eLife Assessment

This manuscript presents a valuable investigation of the peptidoglycan (PG) recycling pathway in Caulobacter crescentus. The authors showed that PG recycling in C. crescentus is essential not only for β-lactam (ampicillin) resistance but also for cell morphology, efficient division, and overall fitness. The study is comprehensive and compelling.

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, which is supported through compelling evidence, has implications beyond animal tracking, potentially connecting with advances in behavioral analysis and computer vision.

eLife Assessment

Karimian et al. present a valuable new model to explain how gamma-band synchrony (30-80 Hz) can support human visual feature binding by selectively grouping image elements, countering recent criticisms that the stimulus dependence of gamma oscillations limits their functional role. Grounded in the theory of weakly coupled oscillators the model captures behavioural patterns observed in human psychophysics, offering support for the potential role of synchrony-based mechanisms in feature-binding. The development of the model in alignment with primate electrophysiology convincingly supports the paper's claims that gamma synchrony may be the underlying mechanism. While the paper does not present electrophysiological results that directly link gamma oscillations to figure-ground segregation in the presented task, the model makes several predictions that can be tested experimentally.

eLife Assessment

This important study provides a nuanced analysis of the impact of cues on cost/benefit decision-making deficits in male rats that could have translational relevance to many addictive disorders. The main findings are that cues paired with rewarded outcomes increase the proportion of risky outcomes, whereas risky choice is reduced when cues are paired with reward loss. The experimental data are compelling, whereas the computational analysis based on the optimisation of different Q-learning models is solid. The findings will be of interest to behavioural neuroscientists and clinicians with an interest in risk, decision making, and gambling disorders.

eLife Assessment

This study provides a useful analysis of the changes in chromatin organization and gene expression that occur during the differentiation of two cell types (anterior endoderm and prechordal plate) from a common progenitor in zebrafish, together with investigations into the molecular factors involved. Although the findings are consistent with previous work, the evidence presented appears to be incomplete and would benefit from more rigorous quantification of live imaging and Cre-Lox experiments, a stronger rationale and controls for experiments manipulating chromatin remodeling factors, and a strong justification for the explant model especially given differences between explant and whole embryo data. This work may be of interest to zebrafish developmental biologists investigating the mechanisms underlying specification.

eLife Assessment

This important study investigates how the Cdv division proteins of Metallosphaera sedula assemble on and interact with curved membranes in vitro, advancing our understanding of this reduced ESCRT-like machinery. The data provide support for sequential protein recruitment and curvature-dependent enrichment at membrane necks, based on well-controlled reconstitution assays and quantitative analysis. The work establishes a convincing experimental framework for dissecting Cdv-mediated membrane remodeling. The study will be of broad interest to evolutionary and synthetic biologists as well as membrane biophysicists.

eLife Assessment

This study systematically characterizes the activity patterns of a lateral supramammillary nucleus (SuM)-medial septum (MS)-hippocampus circuit across sleep-wake cycles and its role in memory consolidation. This work is fundamental because it identifies a previously unrecognized brain hub that helps coordinate how different types of memory are supported during a specific sleep state, advancing our understanding of how sleep contributes to memory organization. The work is well-designed, and the data are solid, supporting clear and significant conclusions; however, some mechanistic details and causal relationships would benefit from further clarification or additional experiments. The paper provides new insights into how distinct memory modalities could be processed by parallel, sleep-active subcortical-hippocampal circuits, which would be of general interest to a broad neuroscience audience.

eLife Assessment

This paper describes an important advance in a 2D in vitro neural culture system to generate mature, functional, diverse, and geometrically consistent cultures, in a 384-well format with defined dimensions and the absence of the necrotic core, which persists for up to 300 days. The well-based format and conserved geometry make it a promising tool for arrayed screening studies. The evidence is compelling and provides a method for generating consistent 3D cortical layer-like organization.

eLife Assessment

This study presents a valuable finding on the neural representation of time from two distinct egocentric and allocentric reference frames. The evidence is solid and largely supports the hypothesis, with one caveat that the task differences could impact the observed effects. The work will be of interest to cognitive neuroscientists working on the perception and memory of time.

eLife Assessment

The study provides important mechanistic insight into the transcriptional control of γδT17 development, elegantly demonstrating how HEB and Id3 act sequentially and cooperatively to regulate γδT17 cell specification and maturation. The study provides compelling evidence that advances the understanding of E-Id protein dynamics in thymic T cell specification. The work is comprehensive, technically rigorous, and conceptually clear, and will be of interest to immunologists, developmental biologists, and those studying the molecular underpinnings of physiological outcomes.

eLife Assessment

This important study examines the role of TNF in modulating energy metabolism during parasite infection. The authors perform an elegant set of studies, however the evidence supporting the major claims of the manuscript is incomplete, particularly in highlighting a direct role for GLUT1 in monocytes. This work integrates an interesting set of observations that will be of interest to the Plasmodium and pathogenesis communities with an expanded set of experiments.

eLife Assessment

This study presents a valuable finding on how the GAP DLC1, a deactivator of the small GTPase RhoA, regulates RhoA activity globally as well as at Focal Adhesions. Using a new acute optogenetic system coupled to a RhoA activity biosensor, the authors present convincing evidence that DLC1 amplifies local Rho activity at Focal Adhesions. Thanks to modeling, they show that DLC1 is needed for a negative feedback loop that engage more RhoA deactivators upon RhoA activation, highlighting the complex regulation of RhoGTPases in space and time.

eLife Assessment

This study represents an important advance in our understanding of how certain inhibitors affect the behavior of voltage gated potassium channels. Robust molecular dynamics simulation and analysis methods lead to a new proposed inhibition mechanism with strength of support being mostly convincing, though computational evidence is limited for some conformations discussed. This study has considerable significance for the fields of ion channel physiology and pharmacology and could aid in development of selective inhibitors for protein targets.

eLife Assessment

Using a transposon sequencing (TN-seq) approach, the authors identified key genetic determinants of drug tolerance in Mycobacterium abscessus. Given that M. abscessus is inherently resistant to multiple antibiotics, this valuable study makes a significant contribution by uncovering how antibiotic tolerance is linked to reactive oxygen species (ROS) in this non-tuberculous mycobacterial (NTM) species. The solid findings further strengthen the growing evidence that ROS play a central role in the mechanism of antibiotic action and tolerance in mycobacteria. However, the use of words persistence or tolerance should follow the consensus definition given in the Balaban 2019 Nat Rev Micro paper.

