent. Although the work does not inform in detail on the underlying mechanisms of doxorubicin action, the demonstration of the effect of systemic inflammation on bone loss is convincing. While not a new finding, the work sets the scene for additional genetic and pharmacologic experiments and a deeper analysis of the bone phenotype presented here, which should speak to the mechanisms involved in doxorubicin-induced bone loss and which may substantiate the clinical relevance of targeting inflammation in order to limit the negative impact of chemotherapies on bone quality.

eLife assessment

The results from this study, which investigates the mechanisms necessary for initiating tissue invagination using a cellular Potts modelling approach, suggests that apical constriction is not sufficient to drive the process by itself. The study highlights how choices inherent to modelling - such as permitting straight or curved cell edges - may affect the outcome of simulations and, consequently, their biophysical interpretation. Despite incomplete evidence supporting their major claims due to a rather coarse-grained exploration of the model, this work is useful for biophysicists investigating complex tissue deformation through computational frameworks.

eLife assessment

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

eLife assessment

In this important manuscript, Abd El Hay and colleagues reveal a clear role of TRPV1 and TRPM2 receptors in warm temperature perception and present a technically unique experimental strategy to measure and analyze temperature preference behavior, which will have a lasting impact on the field. In addition to the behavioral data, which is strong, the study provides an analysis of cultured sensory neurons to controlled warmth stimuli - in this case, the evidence relating the activity of TRPM2 channels to the behavioral responses of animals is incomplete. Overall, the findings are of importance for neuroscientists, physiologists, and biophysicists, as there is still substantial discussion in the field regarding the contribution of TRP channels to different aspects of thermosensation.

eLife assessment

This work presents an important online platform designed to facilitate the exploration of genes and genetic pathways implicated in human aging. Leveraging a new inference methodology, the tool enables the identification and visualization of key genes and tissues impacted by aging, facilitating scientific discovery. The methods and analyses are convincing and will be broadly used by scientists aiming to mine human aging RNA-seq data.

eLife assessment

This work will be of interest to the motor control community as well as neuroAI researchers interested in how bodies constrain neural circuit function. The authors present "MotorNet", a useful software package to train artificial neural networks to control a biomechanical model of an effector. The manuscript provides solid evidence that MotorNet is easy to use and can reproduce past results in the field, both at the neural and behavioural levels. Validation is limited to planar arm-like plants or point-masses, so future work exploring three-dimensional movements and other types of plants would strengthen the impact of the tool.

eLife assessment

The authors address the function of keratin 17 (K17), a marker of the most aggressive pancreatic ductal adenocarcinomas (PDACs). While this potentially useful study addresses a significant area of pancreatic cancer research, the lack of evidence demonstrating nuclear localization of K17 in human PDAC and the excessive reliance on a single cell line reduce the significance of the work. Moreover, the weak phenotypes of K17 phosphosite mutants provide incomplete support for the authors' mechanistic model.

eLife assessment

This potentially important paper addresses the question of how numerical information is represented in the human brain. Experimental findings are interpreted as providing evidence for a sensorimotor mechanism that involves channels, each tuned to a particular numerical range. While this is an interesting application of methodologies used to identify the presence of channels, the evidence supporting the claim that these have a sensorimotor basis is incomplete.

eLife assessment

In this manuscript, the authors present a wealth of fMRI data at both 3T and 7T to identify a scene-selective region of the intraparietal gyrus ("PIGS") that appears to have some responsivity to characteristics of ego-motion. In a series of experiments, they delineate the anatomical location of PIGS and functionally differentiate it from nearby V6 and OPA. Evidence for these important findings is solid, but further investigations as to the role of this region in processing ego-motion will be needed to confirm this conclusion.

eLife assessment

This valuable study showed convincing evidence that archerfishes can adapt their shooting behaviors to airflow perturbations. The fish also exhibits adaptive behaviors indicative of an egocentric representation of the perturbation, though direct evidence is missing. Hence, this work will be of interest to those interested in cross-species comparisons for motor learning.

eLife assessment

This useful study addresses the brain correlates underlying technical reasoning by a set of fMRI experiments and locates it to PF. If confirmed, this study provides an intriguing framework for our understanding of different types of problem-solving processes. However, the current evidence supporting the claims is incomplete, due to the existence of alternative explanations for the main overlapping results and potential confounding variables across conditions.

eLife assessment

This important study advances our understanding of the mechanisms of neuronal large dense-core vesicle (LDCV) secretion, which mediates neuropeptide and neurotrophin release. It describes a negative regulatory process involving the interaction of the Rab3-effector Rabphilin-3A with the SNARE fusion protein SNAP25, which limits LDCV secretion and neurite growth. The evidence in support of the authors' claims is solid overall, but some conclusions, e.g regarding the exact synaptic localization of Rabphilin-3A, its association with large dense-core vesicles, or the role of Rabphilin-3A-controlled neurotrophin signaling in neurite growth, are incompletely supported. This study will be of interest to the fields of cell biology, cellular neuroscience, and neuroendocrinology.

eLife assessment

This study provides valuable insights into understanding bone fragility in T2D patients through the use of human skeletal tissue, reinforcing previous pre-clinical studies or observational studies using serum samples that the Wnt signaling pathway may play a critical role in T2D-related bone impairment. The methods are solid, but a limited number of subjects and a small set of genes with lack of data in terms of cellular properties of skeletal tissue are viewed as weaknesses.

