eLife Assessment

This work has much novelty, supportive data, and the potential for changing thinking about melanoma biology with the discovery of MRGPRX4 as a relatively melanoma-specific G protein-coupled receptor. MRGPRX4 is normally restricted to peripheral sensory neurons, but it is aberrantly expressed in human melanomas; melanomas with neural-crest-like/invasive features were most likely affected. When ectopically expressed in murine melanocytes, MRGPRX4 drives melanoma development with metastasis; the mechanism appears to involve ligand-independent receptor signaling. Overall, the text presents this as a novel model of oncogenesis driven by re-expression of a sensory GPCR - this is an important study with compelling data.

eLife Assessment

This valuable study reveals a role for lactylation in influenza polymerase function and virus replication. The evidence supporting the claims is solid, although the direct involvement of ATAT1 and SIRT1 in this modification and the functional relevance of the identified sites can be further substantiated. These findings will appeal broadly to influenza virologists studying polymerase regulation, as well as researchers investigating the functional roles of lactylation.

eLife Assessment

This important study shows that self-supervised pretraining on related fungal genomes can substantially improve sequence-to-expression prediction in budding yeast. The evidence for the main conclusion is convincing, with careful comparisons to models trained from random initialization and clear gains on held-out expression data. The broader claims about the optimal evolutionary scope and transfer of regulatory grammar are less fully supported.

eLife Assessment

This important study investigates how experimentally introducing two facultative bacterial endosymbionts into the Russian wheat aphid, Diuraphis noxia, affects aphid performance, dispersal, and damage to cereal host plants. The authors provide solid evidence that the two symbionts can generate contrasting phenotypes: Rickettsiella increases plant damage while reducing wing formation and dispersal, whereas Regiella reduces aphid population growth and feeding damage. The successful establishment and stable transmission of these novel symbiont-host associations, combined with experiments spanning individual, whole-plant, population and mesocosm scales, are notable strengths of the work; however, the mechanisms underlying these effects remain unresolved, evidence for horizontal transmission is indirect, and some population-level conclusions rely on relatively small sample sizes or effects that are not consistently detected across time points, and therefore the potential application of these findings to pest management remains promising but speculative. The study will be of broad interest to researchers working on insect symbiosis, plant-insect interactions, and biologically based approaches to pest management.

eLife Assessment

Using a range of complementary approaches, this study examines how type I and type II interferon (IFN) programs exert opposing effects on macrophage responses relevant to tuberculosis. The work addresses a key biological question and provides valuable mechanistic insights. However, the data to support several key conclusions is incomplete and requires further strengthening; in particular, the role of ferritin needs to be established more definitively, the TNF stimulation findings should be validated in the context of M. tuberculosis infection, and in vivo evidence is needed to support the proposed therapeutic strategy. Additionally, aspects of iron metabolism, lipid peroxidation, and the translatability of the findings between mouse and human macrophages would benefit from greater clarity and deeper mechanistic investigation.

eLife Assessment

This valuable study provides a proof of concept for the utility of transcriptomic methods to develop novel diagnostic tests for bovine tuberculosis. A comprehensive analysis using a suite of machine learning models provides convincing evidence for the use of mRNA biomarkers to distinguish between infected and disease-free animals. The analysis also provides major insights into both the levels of individual variation in expression between animals as well as systematic changes with respect to the time from infection.

eLife Assessment

In this fundamental manuscript, Richter et al. present a thorough anatomical characterization of the Drosophila melanogaster larval pharyngeal sensory system, which is involved in taste-guided behaviors.This study fills a major gap in the larval sensory map, providing a detailed neuroanatomical foundation for future investigations into sensory circuits and behavior. The exceptional data will significantly enrich the field of Drosophila neurobiology.

eLife Assessment

This study presents a potentially valuable approach to generate a systems vaccinology framework for enabling the design of optimized poxvirus-based MVA vaccines. The developed Boolean modelling framework provides a novel computational approach to predict immune response dynamics against vaccine candidates, which is validated against previously published data and used to test/predict the response for new genetically modified MVA vaccine candidates. However, the strength of evidence is currently incomplete, as key aspects of model construction, calibration, interpretation, validation, and reproducibility, as well as comparability of the used vaccine candidates, require further clarification and supporting information.

eLife Assessment

This study presents a valuable finding on a potential new regulatory mechanism for cellular proliferation in the mammalian cochlea, taking advantage of the organoid-forming potential of cells from the greater epithelial ridge (GER), or Kolliker's organ, a transient structure in the developing cochlea. The authors highlight three potential regulators - galectin 1, galectin 3, and Myc - providing solid evidence for potential roles in modulating the proliferation of cochlear GER cells using gene expression studies, single-cell profiling, pharmacological inhibition, and genetic overexpression both in vitro and in vivo. However, some of the analyses and interpretations are incomplete, and a better understanding of how the compounds and the gene overexpression studies affect the cells and modulate cell survival/death would aid a fuller interpretation of the data.

eLife Assessment

This is an important study that uses a tripartite transdiagnostic framework to separate depression-specific, anxiety-specific, and shared psychopathology dimensions and relate them to mood variability and mood reactivity to reward prediction errors across several large non-clinical cohorts and a clinical sample. The evidence is compelling: large samples, a well-characterised gambling task, rigorous computational and psychometric analyses (i.e., split-half replication of the factor structure, convergent results with non-orthogonalised factors, an explicitly specified risk-attitude model, diagnostic breakdown and power analyses for the clinical cohort) and replication of the depression-specific blunting of reward prediction error sensitivity in patients. Anxiety-specific associations emerge reliably only when data are pooled and are likely underpowered clinically given co-morbid anxious depression, a constraint the authors now state explicitly. The work advances a mechanistic account of how distinct symptom dimensions shape reward-based mood updating.

eLife Assessment

This important study reports that Sox17 is key to the formation and function of the Sertoli valve, a transition region between the rete testis and seminiferous tubules that remains an understudied domain of testicular biology. The supporting data are convincing. This work will be of interest to developmental and reproductive biologists, as well as andrologists who work on male fertility and men's health.

eLife Assessment

The results of this study are important and the approach to dissect the developmental contribution of RIF1 function is convincing. The finding that replication timing and gene expression may be independently controlled is intriguing and provides a strong foundation for future research. The work will be of interest for researchers both in the transcription and the replication field, especially for scientists investigating the interplay between the two processes.

