eLife Assessment

You et al. present an important study that applied a high-resolution transposon-based barcoding system to show the clonal contribution of hematopoietic stem and progenitor cells during aging, after 5-FU treatment, and upon transplantation. The results are convincing and show that there are different categories of multipotent progenitors that are either active or indolent, and that long-term fates are dominated by clones that either favor differentiation or self-renewal. This study will be of broad interest to stem-cell biologists and could reach an even wider audience with a clearer and more concise presentation and discussion of the results.

eLife Assessment

This study reports important advances in understanding how pyrazinamide, a first-line antibiotic for tuberculosis treatment, is effective in vivo. The experimental design and data provide solid evidence that the production of reactive oxygen species by host cells contributes to how pyrazinamide is more potent in the host than in culture conditions; however, additional experiments and controls would strengthen these conclusions. This work is of interest to the antibiotic drug development field.

eLife Assessment

This study demonstrated that the conditional knockout of afadin disrupts retinal laminar organization and reduced number of photoreceptors while preserving some of the structure and light responsiveness of retinal ganglion cells. These findings are solid and useful for understanding afadin's role in retinal cell generation, lamination, and functional organization. However, the study provides limited new insights into the relationship between retinal lamination defects and overall retinal function.

eLife Assessment

This useful study integrates experimental methods from materials science with psychophysical methods to investigate how frictional stabilities influence tactile surface discrimination. The authors argue that force fluctuations arising from transitions between frictional sliding conditions facilitate the discrimination of surfaces with similar friction coefficients. However, the reliance on friction data obtained from an artificial finger, together with the ambiguous correlative analyses relating these measurements to human psychophysics, renders the findings incomplete.

eLife Assessment

This valuable study offers insights into the role of Leiomodin-1 (LMOD1) in muscle stem cell biology, advancing our understanding of myogenic differentiation and indicating LMOD1 as a regulator of muscle regeneration, aging, and exercise adaptation. The integration of in vitro and in vivo approaches, complemented by proteomic and imaging methodologies, is solid. However, certain aspects require further attention to improve the clarity, impact, and overall significance of the work, particularly in substantiating the in vivo relevance. This work will provide a starting point that will be of value to medical biologists and biochemists working on LMOD and its variants in muscle biology.

eLife Assessment

ProtSSN is a valuable approach that generates protein embeddings by integrating sequence and structural information, demonstrating improved prediction of mutation effects on thermostability compared to competing models. The evidence supporting the authors' claims is compelling, with well-executed comparisons. This work will be of particular interest to researchers in bioinformatics and structural biology, especially those focused on protein function and stability.

eLife Assessment

This study describes the impact of mycobacterial genetic diversity on host-infection phenotypes by assessing the effect of different M. tuberculosis lineages on granulomatous inflammation using a 3D in vitro granuloma model. Despite being descriptive and showing mostly correlative relationships, the findings are useful and provide some solid support regarding the functional impact of M. tuberculosis's natural diversity on host-pathogen interactions. The study will interest researchers working on mycobacteria and motivate future studies to understand how genetic diversity influences virulence and immunity outcomes.

eLife Assessment

The study by Chen and Phillips provides evidence for a dynamic switch in the small RNA repertoire of the Argonaute protein NRDE-3 during embryogenesis in C. elegans. The work is supported by convincing experimental data, shedding light on RNA regulation during development. While the functional relevance of this process warrants further investigation, this study provides valuable insights into small RNA pathways with broader implications for developmental biology and gene regulation in other systems.

eLife Assessment

This useful study presents findings on the efficacy and mechanisms of linalool protection against Saprolegnia parasitica oomycetes in the grass carp model. The evidence presented is solid since the methods, data and analyses broadly support the claims with only minor weaknesses. This work will be of great interest to scientists within the fields of aquaculture, ichthyology, microbiology, and drug discovery.

eLife Assessment

This useful study uses a model of Streptococcus suis (a pig pathogen) infection in mice using an intranasal route, the natural route of infection ignored in most of the literature. The study aims to understand how capsular polysaccharides (CPS) contribute to neuropathology and virulence. The findings suggest that the olfactory route may lead to meningitis before bacteremia occurs and that CPS down-regulation may play a role in this process. However, the study remains incomplete as presented.