eLife Assessment

This important study analyzed the impact of amino acid homorepeats on protein expression and solubility in yeast and E. coli. The authors provided convincing evidence that hydrophobic and positively charged amino acids are toxic and that counterselection during evolution reduced the occurrence of such proteotoxic protein sequences. This study will be of interest to cell biologists and biochemists, particularly those working on proteostasis.

eLife Assessment

This valuable study identifies a novel neurodevelopmental syndrome caused by variants in ARID5B, supported by solid human genetic evidence from a well-characterized cohort. While the clinical data establish a clear genotype-phenotype correlation, the functional evidence regarding the proposed molecular mechanisms remains incomplete. Addressing the gaps in the functional characterization and refining the clinical assertions would significantly strengthen the conclusions.

eLife Assessment

This study presents important findings by identifying small molecules that can stabilize and refold missense-mutated VHL tumor suppressor protein, offering a potential therapeutic approach for clear cell renal cell carcinoma. The computational design approach is well-executed, but the evidence is incomplete due to insufficient demonstration that HIF2 downregulation occurs through on-target VHL rescue rather than off-target effects. Additional experiments with appropriate controls are needed to establish the specificity of the mechanism.

eLife Assessment

This important study advances our understanding of developmental timing mechanisms by studying the cleavage, nuclear translocation, and oscillation of the transcription factor MYRF-1 (vertebrate MYRF) during C. elegans larval development. The evidence supporting the conclusions is solid, with elegant genome engineering experiments and state-of-the-art microscopy. The work will be of broad interest to cell and developmental biologists.

eLife Assessment

This manuscript by Feng et al. provides valuable evidence regarding the hematopoietic differentiation of bone marrow endothelial cells in the adult mouse. Overall, the authors have addressed our main concerns. Solid data now more strongly support long-term multi-lineage reconstitution of the adult hemogenic endothelial cells. However, critical data, especially regarding the endothelial cells' hematopoietic identity and functional capacity, remain insufficient, which limits the strength of the hemogenic claim, especially the assertion that these adult hemogenic ECs generate bona fide HSCs. Additional experiments would be necessary to fully rule out alternative explanations.

eLife Assessment

This study provides valuable insights into addressing the question of whether the prevalence of autoimmune disease could be driven by sex differences in the T cell receptor (TCR) repertoire, correlating with higher rates of autoimmune disease in females. The authors compared male and female TCR repertoires using bulk RNA sequencing, from sorted thymocyte subpopulations in pediatric and adult human thymuses; however, the analyses provided do not provide sufficient discrimination and incompletely support the central claims regarding sex differences in the TCR repertoire and potential autoimmune bias.

eLife Assessment

This fundamental study investigates whether neural prediction of words can be measured through pre-activation of neural network word representations in the brain; convincing evidence is provided that neural network representations of neighboring words are correlated in natural language. This study urges future studies to carefully differentiate between neural activity that predicts the upcoming word and neural activity that encodes the current words, which contain information that can be used to predict the upcoming word. The study is of potential interest to researchers investigating language encoding in the brain or in large language models.

eLife Assessment

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

eLife Assessment

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. The data supporting the precise neurobiological basis of these effects however, remains incomplete.

eLife Assessment

This important study introduces LUNA, a new autofocusing method that achieves nanoscale precision and robustly corrects focus drift during time-lapse microscopy, improving imaging under temperature shifts. The authors exploit this technical advance to investigate the bacterial cold shock response, providing solid evidence that individual cells continue to grow and divide in a highly coordinated process that cannot be observed in population-level measurements. This work offers a technical and conceptual framework for reconciling discrepancies between bulk and single-cell growth measurements, with broad relevance for cell biology and microbiology.

eLife Assessment

This valuable study introduces MPS, an open-source pipeline that addresses a significant technical bottleneck by making miniscope data analysis more accessible. Characterized by speed and a low barrier to entry, the software's performance is supported by solid evidence. This work will be of interest to miniscope users seeking a streamlined, memory-efficient, end-to-end analysis solution.

eLife Assessment

With the goal of investigating the assembly and fragmentation of cellular aggregates, this manuscript examines cyanobacterial aggregates in a laboratory setting. This quantitative investigation of the conditions and mechanisms behind aggregation is an important contribution as it yields a basic understanding of natural processes and offers potential strategies for control. The combination of computational and experimental investigations in this manuscript provides convincing support for the role of shear on aggregation and fragmentation.

eLife Assessment

There is a growing interest in understanding the individuality of animal behaviours. In this important article, the authors build and use an impressive array of high throughput phenotyping paradigms to examine the 'stability' (consistency) of behavioural characteristics in a range of contexts and over time. The results show that certain behaviours are individualistic and persist robustly across external stimuli while others are less robust to these changing parameters. The data supporting their findings is extensive and convincing. At the same time, the main analyses focus on a selected subset of the many behavioural metrics recorded, so a large fraction of the acquired data remains only lightly explored; by making these additional data available, the authors provide an invaluable resource for future work to apply alternative analytical frameworks and further mine this rich dataset.

eLife Assessment

This valuable study advances our understanding of best practices for analyzing population-level data using advanced functional alignment methods. It provides convincing evidence that demographic-specific functional templates improve functional neuroimaging studies that use hyperalignment. This study will be of interest to cognitive neuroscientists, neuroimaging methodologists, and computational researchers with an interest in the human brain.

eLife Assessment

This important study demonstrates that Mycobacterium tuberculosis suppresses protective Th17/IL-17 responses in C57BL/6 mice via a Tbet-dependent mechanism involving the virulence factors ESX-1 and PDIM, as mutants lacking these factors induce significantly higher IL-17-producing CD4 T cells and IL-17A in the lungs compared to wild-type bacteria. The experiments are rigorous and well-designed, combining host knockouts and bacterial mutants to yield solid evidence pointing to cross-regulation between Th1 and Th17 pathways, including reduced IL-23 in draining lymph node dendritic cells. However, some of the data on IFN-γ effects or lymph node-specific mechanisms are incomplete and require deeper mechanistic insight, such as direct T cell transcription factor analysis in lymph nodes and broader host validation, to strengthen the work. Overall, the findings provide insight into how bacterial virulence factors limit Th17 induction, thereby promoting persistence, and will interest immunologists and TB researchers focused on host-pathogen balance and vaccine strategies.

