eLife Assessment

This important study, which tackles the challenge of analyzing genome integrity and instability in unicellular pathogens by introducing a novel single-cell genomics approach, presents compelling evidence that this new tool outperforms standard whole-genome amplification techniques. While thorough and rigorous, the work's impact would increase by providing scripts and data, as well as a description of the biological relevance that would make this method more appealing to the broad community studying genetic heterogeneity in diverse organisms.

eLife Assessment

This work reports the characterization of newly identified genetic variants of SLC4A1 in patients with distal renal tubular acidosis. Cell culture studies supplemented with histological analysis of a previously established disease mouse model provide convincing evidence that some of the variants increase intracellular pH, reduce ATP synthesis, and attenuate autophagic degradative flux. The study is valuable in establishing a mechanistic framework for future exploration of the link between intracellular pH and mutations in SLC4A1 in vivo.

eLife Assessment

This important study reports convincing evidence of associations between 35 polygenic indices (PGIs) for social, behavioural, and psychological traits, as well as other health conditions (e.g., BMI) and all-cause mortality, based on data from Finnish population-based surveys and a twin cohort linked to administrative registers. PGIs for education, depression, alcohol use, smoking, BMI, and self-rated health showed the strongest associations with all-cause mortality, in the order of ~10% increment in risk per PGI standard deviation. Effect sizes from twin-difference analyses tended to be slightly larger than those from population cohorts, a pattern opposite that generally observed when testing PGI associations with their target phenotypes, and supporting the robustness of findings to confounding by population stratification.

eLife Assessment

This work significantly advances our understanding of chromatin organization within regions of repetitive sequences in the parasitic protozoan Trypanosoma brucei. Using cutting edge interdisciplinary tools, the authors provide compelling evidence for two discrete types of repetitive DNA element-associated proteins- one set involved in essential centromere function; and, the other involved in glycoprotein antigenic variation via homologous recombination. Thus, these fundamental findings have implications for this parasite's biology, and for therapeutic targeting in kinetoplastid diseases. This work will be exciting to those in the centromere/mitosis and parasite immunity fields.

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

eLife Assessment

This important study examines the role of map3k1, a MAP3K family member that has both kinase and ubiquitin ligase domains, in the differentiation of progenitors in the flatworm Planaria. The convincing analyses demonstrate that map3k1 acts within progenitors to restrict their premature differentiation and to prevent formation of teratomas. This work would be of interest to researchers in the fields of regeneration, developmental biology, and aging.

eLife Assessment

This important study employs a closed-loop, theta-phase-specific optogenetic manipulation of medial septal parvalbumin-expressing neurons in rats and reports that disrupting theta-timescale coordination impairs performance of challenging aspects of spatial behaviors, while sparing hippocampal replay and spatial coding in hippocampal place cells. The findings are expected to advance theoretical understanding of learning and memory operations and to provide practical implications for the application of similar optogenetic approaches. The experiments were viewed as technically rigorous, but the strength of evidence provided in the current version of the manuscript was viewed as incomplete, mostly due to limited analyses and the descriptions of some of the experimental protocols.

eLife Assessment

This is a useful study that investigates the role of the long non-coding RNA Dreg1 for the development, differentiation, or maintenance of group 2 ILC (ILC2). The authors generate Dreg1-/- mice and show a reduction of group 2 innate lymphoid cells (ILC2). However, the strength of evidence supporting the impact of Dreg1 on Gata3 expression, a transcription factor required for ILC2 cell fate decisions, and the cell-intrinsic requirement of Dreg1 for ILC2 remain incomplete. This study will be of interest to immunologists.

eLife Assessment

This study presents a platform to implement closed-loop experiments in mice based on auditory feedback. The authors provide convincing evidence that their platform enables a variety of closed-loop experiments using neural or movement signals, indicating that it will be a valuable resource to the neuroscience community. The paper could be strengthened by the addition of additional tutorials, such as on how to run an experiment.

eLife Assessment

This is a valuable study that integrates behavioral and molecular approaches to identify neuromodulators influencing blood-feeding behavior in the disease vector Anopheles stephensi. Through gene expression analyses across blood-seeking life stages and RNA interference experiments, the authors present solid evidence that co-knockdown of the neuromodulators short Neuropeptide F and RYamide affects blood-seeking states in A. stephensi. However, evidence demonstrating that these neuropeptides are sufficient to promote host-seeking is lacking.

