eLife Assessment

This manuscript shows that chronic chemogenetic excitation of dopaminergic neurons in the mouse midbrain results in differential degeneration of axons and somas across distinct regions (SNc vs VTA). These findings are important for two reasons. This approach can be used as a mouse model for Parkinson's Disease without the need for the infusion of toxins (e.g. 6-OHDA or MPTP) — this mouse model also has the advantage of showing axon-first degeneration over a time course (2–4 weeks) that is suitable for experimental investigation. Also, the findings that direct excitation of dopaminergic neurons causes differential degeneration sheds light on the mechanisms of dopaminergic neuron selective vulnerability. The evidence that activation of dopaminergic neurons causes degeneration, alters motor behavior, and alters mRNA expression is convincing. This is an exciting paper that will have an impact on the Parkinson's Disease field.

eLife assessment

In this manuscript, Rademacher and colleagues examined the effect of a chemogenetic approach on the integrity of the dopamine system in mice with chronically stimulating dopamine neurons. These findings are important: (1)This approach led to an axon-first degeneration over an experimentally useful time course (2-4 weeks); (2) The finding that direct excitation of dopaminergic neurons causes differential degeneration sheds light on dopaminergic neuron selective vulnerability mechanisms. Overall, the strength of the evidence is solid, but the behavior experiments that do not include a CNO control provide incomplete support for the findings.

eLife Assessment

This valuable study reveals that the structural protein vimentin promotes the epithelial-mesenchymal transition in breast cancer cells. Utilizing robust and validated methodologies, the data collected provide a solid foundation for further investigation into metastasis models. This work will be of significant interest to researchers in the field of breast cancer.

eLife Assessment

This study provides compelling evidence that SLC7A11 may serve as a potential therapeutic target for trastuzumab-resistant HER2-positive breast cancer. While the findings are well-supported by robust data, the study could have been further strengthened by incorporating additional cell line experiments and providing more detailed clarification on patient sample selection. Nevertheless, this valuable work represents a significant contribution and will be of considerable interest to researchers in the field of breast cancer.

eLife Assessment

This study addresses the structural basis of voltage-activation of BK channels using atomistic simulations of several microseconds, to assess conformational changes that underlie both voltage-sensing and gating of the pore. Simulated effects of voltage on the movement of charged amino acids appear solid as they are generally consistent qualitatively and quantitatively with previous experimental and structural results, providing a potentially valuable way to calculate the contribution of individual charges to voltage-sensitivity. Simulations of conformational changes and interactions associated with channel opening and K+ conduction are likely incomplete owing to the timescale of the simulation and theoretical limitations in simulating K+ and water movement, but nonetheless provide helpful initial predictions and a framework for future improvement. This paper will likely be of interest to ion channel biologists and biophysicists focused on voltage-dependent channel gating mechanisms.

eLife Assessment

This study presents a valuable investigation into cell-specific microstructural development in the neonatal rat brain using diffusion-weighted magnetic resonance spectroscopy. The evidence supporting the core claims is solid, with innovative in vivo data acquisition and modeling, although some conclusions would benefit from stronger validation and methodological justification. The work will be of interest to researchers studying brain development and biophysical imaging methods.

eLife Assessment

This valuable study demonstrates that silencing of inhibitory interneurons in zebra finch HVC, a premotor nucleus critical for song production, disrupts song. However, song naturally recovers in a way that is surprisingly independent of LMAN, a distinct premotor nucleus required for normal song plasticity. The authors provide solid evidence that disruption is associated with microglial activation, activation of MHCI, synaptic changes, and altered neural dynamics in HVC. However, the manuscript would benefit from a clearer narrative structure, contextualization of the microglial results, and quantitative analyses to fully characterize song syntax and recovery after LMAN lesions.

eLife Assessment

The manuscript represents a fundamental advance in designing peptide inhibitors targeting Cdc20, a key activator and substrate-recognition subunit of the APC/C ubiquitin ligase. Supported by compelling biophysical and cellular evidence, the study lays a strong foundation for future developments in degron-based therapeutics. The revised manuscript has been strengthened by additional clarifications and data that address prior reviewer concerns. The work provides a robust framework for developing tools to manipulate protein degradation and will be of broad interest to researchers in protein engineering, cell cycle regulation, and targeted protein degradation.

eLife Assessment

This is an interesting study that adds useful new data addressing how different DAG pools influence cellular signaling. The study dissects how the enzyme Dip2 modulates the minor lipid signaling DAG pool, which is distinct from the lipid metabolism DAG pool utilized in membrane production. Overall the analysis is solid and broadly supports the claims.

eLife Assessment

The authors show that an automated approach using artificial neural networks, which focuses on behaviourally relevant dimensions, can predict human similarity data up to a certain level of granularity. This study has the potential to be a valuable contribution to the broader field of cognitive computational neuroscience, as it provides a tool for the automated collection of similarity judgments under certain conditions. However, as of now, the significance of this method is somewhat limited because of its inability to generalise beyond between-category distinctions and the limited model evaluation. In terms of broader implications, the degree to which this work provides insights into DNN-brain alignment and a better understanding of the functional organisation of the visual system is supported by incomplete evidence.

eLife Assessment

This study presents a valuable finding on the direct cytotoxic effects of DuoHexaBody-CD37 in diffuse large B-cell lymphoma, mediated via SHP-1 activation and antibody clustering, independent of complement. The evidence supporting this mechanism is incomplete, with additional work needed to clarify SHP-1's role, the contribution of Fc receptor crosslinking, and the biological relevance across normal and malignant B cells. As the findings are based primarily on in vitro models, further validation would be required to support broader translational conclusions.

eLife Assessment

This important study uses standard single-cell RNA-seq analyses combined with methods from the social sciences to assess heterogeneity in gene expression in Drosophila imaginal wing disc cells treated with 4000 rads of ionizing radiation. The use of this methodology from social sciences is novel in Drosophila. A cell cycle based clustering approach allows them to identify a subpopulation of cells that is disproportionately responsible for much of the radiation-induced gene expression. Their convincing analyses reveal genes that are expressed regionally after irradiation, including ligands and transcription factors that have been associated with regeneration, as well as others whose roles in response to irradiation are unknown. This paper would be of interest to researchers in the field of DNA damage responses, regeneration, and development.

