eLife Assessment

This manuscript presents a fundamental advance in our understanding of nuclear receptor pharmacology by expanding on previous work demonstrating dual ligand occupancy in the peroxisome proliferator-activated receptor-gamma (PPARγ). Using a compelling combination of biophysical, biochemical, and cellular approaches, the authors show that covalent inverse agonists with enhanced efficacy shift the receptor conformation toward a transcriptionally repressive state that limits orthosteric ligand co-binding more effectively. This revised manuscript further strengthens support for a proximal, bidirectional allosteric model of dual ligand occupancy by sharpening the distinction between prior and new findings, adding clear conceptual figures, and strengthening statistical rigor.

eLife Assessment

This study addresses an important problem in gene regulation, namely, which features of chromatin regulate potential RNA Polymerase 2 activity at a locus. The authors provided evidence that specific post-translational modifications of histones within the gene body are correlated with Pol II transcription, that these modifications are dynamic, and that they can be regulated by Pol II activity. The manuscript contributes to the concept of "fragile nucleosomes" as a unifying framework for key epigenetic drivers of transcription; however, the quality of the evidence provided is inadequate in support of the claims made, and further evidence teasing out the mechanistic aspects of the work would strengthen its impact. This work will be of interest to the fields of transcriptional regulation, chromatin structure, and epigenetics.

eLife Assessment

This is an important study on the sensory roles of Cerebrospinal fluid-contacting neurons (CBF-cn) in mammals. The authors identify PKD2L1 as the predominant pH-sensing channel CBF-cn and show how the apical extension is used as an amplifier of chemical changes in the content of the Cerebrospinal fluid. The evidence is solid in experimental design but limited in mechanistic interpretation, as the electrophysiological analyses require re-evaluation.

eLife Assessment

This study presents important findings on how cardiac regenerative capacity diverges across species by examining heart repair in two species of livebearers, platyfish and swordtails. In contrast to zebrafish, the livebearer species show persistent scarring after cryo-injury, and the work highlights how lineage-specific anatomical and immunological traits may constrain regenerative competence. The study is compelling, the data are convincing, and the results contribute to our understanding of the mechanisms underlying heart regeneration across vertebrates.

eLife Assessment

In this work, the authors intend to assess the existence of a redox potential across germline stem cells and neighbouring somatic stem cells in the Drosophila testis. Some aspects of the manuscript are convincing, like the clear effect of SOD KD on cyst cell differentiation state. Other conclusions of the work, such as the non-autonomous effect of this KD on germ cells are not sufficiently supported by the data. This remains true even with the revised version of the paper, as the effect of redox state of the soma on the germline is a major point of the paper, and this remains a critical flaw. The work could be potentially useful if the critiques of the reviewers were fully addressed; the strength of the evidence of the manuscript as it stands is still inadequate. Readers should use their own judgment about the validity and meaningfulness of different findings.

eLife Assessment

This important work advances our understanding of the development of the visual system. The data presented is compelling and provides a detailed single-cell atlas of post-natal anterior chamber development in mice, highlighting the trabecular meshwork and Schlemm's canal.

eLife Assessment

This important study introduces a new biology-informed strategy for deep learning models aiming to predict mutational effects in antibody sequences. It provides solid evidence that separating selection from the nucleotide-level mutation process improves performance over the objectives of protein language models inspired by natural language processing. This paper should be of interest to computational immunologists, but also to the broader community interested in deep learning for biological sequence data and evolution.

eLife Assessment

This potentially valuable manuscript focuses on the phosphorylation of residue T495 as a mechanism to inactivate HSP70 and disrupt cell cycle progression in response to DNA damage. The evidence supporting this model is incomplete and would be strengthened by additional studies defining the extent of T495 phosphorylation induced by DNA damage, identifying the kinase responsible for phosphorylating T495 of HSP70, and further elucidation of the functional implications of T495 phosphorylation in human cells. This work will be of interest to scientists focused on topics including chaperone biology, proteostasis, cell cycle progression, and DNA damage.

eLife Assessment

Rickert and colleagues demonstrate that the host peptidoglycan-binding protein PGLYRP1 has both beneficial and detrimental effects on Bordetella pertussis infection in mice. Using a solid array of techniques, the study provides useful insights into how peptidoglycan species may alter host immune responses. The data on the bactericidal effects on B. pertussis are incomplete, and further experiments are needed to draw conclusions on this question.

eLife Assessment

This fundamental work substantially advances our understanding of a major research question: whether collagen can be directly imaged with MRI. The evidence supporting the conclusion is compelling, with methods, data, and analyses that are more rigorous than those currently considered state-of-the-art. The work will be of high interest to MR physicists and clinicians, as collagen is the most abundant protein in the human body and plays an essential role in health.

eLife Assessment

This study presents a valuable analysis of a large dataset of [NiFe]-CODHs, integrating genomic context, operon organization, and clade-specific gene neighborhoods to discern patterns of functional diversification and adaptation. Carefully looking at the CODH genomic context, e.g., CODH-HCP co-occurrence, the authors gain insight into enzymatic activity, biotechnological potential, and differential functional roles. The approach aligns with current standards in genomic enzymology to characterize newly identified enzymes. With solid support, this work provides a broadly informative contribution to the field.

eLife Assessment<br /> <br /> This study examines an important question regarding the developmental trajectory of neural mechanisms supporting facial expression processing. Leveraging a rare intracranial EEG (iEEG) dataset including both children and adults, the authors reported that facial expression recognition mainly engaged the posterior superior temporal cortex (pSTC) among children, while both pSTC and the prefrontal cortex were engaged among adults. In terms of strength of evidence, the solid methods, data and analyses broadly support the claims with minor weaknesses.

eLife Assessment

This important contribution to enzyme annotation offers a deep learning framework for catalytic site prediction. Integrating biochemical knowledge with large language models, the authors demonstrate how to extract meaningful information from sequence alone. They introduce Squidly, a freely available new ML modeling framework, that outperforms existing tools on standard benchmarks, including the CataloDB dataset. The evidence is convincing, with an extensively and carefully addressed narrative upon revision.

