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 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

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

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 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 *

Editors Assessment:

This paper describes a new spatial transcriptomics method that that utilizes cell nuclei staining images and statistical methods to generate high-confidence single-cell spatial gene expression profiles for Stereo-seq data. STCellbin is an update of StereoCell, now using a more advanced cell segmentation technique, so more accurate cell boundaries can be obtained, allowing more reliable single-cell spatial gene expression profiles to be obtained. After peer review more comparisons were added and more description given on what was upgraded in this version to convince the reviewers. Demonstrating it is a more reliable method, particularly for analyzing high-resolution and large-field-of-view spatial transcriptomic data. And extending the capability to automatically process Stereo-seq cell membrane/wall staining images for identifying cell boundaries.

This evaluation refers to version 2 of the preprint

Editors Assessment:

For better data quality assessment of large spatial transcriptomics datasets this new BatchEval software has been developed as a batch effect evaluation tool. This generates a comprehensive report with assessment findings, including basic information of integrated datasets, a batch effect score, and recommended methods for removing batch effects. The report also includes evaluation details for the raw dataset and results from batch effect removal methods. Through peer review and clarification of a number of points it now looks convincing that this tool helps researchers identify and remove batch effects, ensuring reliable and meaningful insights from integrated datasets. Potentially making the tool valuable for researchers who need to analyze large datasets of this type, as it provides an easy and reliable way to assess data quality and ensures that downstream analyses are robust and reliable.

This evaluation refers to version 1 of the preprint

eLife assessment

This important study advances our understanding of how landscape context affects the relationship between grassland plant diversity and biomass. This study used very well-designed approaches to analyze complex ecological relationships in real-world landscapes and thus provides compelling evidence to support its findings. The work will be of interest to landscape ecologists and community ecologists.

eLife assessment

This important study could potentially represent a step forward towards personalized medicine by combining cell-based data and a prior-knowledge network to derive Boolean-based predictive logic models to uncover altered protein/signaling networks within cancer cells. The level of evidence supporting the conclusions is solid, as the authors present analyses on independent, real-world data to validate their approach. These findings could be of interest to medical biologists working in the field of cancer, as the work should inform drug development and treatment choices in the field of oncology.

eLife assessment

This important, large experimental study examines the effects of plant species richness, plant genotypic richness, and soil water availability on herbivory patterns for Piper species in several tropical sites. The authors find solid evidence that water availability, as well as intra- and interspecific plant diversity, influence herbivory and herbivore diversity, but that the effects differ geographically.

eLife assessment

This study presents important findings on how cells sense and respond to their surroundings, in particular when two environmental signals are presented periodically, in alternation or conjunction. The compelling analyses reveal some unexpected behaviors that could not have been drawn, from simpler experimental designs, related to the dynamic interplay between the starvation and hyper-osmotic stress responses in budding yeast, exemplifying that applying complex signals can unveil new biological insights, even for well-studied systems. The work will be of broad interest to researchers interested in fungal biology, dynamic systems, cell signaling, and cell biology.

eLife assessment

This study of extrachromosomal DNA (ecDNA) identifies genes that distinguish ecDNA+ and ecDNA- tumors. The findings in the manuscript are important and the genomic analyses convincing. However, some of the data remain observational and the inferences would therefore be more robust with experimental validation. This manuscript could well be of relevance to biologists interested in cancer biology and gene regulation.

eLife assessment

This important study extends existing sequentially Markovian coalescent approaches to include the use of hypervariable loci such as epimutations. This is an intriguing addition and the authors provide solid validation of their methods via simulation and analysis of empirical data in Arabidopsis thaliana. Given the increasing availability of such data -- and thus the potential use of this approach -- there would be additional value in more extensive consideration of when and where these methods are best used.

eLife assessment

This useful study provides the first assessment of the potentially interactive effects of seasonality and blood source on mosquito fitness, together in one study. However, the experimental approach is incomplete because it is limited without replication of the experiments and because of the small sample sizes for some groups. The work will be of interest to those studying mosquito biology.