eLife Assessment

This paper provides a useful new theory of the hallucinatory effects of 5-HT2A psychedelics. The authors present convincing evidence that a computational model trained with the Wake-Sleep algorithm can reproduce some features of hallucinations by varying the strength of top-down connections in the model, though it is not clear that this model applies to 5-HT2A hallucinogens in particular. The work will be of interest to researchers studying hallucinations or offline activity and plasticity more broadly.

eLife Assessment

This work describes the establishment of an image analysis pipeline for signal correction, segmentation and quantitative data analysis of multilayered organoid and tumoroid systems. The revised study is important for the field to address many practical challenges in deep-tissue visualization. The image analysis pipeline is well-designed and compelling.

eLife Assessment

This important work compares the size of two brain areas, the amygdala and the hippocampus, across 12 species belonging to the Macaca genus. The authors find, using a convincing methodological approach, that amygdala - but not hippocampal - volume varies with social tolerance grade, with high tolerance species showing larger amygdala than low tolerance species of macaques. Interestingly, their findings also suggest an inverted developmental effect, with intolerant species showing an increase in amygdala volume across the lifespan, compared to tolerant species exhibiting the opposite trend. Overall, this paper offers new insights into the neural basis of social and emotional processing.

eLife Assessment

The current work uses DNA-tethered motor trapping to reduce vertical forces and improve datasets for kinesin-1 motility under load. The evidence is compelling and the significance is important to the kinesin field. Kinesin-1 is more robust and less prone to premature detachment than previously indicated. This represents a significant advancement in the field and is generally applicable to work with optical tweezers.

eLife Assessment

This paper undertakes an important investigation to determine whether movement slowing in microgravity is due to a strategic conservative approach or rather due to an underestimation of the mass of the arm. The experimental dataset is unique, the coupled experimental and computational analyses comprehensive, and the effect is strong. However, the authors present incomplete results to support the claim that movement slowing is due to mass underestimation. Further analysis is needed to rule out alternative explanations.

eLife Assessment

In this useful study, the authors conducted an impressive amount of atomistic simulations with a realistic asymmetric lipid bilayer to probe how the HIV-1 envelope glycoprotein (Env) transmembrane domain, cytoplasmic tail, and membrane environment influence ectodomain orientation and antibody epitope exposure. The simulations convincingly show that ectodomain motion is dominated by tilting relative to the membrane and explicitly demonstrate the role of membrane asymmetry in modulating the protein conformation and orientation. However, due to the qualitative nature of the conducted analyses, the evidence for the coupling between membrane-proximal regions and the antigenic surface is considered incomplete. With stronger integration of prior experimental and computational literature, this work has the potential to serve as a reference for how Env behaves in a realistic, glycosylated, membrane-embedded context.

eLife Assessment

This valuable study uses NAD(P)H fluorescence lifetime imaging (FLIM) to map metabolic states in the Drosophila brain. The authors reveal subtype-specific metabolic profiles in Kenyon cells and report learning-related changes, supported by solid evidence and careful methodology. However, the FLIM shifts observed after memory formation in α/β neurons are small and only weakly significant, so the ability of FLIM to detect subtle physiological changes still requires further validation. Nevertheless, this work provides a strong starting point and demonstrates the promising potential of FLIM for probing neural metabolism in vivo.

eLife Assessment

This study provides a useful application of computational modelling to examine how people with chronic pain learn under uncertainty, contributing to efforts to link pain with motivational processes. However, the evidence supporting the main claims is incomplete, as the modelling differences are not reflected in observable behaviour or pain measures, and the interpretation extends beyond what the data can substantiate. The conclusions would benefit from a clearer explanation of the behavioural differences that underlie the computational findings.

eLife Assessment

This manuscript proposes a lateralized, lobe-specific brain-liver sympathetic neurocircuit regulating hepatic glucose metabolism and presents anatomical evidence for sympathetic crossover at the porta hepatis using viral tracing and neuromodulation approaches. While the topic is of important significance and the methodologies are, in principle, state-of-the-art, significant concerns regarding experimental design, incomplete methodological reporting, sparse and ambiguous labeling, and overi-nterpretation of the data substantially weaken support for the study's central conclusions, thereby limiting the study's completeness. The work will be of interest to biologists, clinicians, and physiologists.