eLife Assessment

This important study presents a well-constructed multiscale simulation framework to investigate ATP-driven DNA translocation by prokaryotic SMC complexes, supporting a segment-capture mechanism. The strength of evidence is convincing, highlighting the necessity of a precise balance between electrostatic interactions and hydrogen bonding, as well as the critical role of kleisin asymmetry in ensuring unidirectional movement.

eLife Assessment

This important study reports three experiments examining how the subjective experience of task regularities influences perceptual decision-making. Although the evidence linking subjective ratings to behavioral measures is solid, the study would be strengthened if potential reverse influences of response times on subjective ratings were ruled out and if more comprehensive model comparisons supporting the main claims were performed. The findings will appeal to a wide range of researchers in decision-making and perception.

eLife Assessment

This paper uses a new computational method that integrates bulk sequencing and single-cell sequencing data to provide refined gene expression datasets for 52 neuron classes in C. elegans. The paper's findings are convincing, presenting an approach that alleviates a key shortcoming of single-cell RNA sequencing. While the datasets have some limitations that the authors acknowledge, the new methodology and refined datasets will be important resources for those interested in understanding how gene expression shapes neuronal morphology and physiology.

eLife Assessment

This valuable study describes an interesting infection phenotype that differs between adult male and female zebrafish. The authors present data indicating that male-biased expression of Cyp17a2 appears to mediate viral infection through STING and USP8 activity regulation. Through experimentation on male fish, the authors present solid evidence linking this factor to direct and indirect antiviral outcomes through ubiquitination pathways. These findings raise interesting questions about immune mechanisms that underlie sex-dimorphism and the selective pressures that might shape it.

eLife Assessment

This study makes an important contribution by revealing how saccades selectively disrupt spatial working memory while sparing other object features, and by demonstrating how this mechanism is altered in aging and neurodegeneration. The findings are supported by convincing evidence derived from well-controlled eye-tracking experiments and systematic generative model comparisons. Together, the work provides a computationally grounded framework that is of importance for understanding trans-saccadic memory and its clinical relevance.

eLife Assessment

This important study presents the rational redesign and engineering of interleukin-7. The data from the integrated approach of using computational, biophysical, and cellular experiments are convincing. This paper is broadly relevant to those studying immunomodulation using biologics.

eLife Assessment

This study addresses a key question in developmental cognitive neuroscience by identifying early neural correlates of variability in language learning and showing how syllable tracking and word segmentation develop from birth to two years in infants with differing likelihoods of autism. The evidence is generally strong, with rigorous longitudinal EEG acquisition, careful preprocessing, and validated statistical approaches, though several methodological clarifications would further strengthen confidence in the inferences. Overall, the findings offer important insights with clear theoretical implications for understanding early mechanisms of speech perception and statistical learning, supported by convincing evidence.

eLife Assessment

This is an important study showing that movement vigor is not solely an individual property but emerges through interaction when two people are physically linked. The evidence is convincing, supported by a well-controlled experimental design and modeling that closely match the observed behavior. While the authors provided a helpful comparison of several candidate models of human-human interaction dynamics, the statistical power and the statistical analyses could be further improved.

eLife Assessment

This important study combines optogenetic manipulations and wide-field imaging to show that the retrosplenial cortex controls behavioral responses to whisker deflection in a context-dependent manner. The evidence is convincing, but the study would benefit from additional analyses to disentangle the contributions of movement initiation to the recorded neural signals. The paper should be of strong interest to neuroscientists studying cortical mechanisms of sensorimotor processing.

eLife Assessment

This study presents SynaptoGen, a differentiable extension of connectome models that links gene expression, protein-protein interaction probabilities, synaptic multiplicity, and synaptic weights, and demonstrates its use in reinforcement learning agents and a C. elegans-inspired case study. The work is a valuable contribution to computational connectomics and neuro-inspired machine learning, with solid mathematical and computational evidence supporting the proposed optimization framework. However, the broader biological and synthetic-biology claims - particularly genomic control of synaptogenesis and drug-discovery applications - are currently overstated and would benefit from a more tempered framing and clearer articulation of biological limitations.

eLife Assessment

This is an important contribution that largely confirms prior evidence that word recognition - a cornerstone of development - improves across early childhood and is related to vocabulary growth. This study is distinguished by its use of a large, multi-study dataset that is uncommon in prior research on cognitive development. It provides solid evidence that speed, accuracy, and consistency of word learning improve with age, and will therefore prove of interest to those studying language, and more broadly, perception and development.

eLife Assessment

This important work investigates cooperative behaviors in adolescents using a repeated Prisoner's Dilemma game. The computational modeling approach used in the study is solid and rigorous. The work could be further strengthened with the consideration of modeling higher-order social inferences and non-linear relationships between age and observed behavior. Findings from this study will be of interest to developmental psychologists, economists, and social psychologists.

eLife Assessment

This study offers important insights into how entorhinal and hippocampal activity support human thinking in feature spaces. It replicates hexagonal symmetry in entorhinal cortex, reports a novel three-fold symmetry in both behavior and hippocampal signals, and links these findings with a computational model. The task and analyses are sophisticated, and the results appear solid and of broad interest to neuroscientists.

eLife Assessment

TrASPr is an important contribution that leverages transformer models focused on regulatory regions to enhance predictions of tissue-specific splicing events. The revisions strengthen the manuscript by clarifying methodology and expanding analyses across exon and intron sizes, and the evidence supporting TrASPr's predictive performance is compelling. This work will be of interest to researchers in computational genomics and RNA biology, offering an improved model for splicing prediction and a promising approach to RNA sequence design.

eLife Assessment

This important work advances our understanding of the role of kisspeptin neurons in regulating the luteinizing hormone (LH) surge in females. The evidence demonstrating increased neuronal activity in anterior hypothalamic kisspeptin neurons just before the LH surge is compelling, though additional neuroanatomical evidence showing the specificity of the methods would strengthen the study. It also confirms that high circulating levels of estradiol, but also other unidentified factors, are required for the full daily activation. This research will be of interest to reproductive biologists and neuroscientists studying the female ovarian cycle.