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 DNA-Paint 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 convincing, using complementary super-resolution imaging techniques and subsequent computational modelling that enabled a quantitative assessment of the resulting data.

eLife Assessment

This important study compares how different classes of drugs act on the SARS-CoV-2 main protease, a key antiviral target, and shows that many of them work by controlling whether the enzyme assembles into its active dimeric form. The evidence, based on a range of complementary biophysical methods, is convincing and points to the interface between the two protein protomers, including a newly found binding site, as a promising target for broad-spectrum antiviral drugs. This work will be of interest to biochemists and virologists working on treatments for coronaviruses.

eLife Assessment

This is a fundamental study on the sensory roles of cerebrospinal-fluid-contacting neurons (CSF-cNs) in mammals, revealing how the apical extension is used as an amplifier of chemical changes in content of the CSF. Specifically, the authors show compelling evidence that PKD2L1 is predominantly a pH-sensing channel in CSF-cNs and link its apical localization to dual phasic and sustained responses underlying CSF chemosensation.

eLife Assessment

This important study reports that neural activity in the auditory cortex (field L) of singing male zebra finches can be modulated by the presence of a female conspecific. These findings extend recent work showing that the activity of dopaminergic neurons in songbirds is also affected by an audience. Solid evidence is presented for the importance of singing context in modulating auditory processing during vocal production, but the study does not yet fully establish that these effects arise specifically from audience-dependent modulation of auditory feedback, as opposed to possible acoustic, temporal, or recording-related confounds. This work should be of interest to researchers studying the context dependence of sensory processing, the role of auditory feedback, and vocal communication during courtship behavior.

eLife Assessment

This important study provides mechanistic evidence for how the tea-adapted Kanzawa spider mite, Tetranychus kanzawai, overcomes the catechin-based defenses of green tea plants. The work identifies the horizontally transferred dioxygenase DOG15 as a key contributor to host adaptation and supports a two-step model involving evolutionary modification of enzyme activity together with strong inducible upregulation upon feeding on tea. The evidence is convincing because comparative behavioral and toxicological assays, transcriptomic and proteomic analyses, RNAi-mediated functional validation, and recombinant enzyme assays converge to link DOG15 activity and expression with improved performance on tea. The revised manuscript appropriately acknowledges that the products of catechin cleavage have not yet been characterized and that additional detoxification pathways may contribute to tea adaptation, providing a balanced interpretation of the otherwise strong mechanistic evidence.

eLife Assessment

This valuable study presents a real-time system for identifying multiple unrestrained marmosets in a home cage setting using a combination of facial features and color-coded beads. While there is solid evidence that the system has a precision comparable to human experimenters in the tested scenarios, there is limited evidence that this would generalize to unconstrained multi-animal environments

eLife Assessment

This important study investigates how distinct honeybee viruses differentially alter flight performance through interactions with octopamine signaling pathways. The combination of behavioral flight assays, pharmacological perturbation, and transcriptomic analyses provides solid evidence that virus-specific effects on flight are associated with octopamine signaling. The data presented also establish a framework for additional analyses that may strengthen the proposed mechanistic model, including quantification of endogenous octopamine levels and receptor specificity studies.

eLife Assessment

This manuscript reports an important study in which the authors apply smFRET imaging to probe HIV-1 Env conformational dynamics in the presence of antibodies. Previous implementations of smFRET imaging of HIV-1 Env, which focus on gp120 conformation, have yielded limited information on antibodies that target gp41. Through the cutting-edge application of smFRET imaging, the study provides convincing insights into the mechanisms of action of relevant antibodies.

eLife Assessment

This important study investigates the role of Nav1.7 voltage-gated sodium channels in regulating excitability of human dorsal root ganglion (hDRG) neurons. The authors characterize a previously identified Nav1.7 channel inhibitor using recombinant channels and human neurons. The study convincingly shows that inhibition of Nav1.7 channels with AM-2099 causes a modest decrease in neuronal excitability and prolongs the refractory period. This work offers new insights into the mechanism of clinically relevant pharmacological targets for pain relief.

eLife Assessment

A computational model potentially provides important new insights into the circuit mechanisms underlying navigational control in insects. The authors compare high speed video recordings of ants with detailed predictions from a new computational model. The similarities between model and behavioral data are striking and convincingly suggest how complex behavioral motifs can emerge from a simple neural circuit.

eLife Assessment

This valuable study advances our understanding of habituation and related potentiation behavior in a single-celled organism, Stentor. The authors provide convincing evidence for their claims in the form of extensive data on habituation behavior. The work will be of interest to cell biologists, neuroscientists, and also scientists broadly interested in behavior in non-neural organisms.

eLife Assessment

This valuable work discusses the phylogenetic conservation of the hippocampal region and primary sensory cortical regions in mammalian species. The authors propose that species-specific differences in behavior and mnemonic functions may be due to differences in cortico-hippocampal connectivity patterns. However, the manuscript, in its present form, is speculative, and the strength of evidence for this proposition is incomplete.

[Editors’ note: the final version of this work has been published in the journal Hippocampus (https://doi.org/10.1002/hipo.70119)]

eLife Assessment

In this study, electroencephalography was recorded during a binocular-rivalry paradigm in which participants viewed a target and a distractor stimulus. The stimuli were independently frequency-tagged, allowing the researchers to track target and distractor processing over time. The findings suggest that parietal alpha oscillations initially segregate competing inputs, followed by frontal theta activity associated with suppression of distractor representations. The significance of these findings is valuable, although the strength of the evidence remains incomplete, because of specific experiment design choices and methodological limitations.

eLife Assessment

This important study introduces a method, based on active control, for determining the functional connectivity between neurons or groups of neurons. While the theory is derived for a linear model with a perfectly observed control signal, the authors present compelling evidence that their method will work even when the system is nonlinear and the control signal is not fully observed. Furthermore, they provide a practical recipe for doing so.

eLife Assessment

This work presents a software and hardware suite for targeted photostimulation that can be used in vivo. The package is a well-designed and documented hardware/software suite with a comprehensive build guide. This tool will likely promote important neuroscience advances through targeted real-time perturbation of the cerebral cortex. Overall, this manuscript makes a compelling case on how to design and make available power tools for the research community.

eLife Assessment

Mechanical transduction channels of sensory hair cells possess lipid scramblase activity. Membrane lipid disruption resulting from mechanical transduction is thought to be restored by flippase activities. This fundamental study provides compelling evidence that ATP8B1, a P4-ATP flippase and its subunit TMEM30B, are key in mediating this restorative function in outer hair cells of the mammalian cochlea.