eLife Assessment

The article presents important findings describing the role of IL27 in maintaining HSCs at steady state, and in emergency haematopoiesis in response to T. goodii by limiting the inflammatory monocyte outcomes. However, the evidence is still incomplete, as not enough evidence is provided to support that IL27 only acts at the level of HSCs and not downstream. This study will be of interest to immunologists and hematologists, as well as infectious disease researchers.

eLife Assessment

The granularity with which neural activity in the sensorimotor cortex of mice corresponds to voluntary forelimb motion is a key open question. This paper provides convincing evidence for the encoding of low-level features like joint angles and represents an important step forward toward understanding the cortical origins of limb control signals.

eLife Assessment

This useful study reports a method to detect and analyze a novel post-translational modification, lysine acetoacetylation (Kacac), finding it regulates protein metabolism pathways. The study unveils epigenetic modifiers involved in placing this mark, including key histone acetyltransferases such as p300, and concomitant HDACs, which remove the mark. Proteomic and bioinformatics analysis identified many human proteins with Kacac sites, potentially suggesting broad effects on cellular processes and disease mechanisms. While the data presented are solid, the functional validation of the sites would add significantly to the manuscript's description of this modification; the study will be of interest to those studying protein and metabolic regulation.

eLife Assessment

This paper investigates how isoform II of transcription factor RUNX2 promotes cell survival and proliferation in oral squamous cell carcinoma cell lines. The authors used gain and loss of function techniques to provide convincing evidence showing that RUNX2 isoform silencing led to cell death via several mechanisms including apoptosis and ferroptosis that was partially suppressed through RUNX2 regulation of PRDX2 expression. The study provides valuable insight into the underlying mechanism by which RUNX2 acts in oral squamous cell carcinoma.

eLife Assessment

This important study offers a molecular characterization of neurons and glia in the adult nervous system of the fruit fly Drosophila melanogaster. The study focuses on the progeny of a specific set of neural stem cells that contribute to the central complex, a conserved brain region that plays key roles in sensorimotor integration. The data are convincing and collected using validated methodology, generating an invaluable resource for future studies. The study will be of interest to developmental neurobiologists.

eLife Assessment

This manuscript presents an important contribution to the field of single-cell transcriptomic analysis in cancer by introducing a novel computational framework-SCellBOW-which applies embedding techniques from natural language processing to model phenotypic heterogeneity in tumors. The revised version includes new validation experiments and significant clarifications that provide convincing evidence for the method's utility. The authors have benchmarked SCellBOW across diverse datasets, including glioblastoma, breast, and metastatic prostate cancer, and have demonstrated its superior performance compared to existing state-of-the-art methods.

eLife Assessment

The submission by Praveen and colleagues reports important findings describing the structure of genetic and colour variation in its native range for the globally invasive weed Lantana camara. Whilst the importance of the research question and the scale of the sampling is appreciated, the analysis, which is currently incomplete, requires further tests to support the claims made by the authors.

eLife Assessment

The authors present an algorithm and workflow for the inference of developmental trajectories from single-cell data, including a mathematical approach to increase computational efficiency. In this latest version, the authors addressed the benchmarking of the novel method, but the absence of quantitative comparisons to state-of-the-art methods still make this study incomplete. Based on the shown validation approaches, one can neither ultimately judge if the shown method will be an advance over previous work nor whether the approach will be of general useful applicability.

eLife Assessment

This study provides a valuable and comprehensive dataset on transcription factor binding in Pseudomonas aeruginosa, along with analyses of its regulatory network, key virulence and metabolic regulators, and a pangenomic examination of transcription factors. Utilizing large-scale ChIP-seq and multi-omics integration, the research convincingly supports the hierarchical regulatory structures and offers insights into virulence mechanisms. While further experimental validation is needed, this publicly accessible PATF_Net database enhances its utility for researchers investigating this significant pathogen associated with hospital infections and antibiotic resistance.

eLife Assessment

In contrast with mammals, measures of cochlear tuning in budgerigars do not match the frequency dependence of behavioral tuning. Earlier behavioral data in the budgerigar had shown good selectivity at around 3-4 kHz, but it was unknown whether this unusual selectivity arose in the inner ear or was a more central adaptation. The authors measured both auditory-nerve tuning curves and stimulus-frequency otoacoustic emissions and found fairly normal-looking cochlear tuning in the budgerigar. These important findings imply that any behavioral/perceptual differences in frequency selectivity are likely more central in original. These solid new data also provide significant support for the utility of otoacoustic estimates of cochlear tuning.

eLife Assessment

This important study provides compelling evidence for the evolutionary diversification and conserved NFκB-inducing function of RHIM-containing RIP kinase proteins across animal lineages, combining thorough bioinformatic analysis with functional assays in human cells. The findings are of broad interest to immunologists and evolutionary biologists, though some novel observations would benefit from deeper conceptual integration.

eLife Assessment

This important study investigates the molecular mechanisms by which the p53 isoforms Δ133p53α and Δ160p53α exert dominant-negative effects on full-length p53 (FLp53). Through a combination of chromatin immunoprecipitation, transcriptional reporter assays, subcellular localization analyses, and protein aggregation experiments, the authors provide solid evidence that these N-terminally truncated isoforms promote co-aggregation with FLp53, disrupting its transcriptional activity and cellular distribution. The revised manuscript successfully addresses prior reviewer concerns, and the findings are well supported by the experimental data.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

This important study advances our understanding of maladaptive innate immune training. The experimental evidence supporting the conclusions is convincing and the expert reviewers strongly endorse the manuscript. The work will be of high interest to both researchers in the trained immunity field and clinician scientists.

eLife Assessment

In this preregistered study, Kunkel and colleagues set out to compare the magnitude and duration of placebo versus nocebo effects in healthy volunteers, and also to examine the different factors contributing to these effects. The authors follow a rigorous methodology in a within-subjects design, taking into consideration standard conventions for manipulation of expectations, and using an appropriate sham condition. They present compelling evidence of long-lasting placebo and nocebo effects, with nocebo responses demonstrating consistently greater strength. These valuable results have the potential for a great impact in the field of experimental and clinical pain.

eLife Assessment

This paper describes the study of the evolution of the N-terminal domain of the MSH6 mismatch repair protein in regard to the presence or absence of histone reader domains. While the presence of the histone reader domains was previously known, the phylogenetic analysis of these domains performed here establishing their insertion through convergent evolution is important, definitively done, and establishes an interesting feature of the MSH6 family of proteins. The work is convincing but the presentation of the structural features of MSH6 could be improved.