eLife Assessment

This study aims to identify the proteins that make up the electrical synapse, which are much less understood than those of the chemical synapse. These findings represent an important step toward understanding the molecular function of chemical synapses and will have broad utility for the wider neuroscience field. The experimental evidence is convincing.

eLife Assessment

This study presents a valuable finding on how the locus coeruleus modulates the involvement of medial prefrontal cortex in set shifting using calcium imaging. The evidence supporting the claims was viewed as incomplete in comparisons of extra- (EDS) and intradimensional shifts (IDS). The work is of broad interest to those studying flexible cognition.

eLife Assessment

This study introduces a novel method for estimating spatial spectra from irregularly sampled intracranial EEG data, revealing cortical activity across all spatial frequencies, which supports the global and integrated nature of cortical dynamics. It showcases important technical innovations and rigorous analyses, including tests to rule out potential confounds. However, further direct evaluation of the model, for example by using simulated cortical activity with a known spatial spectrum (e.g., an iEEG volume-conductor model that describes the mapping from cortical current source density to iEEG signals, and that incorporates the reference electrodes and the particular montage used), would even further strengthen the incomplete evidence.

eLife Assessment

This study offers important insight into the pathogenic basis of intragenic frameshift deletions in the carboxy-terminal domain of MECP2, which account for some Rett syndrome cases, yet similar variants also appear in unaffected individuals. Using base editing and mouse models, the authors present convincing evidence supporting the pathogenicity of select deletion variants, with potential implications for therapeutic development. However, comments regarding the analysis of publicly available genetic databases should be addressed to strengthen the conclusions and provide greater clarity to the field.

eLife Assessment

This study provides an important assessment of how body size influences the occurrence of macro-organisms in urban areas across the globe. Size in most plants, but only some animal families, was positively associated with urban tolerance. The data set is impressive, but the evidence for broad-scale conclusions is incomplete due to methodological issues that need to be resolved.

eLife Assessment

The goal of this useful study is to examine learning-related changes in neural representations of global and local spatial reference frames in a spatial navigation task. Although the study addresses an interesting question, the evidence for neural representations in the hippocampus and retrosplenial cortex remains incomplete because of confounds in the experimental design and partial data analysis. There are further concerns about the framing of the study in the context of the relevant literature as well as the discussion.

eLife Assessment

This study presents a valuable approach for revealing large-scale brain attractor dynamics during resting states, task processing, and disease conditions using insights from Hopfield neural networks. The evidence supporting the findings is convincing across the many datasets analysed. The work will be of broad interest to neuroscientists using neuroimaging data with interest in computational modelling of brain activity.

eLife Assessment

O'Brien and co-authors provide important data demonstrating that tissue-resident macrophages can exert physiological functions and influence endocrine systems.Their model in which AMs negatively regulate aldosterone production via effects exerted in the lung is solid. The work will be of broad interest to cell biologists and immunologists.

eLife Assessment

This is an important account of replay as recency-weighted context-guided memory reactivation that explains a number of empirical findings across human and rodent memory literatures. The evidence is compelling and the work is likely to inspire further adaptions to incorporate additional biological and cognitive features.

eLife Assessment

This study combines genetic, cell biological, and interaction data to propose a model of meiotic double-strand break regulation in C. elegans. Solid evidence supports the main conclusions, while by nature of a screening-type study, more may be needed to solidify speculations in future studies. Yet, comprehensive cataloging of the physical and genetic interactions of factors required for meiotic double-strand break is useful information for the field.

eLife Assessment

This study reports important advances in our understanding of how enteropathogenic E. coli (EPEC) interacts at the intestinal interface. Solid data describe a novel model of spatially coordinated calcium signaling to modulate NF-kB activation; additional data and clarification of methods would improve the strength of these conclusions. These findings, which integrate imaging, genetics, and computational modeling, provide a new way to consider host-pathogen interactions in EPEC infections that may lead to improved therapies.

eLife Assessment

The authors investigate arrestin2-mediated CCR5 endocytosis in the context of clathrin and AP2 contributions. Using an extensive set of NMR experiments, and supported by microscopy and other biophysical assays, the authors provide compelling data on the roles of AP2 and clathrin in CCR5 endocytosis. This important work will appeal to an audience beyond those studying chemokine receptors, including those studying GPCR regulation and trafficking. The distinct role of AP2 and not clathrin will be of particular interest to those studying GPCR internalization mechanisms.

eLife Assessment

This revised paper provides a valuable and novel neural network-based framework for parameterizing individual differences and predicting individual decision-making across task conditions. The methods and analyses are solid yet could benefit from further validation of the superiority of the proposed framework against other baseline models. With these concerns addressed, this study would offer a proof-of-concept neural network approach to scientists working on the generalization of cognitive skills across contexts.

eLife Assessment

This study presents compelling new data that combine two FTD-tau mutations, P301L/S320F (PL-SF), that reliably induce spontaneous full-length tau aggregation across multiple cellular systems. The findings are important for the field of neurodegenerative disease. The strength of evidence is solid; however, several conclusions would benefit from more validation.

eLife Assessment

This study investigates the role of developmental oligodendrocytes in synchronising spontaneous activity in neuronal circuits and influencing cerebellar-dependent behaviour. The authors use advanced viral targeting techniques to deplete oligodendrocytes in a cell-specific manner, paired with in vivo calcium imaging of Purkinje cells, to establish a relationship between oligodendrocyte-mediated neuronal synchrony and complex brain function. The authors present compelling evidence of oligodendrocyte-regulated neuronal synchrony. Overall, this manuscript holds promise as an important contribution to neurodevelopment research.

eLife Assessment

By investigating spine nanostructure and dynamics across multiple genetic mouse models for neurodevelopmental disorders, this important study has the potential to uncover convergent or divergent synaptic phenotypes that may be specifically associated with autism versus schizophrenia risk. While the imaging and breadth are impressive, there are potential methodological concerns, especially around statistical analyses, which render the evidence incomplete and should be addressed. The purely in vitro nature of the study also slightly limits the generalisability of the findings.