eLife Assessment

This valuable manuscript demonstrates that embryonic exposure to the pesticide chlorpyrifos (CPF) impairs juvenile zebrafish social behavior and sets out to define the underlying mechanism. The authors provide solid evidence that butyrate and class I histone deacetylases are involved, as their modulation rescues the phenotype. However, claims that CPF acts through the microbiome and nitric oxide signaling remain correlative and incomplete. Additional validation would strengthen the intriguing hypotheses raised by this work.

eLife Assessment

This work provides an important modeling-based framework for understanding the processes of temporal integration in the claustrum. These mechanisms could support a broader range of integrative brain function. However, at present, the evidence remains at least in part incomplete, primarily because of over-interpretation of the results and their connection to neurophysiology.

eLife Assessment

This important study combines electrocardiographic (ECG) and heart/torso anatomy data from subjects included in the UK Biobank to analyze sex-specific differences in relationships between those two characteristics. The study has several compelling strengths, including the development of an open-source pipeline for reconstruction and analysis of heart/torso geometry from a large cohort. Nevertheless, technical analysis of the data as presented is incomplete, specifically as it pertains to assessment of co-linearity between regressed parameters, interpretation of regression coefficients for sex and/or presence of myocardial infarction, and discussion of potential roles played by underlying electrophysiological derangements. With improvements to these aspects of the analysis, the paper would be of interest to the cardiovascular research community, especially those studying highly relevant health and treatment disparities arising from sex differences.

eLife Assessment

This fundamental work shows that a history of cocaine self-administration disrupts the orbitofrontal cortex's ability to encode similarities between distinct sensory stimuli that possess identical task information - hidden states. The evidence supporting these conclusions is compelling, with methods and analyses spanning self-administration, a novel 'figure 8' sequential odor task, recordings from 3,881 single units, and sophisticated firing analyses revealing complex orbitofrontal representations of task structure. These results will be of broad interest to psychologists, neuroscientists, and clinicians.

eLife Assessment

This valuable study provides evidence that locus coeruleus activity is coordinated with heart rate during sleep, confirming previous work in mice and humans, with a possible role for sleep-dependent memory consolidation. The claims are supported by solid evidence, although the underlying mechanisms and the predictive value of the correlative dataset would benefit from additional controls. This work will be of interest to neuroscientists focusing on sleep, memory, and autonomic functions.

eLife Assessment

This important study investigates the impact of BRCA1/2 mutations on immunotherapy in lung adenocarcinoma using multi-omics approaches. The detailed genetic analysis of two cancer genes (BRCA1 and BRCA2) demonstrated new roles for these genes in causing the tumor microenvironment in lung cancer. Further experimental explorations of the immune-related changes may still be required. The solid findings of this study provide a foundation for further developing drugs targeting BRCA1/2 in lung cancer therapy.

eLife Assessment

The findings of this study are important since they cover the repurposing of small molecules as metalloprotease and phospholipase inhibitors for early intervention in the treatment of bothropic envenoming in the Neotropics, and thus provide a strong rationale for the progression of these inhibitors into future preclinical and clinical evaluation for snakebite indications across various ecological zones. The strength of the evidence is solid; however, there are some weaknesses, such as a lack of translatability of the in vivo model and insufficient venom characterisation. Thus, the strength of the evidence can be enhanced by the use of a mouse model. The paper remains of interest to ophiologists, biochemists and medicinal chemists.

eLife Assessment

This useful study supplements previous publications of willed attention by addressing a frontoparietal network that supports internal goal generation. The evidence is solid in analyzing two datasets collected at different independent sites, using the same willed-attention paradigm and combining fMRI and EEG. This work will interest cognitive psychologists and neuroscience researchers.

eLife Assessment

This study presents a valuable examination of two measurements of physical activity (self-report and objective) in relation to widely studied structural MRI measures of the brain (hippocampal volume and BrainAGE) and cognitive function (Trail Making Test). Cross-sectional and longitudinal data were analyzed using established and validated methodology. The results convincingly suggest that brain health is more likely a cause of physical activity than an outcome of it, although limitations to the data could mask evidence of benefits to brain health. This work will be of interest to neurologists and epidemiologists studying the etiology of cognitive decline, to clinicians interested in advising patients on strategies for preserving brain health in aging, and to members of the lay public.

eLife Assessment

This study provides valuable contributions to establish canonical Dhh signaling as a primary mediator in the differentiation of Leydig cells and their steroidogenic capacity. Together, the experimental design using their established stem Leydig cell line alongside relevant genetically mutated models, both derived using the relevant Nile tilapia animal system, provided largely convincing evidence to support their conclusions. The work could benefit from a more rigorous dissection of current literature on this pathway that might better inform their conclusions. The work will be of broad interest to developmental biologists interested in differentiation of steroidogenic or hormone producing cells.

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

eLife Assessment

This paper presents a computational method to infer from data a key feature of affinity maturation: the relationship between the affinity of B-cell receptors and their fitness. The approach, which is based on a simple population dynamics model but inferred using AI-powered Simulation-Based Inference, is novel and valuable. It exploits recently published data on replay experiments of affinity maturation. While the method is well-argued and the validation solid, the potential impact of the study is hindered by its complex presentation, which makes it hard to assess its claims reliably.

eLife Assessment

This paper presents a computational method to infer from data a key feature of affinity maturation: the relationship between the affinity of B-cell receptors and their fitness. The approach, which is based on a simple population dynamics model but inferred using AI-powered Simulation-Based Inference, is novel and valuable. It exploits recently published data on replay experiments of affinity maturation. The method is well argued and presented, and the validation is compelling.