[Editors’ note, September 9, 2026: There is a potential confound with the findings shown in Figure 7 suggesting that specific targeting of ATP8B1 and TMEM30B subunits to the hair cell stereocilia is dependent on mechanoelectrical transduction channel activity. This does not affect the central findings or conclusions, but readers should be aware that a revised version of the paper is being prepared.]

eLife Assessment

This study used several approaches (computational modeling, neuronal cultures, rodent epilepsy model, and human intracranial recordings) to address a significant question in epilepsy research, with additional relevance to EEG studies more broadly: Are high frequency oscillations (or "fast ripples", defined as >200 Hz by the authors) distinct from randomly occurring clustering of spikes? The results suggest fast ripples can occur by chance and how this may occur. The significance was considered important and the strength of evidence convincing, with minor limitations related to the need to address behavioral state, explaining the results in relation to epileptiform activity described by others, and discussing implications.

eLife Assessment

This valuable study demonstrates molecular changes associated with age related impairment in oligodendrocyte differentiation and ability to myelinate. The identification of particular genes that are associated with this decline will provide potential future targets for therapeutic interventions. The reviewers felt that the quality of the evidence was convincing while identifying some minor weaknesses that were largely addressed in the review process.

eLife Assessment

This important work sets out to identify the neural substrates of associative fear responses in adult zebrafish. Through a compelling and innovative paradigm and analysis, the authors identify brain regions associated with individual differences in fear memory expression. While most findings are well supported, there is limited evidence that the four behavioral clusters represent discrete forms of associative fear-memory expression and the related interpretations would benefit from additional analysis or more cautious framing. Nonetheless, this study showcases the strength of zebrafish for systems-level neuroscience and will be of broad interest to the neuroscience community.

eLife Assessment

This study provides useful information for the Drosophila ageing community by characterising the auxin-based gene expression system (AGES) and identifying caveats associated with its use in adult flies. The authors provide solid evidence for sex-, age-, tissue- and dose-dependent variability in transgene induction, as well as effects of auxin feeding and AGES activation on stress resistance, metabolism, and lifespan. While the study would benefit from a broader characterisation of some of these limitations, the findings provide a helpful benchmark for researchers using AGES in ageing studies.

eLife Assessment

This important study integrates mouse genetics with sequencing, electrophysiological and behavioral tools to uncover the behavioral role and molecular profile of a developmentally defined subpopulation in the lateral septum. The data collected and analyzed are convincing, highlighting the role of this subpopulation in threat avoidance and stress, providing a framework by which developmental origin is linked to mature neuronal function. The work will be of interest to biologists and neuroscientists working on development and behavior.

eLife Assessment

This study examines how prefrontal population dynamics tune social behaviors, providing important findings that oxytocin receptor-expressing interneurons support sociosexual choice in female mice. The multidisciplinary evidence is convincing and could be strengthened by more comprehensive reporting of the methodology and a clearer distinction between inferential and directly tested insights from modelling. This work will be of interest to those interested in prefrontal cortex, oxytocin, and/or social behavior.

eLife Assessment

This important paper provides evidence that visual representations, as observed through drawing, preferentially preserve topological features over metric features. Across three experiments with different age groups and creative converging methods, they demonstrate that holes and T-junctions are relatively preserved as compared to topologically irrelevant L-junctions, and Euclidian features like length or precise angle. Together, these data provide convincing evidence for topology as an organizing principle for spatial representation, but the work would be strengthened by considering a broader range of topological features, or by ruling out alternative accounts, like preserved memory for complex features, motor production limitations, or noisy compression, that may produce a similar pattern without a topological prior.

eLife Assessment

This important study introduces a Bayesian method to determine bacterial counts that accounts for the experimental noise inherent to dilution and plating methods and distinguishes it from biological uncertainty. The evidence supporting the conclusions is compelling, combining simulated data and experimental data. The method will be of interest to microbial ecologists, and potentially to the broader community interested in inference from biological data, even more so if the domain of application and the limitations are further clarified.

eLife Assessment

This valuable study examines how the prelimbic cortex represents learned and generalized threat over time and identifies potentially distinct stable and dynamic subnetworks that may support these functions. The work is conceptually interesting and is strengthened by the longitudinal calcium imaging approach and the inclusion of key control groups. However, the evidence supporting the claims is incomplete, particularly because the interpretations regarding inference, time-dependent representational change, and the dissociation of neural activity from freezing behavior extend beyond what is currently established by the data.

eLife Assessment

This work provides a fundamental advance through a detailed, integrative analysis of how the tsetse fly feeds on blood, demonstrating that successful penetration depends on subtle structural adaptations rather than extreme forces or unusual anatomy. By combining high-resolution imaging, innovative biomechanical measurements, and experiments on artificial skin, the study offers complementary and compelling evidence, with clear data supporting a robust mechanistic interpretation. These findings have broad significance, as they clarify the biomechanics of vector feeding and have implications for the transmission of diseases such as African trypanosomiasis across diverse hosts.

eLife Assessment

This important work addresses a very relevant biological question: what is the cellular basis of wound healing? Using the Drosophila pupal notum as a model, the paper provides an elegant, thorough, descriptive characterization of syncytia-driven wound closure using state-of-the-art confocal live imaging of the pupal notum. The authors meticulously characterize the cell-cell fusion events during wound healing and inhibit cell fusion to show to that it is necessary to speed wound closure. This study provides convincing evidence that cell fusion allows actin resources at be partitioned to the leading edge.

eLife Assessment

This valuable study addresses the effects of selection for aggression on fitness and life-history trade-offs in Drosophila melanogaster. The evidence presented is overall solid, however, the data as they are do not completely support the claims of increased survival of highly aggressive males at the expense of reproductive success. The main limitation is the choice to use males from only one aggressive Drosophila line, that do not allow disambiguation between nonaggression-related factors and aggression-related factors influencing lifespan.

eLife Assessment

This potentially valuable study investigates the anti-senescence effects of red light exposure, proposing that reduced SIRT4 levels enhance fatty acid metabolism and H3K9ac, thereby attenuating ageing-related phenotypes. The authors use multiple approaches, including cultured cells, animal models, and molecular analyses, to support their conclusions. Following revision, many of the concerns previously raised by the reviewers have been addressed. The evidence is solid, whereas additional controls and stronger mechanistic data are still needed to fully substantiate the proposed pathway, particularly the mechanism by which red light exposure leads to reduced SIRT4 levels.