eLife assessment

This work presents important insights regarding the mechanism underlying the assembly, maintenance, and disassembly of a very stable microtubule-based structure, termed quiescent-cell nuclear microtubule (Q-nMT) bundle, which is formed in quiescent yeast cells to ensure cell survival and viability. This insight will help to elucidate how very stable microtubules can exist alongside very dynamic microtubules, which is still poorly understood. While the experimental support is overall solid, additional analyses using state-of-the-art methodology would further strengthen some of the claims.

eLife assessment

This valuable study seeks to disentangle the different selective forces shaping the evolutionary dynamics of transposable elements (TEs) in the wild grass Brachypodium distachyon. Using haplotype-length metrics, and genetic and environmental differentiation tests, the authors present convincing evidence that positive selection on TE polymorphisms is rare and that the distribution of TE ages points to purifying selection being the main force acting on TE evolution in this species. This study will be relevant for anyone interested in the role of TEs in evolution and adaptation.

eLife assessment

This study presents a valuable finding on the impact of metformin-induced shifts in gut microbial community structure and metabolite levels for drug efficacy in a mouse model of liver injury. The current evidence supporting the claims of the authors is solid. This paper will be of broad interest to researchers across multiple disciplines, including the microbiome, liver disease, and pharmacology.

eLife assessment

This important study provides new insights into the development and function of medullary thymus epithelial cells (mTEC). The authors provide compelling evidence to support their claims as to the differentiation and lineage outcomes of CCL21+ mTEC progenitors, which further our understanding of how central tolerance of T cells is enforced within the thymus.

eLife assessment

The fMRI study is important because it investigates fundamental questions about the neural basis of multimodal binding using an innovative multi-day learning approach. The results provide solid evidence for learning-related changes in the anterior temporal lobe, however, the interpretation of these changes is not straightforward, and the study does not (yet) provide direct evidence for an integrative code. This paper is of potential interest to a broad audience of neuroscientists.

eLife assessment

This valuable study advances our understanding of how the viral protease in a D-type retrovirus is activated and in particular how the exposure of the myristoyl group is required for processing of the Gag matrix precursor. The supporting evidence is convincing, but the work would benefit from additional data in support of the claims. This manuscript is of interest to retrovirologists and structural biologists.

eLife assessment

This study presents a useful assessment of the possible role of type I interferons in inhibiting Adam17 protease/sheddase activity and their correlation with decreased Langerhans Cells signature in lesional and nonlesional CLE and murine models as cause of photosensitive lupus. The data were collected and analyzed using a solid methodology. This work will be of interest to scientists interested in photosensitivity in the setting of lupus.

eLife assessment

This important study used a novel method to relate gastric acidity to subjective ratings of emotions induced by video clips. The findings are solid but could be strengthened by additional analyses and/or visualization. The findings have broad implications for the field of emotion research and opens new avenues of research for understanding psychosomatic disorders.

eLife assessment

This manuscript presents the lack of effect of closed-loop SWR disruption in guiding behavior and remembering the recent past in short-term memory tasks in rats. These negative results may have important theoretical and practical implications in the field of memory and learning. However, while SWR detection methods are carefully validated, the strength of evidence is incomplete and some additional controls are required.

eLife assessment

This study presents valuable findings on the role of the Drosophila ubiquitin-conjugating enzyme UBE2D/eff in maintaining proteostasis during aging. Protein levels of UBE2D decrease with age, and knockdown of UBED2 leads to an accumulation of ubiquitinated proteins, and a shortened lifespan that can be rescued by ectopic expression of the human homologous gene. The work supports a role of this ubiquitin conjugating enzyme in proteostasis, although the evidence is still incomplete. The study will be of broad interest to cell biologists working in aging and age-related diseases.

eLife assessment

Pak et al. examined the relationship between the most common spatial patterns of neurodegeneration and transcriptional markers of the density of different cell types in the cerebral cortex. This valuable study uses innovative methods to provide convincing evidence that patterns of grey matter loss in various forms of dementia are correlated with the anatomical distribution of non-neuronal cell types.

eLife assessment

This important work identifies a previously uncharacterized capacity for songbird to recover vocal targets even without sensory experience. The evidence supporting this claim is convincing, with technically difficult and innovative experiments exploring goal-directed vocal plasticity in deafened birds. This work has broad relevance to the fields of vocal and motor learning.