eLife Assessment

This valuable manuscript provides solid evidence regarding the role of alpha oscillations in sensory gain control. The authors use an attention-cuing task in an initial EEG study followed by a separate MEG replication study to demonstrate that whilst (occipital) alpha oscillations are increased when anticipating an auditory target, so is visual responsiveness as assessed with frequency tagging. The findings offer a re-interpretation of the inhibitory role of the alpha rhythm, supporting that alpha oscillations contribute to interareal communication.

eLife assessment

The ability to estimate the force of infection for Plasmodium falciparum from other more directly measurable epidemiological quantities is a useful contribution to malaria epidemiology. The authors propose a method to accomplish this using genetic data from the var genes of the Pf genome and novel applications of existing methods from queueing theory. While the simulations are sophisticated, the real-world application of the method is incomplete in its analysis and would benefit from clearer articulation of the assumptions being made. Given the lack of clarity in the methods and presentation of results, it is difficult to fully assess the performance of their proposed estimation procedure.

eLife Assessment

The ability to estimate the force of infection for Plasmodium falciparum from other more directly measurable epidemiological quantities would contribute to malaria epidemiology. The authors propose a method to accomplish this using genetic data from the var genes of the Pf genome and novel applications of existing methods from queueing theory. After revising the manuscript, this is a useful contribution to the field and the authors provide solid evidence to support it.

eLife Assessment

This study provides valuable insights through the elucidation of the first full-length structure of the heterohexameric (MmpS4)₃-(MmpL4)₃ transporter complex from Mycobacterium tuberculosis, advancing understanding of its transport mechanism, linked to virulence and drug resistance. The structural analysis is convincing, offering a clear framework for future mechanistic studies. Major strengths include a comprehensive structural characterization of the complex, though some conclusions require further validation.

eLife Assessment

Maloney et al. offer an important contribution to understanding the potential ecological mechanisms behind individual behavioral variation. By providing compelling theoretical and experimental data, the study bridges the gap between individual, apparently stochastic behavior with its evolutionary purpose and consequences. The work further provides a testable and generalizable model framework to explore behavioral drift in other behaviors.

eLife Assessment

This paper describes useful findings on the effects of isoflurane anesthesia on the visual cortical circuitry of the mouse. It provides solid evidence that the visual spatial frequency sensitivity becomes coarser (lower resolution) during anesthesia, with distinct effects described in excitatory neurons, and parvalbumin (PV) and somatostatin (SOM) positive interneurons. This study should be of interest to neuroscientists studying the mouse visual cortex and the effects of anesthesia on cortical circuitry.

eLife Assessment

This important study experimentally probes potential antibiotic activity against hypothetical "mirror bacteria" with reversed chirality, showing that D-enantiomers of several approved antibiotics largely lack activity against natural bacteria (as a proxy for mirror organisms) and that conjugated D-peptides can elicit strong binding antibody responses in mice when adjuvanted. The evidence is solid for these core observations but incomplete on issues of chiral purity, functional antibody assays, replicates, and pharmacodynamic readouts; the work also overreaches in extrapolations without deeper mechanistic integration or native-format validation. Overall, the work offers a cautious, relevant contribution to mirror microbiology discussions and will interest infectious disease researchers.

eLife Assessment

AIRE has been well known to contribute to immune self-tolerance in the thymus by expressing auto-antigens; in this manuscript, the authors describe unexpected findings about the interaction of AIRE with AID in B cells, and its function in the immune system, thereby contributing to a fundamental understanding of the broader functions of AIRE. The strength of this manuscript is that, by employing biochemical and genetic experiments, the authors convincingly show interaction between AIRE and AID and subsequent AIRE's function in the GC responses. However, two weak points exist: first, the connection between AIRE, auto-anti IL17 Abs, and IL17-positive effector T cells, and second, like the thymus, expression of auto-antigens by AIRE in the GC B cells has not been tested.

eLife Assessment

This study used pupillometry to provide an objective assessment of a form of synesthesia in which people see additional color when reading numbers. It provides convincing evidence that subjective color ratings are matched by changes in pupil size that recapitulate brightness-mediated changes when exposed to the real color. The work provides a valuable contribution to the literature on both synesthetic perception and the use of pupillometry to probe perception and related psychological processes.

eLife Assessment

This study provides an important, comprehensive, large-scale dataset on transcription factor binding in Pseudomonas aeruginosa, along with analyses of its regulatory network, key virulence and metabolic regulators, and a pangenomic examination of transcription factors. Utilizing large-scale ChIP-seq and multi-omics integration, the research convincingly supports the hierarchical regulatory structures and offers insights into virulence mechanisms. This dataset, made available through an online database, should be an invaluable resource to the research community studying P. aeruginosa, a key pathogen at risk for hospital infections and development of antibiotic resistance.

eLife Assessment

This useful study characterizes the evolution of medial prefrontal cortex activity during the learning of an odor-based choice task. The evidence provided is solid, providing quantification of functional classes of cells over the course of learning using the longitudinal calcium recordings in prefrontal cortex, and quantification of prefrontal sequences. However, the experimental design appears to provide limited evidence to support strong conclusions regarding the functional relevance of neural sequences. The study will be of interest to neuroscientists investigating learning and decision-making processes.

eLife Assessment

The authors make an important contribution to comparative functional genomics by developing a semi-automated computational pipeline that integrates classification and marker-based cluster annotation to identify orthologous cell types. Using a single-cell RNA-seq dataset of induced pluripotent stem cells and derived embryonic bodies from four primate species: humans, orangutans, cynomolgus macaques, and rhesus macaques, the authors provide convincing evidence that cell type-specific marker genes are substantially less transferable across species than broadly expressed genes, with transferability declining as phylogenetic distance increases. This study establishes a key framework and reference dataset for comparative single-cell analyses and encourages more rigorous evaluation of marker gene transferability across species.

eLife Assessment

Varani et al present important findings regarding the role of distinct cerebellothalamic connections in motor learning and performance. The evidence supporting the main claims is convincing, with multiple replications, validation of their techniques, and appropriate controls. The work will be of broad interest to neuroscientists interested in central mechanisms of motor learning and control, as well as thalamic physiology.