eLife Assessment

This study provides valuable insights into how auditory stimuli influence the temporal dynamics of visual perception by modulating brain rhythms (oscillations) in the alpha band. The authors present convincing evidence that auditory input induces a drop in visual alpha frequency, increasing the time window for audio-visual integration, and subsequently shifting the predictive role from prestimulus alpha frequency to alpha phase. The conclusions are well-supported by the combination of psychophysics, electrophysiological recordings (EEG), non-invasive brain stimulation (tACS), and computational modelling.

eLife assessment

In this useful study, the authors tested the ability of bumblebees to use bird-view and ground-view for homing in cluttered landscapes using modeling and behavioral experiments, claiming that bumblebees rely most on ground-views for homing. However, due to a lack of analysis of the bees' behavior during training and a lack of information as to how the homing behavior of bees develops over time, the evidence supporting their claims is currently incomplete. Moreover, there was concern that the experimental environment was not representative of natural scenes, thus limiting the findings of the study.

eLife Assessment

This important study investigates whether neural prediction of words can be measured through pre-activation of neural network word representations in the brain; solid evidence is provided that neural network representations of neighboring words are correlated in natural language. Therefore, it is crucial to differentiate between neural activity that predicts the upcoming word and neural activity that encodes the current words - information that can be used to predict the upcoming word. The study is of potential interest to researchers investigating language encoding in the brain or in large language models. Additional discussions are needed regarding the distinction between prediction and stimulus dependency and potential methods to distinguish them.

eLife Assessment

This study offers valuable insights into brain responses to words in the visual cortex of blind and sighted individuals. However, the evidence supporting the authors' claims remains incomplete, and the conclusions would benefit from a more comprehensive characterization of the conceptual properties of the word stimuli. This work will be of broad interest to cognitive neuroscientists, psycholinguists, and neurologists investigating meaning representation in the brain.

eLife Assessment

In this important study, the authors advance our understanding of copper uptake by chalkophores and their targeted metalloproteins in Mycobacterium tuberculosis. These convincing data demonstrate that chalkophore-acquired copper is solely incorporated into the Mtb bcc:aa3 copper-iron respiratory oxidase under low copper conditions, and that chalkophore-mediated protection of the respiratory chain is critical to Mtb virulence. These findings may be leveraged for drug discovery and will be of broad interest to those studying bacterial pathogenesis.

eLife Assessment

This is a valuable study that tests the functional role of food-washing behavior in removing tooth-damaging sand and grit in long-tailed macaques and whether dominance rank predicts level of investment in the behavior. The evidence that food-washing is deliberate is compelling and the evidence that individual investment in the behavior varies is solid. Overall, the paper should be of interest to researchers interested in foraging behavior, cognition, and primate evolution.

eLife Assessment

This important study identifies a mechanism by which caspases are activated in a non-lethal context to induce functional modulation in Drosophila olfactory receptor neurons. To deliver, the authors generated a new reporter of caspases, used TurboID to identify proteins proximal of the Drosophila executioner caspases Drice, and then focused on Fasciclin 3 as a mediator. The experimental results and the main conclusions are convincing. This substantial body of work will be of interest to researchers across fields, from neuroscience of olfaction to development and cell biology.

eLife Assessment

In this useful study, the authors tested the ability of bumblebees to use bird-view and ground-view for homing in cluttered landscapes using modeling and behavioral experiments, claiming that bumblebees rely most on ground-views for homing. However, due to a lack of analysis of the bees' behavior during training and a lack of information as to how the homing behavior of bees develops over time, the evidence supporting their claims is currently incomplete. Moreover, there was concern that the experimental environment was not representative of natural scenes, thus limiting the findings of the study.

eLife Assessment

These important findings detail the role of Pim1 and Pim2 in controlling the behaviour and activity of 'killer' T cells; a vital cell within of our immune system. The authors capitalized on high resolution quantitative analysis of the proteomes and transcriptomes of Pim1/Pim2-deficient CD8 T cells to provide compelling evidence for how the PIM1/2 kinases control TCR-driven activation and IL-2/IL-15-driven proliferation and differentiation into effector T cells. It's also noteworthy that Pim1/Pim2 impact is better revealed through quantitative proteomics than transcriptomics.

eLife Assessment

This article presents a valuable genetic spatio-temporal analysis of malaria-infected individuals from four villages in a highly seasonal transmission setting in The Gambia, covering the period between December 2014 and May 2017. Evidence generated by the study's laboratory and data processing approaches is solid and helps to advance the understanding of malaria in The Gambia, particularly due to its longitudinal design and the inclusion of asymptomatic cases.

eLife Assessment

The authors show MRI relaxation time changes that are claimed to originate from cell membrane potential changes. This would be a substantial contribution if true because it may provide a mechanism whereby membrane potential changes could be inferred noninvasively. However, the membrane potential manipulations applied here are performed on a slow time scale and are known to induce cell swelling. Cell swelling has been previously shown to affect relaxation time. Experiments could be performed to rule out this hypothesis, but the authors have chosen not to perform these experiments. The study is therefore useful, but the evidence is incomplete.

eLife Assessment

A regression discontinuity analysis finds essentially no effect of 1 additional year of secondary education on brain structure in adulthood. This is a valuable finding that adds to the literature on the impact of education on brain health. While the finding is convincing on its own, as the analysis was pre-registered and very carefully conducted, the impact is limited as the manipulated variable only relates to a single additional year of education (remaining in education to 15 vs 16 years of age).

eLife Assessment

The work presented is important for our understanding of the development of the cardiac conduction system and its regulation by T-box transcription factors. The conclusions are supported by convincing data. Overall this is an excellent study that advances our understanding of cardiac biology and has implications beyond the immediate field of study.

eLife Assessment

This manuscript makes important contributions to our understanding of cell polarization dynamics by demonstrating how compensatory regulatory and spatial mechanisms enhance the robustness of polarization patterns. By integrating a computational pipeline with comparisons to experimental data, the authors provide convincing evidence that stability and asymmetry in reaction-diffusion networks are crucial for polarization in C. elegans zygotes. Their findings offer novel insights into essential biological processes such as cell migration, division, and symmetry breaking. Future theoretical and experimental work could refine the model by addressing its acknowledged limitations.