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 convincing 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

In this solid work, Fukui et al. re-examined the ATP hydrolysis mechanism in GHKL ATPases, revealing a cooperative role for two conserved acidic residues rather than a single one. This valuable study used a range of biochemical and structural techniques on various mutants from different members of the GHKL ATPase family to test and validate their proposed mechanism. An updated and extended mechanistic model of ATP hydrolysis by this class of enzymes is proposed.

eLife Assessment

This study offers valuable insights into brain responses to somatosensory and visual temporal and spatial tasks in the auditory cortex of Deaf and hearing individuals. The evidence for a sensorily-bound representation in the deprived cortex -- rather than abstract -- is solid; however, the study will benefit from some additional analyses to better clarify and contextualise the results. This work will be of broad interest to neuroscientists investigating brain plasticity and development.

eLife Assessment

This study provides a useful investigation of machine learning approaches that can lessen potential gaps in the prediction of behaviour from brain imaging data across majority and minority samples. The authors provide incomplete evidence to suggest that domain adaptation methods can mitigate these gaps. The analysis would benefit from further testing of model generalisability and the inclusion of recommended workflows for how the tested approaches can be used in future research. This work will be of interest to scientists using machine learning in brain imaging.

eLife Assessment

This study addresses a fundamental question about how large-scale brain networks interact, and specifically how the default mode network exchanges information with sensory cortex. The analyses provide solid evidence for the claims made in the paper. The findings should be of broad interest to researchers studying brain network organization and dynamics.

eLife Assessment

This important study combines chromatin accessibility and genomic DNA sequence conservation data from low-coverage genome sequencing of related species (without assembly), for the in-silico identification of cis-regulatory elements in large genomes. The approach and results are compelling and well supported by the experimental validations. The work will be of interest to researchers working in the field of gene regulation and evolution, particularly because the methodology proposed can be applied to a large variety of experimental organisms.

eLife Assessment

The report by Liu and colleagues reports on an analysis of environmental adaptation across diverse lineages of the grass Phragmites australis differing by their level of ploidy. These results represent important findings for understanding the environmental adaptation of species complexes with mixed ploidy and the analysis reports solid evidence that lineages with distinct levels of ploidy occupy different climate niches. The use of regional survey in tandem with common garden experiment represents a convincing approach to suggest a correlation between ploidy and climate adaptation. This manuscript will be of interest to a broad community of ecological genomicists interested in how structural variation in gene dosage potentially affects the pattern of adaptation.

eLife Assessment

This study provides valuable insights into the cellular dynamics underlying accelerated tooth regeneration in a vertebrate model. Using single-nucleus RNA sequencing across multiple time points, the authors present a well-structured analysis of cell populations, trajectories, and intercellular signaling events associated with this process. The strength of evidence is solid but only partially supported, as the conclusions are primarily supported by computational inference, without experimental validation of key findings.

eLife Assessment

This manuscript provides an important contribution to the field of platelet biogenesis, and the convincing evidence will advance our understanding of signal transduction driving the development of late megakaryopoiesis and platelet reactivity that results in bleeding diathesis. The paper is noteworthy for analyzing two related tyrosine phosphatases, using single or combined conditional gene knockouts at different developmental stages. Because SHP1 is a negative regulator and SHP2 is an activator, the synergistic effects found in the double knockout were surprising.

eLife Assessment

This important study demonstrates how ablation or silencing of hilar mossy cells in the mouse influences the primary location where the mossy cells project, the inner molecular layer of the dentate gyrus. The anatomical findings are convincing and include altered adult-born granule cells and the shrinkage of the inner molecular layer following mossy cell ablation. However, the mechanisms and their functional significance are unclear, so more of these types of experiments/analyses would strengthen the study, especially the support for the broader conclusions.

eLife Assessment

This important study proposes a framework in which tutor-song memorization and performance-error computation arise from a shared predictive-cancellation circuit. The approach is solid, but the choice of learning rules, circuit architecture, and sparsity assumptions is not always sufficiently justified, and the model would benefit from a clearer mechanistic derivation and more concrete experimental predictions. This study would be relevant for researchers studying vocal learning and motor learning in general.

eLife Assessment

This valuable study analyzes how recurrent neural network can flexibly switch between multiple tasks. The evidence is solid, but reviewers have raised questions about the impacts of transient dynamics, whether the activity is actually chaotic, can inputs be used to switch between tasks, what determines overlap between tasks and others. In addition, there were more minor questions pertaining to whether the analyses are actually analytic or primarily based on numerical simulations, as well as the relationship to prior studies where the same network was optimized to perform multiple tasks simultaneously with different readouts.

eLife Assessment

The manuscript presents a compelling application of the microfluidic mother machine as a "selection" machine. While individual elements of the work have existed for many years across various research communities, the simplicity and elegance of this particular application should make it readily implementable and therefore a useful contribution. The proposed plans for revision are sound, particularly in light of the senior author's stated logistical constraints.

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

eLife Assessment

This study uses convincing analyses of publicly available connectomic and transcriptomic datasets to survey the anatomy and connectivity of neurosecretory cells in the Drosophila brain. The systems-level description of the neurosecretory system is complemented by selected functional experiments and predictions for circuit function and paracrine signaling networks that can now be tested in future studies. This important work will be of interest to neuroscientists working on hormonal signaling in Drosophila and other animals.

eLife Assessment

This study reports results characterizing two boundaries (homie and nhomie) flanking the TAD of a developmental gene. The study's thorough and mechanistic characterization of these boundaries provides useful information to the field, and the conclusions are well supported by convincing evidence. The novelty of the work is somewhat limited because the major conclusion is confirmatory in nature.

eLife Assessment

This study presents important evidence showing that the high susceptibility to sepsis of Kit-mutant mice is not due to mast cell deficiency. The revised manuscript, with solid data, focuses on refuting the notion that mast cells play a major role in sepsis. This paper would be of interest to researchers in mast cell biology and mucosal immunology.

eLife Assessment

This study presents a systematic analysis of interactions involving components of the outer membrane protein biogenesis machinery in Escherichia coli. The authors identify interactions between Bam-associated proteins and several pathways. The evidence supporting the principal conclusions is convincing, including several newly identified interactions as well as findings that reinforce previously proposed connections described in the literature. The resulting dataset provides a useful resource for future investigations of bacterial envelope homeostasis and the functions of poorly characterized genes.

eLife Assessment

This valuable study presents findings on how prokaryotic antibiotics affect translation in mitochondrial ribosomes. Using mitoribosome profiling, the authors provide solid evidence that most tested antibiotics act similarly on bacterial and mitochondrial translation. Additionally, this work shows that alternative translation initiation events exist in two specific mt-mRNAs (MT-ND1 and MT-ND5).

eLife Assessment

This study provides important insights into the crosstalk between ATG2A and components of the early secretory pathway. The authors employ an elegant proximity-labelling approach to identify two ER-Golgi intermediate compartment (ERGIC)-localized proteins. They further identify ARFGAP1 and Rab1A as components of early autophagic membranes, which accumulate at the periphery of pre-autophagosomal structures induced by loss of ATG2. Overall, the study is well executed, and the evidence supporting the claims is convincing.