eLife Assessment

This valuable study reports the link between a disruption in testicular mineral (phosphate) homeostasis, FGF23 expression, and Sertoli cell dysfunction. The data supporting the conclusion are solid. This work will be of interest to biomedical researchers working on testis biology and male infertility. The assessment is based on the editors' critical evaluation of the authors' responses.

eLife Assessment

This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, findings that have theoretical or practical implications for a subfield and may be clinically useful. The intervention to entice participants to adhere to specific meal times represents a restrictive diet (even though it does not ask to limit caloric intake) similar to a time-restricted feeding diet, while the control subjects are not experiencing or adhering to dietary restrictions. The authors report significant weight loss but did not rigorously assess caloric intake which remains a weakness of this study as food diaries are notoriously unreliable. While the concept is very interesting, the study is considered incomplete, and the rigor of the results should be strengthened in follow-up studies to add more stringent methods to assess caloric intake. Additionally, the study hypothesizes that the intervention resets the circadian clock. However, the study needs an objective method for assessing circadian rhythms, such as actigraphy, in addition to a subjective questionnaire.

eLife Assessment

This study provides a comprehensive exploration of the role of IL-1β signaling during development of lung injury induced by a combination of underlying inflammation and mechanical ventilation. The data are convincing, and while the translatability of the findings related to therapeutic hypothermia may be somewhat complicated, they have the potential to be very valuable to the field.

eLife Assessment

This study highlights ITCH as a regulator of SARS-CoV-2 replication by promoting K63-linked ubiquitination of M and E proteins. While the findings are potentially useful, the approaches are overly reliant on ectopic expression models and lack direct mechanistic evidence that ubiquitination of M and E has functional relevance. Accordingly, the strength of evidence is incomplete, as further experiments are needed to validate the findings and address potential confounding factors.

eLife Assessment

NCX1 is an important cardiac Ca2+/Na+ exchanger whose activity is tightly regulated. This manuscript describes the structural basis of activation by the lipid PIP2 and inhibition by binding of a small molecule to NCX1. These results provide key insights into NCX1 regulation and cellular Ca2+ signaling, but the evidence presented is still incomplete.

eLife Assessment

This valuable paper reports machine learning-based image analysis pipelines for the automated segmentation of micronuclei and the detection and sorting of micronuclei-containing cells. These are powerful new tools for researchers who study micronuclei and their physiologic consequences. The analysis of the new tools and their benchmarking is rigorous and convincing; applications and remaining limitations are well explained in the paper.

eLife Assessment

This valuable study introduces a new method for detecting RNA modification. Since it does not rely on chemical modification of RNA, which often results in RNA degradation and therefore loss of RNA molecules, it complements other approaches for detecting RNA modification, and it might be of particular interest for sites where modifications are found in only a minority of interrogated molecules. The information provided is incomplete, however, to allow for comparison with other methods, since there is uncertainty regarding false positive and false negative rates.

eLife Assessment

This important study shows how genetic variation is associated with fecundity following a period of reproductive diapause in female Drosophila. The work identifies the olfactory system as central to successful diapause with associated changes in longevity and fecundity. While the methods used are convincing, a limitation of the study, as of any other laboratory-based investigation is the challenge of demonstrating how well measures for fitness related to diapause and its recovery correlates with realities encountered during development in the wild.

eLife Assessment

This useful manuscript reports mechanisms behind the increase in fecundity in response to sub-lethal doses of pesticides in the crop pest, the brown plant hopper. The authors hypothesize that the pesticide works by inducing the JH titer, which through the JH signaling pathway induces egg development. Evidence for this is, however, incomplete.

eLife Assessment

This valuable study confirms the association between the human leukocyte antigen (HLA)-II region and tuberculosis (TB) susceptibility in genetically admixed South African populations, specifically identifying a near-genome-wide significant association in the HLA-DPB1 gene, which originates from KhoeSan ancestry. The evidence supporting the association between the HLA-II region and TB susceptibility is solid, and the work will be of interest to those studying the genetic basis of tuberculosis susceptibility/infection resistance.