eLife Assessment

This important study uses the delay line axon model in the chick brainstem auditory circuit to examine the interactions between oligodendrocytes and axons in the formation of internodal distances. This is a significant and actively studied topic, and the authors have used this preparation to support the hypothesis that regional heterogeneity in oligodendrocytes underlies the observed variation in internodal length. In a solid series of experiments, the authors have used enhanced tetanus neurotoxin light chains, a genetically encoded silencing tool, to inhibit vesicular release from axons and support the hypothesis that regional heterogeneity among oligodendrocytes may underlie the biased nodal spacing pattern in the sound localization circuit.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

The authors use a multidisciplinary approach to provide a valuable link between Beta-alanine and S. Typhimurium (STM) infection and virulence. The work shows how Beta-alanine synthesis mediates zinc homeostasis regulation, possibly contributing to virulence. The work is convincing as it adds to the existing knowledge of metabolic flexibility displayed by STM during infection. However, the authors need to address some lingering concerns.

eLife Assessment

By taking advantage of noise in gene expression, this important study introduces a new approach for detecting directed causal interactions between two genes without perturbing either. The main theoretical result is supported by a proof. Preliminary simulations and experiments on small circuits are solid, but further investigations are needed to demonstrate the broad applicability and scalability of the method.

eLife Assessment

This important study provides compelling data from in vitro models and patient-derived samples to demonstrate how modulation of GSK3 activity can reprogram macrophages, revealing potential therapeutic applications in inflammatory diseases such as severe COVID-19. The study stands out for its clear and systematic presentation, convincing experimental approach, and the relevance of its findings to the field of immunology.

eLife Assessment

This important work presents a stochastic branching process model of tumour-immune coevolution, incorporating stochastic antigenic mutation accumulation and escape within the cancer cell population. They then used this model to investigate how tumour-immune interactions influence tumour outcome and the summary statistics of sequencing data of bulk and single-cell sequencing of a tumour. The evidence is currently incomplete: statistical comparisons between the observed mutational burden distribution and theoretical predictions in the absence of immune selection should be carried out. Conclusions should be tested extensively for robustness/sensitivity to parameters.

eLife Assessment

This valuable study shows that locomotion-related modulations in the mouse visual cortex are not uniform but primarily affect neurons in muscarinic receptor-negative patches, which receive projections from specific cortical areas. While the evidence is mostly solid, some uncertainties remain regarding the link between anatomical data and functional measurements. The study should be of interest to neuroscientists interested in state modulation of cortical function.

eLife Assessment

The findings are important and intriguing, with theoretical or practical implications beyond a single subfield. The computational methods employed are clever and sophisticated and the strength of evidence is convincing. Many of the methodological concerns raised after the first round of review were addressed in the revised version, although all three reviewers also highlighted that the exploratory nature of the paper and the lack of clarity regarding the hypotheses make it hard to assess the impact of the results on existing theories.

eLife Assessment

This work provides important insights into mucosal antibody responses against SARS-CoV-2 following intranasal immunization by characterizing a large number of monoclonal antibodies at both mucosal and non-mucosal sites. The evidence supporting the claims is solid. The demonstrated in vitro antiviral activity of antibodies characterized provides a rationale for developing mucosal vaccines, especially if confirmed in vivo and benchmarked against antibodies generated following intramuscular vaccination.

eLife Assessment

This study uses C. elegans to investigate how the Calcium/Calmodulin-dependent kinase CMK-1 regulates adaptation to thermo-nociceptive stimuli. The authors use compelling approaches to identify Calcineurin as a phosphorylation target of CMK-1 and to investigate the relationship between CMK-1 and Calcineurin using gain and loss of function genetic and pharmacological methods. The findings of this study are valuable as they show that CMK-1 and Calcineurin act in separate neurons in an antagonistic and complex manner to regulate thermo-nociceptive adaptation, and these results may be relevant for understanding some chronic human pain conditions.

eLife Assessment

The authors developed a methodology to graph antigenic surface loops on influenza virus neuraminidases. The hybrid proteins retained the structure of the neuraminidase scaffold and the antigenicity of the grafted loops. This fundamental work should help in developing novel neuraminidase constructs for use in influenza virus vaccines. The paper presents compelling evidence supporting the conclusions arrived at by the authors.

eLife Assessment

This is an important study that examines the role of TFAM, a protein that helps maintain mtDNA, in mtDNA mutator mice. With convincing evidence, the authors have demonstrated that TFAM's counteractive role in mtDNA mutator mice is tissue-specific. The study does a thorough job of assessing the impact of modulating TFAM levels in a polg mutator mouse model of aging. The authors have thoroughly addressed all the points raised during the first round of review.

eLife Assessment

This important paper describes the regulatory pathway of rRNA synthesis by Meioc-Piwil1 in germ cell differentiation in zebrafish. Using the molecular genetic and cytological approaches, the authors provide convincing evidence that Meioc antagonizes Piwil1, which downregulates the 45S pre-rRNA synthesis by heterochromatin formation for spermatocyte differentiation. The results will be of use to researchers in the field of germ cell/meiosis as well as RNA biosynthesis and chromatin.

eLife Assessment

This study provides new insights into the expression profile of ILCs that demonstrate a history of RAG expression. It examines in part the potential intrinsic regulation of RAG expression and seeks to understand how the epigenetic state of ILCs is established, although a full understanding of intrinsic factors is only partially supported. The work provides a convincing and important molecular dataset, and strengthens our understanding of intrinsic regulation, and would be of interest more broadly to cell biologists seeking to understand immune cell development.

eLife Assessment

This important revised manuscript presents compelling findings by delineating two molecularly distinct liver cancer subtypes through comprehensive multi-omics integration and constructing a rigorously validated prognostic model. The authors have strengthened the analytical framework and validation across multiple datasets, including single-cell RNA sequencing. The evidence remains robust, with enhanced methodological clarity and expanded validation in both internal and independent cohorts. The revisions have improved the study's rigor and translational relevance.

eLife Assessment

In this important work, a quantitative analysis method for three-dimensional morphogenetic processes during embryonic development is introduced. The proposed method is a pipeline combining several methods, allowing quantitative analysis of developmental processes without cell segmentation and tracking. Upon application of their method, the authors obtain convincing evidence that ascidian gastrulation is a two-step process. This work should be of interest to a broad range of developmental biologists who aim to obtain a quantitative understanding of morphogenesis.

eLife Assessment

This important manuscript by Genzoni et al. reports the striking discovery of a regulatory role for trophic eggs in ant caste determination. Prior to this study, trophic eggs were widely assumed to play only a nutritional role in the colony, but this compelling study shows that trophic eggs can suppress queen development, and therefore regulate caste determination in specific social contexts.