eLife Assessment

In this valuable study, the authors report on an innovative chemostat propagation system to reduce eukaryotic viruses while retaining phages in mixtures used for FVTs (fecal virome transplant). The authors hypothesized that chemostat-propagated viromes could modulate the gut microbiota and reduce necrotizing enterocolitis (NEC) lesions while avoiding potential side effects, such as earlier onset of diarrhea. Although no effect on NEC could be demonstrated, the revised document addressed the other concerns and is much improved from its original version. The study is convincing in that it integrates in vitro fermentation, high-resolution metagenomics, immunogenicity assays, and in vivo validation, demonstrating the potential of FVT using eukaryotic-free virome-based therapeutics.

eLife Assessment

This important study combines microfluidic experiments with mathematical modeling to elucidate the reciprocal interplay between flow dynamics and biofilm growth and detachment. Using Pseudomonas aeruginosa as a model organism, the authors identify several key regimes and stages of biofilm development. Overall, the comparison between experimental observations of biofilm behavior under varying flow conditions and corresponding theoretical predictions forms a compelling understanding of the processes involved in biofilm dynamics. The results will be of interest to researchers studying biofilms and their technological and biological applications.

eLife Assessment

This fundamental study introduces a new biology-informed strategy for deep learning models aiming to predict mutational effects in antibody sequences. It provides convincing 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 valuable study identifies a novel regulator of stress-induced gene quiescence in C. elegans: the multi-Zinc-finger protein ZNF-236. The work provides evidence for an active mechanism that maintains the repressed state of inducible genes under basal conditions in the absence of stress. The claims for discovery made in the title and abstract are supported by solid experimental data. However, a deeper investigation into the mechanisms of ZNF-236 action could substantially enhance the manuscript's impact and value.

eLife Assessment

This important work by Qin et al. delineates layered neuropeptidergic mechanisms that regulate sugar intake in a hunger state-dependent manner. Using a combination of genetic, physiological, and behavioral experiments, the authors convincingly show that Hugin- and Allatostatin A-releasing neurons are selectively active in sated flies and suppress sugar feeding by reducing the sensitivity of Gr5a-expressing gustatory neurons. They further demonstrate that Neuromedin U neurons share key physiological properties with fly Hugin neurons, highlighting conserved peptide functions across animal phyla.

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 solid evidence.

eLife Assessment

In this important work, the authors present a new transformer-based neural network designed to isolate and quantify higher-order epistasis in protein sequences. They provide solid evidence that higher-order epistasis can play key roles in protein function. This work will be of interest to the communities interested in modeling biological sequence data and understanding mutational effects.

eLife Assessment

This study uses the yeast two-hybrid assay to identify proteins that may interact with yeast Set1 and other subunits of COMPASS/Set1C, the histone H3K4 methyltransferase, providing also some evidence for Set1 sumoylation and a role of SET1C methylating other factors in vitro. The results are valuable, and they should contribute to understanding the functions of the conserved SET1C complex, as they suggest potential functional connections with RNA biogenesis, chromatin remodeling, and non-histone methylation, whose implications would yet need to be explored. Nevertheless, apart from the fact that only a small subset of the Y2H interactions is further examined, the validating experiments are only partial or inconclusive, the strength of evidence being at this point incomplete.

eLife Assessment

This study presents valuable findings for identifying biotypes of depression patients using white matter measures, which are under-utilised and under-appreciated in current biological and computational psychiatry work. The evidence supporting the claims is solid, although enhanced interpretability of the identified biotypes across both white matter and symptom levels, and better justification of the choice of models would strengthen the paper. Overall, this study will be of interest to the broad community of neuroimagers, clinicians, and biological and computational psychiatry researchers.

eLife Assessment

This useful study analyzes demographic history and selection using whole-genome sequencing data from 40 Faroese individuals, generating results of value beyond the study region. The analyses are convincing, and revisions have satisfactorily addressed prior concerns, including clarification of selection analyses and expanded discussion of population structure and admixture timing. While a more fine-scale reconstruction of demographic history could still yield more insights, and access restrictions on individual-level data continue to limit broader reuse, the provision of summary statistics partially mitigates this constraint.

eLife Assessment

This important work provides a fresh perspective on merozoite surface biology and its implications for vaccine design, challenging the prevailing dogma that MSPs are indispensable invasion engines. The revised manuscript strengthens the compelling evidence that, although MSP2 is dispensable for parasite growth, it acts as an immune modulator of AMA1. While the study is commendable for its use of state-of-the-art technologies and the skillful application of monoclonal antibodies, the inclusion of human monoclonal antibodies and electron microscopy imaging approaches would significantly add to the importance of these observations. Overall, this work will be of considerable interest to investigators studying Plasmodium biology and vaccine development.

eLife Assessment

This manuscript describing the phenotypes associated with loss and gain of RVCL-S documents important findings that have practical implications. Although the data and methods are solid and support many claims, there remain some concerns about mechanisms.

eLife Assessment

This study reports important findings regarding the role of the NF-kB signaling pathway in the development and long-term survival of gamma delta T cells. The authors report disparate roles of IKK-dependent NF-kB activation in the development and long-term survival of gamma delta T cell subsets. The approach and methodology employed is convincing. This work will be of great interest to immunologists interested in innate-like T cell biology and in T cell development.

eLife Assessment

This study provides valuable insights into the protein composition of the C2a projection in mouse motile cilia, building upon prior work in Chlamydomonas. The evidence supporting the claims of the authors is solid. The work will be of interest to biologists and clinicians studying cilia and ciliopathies.

eLife Assessment

This important work identifies phlda2 as a specific marker for primordial cardiomyocytes in the adult zebrafish heart and demonstrates their essential role in myocardial morphogenesis and coronary vascularization, but not in heart regeneration. The conclusions are well supported by single-cell transcriptomics, new genetic tools, and cell-specific ablation experiments. Overall, the evidence is solid and provides insight into the difference between developmental and regenerative cardiac programs. This work will be of interest for those studying cardiac development and regeneration.

eLife Assessment

This study presents a useful methodological advance that better enables the simultaneous measurement of gene expression and chromatin accessibility in individual cells. The evidence supporting the improved detection of gene expression is solid, though the reduced performance in detecting chromatin accessibility represents a limitation. This method will be of interest to those studying transcription and gene regulation.