eLife Assessment

Studying several allergens in different mouse strains, the authors assessed the role of IgM in airway inflammatory responses and show that IgM deficient mice have reduced airway hyperresponsiveness. Although the findings are useful and interesting and among others show the expression of a protein that regulates actin in smooth cells, the study remains incomplete as the data and analyses only partly support their primary claim.

eLife Assessment

This important study describes how a single effector of the Type Six Secretion System (T6SS) has two distinct functions, which may contribute to bacterial survival and the development of novel antibacterials. The authors utilized various methods in biochemistry, microbiology, and microscopy to produce convincing data supporting their claims about the protein's function; however, they could clarify the implications for non-experts to enhance the accessibility of this work. This manuscript is of interest to those studying T6SS, particularly those interested in effectors and bacterial enzymes.

eLife Assessment

This manuscript reports an important new statistical method for calculating the significance of correlations between two time-series, which provides more accuracy than other methods when the data has few replicates. The proposed method solves a real-life problem that is frequently encountered and is broadly applicable to many realistic datasets in many experimental contexts. The technique is supported with compelling mathematical derivations as well as analysis of both computer-generated and previously published experimental data.

eLife Assessment

This important study uses extensive comparative analysis to examine the relationship between plasma glucose levels, albumin glycation levels, and diet and life history, within the framework of the "pace of life syndrome" hypothesis. The evidence that glucose is positively correlated with glycation levels and lifespan is convincing and, although there are some limitations related to data collection, they likely make the statistically significant findings more conservative. As the first extensive comparative analysis of glycation rates, life history, and glucose levels in birds, the study has the potential to be of interest to evolutionary ecologists and the aging research community more broadly.

eLife Assessment

This important study introduces a fully differentiable variant of the Gillespie algorithm as an approximate stochastic simulation scheme for complex chemical reaction networks, allowing kinetic parameters to be inferred from empirical measurements of network outputs using gradient descent. The concept and algorithm design are convincing and innovative. While the proofs of concept are promising, some questions are left open about implications for more complex systems that cannot be addressed by existing methods. This work has the potential to be of significant interest to a broad audience of quantitative and synthetic biologists.

eLife Assessment

This study presents important insights into the regulation of left-right organ formation. By combining genetic perturbation of all three Meteorin genes in zebrafish and timelapse imaging, the authors identify an essential role for this protein family in the establishment of left-right patterning. They provide convincing evidence that Meteorins are required for the morphogenesis of dorsal forerunner cells, the precursors of the left-right organizer (also named Kupffer's vesicle) in zebrafish. In line with this, Meteorins were shown to genetically interact with integrins ItgaV and Itgb1b to regulate dorsal forerunner cell clustering.

eLife Assessment

This study maps the genotype-phenotype landscapes of three E. coli transcription factors and the topographical features of these landscapes. It shows that ruggedness and epistasis do not hinder the evolution of strong transcription factor binding sites. These convincing findings contribute valuable insights into fitness landscape theories and highlight the role of chance, contingency, and evolutionary biases in gene regulation. The authors then study the topographical features of these landscapes, especially the number and distribution of local maxima, as well as the statistical properties of evolutionary paths on these landscapes.

eLife Assessment

This important study characterizes and validates a new activity marker - fast labelling of engram neurons (FLEN) - which is transiently active and driven by cFos, allowing the monitoring of intrinsic and synaptic properties of engram neurons shortly after the learning experience. The results convincingly demonstrate the utility of this novel viral tool for studying early changes in the properties of engram cells. However, the study would benefit from exploring how accurately FLEN reflects endogenous cFos activity, how this labelling technique compares to previous versions, and from careful consideration of alternative explanations such as changes in release probability.