eLife Assessment

This paper introduces an important theoretical method for characterizing symmetries of cells in biological tissues by capturing their real shape, and it sets results in contrast to related methods. The robustness of the paper's method to correctly capture dynamic and geometric changes that the cells may undergo is determined by convincing computational models, but the experimental support is incomplete and would benefit from better experimental imaging with higher quality and extended analysis. This would not only support the advantage of this method, but also strengthen its application to biological systems.

eLife Assessment

In this manuscript, the authors analyse the nanoscale localisation of α5β1 and αVβ3 integrins in integrin adhesion complexes (IAC) by dual-colour STORM and assess the spatial organisation at the nano and mesoscale of their main adaptors (paxillin, talin and vinculin). This is an important work that provides detailed analyses that reveal how elements of these complex structures are really organised at the nanoscale, an essential perspective for a better understanding of how IACs function and regulate mechanotransduction processes. The evidence presented is solid, with super-resolution imaging experiments conducted using a single, validated methodology and subsequent computational modelling that enabled a quantitative assessment of the resulting data.

eLife Assessment

This paper presents a method for detecting Naegleria fowleri infection, which is almost always fatal, using small RNA from blood. This could be an important advance since early detection might improve treatment outcomes. The mouse work is methodologically solid, but only a very small number of human samples were available for human validation.

eLife Assessment

The study investigates an emerging research field: the interaction between sleep and development. The authors use Drosophila larvae sleep as a study model and provide valuable insight into how neuropeptide circuitry controls larvae sleep. By using a broad range of behaviour and imaging methods and analysis, the authors conclude a sleep regulatory neural pathway of Hugin-PK2-Dilps in the Drosophila neurosecretory centre IPC. However, the evidence that supports this pathway is incomplete - in particular, the methodology in sleep measurement and the specificity at each step of the Hugin-PK2-Dilps pathway require further clarifying experiments or explanation.

eLife Assessment

This valuable study presents an alternative platform for nanobody discovery using phage-displayed synthetic libraries. The evidence supporting the platform is compelling, which is used to isolate and validate nanobodies targeting Drosophila secreted proteins. By making this library openly accessible, this provides an excellent resource to the wider scientific community. The detailed protocol used in this manuscript, associated with various methods for nanobody screening, provides an alternative and reliable platform for nanobody discovery.

eLife Assessment

This valuable study determines the functional requirements for localization and activity of S. cerevisiae septin-associated kinases using in vivo imaging, in vitro and in vivo protein-protein interaction assays, and an instructive in vivo "tethering" approach. In addition to confirming previous results, the study offers evidence that the septin-associated kinases may directly interact with the contractile ring machinery. Although the experiments appear to have been conducted correctly, the quantitative analysis of some experiments is incomplete and should be improved to strengthen the conclusions.

eLife Assessment

This important study presents single-unit activity collected during model-based (MB) and model-free (MF) reinforcement learning in non-human primates. The dataset was carefully collected, and the statistical analyses, including the modeling, are rigorous. The evidence convincingly supports different roles for particular cortical and subcortical areas in representing key variables during reinforcement learning.

eLife Assessment

This is an important study that connects the polymerase-associated factor 1 complex (Paf1C) with Histone 2B monoubiquitination and the expression of genes key to virulence in Cryptococcus neoformans. The provided information is convincing and has the potential to open several opportunities to further understand the basic biology of this significant human fungal pathogen.

eLife Assessment

Goswami and colleagues used rod-specific Gls1 (the gene encoding glutaminase 1) knockout mice to investigate the role of GLS1 in photoreceptor health when GLS1 was deleted from developing or adult photoreceptor cells. This study is fundamental as it shows the critical role of glutamine catabolism in photoreceptor cell health using in vivo model systems. The evidence supporting the authors' claims is compelling. The studies add new insight into how specific metabolites support vision.

eLife Assessment

This fundamental study provides a critical challenge to a great many studies of the neural correlates of consciousness that were based on post hoc sorting of reported awareness experience. The evidence supporting this criticism is compelling, based on simulations and decoding analysis of EEG data. The results will be of interest not only to psychologists and neuroscientists but also to philosophers who work on addressing mind-body relationships.

eLife Assessment

This is a valuable study describing how rhabdomyosarcoma fusion-oncogenes, VGLL2-NCOA2 and TEAD1-NCOA2, function at the genomic, transcriptional, and proteomic levels in multiple systems. The experimental data is convincing, supporting a model in which these fusion-oncogenes leverage TEAD transcriptional signatures independent of YAP/TAZ. This work offers new mechanistic insights into oncogenic gene fusion events and reveals potential therapeutic strategies for the treatment of rhabdomyosarcomas.

eLife Assessment

This important study substantially expands observations of HERV expression in the clinical settings. The evidence provided by the authors that HERV activity is an underlying etiological factor in ME/CFS and fibromyalgia is compelling and suggests further investigation into mechanisms. This work will be of broad interest to clinicians and researchers alike.

eLife Assessment

The study by Power and colleagues is important as elucidating the dynamic immune responses to photoreceptor damage in vivo potentiates future work in the field to better understand the disease process. The evidence supporting the authors' claims is compelling. The current manuscript would further benefit from including limitations/future improvements in the discussion or conclusion, exploring neutrophil recruitment under different degree of photoreceptor loss (mild to severe).

eLife Assessment

This important work presents a self-supervised method for the segmentation of 3D cells in fluorescent microscopy images, conveniently packaged as a Napari plugin and tested on an annotated dataset. The segmentation method is solid and compares favorably to other learning-based methods and Otsu thresholding on four datasets, offering the possibility of eliminating time-consuming data labeling to speed up quantitative analysis. This work will be of interest to a wide variety of laboratories analysing fluorescently labeled images.

eLife Assessment

This important work advances our understanding of the aging trajectory and heterogeneity of hippocampal microglia. The authors provide an in-depth characterization of microglia in young and old mice as well as at intermediate time points, which reveals the existence of intermediate states characterized by a distinct transcriptional signature. The experimental approach is solid, especially with the validation of scRNA-seq findings with other methods. The study should be of interest to neuroimmunologists and biologists interested in aging

eLife Assessment

This useful study examines the neural activity in the motor cortex as a monkey reaches to intercept moving targets, focusing on how tuned single neurons contribute to an interesting overall population geometry. The presented results and analyses are solid, though the investigation of this novel task could be strengthened by clarifying the assumptions behind the single neuron analyses, and further analyses of the neural population activity and its relation to different features of behaviour.