eLife Assessment

In this valuable study, Robben et al. describe a 3D beta-cell spheroid platform, a tool allowing high-throughput monitoring of cytoplasmic calcium concentrations and insulin secretion, with calcium signals comparable to those recorded in primary pancreatic islets. The authors demonstrate 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 highlights the potential utility of the 3D beta-cell spheroids for screening new pharmacological modulators of pancreatic beta-cell function.

eLife Assessment

This study presents valuable findings that could potentially allow a deeper understanding of the immunopathogenesis underlying influenza infection in aged mice. The results are based on solid evidence that define putative immune determinants underlying immunopathology in the aged lung. This study will be of interest to researchers pursuing aging research, as well as to immunologists.

eLife Assessment

This important study investigates how structurally diverse cardenolide toxins in tropical milkweed, especially mixtures containing nitrogen- and sulfur-containing variants, influence monarch caterpillar feeding, growth, and toxin sequestration. The experiments provide solid evidence that chemical diversity within a single group of plant toxins can have combined effects on even highly specialized herbivores that differ from the effects of each toxin alone. However, as the mixture design does not fully separate true diversity effects from the influence of the N,S-cardenolides themselves and the ecological basis for the chosen natural ratios remains weakly justified. As a result, the broader conclusions would require more fully justified concentration regimes, mixture treatments that exclude N,S-cardenolides, and tests on living plants and non-adapted herbivores to firmly support the proposed coevolutionary interpretation.

eLife Assessment

This important study demonstrates that a peri-nuclear actomyosin network, present in some types of human cells, facilitates kinetochore-spindle attachment of chromosomes in unfavorable locations - thereby suppressing their missegregation rate. This actomyosin network and its general role have been studied previously, but this study convincingly clarifies the underlying mechanism using a light-controlled perturbation and detailed tracking of kinetochore movement. The generality of the mechanism could be further supported by confirming the findings in non-synchronized cells and additional cell lines. The results may have implications for understanding chromosome missegregation in cancer cells.

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

eLife Assessment

The study showcases a significant and important enhancement of the MAGIC transgenesis method, by extending it genome-wide to all chromosomes. The authors provide compelling evidence to demonstrate that the MAGIC mosaic clones can be generated for genes from all, including the 4th chromosome. With this toolkit extension, the method is set to complement the classical FRT/Flp recombination system for gene manipulation in flies.

eLife Assessment

This useful study examines the contribution of synaptotagmin 1 and synaptotagmin 7 to metabolite antigen presentation to mucosal-associated invariant T (MAIT) cells; it begins to address a critical gap in our understanding of the antigen presentation mechanisms of these cells. Strengths of the study include the use of Mtb to study the dynamics of antigen presentation to MAIT cells instead of a synthetic antigen. The strength of the evidence to support the conclusion is solid.

eLife Assessment

The important study uses genome-wide CRISPR/Cas9 screenings to identify a novel target B4GALTZ1 that is implicated in modulating CD8+ T cell function in the context of anti-tumor immunity. The strength of evidence is solid but could benefit from more detail, particularly to verify the efficiency of knockout in their single gene KO lines and identification of N-glycosylation sites of TCR and CD8s. This work highlights the role of protein N-glycosylation, particularly B4GALT1 deficiency, in regulating CD8 function and anti-tumor immunity.

eLife Assessment

This valuable work analyzes a large dataset of [NiFe]-CODHs, integrating genomic context, operon organization, and clade-specific gene neighborhoods to discern patterns of diversification and adaptation. A consistent examination of CODH genomic contexts, including CODH-HCP co-occurrence, informs interpretations of enzymatic activity, biotechnological potential, and differential functional roles, in line with current standards in genomic enzymology. With solid support, this work provides a broadly informative contribution to the field.

eLife Assessment

This study presents a valuable application of a video-text alignment deep neural network model to improve neural encoding of naturalistic stimuli in fMRI. The authors provide convincing evidence that models based on multimodal and dynamic embedding features of audiovisual movies predicted brain responses better than models based on unimodal or static features. The work will be of interest to researchers in cognitive neuroscience and AI-based brain modeling.

eLife Assessment

Huang and colleagues examined neural responses in mouse anterior cingulate cortex (ACC) during a discrimination-avoidance task. The authors present useful findings that ACC neurons encode primarily post-action variables or "action content" over extended periods. Though the methodological approach was sound, the evidence in support of action state encoding, ruling out alternative explanations related to movement, is incomplete.

eLife Assessment

This important study addresses the unresolved and long-debated question of whether atypical protein kinase C is required for the maintenance of synaptic potentiation and long-term memory. The results confirm previous findings that persistent activity of PKMζ is required for lasting potentiation of hippocampal synapses and spatial memory. The study also adds new genetic evidence to support the earlier suggestion that enhanced expression of PKC iota/lambda compensates for the genetic reduction of PKM zeta to support synaptic potentiation and memory; however, the results as currently presented were viewed as incomplete.

eLife Assessment

This important study implicates that changes in cell regulation may contribute to the evolution of multicellularity. The evidence supporting the conclusions is convincing, with rigorous methods used to test alternative hypotheses. The work will be of broad interest to cell and evolutionary biologists and those studying the cell cycle and cancer.

eLife Assessment

This study presents valuable findings implicating nuclear export in the regulation of protein condensate behaviour and TDP-43 phase behaviour, suggesting a link to pathogenic aggregation in ALS/FTD. However, the research relies extensively on synthetic, non-physiological protein variants and a homozygous disease model, with limited mechanistic validation, leading to conclusions that remain largely correlative. Furthermore, limitations in the reporting of experimental replication and controls, as well as inconsistencies between cancer cell and neuronal models, diminish confidence in the robustness of the findings. Despite its technical strengths, the findings presented are currently incomplete and do not provide sufficient evidence to substantiate claims about the direct role of nuclear export in pathological protein aggregation and disease.

eLife Assessment

This important study introduces an experimental approach for studying Drosophila oviposition rhythms and identifies the subset of circadian clock neurons that mediate the circadian control of oviposition. The authors try to resolve a known noisy rhythm and provide convincing evidence by using statistical averaging techniques which help reduce this noise but at the cost of variation across individual rhythms. To this end, including the time series of representative individuals for all genotypes tested would have helped in interpreting some of the results. This paper will be of interest to anyone interested in insect ovarian physiology, circadian biology, and reproductive fitness.