eLife Assessment

This study provides important evidence that the postmating behavioral switch in male mice is mediated by distinct stages of synaptic plasticity within the medial amygdala-MPOA-BSTrh pathway. The findings are convincing, supported by rigorous behavioral characterization and electrophysiological approaches that disentangle the contributions of mating, cohabitation, and parental experience to neural circuit changes. While some methodological details and statistical reporting require clarification, the study significantly advances our understanding of the neural mechanisms underlying paternal behavior.

eLife Assessment

This study provides valuable observations indicating that human pyramidal neurons propagate information as fast as rat pyramidal neurons despite their larger size. Convincing evidence demonstrates that this property is due to several biophysical properties of human neurons. This study will be of interest to neurophysiologists.

eLife Assessment

This study is valuable as it provides information about the genes regulated by sex hormone treatment in song nuclei and other brain regions and suggests candidate genes that might induce sexual dimorphism in the zebra finch brain. The analysis presented is thorough and detailed. Whereas the evidence for gene regulation by hormone treatment is well supported, the evidence for an association of those genes with song learning (as written in the title) is incompletely supported as no manipulation of song learning or song analysis was conducted.

eLife Assessment

This valuable paper introduces Heron, lightweight scientific software that is designed to streamline the implementation of complex experimental pipelines. The software is tailored for workflows that require coordinating many logical steps across interconnected hardware components with heterogeneous computing environments. The authors convincingly demonstrate Heron's utility and effectiveness in the context of behavioral experiments, addressing a growing need among experimentalists for flexible and scalable solutions that accommodate diverse and evolving hardware requirements.

eLife Assessment

This important study advances our understanding of the role of dopamine in modulating pair bonding in mandarin voles by examining dopamine signaling within the nucleus accumbens across various social stimuli using state-of-the-art causal perturbations. The evidence supporting the findings is compelling, particularly cutting-edge approaches for measuring dopamine release as well as the activity of dopamine receptor populations during social bonding. Some concerns remain about the statistical analyses.

eLife Assessment

The authors aim to elucidate the mechanism by which pyroptosis (through the formation of Gasdermin D (GSDMD) pores in the plasma membrane) contributes to increased release of procoagulant Tissue Factor-containing microvesicles. The data offers solid mechanistic insights as to the interplay between pyroptosis and microvesicle release with NINJ1. The study provides useful insights into the potential of targeting Ninj1 as a therapeutic strategy.

eLife Assessment

In this valuable study, the authors integrate several datasets to describe how the genome interacts with nuclear bodies across distinct cell types and in Lamin A and LBR knockout cells. They provide convincing evidence to support their claims and particularly find that specific genomic regions segregate relative to the equatorial plane of the cell when considering their interaction with various nuclear bodies. The authors are encouraged to consider citing the relevant work of other labs who have shown the presence of different types of Lamin Associated Domains (LADs).

eLife Assessment

This important study allows for a better understanding of anthelmintic drug resistance in nematodes. The authors provide a detailed analysis of the role of UBR-1 and its underlying mechanism in ivermectin resistance using convincing behavioural and genetic experiments with C. elegans. Although the authors have addressed the concerns of the reviewers, it would be prudent for the authors to disclose the Dyf phenotype in ubr-1 mutants. The authors should at the very least report the Dyf phenotype and the experiment on which they base the argument that the Dyf phenotype does not affect their conclusions.

eLife Assessment

This manuscript describes a resource detailing the econstitution of Holothuria glaberrima gut following self-evisceration in response to a potassium chloride injection, using scRNAseq and fluorescent RNA localization in situ. It provides some new findings about organ regeneration, as well as the origins of pluripotent cells, and places these findings in the context of regeneration across species. The paper's schematic model and HCR images are a valuable foundation for future work. The authors provide convincing RNA localization images to validate their data and to provide spatial context. These validation experiments are of good quality but remain challenging to connect to the complex spatial organization of complex tissues. This resource will be of interest to the field of regeneration, particularly in invertebrates, but also in comparative studies in other species, including evolutionary studies.