eLife Assessment

This useful study provides a systematic and solid comparison of sex-biased enteroendocrine peptide expression, including AstC and Tk, to show that these peptides contribute to female-biased fat storage. The major research question of this study is based on the authors' previous papers, and therefore, the presented results are incremental. This study serves as a foundation for future investigation of regulatory mechanisms for the sex-biased fat content by AstC and Tk.

eLife Assessment

This important study introduces an advance in multi-animal tracking by reframing identity assignment as a self-supervised contrastive representation learning problem. It eliminates the need for segments of video where all animals are simultaneously visible and individually identifiable, and significantly improves tracking speed, accuracy, and robustness with respect to occlusion. This innovation has implications beyond animal tracking, potentially connecting with advances in behavioral analysis and computer vision. The strength of support for these advances is compelling overall, although there were some remaining minor methodological concerns.

eLife Assessment

This important study provides a detailed analysis of the transcriptional landscape of the mouse hippocampus in the context of various physiological states. The main conclusions have solid support: that most transcriptional targets are generally stable, with notable exceptions in the dentate gyrus and with regard to circadian changes. There are some weaknesses and it would improve the manuscript to address them.

eLife Assessment

This valuable study uses fiber photometry, implantable lenses, and optogenetics, to show that a subset of subthalamic nucleus neurons are active during movement, and that active but not passive avoidance depends in part on STN projections to substantia nigra. The strength of the evidence for these claims is solid, whereas evidence supporting the claims that STN is involved in cautious responding is unclear as presented. This paper may be of interest to basic and applied behavioural neuroscientists working on movement or avoidance.

eLife Assessment

This valuable study provides a 3D standardised anatomical atlas of the brain of an orb-weaving spider. The authors describe the brain's shape and its inner compartments-the neuropils-and add information on the distribution of a number of neuroactive substances such as neurotransmitters and neuropeptides. Through the use of histological and microscopy methods the authors provide a more complete view of an arachnid brain than previous studies and also presents convincing evidence about the organisation and homology of brain regions. The work will serve as a reference for future studies on spider brains and will enables comparisons of brain regions with insects so that the evolution of these structures can be inferred across arthropods.

eLife Assessment

This valuable study addresses T cell receptor activation during autoreactive T cell development and how the strength of T cell receptor engagement in naïve cells can predispose T cells to develop into effector/memory T cells. The authors lead with solid results that are largely consistent with data in the field suggesting that, in comparison to their counterparts with relatively lower basal self-reactivity, naive CD5hi CD8 T cells in non-obese diabetic (NOD) mice are poised for activation. They propose that diabetogenic T cells are preferentially found among the naive CD5hi CD8 T cell population. While the evidence does not fully support all the authors' conclusions, the data provide a foundation that sets up future studies.

eLife Assessment

This important study demonstrates that in Drosophila melanogaster, tachykinin (Tk) expression is regulated by the microbiota. The authors present convincing evidence that axenic flies raised with no microbiota are longer-lived than conventionally reared animals, and that Tk expression and Tk receptors in the nervous system are required for this effect. They further test individual bacterial strains for their role in these effects and connect the effect to loss of lipid stores and suggest that FOXO may be involved in the phenotype, results that are of interest to the fields of environmental perception, host microbiome interactions, and geroscience.

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

eLife Assessment

In this important manuscript, the authors establish a vertebrate model for studying the development of circuits that control heart rate. This contribution uses a combination of experimental techniques to provide compelling information for scientists looking to understand how heart rate regulation emerges during development.

eLife Assessment

This paper presents an important advance in genetically encoded voltage imaging of the developing zebrafish spinal cord in vivo, capturing voltage dynamics in neuronal populations, single cells, and subcellular compartments inaccessible to patch clamp, and diverse spike waveforms and subthreshold voltage dynamics inaccessible to calcium imaging. The work identifies a developmental progression from irregular voltage fluctuations to coordinated contralateral and ipsilateral activity, providing insight into how electrical dynamics and cellular morphology evolve during circuit formation. The strength of evidence is solid, with imaging data supporting the main conclusions, although the manuscript would be strengthened by more complete methodological documentation and clearer context relative to earlier calcium imaging studies. Overall, this study provides a resource that is of importance for researchers investigating neural development and circuit assembly, illustrating the value of voltage imaging as a general tool for probing bioelectric mechanisms in morphogenesis and circuit development.

eLife Assessment

This study presents a valuable and practical approach for one-photon imaging through GRIN lenses. By scanning a low numerical aperture (NA) beam and collecting fluorescence with a high NA, the method expands the usable field of view and yields clearer cellular signals. The evidence is solid overall, with strong qualitative demonstrations, but some claims would benefit from additional quantitative tests. The work will interest researchers who need simple, scalable tools for large‑area cellular imaging in the brain.

eLife Assessment

This study provides a valuable advance in understanding how decision boundaries may change over time during simple choices by introducing a method that uses information about non-decision components to improve parameter estimates. The evidence supporting the main claims is convincing, with clear demonstrations on simulated and real data, although additional model comparison work would further strengthen confidence. The findings will be of interest to researchers studying human decision processes and the methods used to analyse them.

eLife Assessment

This study provides important evidence that myristate, a fatty acid commonly present in soil environments, is taken up by arbuscular mycorrhizal fungi during symbiosis with a plant host. The evidence presented is solid, with multiple experimental approaches including stable isotope tracing, transcriptional analysis, and physiological measurements across different plant species and phosphorus conditions. However, the main claims are only partially supported.

eLife Assessment

This important study reports on the relationships between cerebral haemodynamics and a number of factors that relate to genetics, lifestyle, and medical history using data from a large cohort. Compelling evidence suggests that brief arterial spin labelling MRI acquisition can lead to both expected observations about brain health, as manifested in cerebral blood flow, and biomarkers for use in diagnosis and treatment monitoring. The results can be used as a starting point for hypothesis generation and further evaluation of conditions expected to affect haemodynamics in the brain.

eLife Assessment

This valuable study uses state-of-the-art neural encoding and video reconstruction methods to achieve a substantial improvement in video reconstruction quality from mouse neural data. It provides a convincing demonstration of how reconstruction performance can be improved by combining these methods. The goal of the study was improving reconstruction performance rather than advancing theoretical understanding of neural processing, so the results will be of practical interest to the brain decoding community.