eLife assessment

This important study assesses anatomical, behavioral, physiological, and neurochemical effects of early-life seizures in rats, describing a striking astrogliosis and deficits in cognition and electrophysiological parameters. The solid results come from a wide range of convergent techniques that were used to understand the effects of early-life seizures on behavior as well as hippocampal prefrontal cortical dynamics. This paper will be of interest to neurobiologists, epileptologists, and behavioral scientists.

eLife assessment

This is an important study examining the neural profile of weak and strong fear memories using a variety of imagining and interrogation neural techniques. The data are convincing in detailing the neural profile of neutral, aversive and fear conditioned stimuli in the LC and its input to the dorsal hippocampus and support the conclusion that dopaminergic input from the LC is the key instigator of trace fear conditioning in hippocampus. This paper is of interest to behavioural and neuroscience researchers studying learning, memory and neural networks.

eLife assessment

This useful study addresses the interesting and challenging problem of how neural networks (including possibly the brain) can optimize performance while multi-tasking. The authors address this problem by introducing an information-theoretic framework that balances the costs of control and of automaticity to achieve a desired level of overall performance. They present detailed analyses of this framework, but overall the manuscript is not easily accessible to a broad audience, and the supporting evidence is currently incomplete (but could be greatly improved with substantial revisions). They use information-theoretic terminology in non-standard ways that are not clearly explained, leading to difficulties in interpreting the framework and comparing it to other computational approaches, and the relationship between their findings and empirical data is not always clear.

eLife assessment

The manuscript describes human intracranial neural recordings in the auditory cortex during speech production, showing that the effects of delayed auditory feedback correlate with the degree of underlying speech-induced suppression. This is an important finding, as previous work has suggested that speech suppression and feedback sensitivity often do not co-localize and may be distinct processes, in contrast with findings in non-human primates where there is a strong correlation. The strength of the evidence is solid, with appropriate experimental methods, data, and analysis, though some additional analysis would strengthen comparisons with past work.

eLife assessment

This fundamental study substantially advances our understanding of the role of different-sized soil invertebrates in shaping the rates of leaf litter decomposition, using an experiment across seasons along an aridity gradient. The authors provide compelling evidence that the summed effects of all invertebrates (with large-sized invertebrates being more active in summer and small-sized invertebrates in winter) on decomposition rates result in similar levels of leaf litter decomposition across seasons. The work will be of broad interest to ecosystem ecologists interested in soil food webs, and researchers interested in modeling carbon cycles to understand global warming.

eLife assessment

This important work substantially advances our understanding of episodic memory in individuals with aphantasia, and sheds light on the neural underpinnings of episodic memory and mental imagery. The evidence supporting the conclusions is convincing, including evidence from a well-established interview paradigm complemented with fMRI to assess neural activation during memory recall. The work will be of broad interest to memory researchers and mental imagery researchers alike.

eLife assessment

Amacrine cells are a heterogeneous and understudied set of retinal interneurons. This study presents valuable new insights into the structure, function, and circuit connectivity of a particular subset of wide field amacrine cells (WACs). The authors use an impressive set of techniques to study structural and functional properties of these cells and to establish their postsynaptic circuit partners. Evidence for the central conclusions is solid, although some of the most interesting results could be pursued more completely.

eLife assessment

This important study describes patterns of anatomical connectivity between the cortex and the thalamus using magnetic resonance imaging data in humans and non-human primates. The measures are related to numerous other modalities to develop a robust understanding of the organisation of the system. The authors provide solid evidence that there is a difference between sensory and association cortices in terms of their connectivity with the thalamus, which may have downstream effects on brain function. This work will be of interest to neuroscientists interested in the organization and dynamics of cortico-thalamic circuits.

eLife assessment

This important study introduces a new cortical circuit model for predictive processing. Simulations effectively illustrate that, with appropriate synaptic plasticity, a canonical layer 2/3 cortical circuit - comprising two classes of interneurons providing subtractive and divisive inhibition - can generate uncertainty-modulated prediction errors by pyramidal neurons. The model's effectiveness is supported by solid numerical analysis. Although the model is convincing and offers testable predictions, it currently lacks direct comparison to experimental data, and the presentation clarity could be improved. Nonetheless, the model is expected to be of great interest to those involved in cortical and predictive processing research.