eLife assessment

This valuable study combines the use of Fisher Kernels with Hidden Markov models aiming to improve brain-behaviour prediction. The evidence supporting the authors' conclusions is solid, comparing brain-behaviour prediction accuracies across a range of different traits. This work is timely and will be of interest to neuroscientists working on functional connectivity for brain-behaviour association.

eLife assessment

This valuable study presents findings characterising the genomic features of E. coli isolated from neonatal meningitis from seven countries, and documents bacterial persistence and reinfection in two case studies. The genomic analyses are solid, although the inclusion of a larger number of isolates from more diverse geographies would have strengthened the generalisability of findings. The work will be of interest to people involved in the management of neonatal meningitis patients, and those studying E. coli epidemiology, diversity, and pathogenesis.

eLife assessment

This valuable study uses a model to determine when catalytic self-replication of polymers can emerge from a random pool of replicating polymers. The model accounts for the folding and function of polymers in addition to abstract evolutionary dynamics, providing solid evidence for the claims of the authors. The work will be of relevance to those interested in the origin of life, artificial cells, and evolutionary dynamics.

eLife assessment

In this fundamental study, the authors analyzed associations between circulating immune cells and periodontitis. Convincing evidence identifies three immune cell types related to periodontitis, which substantially advances our understanding of periodontitis.

eLife assessment

This valuable study combines in vitro and in vivo experiments designed to test if a deoxycytidine kinase inhibitor provides therapeutic benefit during infection with Staphylococcus aureus. Several in vitro methods used to measure therapeutic efficacy are thorough and compelling with appropriate conclusions drawn, however, the overall analysis is incomplete and would benefit from a more rigorous study design. With a strengthened study design, and more nuanced considerations of the strengths and limitations of the study, this paper would be of interest to bacteriologists, immunologists, and those studying host-microbe interactions.

eLife assessment

This valuable study combines in vitro and in vivo experiments designed to test if a deoxycytidine kinase inhibitor provides therapeutic benefit during infection with Staphylococcus aureus. The authors provide compelling evidence that this putative host-directed therapy has good potential to promote natural clearance of infection without targeting the bacterium. This paper would be of interest to bacteriologists, immunologists, and those studying host-microbe interactions.

Editors Assessment:

This is a Data Release paper describing data sets derived from the Pomar Urbano project cataloging edible fruit-bearing plants in Brazil. Including data sourced from the citizen science iNaturalist app, tracking the distribution and monitoring of these plants within urban landscapes (Brazilian state capitals). The data was audited and peer reviewed and put into better context, and there is a companion commentary in GigaScience journal better explaining the rationale for the study. Demonstrating this data providing a platform for understanding the diversity of fruit-bearing plants in select Brazilian cities and contributing to many open research questions in the existing literature on urban foraging and ecosystem services in urban environments.

This evaluation refers to version 1 of the preprint

eLife assessment

The authors provide solid evidence that any contribution of oligodendrocyte precursors to the developing cortex from the lateral ganglionic eminence is minimal in scope. The methods used support the conclusions, with some technical concerns that the authors can address with further experimentation. These are considered valuable additions to our understanding of the origins of oligodendrocytes in the forebrain during development.

eLife assessment

This useful study presents data regarding the presence of synaptic proteins in the extracellular vesicle pool present in the blood of Parkinson's patients and non-parkinson neurological outpatients, trying to correlate changes in such levels with the progression of Parkinson's symptoms. The results are semi-quantitative and preliminary, suggesting that these biomarkers could be used in the follow up of a specific group of Parkinson patients. The evidence is incomplete at this point, and more quantitative approaches are required to propose this correlation. The isolation of extracellular vesicles was appropriate as revealed by their sizes, but they are not exclusively from neuronal origin. The presented approach is not ready to be used in the clinical setting.

eLife assessment

This study unveils important mechanistic insights into postnatal lung development and bronchopulmonary dysplasia (BPD) pathology. Using two BPD models enhances our comprehension of the disease, utilizing compelling evidence from single-cell sequencing and flow cytometry, revealing a myofibroblast loss. Pharmacological and genetic approaches convincingly argue against the presumed increase in TGFb signaling causing alveolar simplification; instead, it appears to be a compensatory response. The identified weakness is the absence of validation in tissue, leaving the question unanswered regarding whether myofibroblast loss is due to a lack of myofibroblast proliferation or myofibroblast differentiation/specification.

eLife assessment

Herein, Xie and colleagues use a hamster model to show that Leptospira infection leads to gut pathology, an altered gut microbiota, and increased translocation. A combined use of antibiotics and LPS neutralization prolonged survival, providing a potential new therapeutic approach. This fundamental study uses compelling methods to provide new insights into this emerging disease, which could be dissected further in future studies aimed at gaining mechanistic insight and assessing the translational relevance of these discoveries.

eLife assessment

This manuscript provides potentially valuable information suggesting that the earliest appearing T-cells during ontogeny may have properties that are fundamentally distinct from those appearing later in life. At this stage, weaknesses in the experimental design and data interpretation provide inadequate support for the conclusions. With modifications, the paper should be of interest to those interested in T-cell development.