eLife Assessment

The authors present convincing findings on trends in hind limb morphology through the evolution of titanosaurian sauropod dinosaurs, the land animals that reached the most remarkable gigantic sizes. The important results include the use of 3D geometric morphometrics to examine the femur, tibia, and fibula to provide new information on the evolution of this clade and on evolutionary trends between morphology and allometry.

eLife Assessment

This is a valuable study that tests the functional role of food-washing behavior in removing tooth-damaging sand and grit in long-tailed macaques and whether dominance rank predicts level of investment in the behavior. The evidence that food-washing is deliberate is compelling, but the evidence for variable and adaptive investment depending on rank, including the fitness-relevance and ultimate evolutionary implications of the findings, is incomplete given limitations of the experimental design. Overall, the paper should be of interest to researchers interested in foraging behavior, cognition, and primate evolution.

eLife Assessment

This important study characterizes the molecular signatures and function of a type of enteric neuron (IPAN) in the mouse colon, identifying molecular markers (Cdh6 and Cdh8) for these cells. A battery of compelling and comprehensive experimental findings suggests data from other species are likely translatable to mice, bridging the abundant literature from humans and other mammals into this experimentally tractable animal model. This work will be of interest to scientists studying the motor control of the colon and more generally the enteric neuromuscular system.

eLife Assessment

This valuable study reports on the critical role of ANKRD5 (ANKEF1) in sperm motility and male fertility. However, the supporting data remain incomplete. This work will be of interest to biomedical researchers working in sperm biology and andrologists.

eLife Assessment

This study demonstrates the critical role of Afadin on the generation and maintenance of complex cellular layers in the mouse retina. The data are solid, which provides important insights into how cell-adhesion molecules contribute to retinal organization. However, further investigations are needed to clarify the mechanisms underlying the cellular disorganization phenotype in the retina and axonal projection to the brain.

eLife Assessment

Centromeres are specific sites on chromosomes that are essential for mitosis and genome fidelity. This valuable work extends previous studies to convincingly show that the centromere-histone core contributes to force transduction through the kinetochore. The centromere mainly strengthens one of the two paths of force transduction, influenced by the centromeric DNA sequence, the mechanism for which remains to be determined. This work will be of interest to those studying cell division and chromosome segregation.

eLife Assessment

In this work, the authors use a Drosophila melanogaster adult ventral nerve cord injury model extending and confirming previous observations. This important study reveals key aspects of adult neural plasticity. Taking advantage of several genetic reporter and fate tracing tools, the authors provide solid evidence for different forms of glial plasticity, that are increased upon injury. The significance of the generated cell types under homeostatic conditions and in response to injury remains to be further explored and open up new avenues of research.

eLife Assessment

This study presents valuable findings by using Fmr1 knockout mice as a model to investigate the role of Fmr1 in sleep regulation. These mice exhibited clear evidence of sleep and circadian disturbances, including abnormal retinal innervation of the SCN, which may provide a potential mechanistic explanation for the observed behavioral deficits. Interestingly, the results suggest that a scheduled feeding approach could improve sleep and circadian rhythms while enhancing social interactions and reducing repetitive behaviors in a mouse model of Fragile X syndrome. The topic is both intriguing and highly significant; however, while the evidence supporting the authors' claims is solid, several issues hinder the manuscript's clarity and impact.

eLife Assessment

This study presents an important discovery regarding the diversity and evolution of gall-forming microbial effectors. Supported by convincing computational structural predictions and analyses, the research provides insights into the unique mechanisms by which gall-forming microbes exert their pathogenicity in plants. This study also offers guidance that is of value for future studies on pathogen effector function and co-evolution with host plants.

eLife Assessment

This important study reports a detailed computational analysis of the CFTR ion channel's permeation mechanism, advancing our understanding of its structure-function relationship. The conclusions are based on extensive molecular dynamics simulations and thorough analysis, but the use of an approximate chloride ion model, known to underestimate key ion-protein interactions, leaves them incomplete without experimental or alternative computational validation. The work will be of interest to biophysicists working on CFTR and cystic fibrosis.