eLife Assessment

These results add to a growing body of literature demonstrating a role for IL-21 in T follicular helper cell expansion and differentiation, as well as in germinal center formation and maintenance. The authors use an IL21R ENU-induced mutant, together with complementary in vitro and in vivo experiments, to investigate the roles of STAT1 and STAT3 signaling downstream of IL-21R. The experimental approach is valuable, but the main conclusion is incompletely supported by the evidence, as the mutant exhibits a broad reduction in STAT signaling rather than a selective impairment of STAT1 signaling.

eLife Assessment

The study investigates how CD1c-restricted T cells respond to Mtb-infected APCs, leading to increased cytokine production and cytotoxic activity that may help control Mtb infection. The work is important and will interest researchers in the field. The supporting evidence is solid.

eLife Assessment

By using a combination of patch clamp recordings, calcium imaging and computer modeling, the authors analyze the spatial distribution of voltage gated calcium channels at glutamatergic synapses formed between layer 5 pyramidal neurons (L5PNs) and between layer 2/3 and L5PNs in the prefrontal cortex (PFC) and primary somatosensory cortex (S1); they conclude that the calcium channel-vesicle coupling is looser in the PFC compared to S1, and future ultrastructural studies may directly confirm the proposed differences in the spatial organization of voltage-gated calcium channels and vesicular release sites. Overall, these findings are important because they have implications for shaping synaptic plasticity and neural circuit function across brain regions. They are convincing because they are based on the use of a multi-pronged approach, although the presentation would benefit from stronger integration of the current findings with the existing literature and a more explicit discussion of potential limitations and confounding factors for data interpretation.

eLife Assessment

This is a valuable contribution to influenza surveillance. After revisions, addressing methodological and reporting issues, the claims of providing an early warning tool now align more with the reported study results, and ultimately, the evidence presented provide a solid addition to the evidence base.

eLife Assessment

This study explores the phylogeny and macroevolutionary patterns of water striders, linking sexual conflict-driven morphological traits to species diversification. It provides robust and compelling evidence for ILS, introgression, and differential evolutionary rates of male and female antagonistic traits, offering valuable insights into sexual conflict and speciation.

eLife Assessment

This important study elucidates the roles of two lytic transglycosylase (LTG) enzymes in the progression of spore formation in the research model species Myxococcus xanthus. Consistent with previous work indicating loss of peptidoglycan during the laboratory-induced rapid spore formation process, the new data demonstrate a similar loss of peptidoglycan during the normal, slow sporulation process. Solid evidence is provided for the roles of the two LTGs in spore formation and for interplay between the functions of these enzymes and peptidoglycan synthetic systems. These findings may have broader implications for understanding PG metabolism across a range of bacterial species.

eLife Assessment

This valuable paper describes the regulation of the association of meiotic chromosome axis proteins on chromosome ends with sub-telomeric elements in budding yeast. The genome-wide analyses of binding of chromosome components as well as chromatin regulators, complemented with the mapping of meiotic DNA double-strand breaks on chromosome ends, provided solid evidence to support the authors' conclusion. The results in the paper are of interest to researchers studying meiotic recombination and the structure of genomes and chromosomes.

eLife Assessment

This work provides a reassessment of VBIT-4, a compound previously proposed to inhibit oligomerization of the crucial protein known as the mitochondrial voltage-dependent anion channel. Combining complementary experimental approaches with molecular dynamics simulations, the authors provide compelling evidence that VBIT-4 primarily disrupts lipid membranes and induces channel-independent cytotoxicity. The study has fundamental implications for interpreting previous work using VBIT-4 as a probe of channel function and highlights the need to consider membrane-disruptive effects when evaluating drug mechanisms.

eLife Assessment

The study provides important insight into the development of CD8 T cell virtual memory cells by identifying a dose-sensitive role for Bcl11b. The authors define the developmental stages affected by reduced Bcl11b expression and establish its role in promoting the virtual memory fate. The evidence is compelling, supported by multiple genetic models and complementary approaches.

eLife Assessment

This fundamental study advances our understanding of the neural substrate of planning trajectories towards a goal by using recurrent neural networks. The manuscript provides compelling evidence for the proposed mechanism by linking a computational model to previous findings in neural data, designing a hand-crafted implementation of the mechanism, and showing that trained recurrent networks converge to computational principles consistent with the proposed mechanism. The work will be of broad interest to theoretical and systems neuroscientists and to cognitive scientists.

eLife Assessment

This is an important work, using preclinical models and reporting that a shared inflammatory and vascular leakage response following Treg depletion, UVB irradiation, and DNFB contact hypersensitivity facilitates outgrowth of premalignant melanocytes. However, some of the work to support the claims is incomplete; this pertains particularly to the quantification of melanocyte expansion and sample size inconsistencies. With some additional supporting evidence to strengthen the claims, the study will be of broad interest to cancer biologists and immunologists.

eLife Assessment

This useful study reports the application of targeted RNA-probe hybridization-capture metagenomic sequencing to characterize Klebsiella pneumoniae detected in post-mortem lung tissue from infants and young children who died from respiratory illness in Lusaka, Zambia. The findings provide a convincing proof-of-concept for the use of targeted sequencing to recover clinically relevant genomic information from archived post-mortem tissue specimens. However, the evidence supporting broader epidemiological and public health conclusions should be interpreted with caution given the small number of cases, the limitations inherent to culture-independent sequencing, and the fact that the study was not designed to determine the source or setting of acquisition.

eLife Assessment

Using the clownfish model, this study examines how growth, feeding, and agonistic behavior result in socially dominant or subordinate states in size- and age-matched individuals of the clownfish, Amphiprion percula. The authors complement this work with whole-body transcriptomics and find significant variation in genes and gene co-expression modules related to growth and satiety-related pathways, as well as ossification-related genes. They provide solid evidence that emerging dominants grow more, eat more, and behave more aggressively than subordinate or solitary individuals; these phenotypic differences are accompanied by distinct gene expression profiles, including variation in growth- and satiety-related pathways. The work is valuable in advancing our understanding of how the social environment regulates phenotypic change; however, claims regarding the mechanistic role of gene expression are only partially supported by the current analyses.

eLife Assessment

This study presents valuable evidence that activating a lysosomal signaling pathway lowers blood glucose in diabetic mice, pointing to a potential new strategy for treating metabolic disease. However, the evidence for the proposed mechanism is inadequate: the glucose transporter's movement and glucose uptake were not measured in the physiologically relevant tissue, and the measurement that was performed used an unconventional technique. As a result, whether this transporter-dependent pathway explains the glucose-lowering effect has not yet been established.