eLife assessment

This study characterizes the composition and immune diversity of the zebrafish kidney, the immune organ equivalent to human bone marrow, with convincing single-cell transcriptomic data of hematopoietic cells and immunocytes. The key findings suggest that zebrafish kidney is a secondary lymphatic organ, and that hematopoietic stem cells in zebrafish may exhibit trained immunity, which are the unique features of the fish immune system. This study provides new and valuable insights into the antiviral response in teleost fish, which will be of interest to biologists in general, and to immunologists and cancer researchers in particular.

eLife assessment

This work describes a valuable new technique involving proximity labelling to identify Drosophila proteins modified by GlcNAcylation in subsets of cells in vivo. A solid set of experiments shows that several ribosomal proteins are modified in the fly mushroom body. Consistent with a role for GlcNAcylation of ribosomal proteins in control of memory related translational control, the authors show that perturbation of GlcNAc modification in KCs prevents efficient consolidation of long-term memory.

eLife assessment

This important work substantially advances our understanding of how resistant leukemia can arise without changes in mutational patterns by displaying epigenetic changes. The evidence supporting the conclusions is compelling, with rigorous genomic assays done on primary samples. and state-of-the-art microscopy. The work will be of broad interest to hematologists and cancer biologists.

eLife assessment

This important study outlines how the agr quorum sensing system in Staphylococcus aureus confers long-lived protection against oxidative stress, thereby linking bacterial metabolism to virulence in this pathogen. While the findings, which are supported by solid data, seem at first glance to contradict earlier findings that show increased fitness of agr mutants under oxidative stress, the core conclusions of the study are well-substantiated. The authors should, however, re-evaluate their interpretations related to the impact of agr inactivation on bacterial metabolic and redox status following oxidative stress. The topic of the paper holds broad relevance to microbiologists, especially those focusing on host-pathogen interactions and bacterial responses to ROS.

eLife assessment

The report presents the cryo-EM structure of human vesicular monoamine transporter 2 (VMAT2) bound to tetrabenazine, a clinical drug. VMAT2 is critical for neurotransmission, and the study constitutes an important milestone in neurotransmitter transport research. The evidence presented in the report is convincing and provides new opportunities for developing improved therapeutic interventions and furthering our understanding of this vital protein's function.

eLife assessment

This study provides useful information regarding the role of Netrin-1 and Unc5c in developing dopaminergic axons. Several findings are solid. These include that Netrin-1 and UNC5c can guide dopaminergic innervation from the nucleus accumbens to the cortex during adolescence, that the onset of Unc5 expression is sexually dimorphic in mice, and that in Siberian hamsters environmental effects on development are also sexually dimorphic. While this work is novel and provides useful information, the reviewers unanimously agree that support for the main claims remains incomplete. Understanding developmental trajectories of adolescence, and how they can be impacted by environmental factors, is an understudied area of neuroscience that is highly relevant to understanding the onset of mental health disorders. These data will be of interest to those interested in these factors.

eLife assessment

This study provides valuable observations indicating that human pyramidal neurons propagate information as fast as rat pyramidal neurons despite their larger size. Solid evidence demonstrates that this property is due to several biophysical properties of human neurons. This study will be of interest to neurophysiologists.

eLife assessment

This study presents a valuable finding on the spontaneous emergence of structured activity in artificial neural networks endowed with specific connectivity profiles. The evidence supporting the claims of the authors is potentially solid but still incomplete at this stage, as it is important to demonstrate that similar properties are observed with more diverse inputs and in more complex environments. The work will be of interest to systems and computational neuroscientists.

eLife assessment

Varadharajan et al. explore the mechanistic basis of MBOAT7 SNP association with steatotic liver disease and link its function in LPI acylation to altered lipidomics of endosomal/lysosomal system and impaired TFEB mediated lysosomal biogenesis. The findings are important with theoretical and practical implications in MAFLD, alcohol-induced hepatic steatosis, and lysosomal diseases. The strength of evidence is convincing using methodology in line with current state-of-the-art.

eLife assessment

This important study follows up on previous work defining the anti-leukemic effects of a previously characterized cannabis extract on Notch-activated T cells and identifies several pathways that mediate its anti-cancer activity including the ER calcium and integrated stress response. The evidence is solid, but several concerns remain including the over reliance on a single cell line for the majority of the studies and lack of integration of the observations with existing literature

eLife assessment

The authors provide compelling evidence that MSP1 inhibition (leading to chromosomal instability in the cancer cells) increases phagocytosis and that tumors with chromosomal instability respond better to the current state-of-the-art macrophage therapeutics. In this important study, they demonstrate particularly impressive survival rates for mouse models of CIN B16 tumors treated with CD47 blockade and anti-Tyrp1 IgG.

eLife assessment

Using state-of-the-art fate-mapping models and genetic and pharmacological targeting approaches, this study provides important findings on the distinct functions exerted by resident and recruited macrophages during cardiac healing after myocardial ischemia. Evidence supporting the conclusions are solid with the use of the FIRE mouse model in combination with fate-mapping to target fetal-derived macrophages. This study will be of interest for the macrophage biologists working in the heart but also in others tissues in the context of inflammation.

eLife assessment

The study presents important findings regarding a transcription-independent component of the early recovery of proteasome activity from a short pulse of proteasome inhibitor treatment, which has not been appreciated before and which is independent of the DDI2-NRF2 axis. While the evidence is in principle solid, with recapitulation in several cell line models, the proposed alternative underlying mechanism, namely regulation at the level of proteasome assembly, lacks experimental support, and at this point remain speculative.