eLife Assessment

The findings are important, as they identify MIRO1 as a central regulator linking mitochondrial positioning and respiratory chain function to VSMC proliferation, neointima formation, and human vasoproliferative disease. Overall, the strength of evidence is convincing, with comprehensive in vivo and in vitro data, including human cells and added bioenergetic analyses, that broadly support the main claims despite some remaining limitations in mechanistic and mitochondrial assays.

eLife Assessment

This manuscript provides useful insights into how the brain can simultaneously represent events and the times when they occurred. The results include a comparison between two different basis functions for temporal selectivity and how these generate different predictions for the dynamics of neural populations. The conclusions are partly incomplete because of questions such as the impact of the linear separability assumption and whether joint encodings of event type and time can be made without it.

eLife Assessment

This important study establishes a workflow based on environmental sampling for the discovery of bacteriophages capable of infecting antibiotic-resistant pathogens. The experimental design, analysis, and results demonstrating the effectiveness of the workflow are convincing, although a broader sampling scheme and more careful framing of the data within the current limitations of viral taxonomy could strengthen the work. This study will interest researchers working on bacterial infections, environmental microbiology, and phage-based alternatives for addressing antimicrobial resistance.

eLife Assessment

This important 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 important study provides the first direct neuroimaging evidence for the integration-segregation theory of exogenous attention underlying inhibition of return, using an optimized IOR-Stroop fMRI paradigm to dissociate integration and segregation processes and to demonstrate that attentional orienting modulates semantic- and response-level conflict processing. Although the empirical evidence is compelling, clearer justification of the experimental logic, more cautious framing of behavioral and regional interpretations, and greater transparency in reporting and presentation are needed to strengthen the conclusions. The work will be of broad interest to researchers investigating visual attention, perception, cognitive control, and conflict processing.

eLife Assessment

This important work contributes a transcriptional dataset that identifies potential genes involved in axon initial growth and axon regrowth, followed by a characterization of axon phenotypes after knockdown of a subset of these genes. Focused experiments on a single gene, Pmvk, highlight the potential role of the mevalonate pathway in axon regrowth. The methods are convincing, though partially incomplete. The data establish a basis for further studies on axonal development and will be of interest to both developmental neurobiologists and those seeking to develop molecular tools to target, monitor, and manipulate axon morphology and function.

eLife Assessment

This valuable study characterises the activity of motor units from two of the three anatomical subdivisions ("heads") of the triceps muscle while mice walked on a treadmill at various speeds. Altogether, this is the most thorough characterisation of motor unit activity in walking mice to date, providing solid evidence for probabilistic recruitment of motor units that differed between the two heads.

eLife Assessment

This important model-based study seeks to mimic bat echolocation behavior and flight under conditions of high interference, such as when large numbers of bats leave their roost together. The simulations convincingly suggest that the problem of acoustic jamming in these situations may be less severe than previously thought. This finding will be of broad interest to scientists working in the fields of bat biology and collective behaviour.

eLife Assessment

This important mouse study shows that wild-type female progeny of Khdc3 mutants have abnormal gene expression relating to hepatic metabolism, which persists over multiple generations and passes through both female and male lineages. A role for small RNAs on this phenomenon is proposed, and evidence supporting the authors' claims is convincing. Further experiments are required to functionally validate the role of small RNAs in transmission of the phenotype. The work will be of interest to researchers in the field of DNA-independent mechanism of inheritance.

eLife Assessment

The study presents data on the possible connection of respiratory pathologies like pneumonia in a cohort of dolphins with altered composition and concomitant perturbed biophysical properties of pulmonary surfactant complexes. Overall, it is a valuable contribution that could be of interest to scientists in the field. However, the study as it is appears somewhat incomplete and additional clarification and discussions are required in order to explain a few methodological questions that may limit the impact of the work considerably.

eLife Assessment

This is a potentially important paper attempting to identify neutral correlates of memory engram expression in humans, and how they change during forgetting. The questions posed are clear and novel. The methods employed, namely behavioral analysis, high-resolution functional magnetic resonance imaging, and representational similarity analysis, are advanced, integrative, and appropriate. The experiments are well designed and combine analysis of recollection and familiarity of object/face associations. However, substantial questions remain as to the validity of the incomplete statistical analyses applied to the imaging data, as well as the parsing of and interpretation of the behavioral data.