eLife Assessment

Rennert et al. developed a valuable thermodynamic framework to study the force response of branched actin networks from the crucial and unexplored perspective of energetic cost. They used the fact that the entropy production rate must be positive to derive inequalities that set limits on the maximum force produced by branched actin networks, and speculate that the dissipative cost beyond that required to move the load may be necessary to maintain an adaptive steady state. This work is highly innovative, but remains incomplete until the hypotheses of the model are better justified and the conclusions about the dissipative cost of the system are better established.

eLife Assessment

This study presents a potentially fundamental analysis of the original color of a fossil feather from the crest of a 125-million-year-old enantiornithine bird, using sophisticated 3D microscopic and numerical methods to conclude that the feather was iridescent and brightly colored, possibly indicating that this was a male bird that used its crest in sexual displays. At present, the strength of evidence supporting the authors' conclusions is considered incomplete based on methodological incompleteness and questions about taphonomy.

eLife Assessment

This fundamental manuscript comprehensively examines the roles of nine structural proteins in herpes simplex virus 1 (HSV-1) assembly and nuclear egress. By integrating cryo-light microscopy and soft X-ray tomography, the study presents an innovative approach to investigating viral assembly within cells. The research is thoroughly executed, yielding compelling data that explain previously unknown functions of these structural proteins. This work is of broad interest to virologists, cellular biologists, and structural biologists, offering a robust, contextually rich methodology for studying large protein complex assembly within the cellular environment, serving as an excellent starting point for high-resolution techniques.

eLife Assessment

This study provides important insights into the regulation of type-I interferon signaling and anti-tumor immunity, demonstrating that ORMDL3 promotes RIG-I degradation to suppress immune responses. The evidence is convincing, with well-executed mechanistic experiments and in vivo validation in syngeneic tumor models. These findings have significant implications for cancer immunotherapy, highlighting ORMDL3 as a potential therapeutic target.

eLife Assessment

This study addresses an important and longstanding question regarding the molecular mechanism of protein misfolding in Ig light chain (LC) amyloidosis (AL), a life-threatening condition. By combining advanced techniques, including small-angle X-ray scattering, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, the authors provide convincing evidence that the "H state" distinguishes amyloidogenic from non-amyloidogenic LCs. These findings not only offer novel insights into LC structural dynamics but also hold promise for guiding therapeutic strategies in amyloidosis and will be of particular interest to structural biologists, biophysicists, and many others working on amyloid diseases.

eLife Assessment

This study addresses an important and longstanding question regarding the molecular mechanism of protein misfolding in Ig light chain (LC) amyloidosis (AL), a life-threatening condition. By combining advanced techniques, including small-angle X-ray scattering, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, the authors provide convincing evidence that the "H state" distinguishes amyloidogenic from non-amyloidogenic LCs. These findings not only offer novel insights into LC structural dynamics but also hold promise for guiding therapeutic strategies in amyloidosis and will be of particular interest to structural biologists, biophysicists, and many others working on amyloid diseases.

eLife Assessment

The authors present three transgenic models carrying three representative exon deletions of the dystrophin gene. The findings presented are valuable to the field of muscle diseases, particularly muscular dystrophies. The evidence provided in the manuscript is convincing, with rigorous biochemical assays and state-of-the-art microscopy methods.

eLife Assessment

This valuable work provides solid evidence that a neuronal metallothionein, GIF/MT-3, incorporates metal-persulfide clusters. A variety of well-designed assays support the authors' hypothesis, revealing that sulfane sulfur is released from MT-3. The biological role of the persulfidated form is not yet clearly defined. There are caveats to the findings that limit the study, but the work will nevertheless prompt major follow-up work.

eLife Assessment

This fundamental article significantly advances our understanding of FGF signalling, and in particular, highlights the complex modifications affecting this pathway. The evidence for the authors' claims is convincing, combining state-of-the-art conditional gene deletion in the mouse lens with histological and molecular approaches. This work should be of great interest to molecular and developmental biologists beyond the lens community.