eLife Assessment

This valuable manuscript describes the immunogenicity of a bead-on-a-string immunogen that allows the inclusion of multiple HA subtypes. The evidence to support the claims is convincing, and more importantly, this approach could be adapted to other vaccine platforms.

eLife Assessment

This important study introduces a novel split-belt treadmill learning task to reveal distinct and parallel learning sub-components of gait adaptation: slow and gradual error-based perceptual realignment, and a more deliberate and flexible "stimulus-response" style learning process. The behavioural results convincingly support the presence of a non-error-based learning process during continuous movements, and the computational modelling provides comprehensive further evidence for establishing this learning process. These results will be of interest for the broader motor learning community.

eLife Assessment

This study presents a useful reassessment of the potential role of dendritic cell-derived IL-27 p28 cytokine in the functional maturation of CD4+CD8- thymocytes, and CD4+ recent thymic emigrants. The evidence supporting the claims of the authors is solid and serves to reaffirm what has been previously described, with the overall advance in understanding the mechanism(s) responsible for the intrathymic functional programming of CD4+ T cells being limited.

eLife Assessment

This paper present an important theoretical exploration of how a flexible protein domain with multiple DNA binding sites may simultaneously provide stability to the DNA-bound state and enables exploration of the DNA strand. The authors present compelling evidence that their findings have implications for the way intrinsically disordered regions (IDR) of transcription factors proteins (TF) can enhance their ability to efficiently find their binding site on the DNA from which they exert control over the transcription of their target gene. The paper concludes with a comparison of model predictions with experimental data which gives further support to the proposed model.

eLife Assessment

This manuscript applies state-of-the-art techniques to define the cellular composition of the dorsal vagal complex in two rodent species (mice and rats). The result is an important resource that substantially advances our understanding of the dorsal vagal complex's role in the regulation of feeding and metabolism while also highlighting key differences between species. While most of the analyses in the manuscript provide convincing insight into the cellular architecture of the dorsal vagal complex, other aspects are incomplete and could be bolstered by additional evidence.

Editors Assessment:

Acropora pulchra is a species small polyped stony corals in the family Acroporidae from the the Indo-Pacific. This Data Release is the first study in stony corals to present the DNA methylome in tandem with a high-quality genome assembled utilizing PacBio long-read HiFi sequencing. Sequencing an A. pulchra specimen from Mo’orea, French Polynesia. From this single molecule sequencing data DNA methylation data was also called and quantified, and additional short-read Illumina RNASeq data was used for gene annotation. This producing an assembly size is 518 Mbp, with 174 scaffolds, and a scaffold N50 of 17 Mbp, and 40,518 protein-coding genes called. Peer review requested some improved benchmarking, and it is impressive to see from the results that the genome assembly represents the most complete and contiguous stony coral genome assembly to date. As an important indicator species and this data will hopefully serve as a resource to the coral and wider scientific community. Further quantification of the genome-wide methylation is needed aid the study epigenetics of non-model organisms, and specifically future analyses on methylation in coral.

*This evaluation refers to version 1 of the preprint *

eLife Assessment

This useful study presents computational analyses of over 5,000 predicted extant and ancestral nitrogenase structures. While the data and some analyses are solid, the study remains incomplete in demonstrating that the metrics used for comparing nitrogenase structures are statistically rigorous. The data generated in this study provide a vast resource that can serve as a starting point for functional studies of reconstructed and extant nitrogenases.

eLife Assessment

Examination of (a)periodic brain activity has gained particular interest in the last few years in the neuroscience fields relating to cognition, disorders, and brain states. Using large EEG/MEG datasets from younger and older adults, the current study provides compelling evidence that age-related differences in aperiodic EEG/MEG signals can be driven by cardiac rather than brain activity. Their findings have important implications for all future research that aims to assess aperiodic neural activity, suggesting control for the influence of cardiac signals is essential.

eLife Assessment

This comprehensive study presents important findings that delineate how specific dopaminergic neurons (DANs) instruct aversive learning in Drosophila larvae exposed to high salt through an integration of behavioral experiments, imaging, and connectomic analysis. The work reveals how a numerically minimal circuit achieves remarkable functional complexity, with redundancies and synergies within the DL1 cluster that challenge our understanding of how few neurons generate learning behaviors. By establishing a framework for sensory-driven learning pathways, the study makes a compelling and substantial contribution to understanding associative conditioning while demonstrating conservation of learning mechanisms across Drosophila developmental stages.

eLife Assessment

This work presents a valuable approach based on a complex systems theoretical framework to characterize diet-host-microbe interactions and develop targeted bacteriotherapies through a three-phase workflow. Despite the partial support of the description and experimental setup of the 'complex systems theoretical approach,' the collected data are solid and advance our understanding of oxalate bacterial metabolism in microbial communities. This study will interest researchers working on gut microbiomes and the possible modulation of host-microbial interactions.

eLife Assessment

This intracranial EEG study presents important and convincing neural evidence supporting the high spatial specificity (receptive field) of visually driven alpha-band oscillation in human brains and its potential role in exogenous cuing attention. The work challenges the predominant view about the role of alpha-band oscillation in visual attention and advocates that stimulus-driven alpha suppression is precisely tuned and might contribute to exogenous spatial attention.

eLife Assessment

This fundamental study examines whether synaptic cell adhesion molecules neuroligin 1-3 resident on astrocytes, rather than neurons, exert effect on synaptic structure and function. With compelling evidence, the authors report that deletion of neuroligins 1-3 specifically in astrocytes does not alter synapse formation or astrocyte morphology in the hippocampus or visual cortex. This study highlights the specific role of neuronal neuroligins rather than their astrocytic counterparts in synaptogenesis.

eLife Assessment

This important work combines theory and experiment to demonstrate convincingly how humans make decisions about sequences of pairs of correlated observations. The proposed model for evidence integration in correlated environments will be of use for the study of decision-making.

eLife Assessment

This study focuses on the role of a T-cell-specific receptor, ctla-4, in a new zebrafish model of IBD-like phenotype. Although implicated in IBD diseases, the function of ctla-4 has been hard to study in mice as the KO is lethal. Ctla-4 mutant zebrafish exhibited significant intestinal inflammation and dysbiosis, mirroring the pathology of inflammatory bowel disease (IBD) in mammals, providing a new valuable model to the field of IBD research. This is an key study with convincing evidence, comprehensive transcriptomic analysis, histological examinations, and functional assays all supporting the findings.