eLife assessment

The authors build upon prior data implicating the secreted peptidoglycan hydrolase SagA produced by Enterococcus faecium in immunotherapy. Leveraging new strains with sagA deletion/complementation constructs, the investigators reveal that sagA is non-essential, with sagA deletion leading to a marked growth defect due to impaired cell division, and sagA being necessary for the immunogenic and anti-tumor effects of E. faecium. In aggregate, the study utilizes compelling methods to provide both fundamental new insights into E. faecium biology and host interactions and a proof-of-concept for identifying the bacterial effectors of immunotherapy response.

eLife assessment

This study, which seeks to identify factors from the glial niche that support and maintain neural stem cells, unveils a novel role for ferritin in this process. Furthermore, the work shows that defects in larval brain development resulting from ferritin knockdown can be attributed to impaired Fe-S cluster activity and ATP production. These findings will be valuable to both oncologists and neurobiologists, though the supporting evidence is currently incomplete.

eLife assessment

This important work presents a new methodology for the statistical analysis of fiber photometry data, improving statistical power while avoiding the bias inherent in the choices that are necessarily made when summarizing photometry data. The reanalysis of two recent photometry data sets, the simulations, and the mathematical detail provide convincing evidence for the utility of the method and the main conclusions, however, the discussion of the re-analyzed data is incomplete and would be improved by a deeper consideration of the limitations of the original data. In addition, consideration of other data sets and photometry methodologies including non-linear analysis tools, as well as a discussion of the importance of the data normalization are needed.

eLife assessment

This manuscript presents a valuable, lightweight software package that aims to accelerate the implementation of experiment pipelines running on heterogeneous computer environments. The authors present solid evidence of the advantages of their chosen approach, including demonstrating the flexibility, ease of use, and practical utility of this new system. However, questions remain regarding the maturity of the project and its specific advantages in relation to existing widely adopted software packages.

eLife assessment

This important study investigated transcriptional profiles of midbrain dopamine neurons using single nucleus RNA (snRNA) sequencing. The authors found more nuanced subgroups of dopamine neurons than previous studies, and identified some genes that are preferentially expressed in subpopulations that are more vulnerable to neurochemical lesions using 6-hydroxydopamine (6OHDA). The results are convincing and provide critical information on the heterogeneity and vulnerability of dopamine neurons which will be a foundation for future studies.

eLife assessment

This work addresses the connectivity of giant excitatory neurons in a part of CA1 of the hippocampus. Recordings in rat brain slices provide new evidence that these cells excite bistratified and basket inhibitory neurons, and have weak inhibitory input from basket cells, as well as other findings. This circuitry gives these cells unique potential, making the work valuable, however the strength of the evidence is currently incomplete.

eLife assessment

In this important study, Xiong and colleagues studied PKA regulation in synaptic plasticity. They provide convincing evidence that dissociation of PKA catalytic subunits is essential for the proper function of the kinase. Experiments using a PKA regulatory-catalytic subunit fusion establish that dissociative activation is required for both structural long-term potentiation and basal priming of AMPA receptors.

eLife assessment

This useful manuscript reports on a new mouse model for LAMA2-MD, a rare but very severe congenital muscular dystrophy; the knockout mice were generated by removing exon3 in the Lama2 gene, which results in a frameshift in exon4 and a premature stop codon. These animals lack any laminin-alpha2 protein and confirm results from previous Lama2 knockout models. Additionally, this study includes transcriptomics data that might be a good resource for the field. However, the experimental evidence supporting the main claims of the manuscript is incomplete, citations of previous Lama2 null mice studies are lacking, and both data presentation and interpretation need improvement.

eLife assessment

This valuable study addresses one way in which animals identify predator-associated cues and respond in a manner that reflects the imminence of the potential threat. The report shows that, in mice, fresh saliva from a natural predator (cat) elicits a greater defensive response compared to old cat saliva and implicates the vomeronasal organ and ventromedial hypothalamus as part of a circuit that underlies this process. While the study has potential, the results are somewhat preliminary, and as such support for the primary conclusions is incomplete.

eLife assessment

This important study by Lee and colleagues examined how neural representations are transformed between the olfactory tubercle (OT) and the ventral pallidum (VP) using single neuron calcium imaging in head-fixed animals trained in classical conditioning. They show that the dimensionality of neural responses is lower in the VP than in the OT and suggest that VP responses represent values in a more abstract form while OT contains more odor information, potentially enhancing odor contrast. The reviewers found the results overall convincing although the nature of OT responses needs to be investigated further.

eLife assessment

This study addresses the role of FMRP in the migration of newborn neuroblasts in the postnatal brain. Through extensive and convincing analysis of living imaging videos, the authors showed that neurons with FMRP deletion migrate aberrantly and exhibit defects in nucleokinesis and centrokinesis. The study presents a valuable finding on the mechanism of neuroblast migration in the postnatal brain.

eLife assessment

The authors use reinforcement learning modeling to study the alterations following acute ketamine in macaques. The evidence supporting the conclusion that ketamine reduces the impact of losses vs. neutral/gains is solid. In this version of this valuable study, the authors make more measured interpretations about the relationship between the processing of losses and ketamine's antidepressant effects.