eLife Assessment

This valuable study links psychological theories of chunking with a physiological implementation based on short-term synaptic plasticity and synaptic augmentation. The theoretical derivation for increased memory capacity via hierarchical chunking is solid. However, the model robustness and biological grounding of the mechanism - including many aspects that were hard-wired, chunking cues, and parameter ranges - as well as its evaluation in the task settings that motivated the study, are incomplete. Additional simulations to test robustness in more cognitively and biologically realistic settings, a systematic parameter analysis, and stronger links to prior work would substantially strengthen the manuscript and increase its impact across disciplines.

eLife Assessment

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

eLife Assessment

This important study uses an original method to address the longstanding question of why reaching movements are often biased. The combination of a wide range of experimental conditions and computational modeling is a strength. Convincing evidence is presented in support of the main claim that most of the biases in 2-D movement planning originate in misalignment between visuo-proprioceptive reference frames.

eLife Assessment

This valuable study assesses through simulations how several features of local cortical circuits - interneuron subtypes, their specific targeting of dendritic compartments, and certain brain rhythms - together affect the integration of synaptic inputs by a pyramidal cell. Employing several carefully considered simulation setups they convincingly demonstrate that beta rhythms are best suited to modulate and control dendritic Ca-spikes while gamma rhythms affect their coupling to somatic spiking, or how basal inputs are directly integrated into somatic spikes. However, the baseline setup may be idealized for the generation of the events in question and it would be beneficial if the similarity to the in-vivo activity regime was demonstrated further. The results will be relevant for neuroscientists studying local circuits or developing more abstract theories at the systems level.

eLife Assessment

The presented findings are important for the field of cell-cycle control. They provide new insights into the origin of cell size variability in budding yeast. The strength of evidence is solid. However, the conclusions could be more strongly supported by additional analysis.

eLife Assessment

This important paper presents the discovery of the molecular basis of differential apterous expression during early Drosophila wing disc development. The evidence supporting these conclusions is compelling, ranging from classical genetic approaches to state-of-the-art genetic engineering techniques. By opening new questions, this paper is expected to be of broad interest to developmental biologists and geneticists working on transcriptional regulation.

eLife Assessment

In this valuable study, Parrotta et al. showed that it is possible to modulate pain perception and heart rate by providing false heart rate (HR) acoustic feedback before administering electrical cutaneous shocks. The evidence supporting the claims of the authors is rather solid, although what they consider an interoceptive signal is not necessarily supported as such by the results. In this regard, including a larger number of trials per participant, increasing the sample size, and adding a measure of actual pain perception after its induction would have strengthened the study. Although mechanisms and some alternative explanations for this effect remain to be addressed, the work will nonetheless be of interest to neuroscientists working on predictions and perception, health psychologists, pain researchers, and placebo researchers.

eLife Assessment

Using their unique Fish-On-Chips optofluidics platform, the authors make three important findings: the presence of precise coupling between saccades and tail flips can be used to discriminate between turning or gliding behaviours; aversive and appetitive chemosensory cues differentially modulate these behaviours; transformation from cue valence to behaviour is encoded by the pallium. The evidence supporting these findings is solid. The work advances our understanding of the ancient interplay between chemosensation and motor output through the modulation of eye-body coordination.

eLife Assessment

This important study examined age-related changes in cerebellar function by testing a large sample of younger and older adults, including 30 over 80 years old, on motor and cognitive tasks linked to the cerebellum and conducting structural imaging. Their findings show that cerebellar-dependent functions are mostly maintained or even enhanced across the lifespan, with cerebellar-mediated motor abilities remaining intact despite degeneration, in contrast to non-cerebellar measures. Overall, the authors provide solid evidence in support of preserved cerebellar function with age. These results highlight the resilience and redundancy of cerebellar circuits and offer key insights into aging and motor behavior.

eLife Assessment

This important study employs functional magnetic resonance spectroscopy (fMRS) to demonstrate that GABAergic inhibition in the parietal cortex actively suppresses goal-irrelevant distractors, thereby facilitating goal-directed visual tracking. The data and analyses are solid, and the methodology is validated. However, the link between the metabolic changes and the purported functional mechanisms is incomplete due to concerns with experimental design and interpretations. The study will be of interest to researchers studying goal-directed behavior and neurochemical dynamics in cognitive processing.