eLife Assessment

In this valuable report, the authors investigated the effect of mitochondrial transplantation on post-cardiac arrest myocardial dysfunction (PAMD), which is associated with mitochondrial dysfunction. They convincingly demonstrated that mitochondrial transplantation enhanced cardiac function and increased survival rates after the return of spontaneous circulation (ROSC). They have also shown that myocardial tissues with transplanted mitochondria exhibited increased mitochondrial complex activity, higher ATP levels, reduced cardiomyocyte apoptosis, and lower myocardial oxidative stress post-ROSC.

eLife Assessment

These useful findings assigned a novel functional implication of histone acylation, crotonylation. Although the mechanistic insights have been provided in great detail regarding the role of the YEATS2-GCDH axis in modulating EMT in HNC, the strength of evidence for the manuscript is incomplete. The patient cohort is very small, with just 10 patients; to establish a significant result the cohort size should be increased. Furthermore, the functional implication of p300 is also to be looked into.

eLife Assessment

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

eLife Assessment

This manuscript reports fundamental discoveries on how necrotic cells contribute to organ regeneration through apoptotic signalling to produce cells with non-lethal apoptotic caspase activity that contribute to the regenerated tissue. These findings will be of broad interest to those who study wound repair and tissue regeneration. The strength of the evidence is solid and has been improved in the revised version.

eLife Assessment

This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are valuable for future investigation of stem cell division in planarians. The methods are solid, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.

eLife Assessment

This study provides evidence that single-cell multi-omics profiling can reveal key regulators of HIV-1 persistence and early immune dysregulation, particularly implicating KLF2 and Th17 cells as major players in viral reservoir dynamics. The findings are solid, supported by rigorous integration of scRNA-seq and scATAC-seq data, but are limited by sample size and lack of validation with external datasets. Overall, this work makes a valuable contribution to understanding HIV-1 immune evasion and highlights potential therapeutic targets for reservoir eradication.

eLife Assessment

This valuable study describes a software package in R for visualizing metabolite ratio pairs. The evidence supporting the claims of the authors is solid and broadly supports the authors' conclusions. This work would be of interest to the mass spectrometry community.

eLife Assessment

This study provides valuable information on the single nucleus RNA sequencing transcriptome, pathways, and cell types in pig skeletal muscle in response to conjugated linoleic acid (CLA) supplementation. Based on the comprehensive data analyses, the data are considered compelling and provide new insight into the mechanisms underlying intramuscular fat deposition and muscle fiber remodeling. The study contributes significantly to the understanding of nutritional strategies for fat infiltration in pig muscle.

eLife Assessment

This important study reveals that disrupting fatty acid metabolism in macrophages significantly restricts the growth of Mycobacterium tuberculosis, showing that impaired lipid processing triggers various antimicrobial responses. Overall, the approach is robust, utilizing CRISPR-Cas9 knockout of multiple genes involved in lipid metabolism which yielded convincing data. This work highlights how host lipid metabolism affects the ability of tubercle bacilli to thrive intracellularly, pointing to potential new therapeutic targets.

eLife Assessment

This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are important for future investigation of stem cell division in planarians and have implications for analyzing stem cell biology in other systems. The methods are convincing, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.

eLife Assessment

This important and well-written study uses functional neuroimaging in human observers to provide compelling evidence that activity in the early visual cortex is suppressed at locations that are frequently occupied by a task-irrelevant but salient item. This suppression appears to be general to any kind of stimulus and also occurs in advance of any item actually appearing. The work will be of great interest to psychologists and neuroscientists examining attention, perception, learning and prediction.

eLife Assessment

This valuable work presents how PRDM16 plays a critical role during colloid plexus development, through regulating BMP signaling. Solid evidence supports the context-dependent gene regulatory mechanisms both in vivo and in vitro. The work will be of broad interest to researchers working on growth factor signaling mechanisms and vertebrate development.

eLife Assessment

The authors utilize a valuable computational approach to exploring the mechanisms of memory-dependent klinotaxis, with a hypothesis that is both plausible and testable. Although they provide a solid hypothesis of circuit function based on an established model, the model's lack of integration of newer experimental findings, its reliance on predefined synaptic states, and oversimplified sensory dynamics, make the investigation incomplete for both memory and internal-state modulation of taxis.