eLife Assessment

This important study demonstrates the significance of incorporating biological constraints in training neural networks to develop models that make accurate predictions under novel conditions. By comparing standard sigmoid recurrent neural networks (RNNs) with biologically constrained RNNs, the manuscript offers compelling evidence that biologically grounded inductive biases enhance generalization to perturbed conditions. This manuscript will appeal to a wide audience in systems and computational neuroscience.

eLife Assessment

This valuable study explores the role of the chromatin regulator ATAD2 in mouse spermatogenesis. The data convincingly demonstrate that ATAD2 is essential for proper chromatin remodeling in haploid spermatids, influencing gene accessibility, H3.3-mediated transcription, and histone eviction. Using Atad2 knockout (KO) mice, the authors link ATAD2 to the DNA-replication-independent incorporation of sperm-specific proteins like protamines and histone H3.3. Although the findings highlight chromatin abnormalities and impaired in vitro fertilization in KO mice, natural fertility remains unaffected, suggesting possible in vivo compensatory mechanisms. Future experiments will be needed to tease out the precise molecular role of ATAD2 in spermatogenesis. This work will be of interest to the epigenetics and developmental fields.

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. The data presented are solid and the study will be of interest to those studying protein and metabolic regulation.

eLife Assessment

This fundamental study provides new evidence of a change in how microglia survey neurons during the chronic phase of neurodegeneration, which researchers studying neuroinflammation and its role in neurodegenerative disease should find interesting. In this research, using time-lapse imaging of acute brain slices from prion-affected mice, the researchers show that, unlike in healthy brains, microglia become reactive, lose their territorial boundaries, and become highly mobile, exhibiting "kiss-and-ride" behavior, migrating into brain tissue and forming reversible, transient body-to-body contact with neurons. The evidence is compelling, with well-executed time-lapse imaging, good quantitative analysis across several disease stages, pharmacological validation of P2Y6 involvement, and the very surprising finding that this mobile behavior persists after microglia are removed from the brain.

eLife assessment

This important work is the first to suggest a model that the nematode C. elegans prefers specific bacteria (its major food source) that release high amounts of the known attractant isoamyl alcohol when supplemented with exogenous leucine and has also identified a likely receptor for the odorant isoamyl alcohol. The evidence supporting the claims of the authors is solid, and the manuscript would be improved by changes to the text that clarify and address the distinction between "supplemented" versus "enriched". The renaming of srd-12 to snif-1 should also be addressed.

eLife Assessment

This important study characterized and identified clonal MSC populations from human synovium. The authors provide convincing evidence that clonal MSC populations can be isolated and expanded from both normal and osteoarthritic synovium and that CD47 represents a potential marker for improved chondrogenic potential of MSC sub-populations. These findings could provide new avenues for osteoarthritis treatment in the future and deeper mechanistic understanding of the factors involved in the repair.

eLife Assessment

In the gram-positive model organism Bacillus subtilis, the membrane associated ParA family member MinD, concentrates the division inhibitor MinC at cell poles where it prevents aberrant division events. This important study presents compelling data suggesting that polar localization of MinCD is largely due to differences in diffusion rates between monomeric and dimeric MinD. This finding is exciting as it negates the necessity for a third, localization determinant, in this system as has been proposed by previous investigations.

eLife Assessment

Ge et al here report a structural study of the native tripartite multidrug efflux pump complexes from Escherichia coli that identifies a novel accessory subunit, YbjP, the structure of the native TolC-YbjP-AcrABZ complex, as well as structures of the AcrB protein in L, T, and O conformations. The strength of the structural data is compelling, and the importance of the findings is potentially fundamental. However, additional analysis and comparison with pre-existing data would help to put the obtained data and its impact in the proper context, and the inclusion of functional data would help to substantiate some claims that are currently incompletely supported.

eLife Assessment

This important study identifies PRRT2 as an auxiliary regulator of Nav channel slow inactivation, proposing that PRRT2 facilitates entry into, and delays recovery from, the slow-inactivated state. The evidence provided is compelling and well executed, though the work would be bolstered by additional studies of Nav1.6, as well as structural studies to directly investigate the molecular basis of gating modulation. Overall, this study will be of interest to ion channel biophysicists and neurophysiologists, particularly those studying channelopathies.

eLife Assessment

This important study fills a major geographic and temporal gap in understanding Paleocene mammal evolution in Asia and proposes an intriguing "brawn before bite" hypothesis grounded in diverse analytical approaches. However, the findings are incomplete because limitations in sampling design - such as the use of worn or damaged teeth, the pooling of different tooth positions, and the lack of independence among teeth from the same individuals - introduce uncertainties that weaken support for the reported disparity patterns. The taxonomic focus on predominantly herbivorous clades also narrows the ecological scope of the results. Clarifying methodological choices, expanding the ecological context, and tempering evolutionary interpretations would substantially strengthen the study.

eLife Assessment

This Review Article explores the intricate relationship between humans and Mycobacterium tuberculosis (Mtb), providing an additional perspective on TB disease. Specifically, this review focuses on the utilization of systems-level approaches to study TB, while highlighting challenges in the frameworks used to identify the relevant immunologic signals that may explain the clinical spectrum of disease. The work could be further enhanced by better defining key terms that anchor the review, such as "unified mechanism" and "immunological route." This review will be of interest to immunologists as well as those interested in evolution and host-pathogen interactions.

eLife Assessment

This important study describes the progressive transformation of olfactory information across five different brain regions in the olfactory pathway, including a comparison of responses to familiar and unfamiliar odors. This dataset is of broad interest for olfactory researchers and provides a solid analysis of a graded change in representations of odor identity and experience in different locations in the pathway.

eLife Assessment

This work provides a fundamental molecular mechanism of how a single enzyme can coordinate the ordered assembly of hyaluronan, a complex polysaccharide, from two different building blocks in an alternating pattern. The authors present compelling evidence by combining high-resolution structural data with rigorous biochemical validation to define the underlying process. Major strengths of the study include the clarity and coherence of the mechanistic insights and the complementary use of structural and functional approaches to address the research question.