eLife assessment

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

eLife assessment

This is a fundamental resource of snRNA-seq and and chromatin accessibility data from human aortic endothelial cells (ECs), treated with relevant perturbations such as IL1b, TGFB2, or si-EGR. The authors show that ECs can be categorized by distinct subpopulations of differing plasticity. The support for the existence of these subpopulations is compelling, supported also by three publicly available scRNA-seq datasets, and differential enrichment of coronary artery disease associated SNPs in open chromatin in these subpopulations.

eLife assessment

In this valuable study, the discovery and subsequent design of the AF03-NL chimeric antibody led to a tool for studying filoviruses and provides a possible blueprint for future therapeutics. In general, the data presented are solid, although further improvements can be made in the overall presentation of the results. The work will be of interest to virologists studying antibodies.

eLife assessment

This study reports comparative biochemical and structural analysis of two PLP decarboxylase enzymes from plants. The work is useful because of the potential application of these enzymes in industrial theanine production. The results, particularly the x-ray crystal structures, provide a solid basis for understanding substrate specificity. The paper will be of interest to enzymologists studying PLP enzymes and those working on enzyme engineering in plants.

eLife assessment

This study presents valuable data on the antigenic properties of neuraminidase proteins of human A/H3N2 influenza viruses sampled between 2009 and 2017. The antigenic properties are found to be generally concordant with genetic groups. Additional analysis have strengthened the revised manuscript, and the evidence supporting the claims is solid.

eLife assessment

This important study reports comprehensive multi-omics data on the changes induced in young and aged male mouse tail fibroblasts after treatment with chemical reprogramming factors. The authors provide solid evidence to support their claim that chemical reprogramming factors induce changes consistent with a reduction of cellular 'biological' age (e.g., correlations with established aging markers in whole tissues).

eLife assessment

This solid study presents valuable insights into the role of Cers1 on skeletal muscle function during aging, although further substantiation would help to fully establish the experimental assertions. It examines an unexplored aspect of muscle biology that is a relevant opening to future studies in this area of research.

eLife assessment

This important study introduces a novel AI method for the analysis of published data, with practical implications for early cancer diagnosis. The results are supported by compelling evidence.

eLife assessment

This valuable paper examines the role of the WRNIP1 AAA+ ATPase in regulating R-loop formation, which induces a conflict with active replication forks and transcription. The authors provide convincing evidence to support a role of the ubiquitin-binding UBZ domain of WRNIP1 in R-loop suppression generated by this conflict. The work is of interest to researchers who work on genome stability/instability.

eLife assessment

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

eLife assessment

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

eLife assessment

This valuable study advances our understanding that YAP/TAZ, as well as their target genes, play a prominent role in the formation of processing bodies (P-bodies). The evidence supporting the conclusions is convincing. The article could be improved through further analysis to elucidate the mechanistic link between P-body formation and oncogenesis. The work will be of broad interest to scientists working in the field of Hippo signaling and cancer biology.

eLife assessment

This important study identifies a role for triglycerides and lipid droplets in spermatogenesis, with data supporting relevance of this finding across phyla. The work shows with convincing data that a triglyceride lipase is required cell-autonomously for germline differentiation into meiotic stages and haploid spermatids and that an increase in triglycerides is detrimental to spermatogenesis. This paper would be of interest to developmental and cell biologists working on gametogenesis.

eLife assessment

This study presents valuable empirical work and simulations that are relevant for the evolution of genetic load linked to self-incompatibility alleles in Arabidopsis. The evidence supporting the findings is solid but could be improved by a more detailed quantitative assessment of the impacts of deleterious alleles and their dominance. The simulation results are somewhat incomplete, as details of the approach and code do not appear to be available, but this could be easily remedied. The work will be of relevance to geneticists interested in the evolution of allelic diversity in similar systems.

eLife assessment

This valuable study provides the detailed molecular mechanism of how OGT, an O-GlcNac transferase, promotes cancer progression. Using loss-of-function OGT models, the authors demonstrated that OGT cleaves HCF-1, a guardian of genomic stability. These solid findings can lead to some potential approaches to modulate anti-tumor immunity by targeting this process.

eLife assessment

This manuscript provides useful information about the lipid metabolite 15d-PGJ2 as a potential regulator of myoblast senescence. The authors provide experimental evidence that 15d-PGJ2 inhibits myoblast proliferation and differentiation by binding and regulating HRas. However, the manuscript is incomplete in its current form, as it lacks robust support from the data regarding the main conclusions related to senescence and technical concerns related to the senescence models used in this study.

eLife assessment

This study makes a valuable finding, a polyunsaturated fatty acid increases the conductance of a K+ channel by helping its K+ selectivity filter form a conductive state. Overall, support for this major claim is solid, though other claims remain speculative with incomplete support. These findings are expected to be of interest to researchers studying ion channel gating.

eLife assessment

In this useful study, the authors investigate the regulatory mechanisms related to toxin production and pathogenicity in Aspergillus flavus. Their observations indicate that the SntB protein regulates morphogenesis, aflatoxin biosynthesis, and the oxidative stress response, however, the data supporting these conclusions are incomplete. The work will be of interest to bacteriologists.

eLife assessment

How the triplicate interaction between chemokines with both GAGs and G protein-coupled receptors (GPCR) works and how gradients are created and potentially maintained in vivo are poorly understood. The authors provide solid evidence to show phase separation can drive chemotactic gradient formation. The paper is a useful advance in the field of chemokine biology.