eLife Assessment

This important study shows that a controlled pause in gene reading is required for early heart cells to form during development. The authors demonstrate that loss of this pause prevents the proper activation of the heart-producing program across animal and stem cell systems. The evidence is compelling, supported by careful genomic and functional analyses that clearly define the developmental block. Overall, this work will interest developmental biologists and inspire further studies on the origins of early heart defects.

eLife Assessment

This useful study reports that the exogenous expression of the microRNA miR-195 can partially compensate in early B cell development for the loss of EBF1, one of the key transcription factors in B cells. While this finding will be of interest to those studying lymphocyte development, the evidence, particularly with regard to the molecular mechanisms that underpin the effect of miR-195, is currently incomplete.

eLife Assessment

In reporting on a valuable "learning proteome" for a C. elegans gustatory associative learning paradigm, this work identifies a new set of genes to be tested for roles in learning and memory, describes molecular pathways involving these genes and relevant for learning and memory in C. elegans, and deliver a new set of tools for prodding worm behavior. The methods and results convincingly support the findings, which will be of interest to neuroscientists and developmental biologists seeking to understand the self-assembly and operation of neural circuits for learning and memory.

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

eLife Assessment

This valuable work demonstrates that M. tuberculosis protein PPE2 perturbs adipose tissue biology by modulating adipogenesis, lipolysis, and inflammatory remodeling, thereby contributing to fat loss and insulin resistance during TB. Using M. smegmatis overexpression strains, PPE2-deficient Mtb mutants, and mouse models, the study links PPE2 to downregulation of PPAR-γ, C/EBP-α, adiponectin, and broader transcriptional changes in host fatty acid metabolism. These findings convincingly highlight, for the first time, a direct role for a bacterial virulence factor in TB-associated wasting. However, despite strong associative evidence, the mechanistic basis of PPE2-mediated regulation remains unresolved.

eLife Assessment

Combining connectomics, optogenetics, behavioral analysis and modeling, this study delivers important findings on the role of inhibitory neurons in the generation of leg grooming movements in Drosophila. The results include convincing evidence that the identified neuronal populations are key in the generation of rhythmic leg movements, structured in distinct polysynaptic pathways articulating inhibition and disinhibition of antagonistic sets of motor neurons, as mapped from an electron microscopy volume of the ventral nerve cord, which orchestrate an alternation of flexion and extension. By analyzing limb kinematics upon experimentally silencing specific populations of premotor inhibitory neurons, together with computational modelling, the potential role of these neurons in rhythmic leg movement is shown. This work will be of interest to neuroscientists working in motor control and limbed locomotion.

eLife Assessment

This manuscript by Kaur et al. identifies differential gene expression in distinct cell populations, specifically myeloid and lymphoid cells, following short-term exposure to e-cigarette aerosols with various flavors. Their findings are useful because they provide a single-cell sequencing data resource for assessing which genes and cellular pathways could be affected by e-cig aerosols and their components. However, the evidence is incomplete due to limited number of biological replicates per condition, as well as due to the lack of in vivo validation.

eLife Assessment

The IBEX Knowledge-Base is a fundamental tool that will enhance scientific collaboration by providing a centralized, community-driven resource for immunofluorescence imaging and reagent validation. Its detailed use cases, open-source design, and transparent reporting offer exceptional evidence of its broad utility and impact in the life sciences. It is now up to the community to contribute to its growth. Overall, the resource sets a high standard as a blueprint for future community initiatives in reproducibility and standardization.

eLife Assessment

This important study identifies a new key factor in orchestrating the process of glial wrapping of axons in Drosophila wandering larvae. The evidence supporting the claims of the authors is convincing and the EM studies are of outstanding quality. After the revision, the authors have addressed most of the concerns and the manuscript has been significantly improved. Both reviewers have agreed on the significance of the work. The work will be of interest to neuroscientists working on glial cell biology.