eLife Assessment

In their important study, Beaudet, Berger and Hendricks provide a mechanistic link between disease-associated tau hyperphosphorylation, loss of cooperative tau envelope formation on microtubules, and dysregulation of axonal transport prior to aggregation. Using complementary in vitro reconstitution and human iPSC-derived neuronal assays with phosphodeficient and phosphomimetic tau constructs targeting 14 disease-relevant sites, the authors convincingly show that phosphorylation state alters tau organization on microtubules and differentially impacts kinesin- and lysosome-based transport. The evidence is solid and well aligned with the conclusions and will be of interest to the biophysical, cell biology and neurodegenerative communities.

eLife Assessment

This valuable study presents a promising framework for automated spike sorting in high-density extracellular electrophysiology. The core evidence is solid, but could be strengthened with extended simulations, broader benchmarking against existing sorters, and validation via expert curation. It will be of interest to the systems neuroscience community.

eLife Assessment

This important study investigated the effects of the nutrient microenvironment on key elements of cellular morphology, function, and metabolism in both human iPSC-derived and human fetal RPE cultures. The analysis compared commonly used iPSC-RPE media formulations (MEMα, DMEM-HG/F12 basal media), alongside human plasma-like medium (HPLM) in an effort to model a more physiologically relevant culture environment. The authors provide compelling evidence that standard culture media differ significantly in key aspects of retinal pigment epithelium biology, particularly regarding metabolic profiles. Further clarification of the biological replicates and data normalization methods will help maximize the impact of this manuscript.

eLife Assessment

This study reports high-resolution cryo-EM structures of Paracoccus trimethylamine N-oxide demethylase and advances the intriguing hypothesis that the enzyme may be bifunctional, coupling TMAO demethylation to formaldehyde capture at a distal tetrahydrofolate-binding site through an enclosed intramolecular tunnel. Supported by biochemical assays and molecular dynamics simulations, the structural findings are important and potentially of broad interest, particularly the unusual oligomeric architecture and the proposed conduit for a reactive intermediate. However, evidence that the conduit mediates formaldehyde channeling remains incomplete, because the current HCHO-THF measurements do not demonstrate enzyme-dependent transfer or distinguish downstream HCHO consumption from indirect effects of THF on enzyme activity.

eLife Assessment

In this valuable study, Robben et al. describe a 3D beta-cell spheroid culture platform, that allows high-throughput monitoring of cytoplasmic calcium concentrations and insulin secretion. The authors demonstrate measurements of calcium signals comparable to those recorded in primary pancreatic islets. The authors validate the method by culturing MIN6 cells in a 3D-culture system, and show solid evidence of its utility by recording calcium signals in a high-throughput format and characterizing these calcium signals using pharmacological tools. This methodology demonstrates the utility of the 3D beta-cell spheroids for screening pharmacological modulators of pancreatic beta-cell function.

eLife Assessment

This potentially valuable work finds that exposure to the odor diacetyl in the worm C. elegans leads to changes in metabolic nutrient-responsive programs, inducing expression of genes that act in the DHAP-glycerol shunt followed by induction of the flavin-containing monooxygenase fmo-2. The genetic and multi-omic evidence is solid and is based on an extensive set of experiments; however, mechanistic support for underlying metabolic and redox changes remains incomplete without more comprehensive metabolic profiling. The mechanism through which diacetyl or its breakdown products is sensed did not involve known receptors of diacetyl, so it remains unknown whether sensory neurons are involved in these responses.

eLife Assessment

This valuable study examines how abstraction and metacognition relate to transdiagnostic dimensions of psychopathology. It combines a reward-learning task, computational modelling and a large questionnaire. The evidence linking reduced metacognitive sensitivity to a compulsive hypersensitivity dimension is solid, but the evidence for the abstraction findings is currently incomplete. This work will be of interest to researchers studying metacognition and computational approaches to psychiatry.

eLife Assessment

This valuable study compares the anti-HIV activity of human natural killer cell subsets and identifies CD56^dimCD16^dim cells as a potentially key effector population against HIV-infected autologous T cells. The evidence supporting the central conclusions seems incomplete because the interpretation may be substantially confounded by activation-induced CD16 downregulation, making it difficult to distinguish intrinsic functional differences from phenotypic changes that occur during target-cell engagement. Additional experiments using purified NK-cell subsets and appropriate controls would substantially strengthen the evidence supporting the major conclusions.

eLife Assessment

The cell wall and plasma membrane are tightly associated in plant cells, and even after plasmolysis, sites of strong contact remain between the plasma membrane and cell wall. Here, the authors provide solid data to implicate an Arabidopsis lectin-like receptor kinase in plasma-membrane-to-cell-wall contact sites, and propose that these attachment sites are of importance for plant resistance to hyperosmotic stress, yet the evidence remains incomplete without key controls. These important results broaden our view on dynamic modulation of plasma membrane topology and its physiological consequences.

eLife Assessment

This study presents a valuable metagenomic analysis of the gut microbiome in sickle cell disease (SCD) patients, revealing associations between bacteriophage, host immunity, and SCD pathophysiology. This solid dataset and in-depth analysis will be of broad interest to researchers studying SCD, immunology, phage biology, and the microbiome, adding to the small but growing literature suggesting a microbial component to SCD.

eLife Assessment

This valuable study leveraged high-definition transcranial direct current stimulation to the left dorsolateral prefrontal cortex to provide strikingly large effects on procrastination behavior over an extended time span. The cross-sectional, longitudinal study and testing of competing models provided solid evidence for how stimulating dlPFC impacts reveal-world procrastination behavior. Whether these results generalize to a larger population will be a significant future direction. This work will be of interest to those interested in cortical function, procrastination, and related states.

eLife Assessment

This manuscript examines how overexpression of sphingosine 1-phosphate receptor 1 in a mouse model affects neutrophil distribution, metabolism and function. Given the significance of S1PR1 in inflammatory mechanisms, this work is valuable for uncovering novel aspects of S1PR1 signaling in neutrophil dynamics and function. The evidence provided is solid as it integrates single-cell transcriptomics, flow cytometry, and multiple in vivo studies. This work also raises key questions about distinct physiological and pathophysiological roles of S1PR1 signaling in neutrophils that could become therapeutic targets.

eLife Assessment

This paper demonstrates that relocating the MreB-Rod complex to the poles of E. coli can reprogram cell-wall synthesis, causing cells to elongate through peptidoglycan incorporation at the poles rather than along the cell length. This is a valuable finding for understanding how bacterial growth can be spatially reprogrammed and provides insight into how distinct modes of bacterial growth might arise. However, the evidence is currently incomplete, particularly regarding the nature of the polar structures, their relationship to cell shape and growth, and the requirement for a pre-existing pole.

eLife Assessment

This important study leverages a large global dataset of tens of thousands of tuberculosis samples to place recurrent protein-coding mutations into their three-dimensional structural context, offering an expanded view of how antibiotic resistance emerges compared to traditional genetic analyses alone. The strength of evidence is compelling, supported by the scale and breadth of the dataset and the systematic structural analysis, although some of the assumptions made in the modeling approach are only partially supported. Overall, the work will be of broad interest to researchers studying microbial evolution, antibiotic resistance, and structure-function relationships in pathogens.