eLife assessment

Yu and colleagues used two-sample MR to test the effect of PUFA on cerebral aneurysms. They found that genetically predicted omega-3 and DHA decreased the risk for Intracranial Aneurysm and Subarachnoid Haemorrhage. This work is useful, although the evidence is incomplete as it lacks a robust set of analyses to provide credibility to the findings.

eLife assessment

This important study examines SARS-CoV-2 seroprevalence in Bolivia and aims to provide insights into the transmission of the virus and the effects of vaccination on population immunity. However, the evidence for the main claims is incomplete because of the uncertainties about the accuracy of the neutralization assays given the cross-neutralization present across variants, as well as the selected population of blood donors tested. These uncertainties need to be addressed to support the premise of the paper.

eLife assessment

The manuscript provides convincing evidence that both circulating omega-6 and omega-3 PUFAs are associated with lower all-cause, cancer, and cardiovascular mortality in the UK BioBank population and that omega-3s have a stronger effect than omega-6s. The findings have important public health implications.

eLife assessment

This joint computational/experimental study demonstrates the ability of synthetic peptides derived from the stalk-tethered agonist in Polycystin-1 (PC1) to re-activate signaling by a stalkless C-terminal fragment of PC1. The study is valuable as it discovered peptide agonists for PC1 and the integrated in vitro and in silico approach is potentially applicable to the analysis of related systems. The line of evidence presented in the current manuscript is considered incomplete and additional experiments are needed as controls and for validating the simulations.

eLife assessment

This important manuscript reports the cryo-EM structure of the ASK1 protein, which is a critical regulator of the MAPKs, JNKs, and p38 MAPKs in diverse cellular stress responses. The evidence of ASK1 interaction with TRX1 is compelling and will eventually allow the discovery of small molecule inhibitors of ASK1 activity.

eLife assessment

This important study addresses a fundamental question: how do post-translational modifications of tubulin regulate the function of the microtubule cytoskeleton in vivo? The authors generate a large panel of tubulin mutants designed to lack specific modifications and describe their effects using endogenous editing and touch receptor neurons in C. elegans as an in vivo model. While the work presents an impressive amount of data, it is in part incomplete, since the presence and absence of specific tubulin modifications and their effects on microtubules are not demonstrated in all cases.

eLife assessment

This valuable study addresses the role of Rho-associated coiled-coil kinase (ROCK) and the cytoskeleton in the initiation and growth of the calcified endoskeleton of sea urchin embryos. Perturbation by two independent approaches (a morpholino and a selective inhibitor) provide convincing evidence that ROCK participates both in actomyosin regulation and in the gene regulatory network that controls skeletogenesis. Exciting areas of future work will be to elucidate the mechanisms by which ROCK influences gene expression and to further dissect the role of the cytoskeleton in mineralization.

eLife assessment

The manuscript seeks to dissect the molecular underpinnings of poke and stretch activation in OSCA channels. While the structural and functional experiments are well done, and the authors present some important data, the reviewers identified weaknesses in experimental design and interpretation that render the data incomplete in supporting some of the main conclusions of the paper. Nevertheless, this work will be of interest to those working in the fields of mechanosensation, sensory biology, and ion channels.

eLife assessment

In this important study, the authors identify distinct roles for the calcium sensors Synaptotagmin 7 and Doc2alpha in the regulation of asynchronous release and calcium-dependent synaptic vesicle docking in hippocampal neurons. The current work adds to the field by placing the role of the two proteins in a new context, where Synaptotagmin 7 acts to promote synaptic vesicle docking and capture after a stimulus, while Doc2alpha has a role in specifically driving the asynchronous component of release as a calcium sensor. The methods, data, and analyses provide convincing support for the conclusions.

eLife assessment

This important study used single-cell whole-brain imaging of the immediate early gene Fos to identify the brain areas recruited by two anesthetics, ketamine and isoflurane. The utilization of a custom software package to align and analyze brain images for c-Fos positive cells stands out as an impressive component of the approach. The results provide solid evidence that these anesthetics might induce anesthesia via different brain regions and pathways, and raw fos showed shared and distinct activation patterns after ketamine- v. isoflurane-based anesthesia. Though differences could also be due, as the authors note, to differences in dose and route of administration. This paper may be of interest to preclinical and clinical scientists working with anesthetic and dissociative drugs.

eLife assessment

This study presents valuable findings that examine both how Down syndrome (DS)-related physiological, behavioral, and phenotypic traits track across time, as well as how chronic treatment with green tea extracts 25 enriched in epigallocatechin-3-gallate (GTE-EGCG), administered in drinking water spanning prenatal through 5 months of age, impacts these measures in wild-type and Ts65Dn mice. The strength of the evidence is solid, due to high variability across measures, perhaps in part attributable to a failure to include sex as a factor for measures known to be sexually dimorphic. This study is of interest to scientists interested in Down Syndrome and its treatment, as well as scientists who study disorders that impact multiple organ systems.

eLife assessment

This important work provides a thorough and detailed analysis of natural variation in C. elegans egg-laying behavior. The authors present convincing evidence to support their hypothesis that variations in egg-laying behavior are influenced by trade-offs between maternal and offspring fitness. This study establishes a framework for elucidating the molecular mechanisms underlying this paradigm of behavioral evolution.