eLife Assessment

This study presents a valuable finding on the mutational order for common alterations in colorectal cancer. The evidence of in vitro growth assays comparing mutations is solid, although inclusion of biological replicates for the transcriptional assessments and in vivo experiments would have strengthened the study. The work will be of interest to scientists working in the field of colon cancer.

eLife Assessment

This study presents an important investigation of how people approach and avoid uncertainty, with a particular focus on the effects of overall uncertainty. They find that individuals approach uncertainty to a point, but when uncertainty is particularly high, they avoid it. The results are interpreted under a cognitive cost-resource rational framework. The methods are convincing, using appropriate and current methodologies.

eLife Assessment

This paper describes a valuable extension of the Hierarchical Gaussian Filter (HGF) to accommodate the influence of volatility and value, among others. The authors present convincing evidence that the model can recover the generative structure of simulated data. There is not strong evidence that the new model provides a superior account of existing empirical phenomena, and the HGF could be better embedded in the larger filtering and predictive coding literature. This contribution will be of special interest to people in computational psychiatry, where the application of the hierarchical Gaussian filter has been the most prevalent.

eLife Assessment

This important study convincingly demonstrates how bacterial cells can modulate outer membrane-peptidoglycan tethering by expressing two different Lpp homologs with distinct cross-linking efficiencies, revealing that Salmonella typhimurium LppB forms disulfide-based homodimers (or heterotrimers with Lpp when present) and is covalently attached to peptidoglycan primarily via the L,D-transpeptidase LdtB at residue K58. The evidence supporting the authors' claims is solid, including the regulatory role of LppB dimerization for its abundance in E. coli and its ability to inhibit Lpp/A crosslinking to peptidoglycan, although additional analysis and quantification of muropeptides in wild-type E. coli overexpressing LppB would further strengthen the findings. Overall, the work will be of great interest to microbiologists studying cell envelope biogenesis.

eLife Assessment

Foucault and colleagues examine how human adaptive learning depends on the structure of the learning task. The authors provide useful findings clarifying the differences in how people learn in environments that are continuously versus discontinuously changing. While they provide solid evidence for most conclusions, support for some of the claims is incomplete in the current form.

eLife Assessment

This study offers a valuable analysis of how moment-to-moment fluctuations in arousal are associated with structured, non-uniform patterns of brain-wide functional connectivity during wakefulness. Using data-driven analyses of resting-state and naturalistic fMRI with eye tracking, the authors present convincing evidence that arousal is a dynamic, continuous process that shapes brain activity in a structured way beyond a simple global effect. However, the strength of the conclusions is limited by a reliance on specific analytical choices and the need for additional controls and robustness analyses. This paper sheds light on the link between brain activity and ongoing fluctuations in arousal and will be of interest to researchers studying large-scale brain functional organization and links between the brain and body.

eLife Assessment

The new development of Neuroplex, a pipeline that links projection-defined neuronal identity to in vivo calcium activity within the same animal, is a valuable contribution to the field of neuroscience and beyond. The strength of evidence is judged to be solid, as the methods, data, and analyses broadly support the stated claims.

eLife Assessment

This important study describes long-range serial dependence of performance on a visual texture discrimination training task that manipulated conditions to induce differing degrees of location transfer of learning. The authors re-analyzed a previously-published behavioral data set, generating compelling evidence from converging approaches that serial dependence effects can persist across multiple days post-training, and are impacted by whether training promotes more or less location transfer. Although underlying mechanisms for these processes remain unclear, these results will interest neuroscientists in general by informing our understanding of the importance of temporal integration to long-term perceptual learning and its propensity towards specificity or generalizability.

eLife Assessment

This study provides valuable evidence regarding our expectations about task difficulty and how this might influence proactive attention. The findings suggest that anticipated demands enhance the strength of attentional selection at cued locations. The evidence is solid but not definitive, as the conclusions rely on the absence of changes in spatial breadth and would benefit from clearer statistical justification and a more cautious interpretation of alternative mechanisms.

eLife Assessment

This useful manuscript addresses a stability issue for long-term chronically implanted array recordings and electrolytic lesioning, which is relevant to both basic science and translational research. The authors provide a systematic scanning electron microscopy (SEM) of explanted arrays, evaluating electrode damage and sharing extensive datasets accessible through interactive plots. The strength of the evidence is solid, but it can be improved by performing additional analyses on complementary neurophysiology, functional, or histological data.

eLife Assessment

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

eLife Assessment

This valuable study utilizes a newly developed approach to culture T gondii bradyzoites in myotubes, and then takes advantage of the antiparasitic compound collection known as the Pathogen Box, to find compounds that target both tachyzoite and bradyzoite forms of the parasite. A set of compounds yielding patterns consistent with targeting the mitochondrial bc1 complex was explored further, with solid evidence for changes in ATP production in bradyzoites to support the conclusions about the importance of this complex. The paper will be interesting for parasitologists studying drug discovery of apicomplexan parasites.

eLife Assessment

This study provides valuable data regarding gene expression and molecular changes that occur in the mouse spinal cord from exercise and motor activity. Overall, the findings and methods are solid, although additional independent validation experiments would improve the rigor of the study. The work provides resources for neuroscientists who investigate communication between neurons and non-neurons and both basic and translational scientists with interests in how physical activity impacts the nervous system function, with potential therapeutic outcomes.

eLife Assessment

This study provides important insights into how working memory shapes perceptual decisions, using a dual-task design, continuous mouse tracking, and hierarchical Bayesian modeling. By dissociating fast attentional capture effects from slower, sustained perceptual biases within single trials, the authors provide compelling evidence that working memory-perception interactions unfold through distinct dynamic processes rather than a single mechanism. This work will be of interest to researchers studying working memory, perception, decision-making, and mouse-tracking methodology.

eLife Assessment

This important study investigates the self-assembly activity of all 109 human death-fold domains. The data collected using advanced microscopy and distributed amphifluoric FRET-based flow cytometry methods are compelling to support the "phase change battery" model that explains how signal amplification can occur without ATP consumption. This paper provides new insight into the thermodynamic control of protein phase behaviors within cells and will be of interest to those studying a variety of biological pathways involved in inflammatory responses and various forms of cell death.