eLife Assessment

This translational study presents a direct cross-species comparison (between mice, rats, and humans) of choice behavior in the same perceptual decision-making task. The study is rare in opening a window on the evolution of decision-making, and the results will be important for many disciplines including behavioral sciences, psychology, neuroscience, and psychiatry. While the strength of the evidence presented is solid, the manuscript would benefit from additional information and analyses to strengthen and clarify its main conclusions.

eLife Assessment

In this important study, the authors use computational modeling to explore how rapid learning can be reconciled with the accumulation of stable memories in the olfactory bulb, where adult neurogenesis is prominent. They focus on the "flexibility-stability dilemma" and how it is resolved through local mechanisms within the olfactory bulb. These compelling results present a coherent picture of a neurogenesis-dependent learning process that aligns with diverse experimental observations and may serve as a foundation for further experimental and computational studies.

eLife Assessment

This study presents valuable findings related to seasonal brain size plasticity in the Eurasian common shrew (Sorex araneus), which is an excellent model system for these studies. The evidence supporting the authors' claims is convincing. The work will be of interest to biologists working on neuroscience, plasticity, and evolution.

eLife Assessment

The manuscript by de La Forest Divonne et al. offers an important and detailed exploration of the immune cells in the oyster Crassostrea gigas, by correlating distinct hemocyte morphotypes with specific single-cell transcriptional profiles. The evidence supporting the conclusion is convincing, deriving from the comprehensive dataset that not only captures unicellular diversity but also associates these cells with distinct immune roles, making it an invaluable resource for the broader research community.

eLife Assessment

This important study shows how the relative importance of inter-species interactions in microbiomes can be inferred from empirical species abundance data. The methods based on statistical physics of disordered systems are convincing and rigorous, and allow for distinguishing healthy and non-healthy human gut microbiomes via differences in their inter-species interaction patterns. This work should be of broad interest to researchers in microbial ecology and theoretical biophysics.

eLife Assessment

This study makes an important contribution to the molecular mechanisms of neural circuit formation. The data convincingly show that the transcription factor Sp1 regulates ephrin-mediated axon guidance in the spinal cord. Although the authors show that Sp1 and its co-activators p300 and CBP are required to induce ephrin expression, additional discussion and/or experiments are needed to support the claims that Sp1 regulates cis-binding of Epha receptors, or that Sp1 controls ephrin expression in relevant motor neuron populations. The study will be of broad interest to developmental neurobiologists.

eLife Assessment

This study offers valuable insights into the role of miR-283 in ventral-lateral neurons (LNvs) and its impact on senescence, cardiac function, and aging in the Drosophila melanogaster model. However, the evidence supporting some of the conclusions remains incomplete, and further mechanistic studies are needed to clarify how miR-283 affects normal aging and influences exercise adaptations. Nonetheless, the work can be of interest to cell biologists studying miRNA biology, aging, and age-related diseases.

eLife Assessment

This study presents useful findings on the role of AFD thermosensory neurons in locomotory behaviours. The study appears solid with respect to parsing out the non-thermosensory role of AFD and also brings to light the role of AFD and AIB (linked through electrical synapses) in tactile-dependent locomotory modulation.

eLife Assessment

This important study provides a description of how single-neuron firing rates in the human medial temporal lobe and frontal cortex are modulated by theta-burst stimulation of the basolateral amydala. The results are supported by solid evidence obtained from a rigorous task design and analysis of an incredibly rare dataset. The results may help guide future studies incorporating amygdala stimulation to improve patient health. Additional analyses could have been performed, and additional experimental details included, to address open questions related to mechanistic effects of the stimulation protocol on single unit properties and memory-related behavior.

eLife Assessment

This valuable paper provides refined gene expression datasets for 52 neuron classes in C. elegans using a new method that takes advantage of the complementary strengths of bulk sequencing of flow-sorted cells and single-cell sequencing. In general, support for the paper's findings is convincing. However, more rigorous consideration of some of the method's statistical assumptions and validation of the predicted gene sets would improve the work.

eLife Assessment

This study presents valuable findings on the role of specific dopamine neurons for aversive learning and modulation of innate behavior in Drosophila larvae. The authors present solid evidence backed up by detailed behavioral quantification and rigorous testing. Their data confirms previous findings and will be of interest to the learning and memory community.

eLife Assessment

This fundamental work significantly enhances our understanding of how structural variants influence human phenotypes. The conclusion is convincingly supported by rigorous analyses of long-read sequencing data. If the raw data are made publicly available, these high-quality datasets and findings will further advance our knowledge of genetic variation in the human population.

eLife Assessment

Pannexin (Panx) channels are a family of poorly understood large-pore channels that mediate the release of substrates like ATP from cells, yet the physiological stimuli that activate these channels remain poorly understood. The study by Henze et al. describes an elegant approach wherein activity-guided fractionation of mouse liver led to the discovery that lysophospholipids (LPCs) activate Panx1 and Panx2 channels expressed in cells or reconstituted into liposomes. The authors provide compelling evidence that LPC-mediated activation of Panx1 is involved in joint pain and that Panx1 channels are required for the established effects of LPC on inflammasome activation in monocytes, suggesting that Panx channels play a role in inflammatory pathways. Overall, this important study reports a previously unanticipated mechanism wherein LPCs directly activate Panx channels. The work will be of interest to scientists investigating phospholipids, Panx channels, purinergic signalling and inflammation.

[Editors' note: this paper was reviewed and curated by Biophysics Colab]

eLife Assessment

This descriptive study used multiparameter spectral flow cytometry and clustering analysis of a subset of CD4 T cells, termed circulating T follicular helper (cTfh), responding to Plasmodium falciparum antigens, PfSEA -1A and PfGARP. The results from this comprehensive study provide valuable information regarding differences in cTfh response profiles between children and adults living in malaria-endemic Kenya and thus offer a potential usefulness towards improving choices of antigen candidates for malaria vaccines. However, the analysis and interpretation of antigen-specific CD4 cTfh responses remain incomplete.

eLife Assessment

Understanding bacterial growth mechanisms potentially uncover novel drug targets which are crucial for maintaining cellular viability, particularly for bacterial pathogens. In this important study, Kapoor et al, investigate the role of Wag31 in lipid and peptidoglycan biosynthesis in mycobacteria. A detailed analysis of Wag31 domain architecture revealed a role in membrane tethering. More specifically, the N-terminal and C-terminal domains appeared to have distinct functional roles. The data presented are solid and support the conclusion made. This study will be of broad interest to microbiologists and molecular biologists.