eLife Assessment

This valuable study addresses a question related to how we achieve visual stability across saccadic eye movements. The authors' gaze-contingent fMRI design provides convincing evidence that peripherally presented visual stimuli are represented in foveal visual cortex prior to a saccade. The results will be of interest to vision scientists and behavioural neuroscientists.

eLife Assessment

The development of glmSMA represents a valuable advancement in spatial transcriptomics analysis, offering a mathematically robust regression-based approach that achieves higher-resolution mapping of single-cell RNA sequencing data to spatial locations than existing methods. The evidence is convincing, as the authors demonstrate the method's superiority by formulating it as a convex optimization problem that ensures stable solutions, coupled with successful validation across multiple biological systems. The rigorous mathematical framework and validation across diverse tissues enable precise spatial mapping of cellular heterogeneity at enhanced resolution.

eLife Assessment

This valuable study investigates the relationship between pupil dilation and information gain during associative learning, using two different tasks. A key strength of this study is its exploration of pupil dilation beyond the immediate response period, extending analysis to later time windows after feedback, and it provides convincing evidence that pupillary response to information gain may be context-dependent during associative learning. The interpretation remains limited by task heterogeneity and unresolved contextual factors influencing pupil dynamics, but a range of interesting ideas are discussed.

eLife Assessment

This study identifies 53BP1 as an interaction partner of GMCL1 (a likely CUL3 substrate receptor). The study proposes a novel mechanism by which cancer cells evade the mitotic surveillance pathway through GMCL1-mediated degradation of 53BP1, leading to reduced p53 activation and paclitaxel resistance. These data are the most useful aspect of the study, but the data supporting the authors' conclusions as to the clinical relevance of the study are inadequate. The authors have not taken relevant data about the clinical mechanism of taxanes into account.

eLife Assessment

This study presents a valuable advance in reconstructing naturalistic speech from intracranial ECoG data using a dual-pathway model. The evidence supporting the claims of the authors is solid, although the rationale for employing a smaller language model rather than a large language model (LLM) should be further clarified. This work will be of interest to cognitive neuroscientists and computer scientists/engineers working on speech reconstruction from neural data.

eLife Assessment

This fundamental study provides compelling evidence for the functional segregation of the sensorimotor cortex into precisely delineated areas, and highlights a rapid transition in functional properties at the boundaries between these areas. This result further confirms and extends recent work on the diversity of neural response specificities across cortical areas in the context of complex behavioral tasks. This work will be of interest to neuroscientists studying sensory-motor functions.

eLife Assessment

The authors present evidence for a WIPI2-Retriever complex (termed CROP2) that couples cargo selection to carrier fission at endosomes. CROP2 appears to function analogously to the previously described CROP1 complex, formed by WIPI1 and Retromer, with which it shares structural similarities. They provide convincing evidence that CROP1 and CROP2 regulate the trafficking of distinct subsets of cargoes; however, the cellular evidence for the existence of these distinct complexes remains incomplete. Overall, the findings are important and expand our understanding of how cargo selection by Retriever and Retromer is orchestrated at endosomes.

eLife Assessment

This study reports a valuable method to predict the capacity of a candidate probiotic bacterium to metabolically outcompete a bacterial pathogen in the ecological niche of the murine respiratory tract (niche exclusion) based on the overlap of used carbon sources in vitro. The in vivo confirmation of the in vitro/in silico predicted efficacy is, at this stage, incomplete and would require more persuasive experimental evidence for the elimination of alternative mechanisms of action.

eLife Assessment

This is an overall compelling set of findings on the role of centrally produced estrogens in the control of behaviors in male medaka. The significance of the findings rests on the revealed potential mechanism between brain derived estrogens modulating social behaviors in males , supported by the analysis of multiple transgenic lines. The evidence for the broader claim is incomplete since it has not been extended to female medaka, and further experimentation would be necessary to fully validate the conclusions on the role of brain-derived estrogens. Nonetheless, the findings have led to important hypotheses on the hormonal control of behaviors in teleosts that can be tested further.

eLife Assessment

This paper describes a useful Bayesian model to estimate the probabilities of access, use, and use given access of insecticide-treated bed nets (ITNs), by using sub-national cross-sectional survey data and the annual number of ITNs received at the country level. The authors provide convincing evidence to support their modeling approach, which could be enhanced by more validation and exploration of model assumptions.

eLife Assessment

The authors provide a useful integrated analytical approach to investigating MASLD focused on diverse multiomic integration methods. The strength of evidence for this new resource is solid, as analyses highlight the importance of previously-described pathophysiologic processes, as well as unveil several new mechanisms as key features of MASLD in obese patients.

Summary: Defines segmentation as a tool for managing cognitive processing, supporting the claim that structure is necessary for the reader (consumer) to handle the flow of information.

This helps to simplify the approach for those learning a new language, and reduces cognitive load.

eLife Assessment

Argunşah et al. investigate the mechanisms underlying the differential response dynamics of barrel vs septa domains in shaping the responses to single vs multiple whiskers. Based on the observation of a higher density of SST+ interneurons in the septa, the authors investigate the hypothesis that Elfn1-dependent short-term plasticity shapes these responses. This important study is, however, supported by incomplete evidence; factors restricting the strength of evidence are the limited spatial resolution of the multi-unit activity, as well as the lack of a mechanistic explanation. This provocative and intellectually stimulating hypothesis provides a contribution to work on how different cell types shape cortical representation.

eLife Assessment

This important manuscript provides insights into the competition between Splicing Factor 1 (SF1) and Quaking (QKI) for binding at the ACUAA branch point sequence in a model intron, regulating exon inclusion. The study employs convincing, rigorous transcriptomic, proteomic, and reporter assays, with both mammalian cell culture and yeast models.

eLife Assessment

The study presents convincing quantitative evidence, supported by appropriate negative controls, for the presence of low-abundance glycine receptors (GlyRs) within inhibitory synapses in telencephalic regions of the mouse brain. Using sensitive single-molecule localization microscopy of endogenously tagged GlyRs, the authors reveal previously undetected populations of these receptors. Although the functional significance of these low-abundance GlyRs remains to be established, the findings offer valuable insights and methodologies that will be of interest to neuroscientists studying inhibitory synapse biology.