eLife Assessment

This study modeled vocal learning in zebra finches with a network of three components: a pathway with delayed/slow Hebbian learning that mimics the HVC-RA projection, a pathway with reinforcement learning that mimics the HVC-BG-RA projection, and a motor unit that mimics the syrinx and produces song output. The model convincingly reproduces key features of song learning and is a valuable step towards understanding how vocal learning is substantiated in the song system. The generic and simplified nature of the model limits its generalization to other forms of motor learning. Further examination of model assumptions and presentation of testable predictions would increase the impact of the study.

eLife Assessment

The authors investigate how dominance hierarchy shapes defensive strategies in mice under two naturalistic threats: a transient visual looming stimulus and a sustained live rat. This study provides important insights into how social context and dominance hierarchy modulate innate defensive behaviors across distinct naturalistic threats. The strength of evidence is convincing, with detailed classification and analysis of behaviors.

eLife Assessment

This fundamental work substantially advances our understanding of short-term plasticity mechanisms by providing evidence for release-independent low-frequency synaptic depression that reflects a model that proposes a redistribution of vesicles within the readily releasable pool, via a reduction in docking site occupancy due to vesicle undocking. The evidence supporting this model is convincing, with rigorous modeling, electrophysiological data and computational analysis. The work will be of broad interest to cellular neuroscientists and synaptic physiologists.

eLife Assessment

This valuable study compares auditory cortex responses to sounds and cochlear implant stimulation measured with surface electrode grids in rats. Beyond the reduced frequency resolution of cochlear implants observed previously, this study suggests further discrepancies between neuronal representations of cochlear stimulations and natural sounds. The evidence for this result is solid. This study is of interest to researchers in the auditory neuroscience field and clinicians implementing treatments with cochlear implants.

eLife Assessment

These are valuable findings for those interested in how neural signals reflect auditory speech streams, and in understanding the roles of prediction, attention, and eye movements in this tracking. The evidence is solid, as the revised analyses broadly support the main claims and address the key methodological concerns raised during review. Remaining limitations concern the interpretation of some sensor-level and eye-movement effects, but these do not substantially undermine the overall conclusions.

eLife Assessment

This study presents a useful alternate labeling-based approach to identify or profile bioenergetic changes between cells. Overall, the approaches and data are solid, but have limitations in interpretation and so are as yet incomplete. The method itself can be of interest to a variety of biochemists, cell and systems-biologists interested in quantitative cellular metabolism.

eLife Assessment

This valuable pharmacological MEG study implicates GABA-A receptors in the shaping of intrinsic neuronal timescales in the human brain. While the authors provide solid evidence for the claims that (i) GABAergic neuronal inhibition prolongs timescales in specific cortical networks and (ii) NMDA receptor manipulations have no detectable effect, the manuscript could be further strengthened by resolving some apparent discrepancies in the results as well as additional validation of the network analysis used. This work will be of interest for experimental and theoretical neuroscientists studying brain-wide network dynamics and the large-scale organization of neurotransmitter systems.

eLife Assessment

This study presents a valuable investigation of how inhibition of the WNK-SPAK/OSR1 pathway influences neuronal chloride homeostasis and seizure-like activity in organotypic hippocampal slice cultures. The evidence supporting the principal mechanistic conclusions is incomplete because several proposed mechanisms are inferred from changes in chloride dynamics rather than directly demonstrated. The work will be of interest to researchers studying chloride homeostasis, inhibitory neurotransmission, and epilepsy.

eLife Assessment

This valuable study combines free-flight kinematics, aerodynamic modeling, optogenetics, and connectomics to ask how Drosophila stabilize roll perturbations during flight. The kinematic and modeling methods are solid, but the evidence for redundant motor control of roll stabilization is incomplete: optogenetic silencing experiments lack a positive control, and no experiment directly tests the central claim that redundant motor pathways drive robust roll control. This work will interest researchers studying insect flight and robust motor control.

eLife Assessment

This important study provides solid evidence that, in an α-synucleinoathy model, brain atrophy and associated functional decline generalize across host genotype and fibril species, while being strongly shaped by the site of seeding and regional vulnerability. With an unusually large longitudinal in vivo MRI dataset combined with behavioural and computational modelling, the study offers a comprehensive characterization of neurodegeneration across multiple biological and experimental conditions. The openly shared imaging dataset and analysis pipeline are an excellent resource, and the scale, longitudinal design, methodological breadth, and openness of the study make it a substantial contribution to the field. This work will be of interest to scientists in synucleinopathy- and network- neurodegeneration communities.

eLife Assessment

This is a valuable study that contributes to our understanding of transcriptomic responses in microglia to HIV infection in the human brain. The evidence provided remains incomplete, and further analyses are required (i.e., a bigger sample size) to eliminate confounding factors so that the study can unequivocally ascertain the persistent inflammatory state of microglia in HIV-suppressed brains.

eLife Assessment

This valuable study characterizes the population structure and ancestry of Helicobacter pylori in Cabo Verde. Using a carefully sampled population-based cohort and paired host-bacterial genomic data, the authors identify distinct local lineages but with limited concordance between human and bacterial ancestry. The evidence is solid for the principal findings concerning bacterial diversity, ancestry and recent lineage expansion, while the support for the claim that this reflects host adaptation, enhanced transmission, reduced virulence or a mix thereof is weaker. The work has particular relevance for researchers interested in microbial population genomics, host-pathogen coevolution and the genetic consequences of human migration and admixture.

eLife Assessment

In this fundamental study, the authors argue that the most widely used behavioral measure of the ability to stop an action is largely determined by the time it takes for visual signals to reach the brain and for movements to be executed, rather than by the control processes it is assumed to index. The evidence is convincing, combining reanalyses of seven existing datasets with a preregistered new experiment, and its force comes from the authors doing three things at once: identifying the problem, showing that it is present wherever it can be measured, and offering remedies applicable to both archived and future data. Various concerns were raised as to the interpretation of the data and their robustness to experimental manipulations, but if these were properly addressed, the implications of the work could extend across psychology, psychiatry and neuroscience.

eLife Assessment

Winter months with short days are commonly associated with seasonal depression and hypersomnolence; the mechanisms behind this hypersomnolence however, remain unclear. Chen and colleagues identify a genetic basis for this phenomenon in the fly Drosophila - mutations in the circadian photoreceptor cryptochrome resulted in increased sleep under short photoperiods. These findings are valuable insights into the genetic mechanisms regulating sleep under short days. There is solid evidence that cryptochrome acts in GABAergic neurons, but only limited evidence for the proposed site of action. Further work with better techniques will be needed to identify the precise site of action of cryptochrome.