eLife assessment

This valuable study advances our understanding of the below-ground resource acquisition strategies of diverse tree species, integrating the roles of both roots and their associated microbes. The support for the conclusions is incomplete owing to the uncertainties or shortcomings associated with the design and statistical analyses. Regardless of these technical issues, this study can be of broad interest for plant and microbial ecologists.

eLife assessment

This study divided structural brain aging into two groups, revealing that one group is more vulnerable to aging and brain-related diseases compared to the other group. This study is valuable as such subtyping could be utilized in predicting and diagnosing cognitive decline and neurodegenerative brain disorders in the future. However, the authors' claims remain incomplete, as there appears to be a lack of connection between this and the authors' claims.

eLife assessment

This study presents an important finding on the role of telomeres in modulating interleukin-1 signaling and tumor immunity in TNBC. The evidence supporting these findings is solid, presented through comprehensive analyses including TNBC clinical samples, tumor-derived organoids, cancer cells, and xenografts. The work will be of broad interest to cell and medical biologists focusing on TNBC.

eLife assessment

This manuscript presents an important analysis of the role that the nucleosome acidic patch plays in SWR1-catalyzed histone exchange. This manuscript contains convincing data which significantly expands our understanding of the complex process of H2A.Z deposition by SWR1 and therefore would be of interest to a broad readership. The manuscript would benefit from addressing previous models in the field, specifically regarding the insertion of the second dimer of H2A.Z/H2B; and the involvement of the acidic patch recognition by SWR1. These points should be addressed more directly with additional data.

eLife assessment

This study presents a valuable characterization of the biochemical consequences of a disease-associated point mutation in a nonmuscle actin. The study uses well-characterized in vitro assays to explore function. The data are convincing and should be helpful to others.

eLife assessment

This useful study addresses discrepancies in determining bacterial burden in osteomyelitis as determined by culture and enumeration using DNA. The authors present compelling data demonstrating the emergence of discrepancies between CFU counts and genome copy numbers detected by PCR in Staphylococcus aureus strains infecting osteocyte-like cells. Whilst the observations may represent a substantial addition to the field of musculoskeletal infection, the broad applicability and clinical benefit are unclear.

eLife assessment

This valuable work explores death coding data to understand the impact of COVID-19 on cancer mortality. The work provides solid evidence that deaths with cancer as a contributing cause were not above what would be expected during pandemic waves, suggesting that cancer did not strongly increase the risk of dying of COVID-19. These results are an interesting exploration into the coding of causes of death that can be used to make sense of how deaths are coded during a pandemic in the presence of other underlying diseases, such as cancer.

eLife assessment

This work by Shin et al. demonstrated that a different form of PTH (R25C PTH) generated a comparable anabolic signal to rhPTH 1-34 using a large animal model. This valuable finding may have therapeutic potential in promoting bone formation or the healing process, and the methods seem solid.

eLife assessment

This study presents an important finding on the key factors of T cell responses associated with durable antibody responses following COVID-19 mRNA vaccinations. Though the sample size is small, and in-vitro stimulated T cells were used, the analysis and approaches were extensive, and the collected data were mostly solid. The results may greatly impact future COVID-19 vaccine design.

eLife assessment

This study provides valuable findings showing the production of IL-22 from intestinal ILC3 during intermittent fasting promotes beigeing of white adipose tissue. The authors provided solid data and mechanistic insight by which IL-22-derived from ILC3 directly induces beigeing.

eLife assessment

This study based on the use of Cancer Drug Resistance Accelerator (CDRA) chip is valuable as a platform technology to assess chemoresistance mechanisms. The strength is convincing from the technological point of view. However, the use of a single cell line model is a limitation. However we acknowledge the authors' plan to further validate their current findings across multiple TNBC cell lines.

eLife assessment

This is an important study, that adds to the field a new understanding of exercise or mechanical loading, microRNAs, and secreted extracellular vessicles in the field of lung cancer (NSCLC), which may have relevance to other osteolytic cancers. The strength of the evidence was mixed: whereas in vitro microRNA experiments were convincing, other elements were incomplete (e.g., proving the roles of osteocytes, as opposed to other mechanosensitive cells, in vivo). This work would be of broad interest to those investigating osteolytic cancers, and the role of exercise in bone cancer, preclinically.

eLife assessment

This important study defined the physiological function of a conserved meiosis factor during murine spermatogenesis. The genetic and cellular biological evidence supporting the conclusion is convincing. This work will be of broad interest to cell biologists, geneticists, and reproductive biologists.

eLife assessment

This important study reports a potential mechanism by which glutamate transmission from the LepRb PMv neurons influences the neuroendocrine reproductive axis. The genetic method to simultaneously remove glutamate signaling and restore the leptin receptor in LepRb PMv neurons is compelling, and most of the data are solid. The impact of the study would be enhanced if the authors could address the concerns raised by the three reviewers. This study will be of interest to biomedical researchers working on reproduction, endocrinology, and metabolism.

eLife assessment

This useful study reports that a water-soluble analog of heliomycin, 4-dmH, induces protein degradation of not only SirT1 but also tNOX, unlike heliomycin, which induces degradation of SirT1 but not tNOX, a difference that could in principle explain why 4-dmH induces apoptosis while heliomycin induces autophagy. The presented data provide solid support for the authors' conclusions.