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

eLife Assessment

This important study characterizes with rigorous methodology anatomical and functional aspects of the peripheral innervation of the Drosophila male reproductive tract. The convincing analysis reveals two distinct types of glutamatergic neurons that co-release either serotonin or octopamine. While serotonergic neurons are required for male fertility, octopaminergic neurons are dispensable. The work is providing invaluable insight into neurochemical control of insemination, peripheral motor control and neuromodulation in the male reproductive tract.

eLife Assessment

The authors employ an unbiased, affinity-guided reagent to label P2X7 receptor and use super-resolution imaging to monitor P2X7 redistribution in response to inflammatory signaling. The evidence is convincing and the study will be valuable to those studying the dynamics of receptor distribution and clustering.

eLife Assessment

This fundamental manuscript provides compelling evidence that BK and CaV1.3 channels can co-localize as ensembles early in the biosynthetic pathway, including within the ER and Golgi. The findings, supported by a range of imaging and proximity assays, offer insights into channel organization in both heterologous and endogenous systems. The data substantiate the central claims, while highlighting intriguing mechanistic questions for future studies: the determinants of mRNA co-localization, the temporal dynamics of ensemble trafficking, and the physiological implications of pre-assembly for channel function at the plasma membrane.

eLife Assessment

This study investigates how the HIV inhibitor lenacapavir influences capsid mechanics and interactions with the nuclear pore complex. It provides important insights into how drug-induced hyperstabilization of the viral shell can compromise its structural integrity during nuclear entry. While the modeling is technically sophisticated and the results are promising, some mechanistic interpretations rely on assumptions embedded in the simulations, leaving parts of the evidence incomplete.

eLife Assessment

This study offers valuable insights into the anatomical and physiological features of cold-selective lamina I spinal projection neurons. The evidence supporting the authors' claims is compelling, although including a larger sample size and more quantification would have strengthened the study further, and the claims of monosynaptic connectivity would benefit from being stated more cautiously. The work will interest those in the field of somatosensory biology, especially researchers studying spinal cord dorsal horn circuits and projection neuron cell types.

eLife Assessment

This important work advances our understanding of the single neuron coding types in the mouse gustatory cortex and the functional roles of these neurons for perceptual decision-making. The conclusions are based on compelling evidence from rigorous behavioral experiments, high-density electrophysiology, sophisticated data analysis, and neural network modeling with in silico perturbations of functionally-identified units. This work will be of broad interest to systems neuroscientists.

eLife Assessment

This valuable 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 convincing, supported by the scale and breadth of the dataset and the systematic structural analysis, although some of the assumptions made in the 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 valuable study shows that combining reactivation-based training with anodal tDCS yields an unusually broad generalization of visual perceptual learning, while preserving robust learning gains and markedly reducing total training time. Although the empirical evidence is solid, the proposed mechanistic account, i.e., the GABA modulation, disrupted offline consolidation and reduced perceptual overfitting, remains insufficiently substantiated, as these assumptions lack direct neurochemical support, and several alternative behavioral explanations and necessary control comparisons have not been fully addressed. The work will be of broad interest to researchers investigating brain plasticity, perceptual learning, and rehabilitation training.

eLife Assessment

This important study establishes the first vertebrate models of DeSanto-Shinawi Syndrome, revealing conserved craniofacial and social and behavioral phenotypes across mouse and zebrafish that mirror key clinical features. The solid evidence is supported by behavioral, anatomical, and molecular analyses of Wac animal mutants that broadly support the authors' claims, though additional mechanistic investigation would strengthen the conclusions. This study sets a baseline for future mechanistic studies and reports a platform to test approaches to reverse phenotypes.

eLife Assessment

This fundamental study reports solid evidence for early verbal episodic memory formation. The findings demonstrate that speaker identity is a crucial feature, enabling episodic-like memories from birth, and will be of interest to cognitive neuroscientists working on brain development, memory, language learning and social cognition.

eLife Assessment

This study offers a valuable contribution to understanding how working memory (WM) shapes neural processing in extrastriate cortex. By applying spectral decomposition to LFP recordings from primate middle temporal area (MT) during a spatial WM task, the authors show that lower-frequency components (theta, alpha, and beta, but not gamma or high-gamma) correlate with trial-by-trial gain modulation of visually evoked responses. However, certain aspects of the gain-modulation and statistical analyses are incomplete. A clearer and more comprehensive description of these components would substantially strengthen the manuscript.

eLife Assessment

This fundamental work substantially advances our understanding of episodic memory by proposing a biologically plausible mechanism through which hippocampal barcode activity enables efficient memory binding and flexible recall. The evidence supporting the conclusions is convincing, with rigorously validated computational models and alignment with experimental findings. The work will be of broad interest to neuroscientists and computational modelers studying memory and hippocampal function.

eLife Assessment

This paper presents fundamental research showing that the acquisition and expression of Pavlovian conditioned responding are lawfully related to temporal characteristics of an animal's conditioning experience. It showcases a rigorous experimental design, several different approaches to data analysis, careful consideration of prior literature, and a thorough introduction. The evidence supporting the conclusions is compelling. The paper will have a general appeal to those interested in the behavioral and neural analysis of Pavlovian conditioning.

eLife Assessment

The study presents valuable findings of an optimized E. coli cell-free protein synthesis (eCFPS) system that has been simplified by reducing the number of core components from 35 to 7; furthermore, the findings communicate a simplified 'fast lysate' preparation that eliminates the need for traditional runoff and dialysis steps. This study is an advance towards simplifying protein expression workflows, and the evidence provided is solid, starting with nanoluc, a protein that expresses readily in many systems, to applications to more challenging proteins like the functional self-assembling vimentin and the active restriction endonuclease Bsal. Data on the underlying mechanisms and efficiency of the presented system in terms of protein yield relative to other known cell-free systems would greatly enhance the findings' significance and the strength of the evidence. The paper remains of interest to scientists in microbiology, biotechnology and protein synthesis.