eLife Assessment

This important study investigates why the 13-lined ground squirrel (13LGS) retina is unusually rich in cone photoreceptors, the cells responsible for color and daylight vision. The authors perform deep transcriptomic and epigenetic comparisons between the mouse and the 13-lined ground squirrel (13LGS) to provide convincing evidence that identifies mechanisms that drive rod vs cone-rich retina development. Overall, this key question is investigated using an impressive collection of new data, cross-species analysis, and subsequent in vivo experiments.

eLife Assessment

This valuable retrospective analysis identified three independent components of glucose dynamics - "value," "variability," and "autocorrelation" - which may be used in predicting coronary plaque vulnerability. The study is solid and of interest to a wide range of investigators in the medical field who are interested in the role of glycemia on cardiometabolic health. The manuscript has been substantially strengthened by clarifying methods, improving transparency, and validating key findings, resulting in a coherent and persuasive case for autocorrelation as a meaningful third dimension of glucose dynamics despite remaining design-related limitations.

eLife Assessment

This study delivers valuable new insights into the neural circuits involved in post-mating responses (PMR) in Drosophila females, supported by convincing evidence that the circuits for mating receptivity and egg-laying are distinct. The new experimental evidence adds to the current understanding the neural circuits and molecular mechanisms underpinning PMR.

eLife Assessment

This study investigates the function of Chi3l1 in hepatic macrophages in the context of MASLD, providing useful insights at a time when the distinct roles of Kupffer cells or monocyte-derived macrophages in this disease remain incompletely defined. The data suggests that CHI3L1 in Kupffer cells modulates glucose handling in obesity and mitigates systemic metabolic dysfunction and hepatic steatosis during high-fat, high-fructose feeding. However, the loss-of-function studies employing Kupffer cell restricted versus a pan myeloid Cre lines are not sufficient to support the assertion that CHI3L1 activity is confined to resident Kupffer cells. Additionally, the flow-cytometric analyses reveal a modest depletion of Kupffer cells and no recruitment of TIM4low monocyte-derived macrophages, indicating that the system reflects simple steatosis rather than substantial macrophage turnover or niche remodelling. While the findings are intriguing, further experimentation is required to clarify the cellular specificity and mechanistic basis of the phenotypes observed.

eLife Assessment

This study describes a genetic screen to identify deubiquitinases (DUBs) that counteract the activity of small molecule degraders (PROTACs). The presented data is valuable, identifying OTUD6A and UCHL5 as DUBs that impact the efficacy and potency of PROTAC-mediated degradation in distinct subcellular compartments. While the conclusions are broadly supported and the methods employed are solid, the validation of OTUD6A and UCHL5 mechanisms requires additional study. Overall, these findings merit further evaluation by the targeted protein degradation community when developing and optimizing PROTACs and efforts to achieve compartment-specific degradation.

eLife Assessment

This important study contributes to our understanding of how epithelial cells establish polarity by identifying a hierarchy in which Par3 acts upstream of centrosome positioning and apical membrane initiation. The evidence supporting the main conclusions is convincing, although several aspects of the model remain only partially supported due to unresolved questions about microtubule organization and the need for clearer integration of quantitative and conceptual points raised in review. The work will be of interest to cell and developmental biologists, but the conclusions would be strengthened by greater precision in methodology, terminology, and interpretation.

eLife Assessment

This study uses a novel 3D imaging method to identify the Periportal Lamellar Complex (PLC), an important new structure. Although the methodological advancement and morphological descriptions are convincing, the evidence for its proposed function is incomplete, relying on transcriptomic correlation rather than direct experimental validation. The work would therefore be strengthened by focusing its claims on the robust methodological advancement and detailed morphological characterization.

eLife Assessment

In this valuable study, the authors present traces of bone modification on ~1.8 million-year-old proboscidean remains from Tanzania, which they infer to be the earliest evidence for stone-tool-assisted megafaunal consumption by hominins. Challenging published claims, the authors argue that persistent megafaunal exploitation roughly coincided with the earliest Achulean tools. Notwithstanding the rich descriptive and spatial data, the behavioral inferences about hominin agency rely on traces (such as bone fracture patterns and spatial overlap) that are not unequivocal; the evidence presented to support the inferences thus remains incomplete. Given the implications of the timing and extent of hominin consumption of nutritious and energy-dense food resources, as well as of bone toolmaking, the findings of this study will be of interest to paleoanthropologists and other evolutionary biologists.

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.