eLife Assessment

This important study reports dynamic reprogramming of global H3K4me2 during the oocyte-to-embryo transition in mice. The data presented support the main conclusion and are generally convincing. The work will be of interest to researchers working on epigenetic reprogramming during embryonic development.

eLife Assessment

This important study provides new insights into how extracellular-domain disulfide configurations regulate ligand binding and endocytosis of the natural killer cell receptor KIR2DL4, identifying a conformational switch that provides a mechanistic framework for receptor trafficking. The evidence supporting the main conclusions is solid, with complementary biochemical, structural, and functional approaches providing strong support for alternative disulfide configurations and their role in regulating receptor behavior. The work will be of interest to researchers studying natural killer cell biology, immune receptor signaling, and protein disulfide regulation.

eLife Assessment

This study attempts to predict spatial patterns of genetic diversity among coral reef dwellers, estimated with a computationally efficient, standardized k-mer pipeline, from satellite-derived seascape variables. The curated dataset of 18 coral reef taxa across 173 reefs is valuable, but the evidence for the central ecological claims is in its current form incomplete: pairwise genetic distances are modelled as independent observations, the reef-level random effects used as the response in the environmental analysis likely conflate species composition with environmental signal, and , and the coverage is likely too sparse to robustly support conclusions about loss of inter-and intra-specific within-reef diversity over time. The work will be of interest to conservation geneticists, marine biologists, and researchers developing Earth-observation approaches to biodiversity monitoring.

eLife Assessment

This study presents a valuable analysis of the TARA oceans dataset, advancing genome- and ecosystem-scale metabolic modeling. The authors present convincing evidence for the factors that shape microbial ecology at the molecular scale. The work will be of broad interest to oceanographers and scientists in other areas where metabolic interactions in diverse communities are of importance.

eLife Assessment

This is a valuable manuscript that leverages information already being collected in mosquito surveillance, but that is currently discarded, building on ideas developed during the SARS-CoV-2 pandemic. The work is mostly rigorous, involving ample data from real-world surveillance, independent laboratory testing, and simulation modeling to validate the inference method. The evidence is solid for demonstrating feasibility and biological plausibility, although some conclusions would be strengthened by additional sensitivity analyses on key assumptions.

eLife Assessment

An intriguing set of electrophysiological and analytical results suggests that adult rat neurons in the medulla oblongata crucial for mediating descending pain modulation are embedded in a network that generates a specific pattern of oscillatory activity. These valuable findings may broaden our understanding of how descending pain modulation is achieved. The supporting evidence is incomplete, and the authors need to provide several methodological clarifications and additional data interpretations to strengthen the manuscript.

eLife Assessment

This important technical study introduces SCOPE, an optics-free spatial reconstruction method based on bidirectional sender and receiver oligonucleotides on barcoded hydrogel beads. By sequencing proximity-encoded chimeric molecules, the authors computationally reconstruct 2D and 3D spatial information at an impressive scale. The technical demonstrations in synthetic bead systems are convincing and establish proof-of-principle that large spatial domains can be reconstructed without microscopy. The methodological advance is clear and the scale is impressive. This work will be of interest to those working on spatial mapping.

eLife Assessment

This important study investigates how sleep loss and circadian disruption affect whole-organ metabolism in flies (Drosophila melanogaster) and reports that wild-type flies align metabolism in anticipation of diurnal rhythm, while mutant flies with impaired sleep or circadian function shift to reactive or misaligned metabolism. The integration of chamber-based flow-through respirometry with LC-MS metabolomics is innovative, and the significance of the findings is significant. The strength of evidence needed to support the conclusions is generally convincing, although the absence of direct measures of locomotor activity makes it difficult to separate intrinsic metabolic changes from potential behavioral differences in mutants.

eLife Assessment

This study presents fundamental results on questions related to the presence/absence of the Entner-Doudoroff pathway in cyanobacteria. In contrast to an earlier study, compelling evidence is given that Synechocystis PCC 6803 lacks both an Entner-Doudoroff pathway and a related bypass but contains a promiscuous aldolase. This study successfully reconciles data from different studies and lessons learned from a previous misconception.

eLife Assessment

This study applies a relatively novel method, ABR (Automated Behavioural Response system), to an arboreal small mammal, providing some valuable results on the responses of these small primates to both natural predators and human stimuli. However, the study in its current form is incomplete in its framing and methodology and could be improved to appeal more broadly to behavioural biologists.

eLife Assessment

This valuable study identifies an upstream repressive region in the Saccharomyces cerevisiae DDI2/3 promoter and shows that chemical stress induced by cyanamide or MMS is accompanied by reduced histone abundance and decreased nucleosome occupancy across the DDI2/3 locus. Genetic histone depletion is sufficient to enhance DDI2/3 expression, while MNase-seq and genetic analyses support a model in which the transcription factor Fzf1 both activates transcription through its established promoter-binding function and promotes chromatin changes that relieve nucleosome-mediated repression, helping to explain the unusually strong induction of DDI2/3 relative to other Fzf1 targets. The study is significant, as it provides a conceptually interesting extension of Fzf1-mediated stress regulation. The strength of the evidence is solid, although additional controls and a more cautious treatment of whether Fzf1 directly drives nucleosome eviction versus acting indirectly through transcriptional recruitment or chromatin-remodeling factors would further strengthen the mechanistic conclusions.

eLife Assessment

The study addresses a timely problem that is of importance in the cfRNA field, and it provides a potentially valuable resource. The use of a common processing pipeline, publicly available code, and variance-partition analyses are notable strengths. However, several central conclusions, particularly those concerning protocol-level effects, the dominance of technical over biological variation, and the proposed universal QC criteria remain more general than the study design and available data can support. Therefore the evidence is currently incomplete and needs to be improved through the revision process.

eLife Assessment

This study presents a valuable patient-derived human cell platform for investigating LMNA-associated cardiomyopathy and identifies cyproheptadine as a compound that improves abnormal calcium handling across multiple LMNA variants in vitro. The experimental approaches are generally rigorous and establish reproducible disease-associated cellular phenotypes; however, the evidence remains incomplete because the mechanistic basis of the observed rescue is not established, and the translational conclusions substantially exceed the presented data.

eLife Assessment

This study presents a valuable finding on impacts of the common driver mutations APC, KRAS G12D, and TP53 in murine colorectal organoids. In particular, the authors examine how the order of APC and TP53 acquisition influences tumor phenotype. The evidence supporting the claims of the authors is solid. The work will be of interest to scientists working in the field of breast cancer.