eLife Assessment

This study provides important evidence for the mechanism underlying KCNC1-related developmental and epileptic encephalopathy. The authors have generated and characterized a new knock-in mouse with a pathogenic mutation found in patients to determine the synaptic and circuit mechanisms contributing to KCNC1-associated epilepsy. They provide convincing evidence for reduced excitability of parvalbumin-positive fast-spiking interneurons, but not in neighboring excitatory neurons, and suggest that this may contribute to seizures and premature death in the mice.

eLife Assessment

This valuable study provides solid evidence that supports TANGO2 homologs, including HRG-9 and HRG-10, can play a role in cellular bioenergetics and oxidative stress homeostasis. It also challenges the previously reported role of TANGO in heme transport and paves the way for future mechanistic studies addressing the mechanisms of how TANGO2 regulates oxidative stress homeostasis. The strengths include the use of different model systems, genetic tools, behavioral assays and efforts by the authors in using the same reagents to reproduce results of other groups.

eLife Assessment

This important study presents an impressive large-scale effort to assess the reproducibility of published findings in the field of Drosophila immunity. The authors analyse 400 papers published between 1959 and 2011, and assess how many of the claims in these papers have been tested in subsequent publications. In a companion article they report the results of experiments to test a subset of the claims that, according to the literature, have not been tested. The present article also explores if various factors related to authors, institutions and journals influence reproducibility in this field. The evidence supporting the claims is solid, but there is considerable scope for strengthening and extending the analysis. The limitations inherent to evaluating reproducibility based on the published literature should also be acknowledged.

eLife Assessment

This study introduces an important approach using selection linked integration (SLI) to generate Plasmodium falciparum lines expressing single, specific surface adhesins PfEMP1 variants, enabling precise study of PfEMP1 trafficking, receptor binding, and cytoadhesion. By moving the system to different parasite strains and introducing an advanced SLI2 system for additional genomic edits, this work provides compelling evidence for an innovative and rigorous platform to explore PfEMP1 biology and identify novel proteins essential for malaria pathogenesis including immune evasion.

eLife Assessment

This study resolves a cryo-EM structure of the GPCR, human GPR30, which responds to bicarbonate and regulates cellular responses to pH and ion homeostasis. Understanding the ligand and the mechanism of activation is important to the field of receptor signaling and potentially facilitates drug development targeting this receptor. Structures and functional assays provide solid evidence for a potential bicarbonate binding site.

eLife Assessment

The authors present an important approach to identify imported P. falciparum malaria cases, combining genetic and epidemiological/travel data. This tool has the potential to be expanded to other contexts. The data was analyzed using convincing methods, including a novel statistical model. This study may be of interest to researchers in public health and infectious diseases beyond malaria.

eLife Assessment

This study presents an important finding that has identified 27 differentially methylated regions as a signature for non-invasive early cancer detection and predicting prognosis for colorectal cancer. The findings demonstrate promising clinical potential, particularly for improving cancer screening and patient monitoring. In general, the evidence supporting the claims of the authors is solid. A larger sample size will be key to further improving this work in the future. The work will be of interest to researchers interested in cancer diagnosis or colorectal cancer monitoring.

eLife Assessment

This study identifies the uncharacterised protein FAM53C as a novel, potential regulator of the G1/S cell cycle transition, linking its function to the DYRK1A kinase and the RB/p53 pathways. The work is valuable and of interest to the cell cycle field, leveraging a strong computational screen to identify a new candidate. The findings are solid, although confidence in the siRNA depletion phenotypes would have been higher with rescue experiments using an siRNA-resistant cDNA and more robust quantification of some immunoassay data.

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

eLife Assessment

This fundamental work examines how tRNA modifications influence antibiotic tolerance, providing novel insights that may have therapeutic uses. The evidence supporting the conclusions is convincing. Strengths of the manuscript include the mechanism of tRNA modification influencing antibiotic tolerance and the precise measurement techniques used throughout. Further analysis of growth rate impacts and specific identification of the proteins responsible for the effect would further strengthen the manuscript.

eLife Assessment

This valuable study examines how mammals descend effectively and securely along vertical substrates. The conclusions from comparative analyses based on behavioral data and morphological measurements collected from 21 species across a wide range of taxa are convincing, making the work of interest to all biologists studying animal locomotion.

eLife Assessment

This valuable study identifies asymmetric dimethylarginine (ADMA) modification of histones as a potential key determinant of the initial genomic binding of Rhino, a Drosophila-specific chromatin protein essential for piRNA cluster specification. The authors provide correlative genomic and imaging data to support their model, although functional validation of the proposed mechanism remains incomplete. Testing the redundancy between dART4 and dART1, which together could affect the prominent piRNA loci, in addition to the minor ones investigated in the manuscript, may change our assessment.

eLife Assessment

This useful study presents the potentially interesting idea that LRRK2 regulates cellular BMP levels and their release via extracellular vesicles, with GCase activity further modulating this process in mutant LRRK2-expressing cells. However, some of the evidence supporting these conclusions remains incomplete, and additional work is suggested under certain conditions. Overall, the study will be of interest to cell biologists working on Parkinson's disease.

eLife Assessment

This study presents important findings describing the early assembly of vascular basement membrane and how vascular cells switch from responding to cues provided by the external environment to those provided by self-assembled basement membrane. The evidence supporting the claims of the authors is convincing, with state-of-the-art microscopy and several different culture conditions examined. The work will be of interest to cell biologists studying the ECM, vascular development, as well as medical scientists focused on diseases that depend on vascular growth.

eLife Assessment

Amyotrophic lateral sclerosis (ALS) affects nerve cells in the brain and spinal cord. The authors' approach to use genetic code expansion to tag two ALS proteins associated with stress granules has value and should be useful in the ALS field. Parts of the work are well done, but there are concerns that the evidence is incomplete overall, and additional controls would strengthen the study.

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

This is a valuable study that combines biophysical and evolutionary approaches to understand why particular mutations in the SARS-CoV-2 protein N arose during the COVID-19 pandemic. The evidence is solid and supports the conclusions.