eLife Assessment

The authors present useful findings demonstrating that the RNA modification enzyme Mettl5 regulates sleep in Drosophila. Through transcriptome- and proteome-wide analyses, the authors identified downstream targets affected in heterozygous mutants and proposed that Mettl5 regulates the translation and degradation of clock genes to maintain normal sleep function. Through additional analyses, the authors provided solid evidence that Mettl5 regulates translation and degradation of clock genes to maintain normal sleep cycle. The mechanistic details of Mettl5 is unclear and requires further support.

eLife Assessment

This fundamental work advances our understanding of the role of human hippocampal theta oscillations in memory encoding and retrieval. The evidence supporting the conclusions is convincing, using both scopolamine administration and intracranial EEG recordings. This work will be of broad interest to neuroscientists and has translational implications.

eLife Assessment

This valuable manuscript investigates the localisation of nutrient receptors in bloodstream stage trypanosomes, with implications for both nutrient uptake and immune evasion. Results after direct fixation of the cells in culture medium (as opposed to fixation after centrifugation) provide compelling evidence that the amounts of receptors on the surface of the cell, as opposed to the flagellar pocket, have previously been severely underestimated.

eLife Assessment

This fundamental study measures the functional specialization of distinct subregions within the mouse posterior parietal cortex (PPC) using mesoscopic two-photon calcium imaging during visual discrimination and choice history-dependent tasks. It presents compelling evidence supporting the existence of functional specialized subregions within the PPC. The work will be of interest to system and computational neuroscientists interested in decision-making, working memory, and multisensory integration.

eLife Assessment

This valuable study proposes a novel rapid-entry mechanism for S. aureus, involving the rapid release of calcium from lysosomes. The paper's strength lies in its very interesting hypothesis. The methods used are solid and adequately support the conclusions.

eLife Assessment

This paper reports new data on the structure of the human CTF18-RFC clamp loader complex bound to the PCNA clamp. The new and convincing data complement previous reports of CTF-RFC-PCNA structures and as such, represents an important contribution.

eLife Assessment

This important study reports that EEG recordings of the earliest stage of information processing in human visual cortex can be used to predict subsequent choice responses. The findings provide novel, convincing evidence for integrative processing in low-level sensory cortices at the level of scalp-recorded potentials, with the exact nature of the neural signals at the single cell level to be determined. The paper is likely to be of interest to neuroscientists interested in the contribution of early sensory signals to decision making.

eLife Assessment

This important study links allelic expression imbalance with replication timing, suggesting a stochastic model for haploinsufficiency in dosage-sensitive disease. The integration of allele-specific RNA-seq and replication timing in clonal systems provides solid evidence for an association between asynchronous replication and allelic imbalance, although the scope and generality of some conclusions require more cautious interpretation. This study will interest epigeneticists and genome regulation researchers studying replication timing and monoallelic expression, as well as developmental biologists and human geneticists concerned with clonal heterogeneity, haploinsufficiency, and variable disease penetrance.

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

eLife Assessment

This manuscript reports the development and characterization of iGABASnFR2, a genetically encoded GABA sensor that demonstrates substantially improved performance compared to its predecessor, iGABASnFR1. The work is comprehensive and methodologically rigorous, combining high-throughput mutagenesis, functional screening, structural analysis, biophysical characterization, and in vivo validation. The significance of the findings is fundamental, and the supporting evidence is compelling. iGABASnFR2 represents a notable advance in GABA sensor engineering, enabling enhanced imaging of GABA transmission both in brain slices and in vivo, and constitutes a timely, technically robust addition to the molecular toolkit for neuroscience research.

eLife Assessment

In this important contribution, Yan and colleagues describe a powerful and compelling strategy to generate concatamers of the BK channel and their fusion constructs with the auxiliary gamma subunits, which allows exploring contributions of individual subunits of the tetrameric channel to its gating and the study of heteromeric channel complexes of defined composition. Distinct examples are presented, which illustrate great diversity in the stoichiometric control of BK channel gating, depending on the site and nature of molecular perturbations. The molecular approaches could be extended to other membrane proteins whose N and C termini face opposite sides of the membrane.

eLife Assessment

This fundamental study presents experimental evidence on how geomagnetic and visual cues are integrated in a nocturnally migrating insect. The evidence supporting the conclusions is compelling. The work will be of broad interest to researchers studying animal migration and navigation.

eLife Assessment

Laaker et al. make an important finding that the cribriform plate acts as a unique neuroimmune interface that shapes local myeloid cell states during EAE-induced neuroinflammation. Using immuohistochemistry, flow cytometry, and single-cell RNAseq of doublets to interrogate cell-cell interactions, the authors provide solid evidence that macrophages, migratory dendritic cells (DCs), and fibroblasts interact at the site of CSF outflow, with DCs showing characteristics of immune tolerance. While the functional consequences of these cell states remain to be established, the work shows that the cribiform plate can play a key role in influencing immune cell composition and interactions with stromal cells.

eLife Assessment

In this valuable study, DNA and RNA are co-imaged in single cells to show that the proximity of topologically associated domain (TAD) boundaries is uncoupled from the transcriptional activity of nearby genes. The evidence supporting these conclusions is convincing for the regions examined, with high-throughput imaging providing robust statistics. This work will be of interest to researchers studying genome architecture and its relationship to gene regulation.

eLife Assessment

This study presents a high-quality cryo-EM structure of the human kinase PINK1 in complex with the HSP90-CDC37 chaperone complex, capturing a partially folded intermediate in which the C-lobe and C-terminal extension are structured while the N-lobe remains unfolded and engaged by the HSP90 clamp. The structural data are broadly consistent with a recently published structure of the same complex, providing useful insight into early steps of PINK1 maturation and highlighting residues linked to familial Parkinson's disease. However, the mechanistic conclusions remain incomplete because the manuscript does not experimentally validate key hypotheses raised by the structure, including the functional roles of the C-lobe interface, the HPNI motif, the C-terminal extension, or the proposed competition between HSP90 and TOM20.

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 solid while identifying some minor weaknesses that if addressed would enhance the rigor of the study.