eLife assessment

This study presents a valuable finding on the roles and mechanisms of FYN and KDM4 in TNBC tumor cell resistance. The evidence supporting the claims of the authors is somewhat incomplete and the refinement of certain experiments would have strengthened the study. Noteworthy, FYN has been implied in drug resistance previously and this should be carefully discussed in the manuscript. The work will be of interest to scientists working on breast cancer.

eLife assessment

This important study provides insights into the role of FBXO24 in controlling spermiogenesis and male fertility in mice. The mouse models used and the data are convincing. This paper will interest biomedical researchers working on reproductive biology and fertility control.

eLife assessment

This potentially useful study reports a new method for restoring sperm motility. Strengths are in the methodology being developed, but the conclusions require additional experimental support. The authors provide inadequate evidence for the success of the method or its mechanism.

eLife assessment

Maestri et al report the absence of phylogenetic evidence supporting codiversification of mammalian coronaviruses and their hosts, leading to the important conclusion that the evolutionary history of the virus and its hosts are decoupled through frequent host switches. The evidence for frequent host switching, derived from a probabilistic model of co-evolution, appears convincing, but evidence for quantitative statements about the time of the last common ancestor of extant mammalian coronaviruses remains incomplete. The results would be strengthened by a reconstruction of the evolutionary timescale and further investigation of robustness to sampling biases and unsampled diversity.

eLife assessment

This important study links the activity of polymerase III to the regulation of virulence gene expression in the deadliest malaria parasite, Plasmodium falciparum. It identifies Maf1 as a Pol III inhibitor that enables the parasite to respond to external stimuli such as magnesium chloride plasma levels by downregulating Pol III-transcribed ruf6 genes and subsequently regulated var genes. While the evidence presented is generally convincing, some of the results are incomplete, and the mechanistic link between external signals and Maf1 activation remains unknown.

eLife assessment

This important work by Park et al. demonstrates an open-top two-photon light sheet microscopy (OT-TP-LSM) for lesser invasive evaluation of intraoperative 3D pathology. The authors provide convincing evidence for the effectiveness of this technique investigating various human cancer cells. This article will be of broad interest to biologists and, specifically, pathologists utilizing 3D optical microscopy.

eLife assessment

This study provides useful initial information on how humans represent two-dimensional abstract spaces in relation to the social traits of warmth and competence. While the study poses an interesting question, the evidence for a grid-like code at present is incomplete. This study will be of interest to researchers working in the field of spatial navigation as well as the navigation of conceptual abstract space.

eLife assessment

This important study presents a series of results to uncover the role of C-terminal half of the Syx1 SNARE domain. The evidence supporting the conclusions is convincing. The paper will be of broad interest to biophysicists and neurobiologists.

eLife assessment

This manuscript provides convincing evidence for the involvement of membrane actin, and its regulatory proteins, mDia1/3, RhoA, and Rac1 in the mechanism of synaptic vesicle re-uptake (endocytosis). These important data fill a gap in the understanding of how the regulation of actin dynamics and endocytosis are linked. The manuscript will be of interest to all scientists working on cellular trafficking and membrane remodeling.

eLife assessment

This important study proposes a framework to understand and predict generalization in visual perceptual learning in humans based on form invariants. Using behavioral experiments in humans and by training deep networks, the authors offer evidence that the presence of stable invariants in a task leads to faster learning. However, this interpretation is promising but incomplete. It can be strengthened through clearer theoretical justification, additional experiments, and by rejecting alternate explanations.

eLife assessment

This paper presents valuable findings that gustation and nutrition might independently influence the preferred environmental temperature in flies. While some of the evidence is solid, support for other claims appears incomplete at this stage but can be addressed with some further experimentation. The finding that flies might thus exhibit a cephalic phase response similar to mammals will be of value for future investigations.

eLife assessment

The important study established a large-scale objective and integrated multiple optical microscopy systems to demonstrate their potential for long-term imaging of the developmental process. The convincing imaging data cover a wide range of biological applications, such as organoids, mouse brains, and quail embryos, but enhancing image quality can further enhance the method's effectiveness. This work will appeal to biologists and imaging technologists focused on long-term imaging of large fields.

eLife assessment

This important work contributes to our understanding of the combined effects of metabolic syndrome on fronto-temporal gray matter morphology from two large-scale datasets. The evidence based on state-of-the art multivariate imaging analysis and detailed micro- and macrostructural contextualization analyses is convincing and provides an understanding of the neurological correlates of metabolic syndrome, although the study would have benefitted from the inclusion of longitudinal data.

Editors Assessment:

One limiting factor in the adoption of spatial omics research are workflow systems for data preprocessing, and to address these authors developed the SAW tool to process Stereo-seq data. The analysis steps of spatial transcriptomics involve obtaining gene expression information from space and cells. Existing tools face issues with large data sets, such as intensive spatial localization, RNA alignment, and excessive memory usage. These issues affect the process's applicability and efficiency. To address this, this paper presents a high-performance open-source workflow called SAW for Stereo-Seq. This includes mRNA position reconstruction, genome alignment, matrix generation, clustering, and result file generation for personalized analysis. During review the authors have added examples of MID correction in the article to make the process easier to understand. And In the future, more accurate algorithms or deep learning models may further improve the accuracy of this pipeline.

*This evaluation refers to version 1 of the preprint *