eLife Assessment

This important study reports a reanalysis of one experiment of a previously-published report to characterize the dynamics of neural population codes during visual working memory in the presence of distracting information. This paper presents solid evidence that working memory representations are dynamic and distinct from sensory representations of intervening distractions. This research will be of interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife Assessment

This study describes an improved adaptive sampling approach, multiple-walker Supervised Molecular Dynamics (mwSuMD), and its application to G protein-coupled receptors (GPCRs), which are the most abundant membrane proteins and key targets for drug discovery. The manuscript provides solid evidence that the mwSuMD approach can assist in the sampling of complex binding processes, leading to useful findings for GPCR activity, including resolution of interactions not seen experimentally. The method has the potential to have broad applicability in structural biology and pharmacology.

eLife Assessment

In Plasmodium male gametocytes, rapid nuclear division occurs with an intact nuclear envelope, requiring precise coordination between nuclear and cytoplasmic events to ensure proper packaging of each nucleus into a developing gamete. This valuable study characterizes two proteins involved in the formation of Plasmodium berghei male gametes. By integrating live-cell imaging, ultrastructural expansion microscopy, and proteomics, this study convincingly identifies SUN1 and its interaction partner ALLAN as crucial nuclear envelope components in male gametogenesis. A role for SUN1 in membrane dynamics and lipid metabolism is less well supported. The results are of interest for general cell biologists working on unusual mitosis pathways.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

In this valuable study, the authors used rats to determine the receptor for a food-related perception that has been characterized in humans. The data are solid in terms of methods and analysis: the data show that this stimulus (ornithine) has some additive effects in terms of increasing preference and taste response in rats when it is mixed with other more common taste stimuli. Therefore, the combinations of experiments generally support (but do not conclusively prove) the hypothesis that the "kokumi" taste effect elicited by this stimulus in humans may be mediated by the specific receptor examined in the study.

eLife Assessment

This valuable study uses consensus-independent component analysis to highlight transcriptional components (TC) in high-grade serous ovarian cancers (HGSOC). The study presents a convincing preliminary finding by identifying a TC linked to synaptic signaling that is associated with shorter overall survival in HGSOC patients, highlighting the potential role of neuronal interactions in the tumour microenvironment. This finding is corroborated by comparing spatially resolved transcriptomics in a small-scale study; a weakness is it being descriptive, non-mechanistic, and requires experimental validation.

eLife Assessment

Xenacoelomorpha is an enigmatic phylum, displaying various presumably simple or ancestral bilaterian features. This valuable study characterises the reproductive life history of Hofstenia miamia, a member of class Acoela in this phylum. The authors describe the morphology and development of the reproductive system, its changes upon degrowth and regeneration, and the animals' egg-laying behaviour. The evidence is convincing, with fluorescent microscopy and quantitative measurements as a considerable improvement to historical reports based mostly on histology and qualitative observations.

eLife Assessment

The study presents valuable findings on the role of Aff3ir, a gene implicated in flow-induced atherosclerosis and regulating the inflammation-associated transcription factor, IRF5. The in vivo data are solid in providing evidence on the role of Aff3ir in shear stress and formation of atheromatous plaques. The work will be of interest to clinical researchers and biologists focusing on inflammation and atherosclerosis in cardiovascular disease with a broad eLife readership.

eLife Assessment

Shihabeddin et al utilized single-cell RNA-Seq analysis of adult P23H zebrafish animals to identify transcription factors (e2fs, Prdm1a, Sp1) expressed selectively in neural progenitors and immature rods, and validated their necessity for regeneration using morphant analysis. The finding is useful, and the evidence is convincing. The deeper mechanistic analysis could further strengthen the current work by (1) distinguishing developmental vs regenerative transcriptional factors, (2) the addition of matched scATAC-Seq data, and (3) integration with single-cell multiome data from developing retina.

eLife Assessment

The authors provide valuable insights into the candidate upstream transcriptional regulatory factors that control the spatiotemporal expression of selector genes and their targets for GABAergic vs glutamatergic neuron fate in the anterior brainstem. The computational analysis of single-cell RNA-seq and single-cell ATAC-seq datasets to predict TF binding combined with cut and tag-seq to find TF binding represents a solid approach to support the findings in the study, although the display and discussion of the datasets could be strengthened. This study will be of interest to neurobiologists who study transcriptional mechanisms of neuronal differentiation.

eLife Assessment

The study presents a valuable finding on the role of cholesterol-binding sites on GLP-1 receptors although the clinical ramifications are unclear and not eminent at this point. Based on the detailed and persuasive responses provided by authors to the concerns raised by reviewers, the revised manuscript is improved substantially and is convincing enough in its scientific merit. The study is a good addition to the scientific community working on receptor biology and drug development for GLP-1 R.

eLife Assessment

This important study dissects the mathematical and biological assumptions underlying the commonly used Activity-by-Contact model of enhancer action in transcriptional regulation. The authors provide a convincing mathematical analysis that links this (mostly phenomenological) model to concrete molecular mechanisms of enhancer function. This work provides a strong foundation from which to analyze a broad swath of genome-wide data such as that generated by CRISPRi screens.

eLife Assessment

The authors examined the evolution of hepatitis C virus (HCV) in a cohort of 14 subjects with recent HCV infections. They showed that viral fitness declines as the virus mutates to escape the immune response and can rebound later in infection as HCV accumulates additional mutations. The study contributes to an important aspect of viral evolution. The combination of approaches contributes to a convincing study.

eLife Assessment

Zhang et al. present important findings that reveal a new role for TET2 in controlling glucose production in the liver, showing that both fasting and a high-fat diet increase TET2 levels, while its absence reduces glucose production. TET2 works with HNF4α to activate the FBP1 gene upon glucagon stimulation, while metformin disrupts TET2-HNF4α interaction, lowering FBP1 levels and improving glucose homeostasis. The results are convincing and expand our understanding of gluconeogenesis regulation.

eLife Assessment

This valuable paper describes the crystal structure of a complex of Sld3-Cdc45-binding domain (CBD) with Cdc45, which is essential for the assembly of an active Cdc45-MCM-GINS (CMG) double hexamers at the replication origin. Although the results shown in the paper are of interest to researchers in DNA replication and genome stability, the biochemical analysis of protein-protein interaction and DNA binding is incomplete, and the paper needs additional data.