eLife Assessment

This important study examines the role of pericytes in patterning the zebrafish blood-brain barrier (BBB) and controlling its permeability. Using pdgfrb mutant zebrafish models lacking brain pericytes, the authors report that pericyte-deficient cerebrovasculatures are ill-patterned, yet display unaltered restrictive BBB permeability properties at larval and juvenile stages. More severe phenotypes are detected in adults, with focal leakage sites associated with hemorrhages and aneurysms. Using solid and beautifully documented imaging, the authors suggest that, contrary to the situation described in rodent models, pdgfrb-dependent pericytes are not required to maintain the BBB in the zebrafish brain; these unexpected and intriguing findings reshape our understanding of BBB permeability regulation in vertebrates.

eLife Assessment

This important manuscript proposes a new strategy for the identification of new mechanisms of drug resistance based on SAturated Transposon Analysis in Yeast (SATAY), a powerful transposon sequencing method in Saccharomyces cerevisiae. This method allows us to uncover loss- and gain-of-function mutations conferring resistance to 20 different antifungal compounds. The method is convincing, allowing the authors to identify a novel interaction of chitosan with the cell wall mannosylphosphate, and show that the transporter Hol1 concentrates the novel antifungal ATI-2307 within yeast.

eLife Assessment

This important study seeks to examine the relationship between pupil size and information gain, showing opposite effects dependent upon whether the average uncertainty increases or decreases across trials. Given the broad implications for learning and perception, the findings will be of broad interest to researchers in cognitive neuroscience, decision-making, and computational modelling. Nevertheless, the evidence in support of the particular conclusion is at present incomplete - the conclusions would be strengthened if the authors could both clarify the differences between model-updating and prediction error in their account and clarify the patterns in the data.

eLife Assessment

This important study analyzes a large dataset of Salmonella gallinarum whole-genome sequences and provides findings regarding the population structure of this avian-specific pathogen. The convincing results indicate regional adaptation of the mobilome-driven resistome and a role in the evolutionary trajectory of this pathogen that will interest microbiologists and researchers working on genomics, evolution, and antimicrobial resistance.

eLife Assessment

In this valuable study, Tutak and colleagues set out to identify factors that mediate Repeat Associated Non-AUG (RAN) translation of CGG repeats in the FMR1 mRNA which are implicated in toxic protein accumulation that underpins ensuing neurological pathologies. The authors provide solid evidence that RPS26 may be implicated in mediating the RAN translation of FMR1 mRNA. This article should be of broad interest to researchers in the variety of disciplines including post-transcriptional regulation of gene expression and neurobiology.

eLife Assessment

This valuable study uses a massive and long-term experimental data set to provide solid evidence on how tree diversity affects host-parasitoid communities of insects in forests. The work will be of interest to ecologists working on biodiversity conservation, community ecology, and food webs.

eLife Assessment

This important study provides new insights into the mechanisms that underlie perceptual and attentional impairments of conscious access. The paper presents convincing evidence of a dissociation between the early stages of low-level perception, which are impermeable to perceptual or attentional impairments, and subsequent stages of visual integration which are susceptible to perceptual impairment but resilient to attentional manipulations. This study will be of interest to scientists working on visual perception and consciousness.

eLife Assessment

This important manuscript sets out to identify sleep/arousal phenotypes in larval zebrafish carrying mutations in Alzheimer's disease (AD)-associated genes. The authors provide detailed phenotypic data for F0 knockouts of each of 7 AD-associated genes and then compare the resulting behavioral fingerprints to those obtained from a large-scale chemical screen to generate new hypotheses about underlying molecular mechanisms. The data presented are solid, although extensive interpretation of pharmacological screen data does not necessarily reflect the limited mechanistic data. Nonetheless, the authors address most reviewer concerns in their revised version, providing invaluable new analyses. Phenotypic characterization presented is comprehensive, and the authors develop a well-designed behavioral analysis pipeline that will provide considerable value for zebrafish neuroscientists.

eLife Assessment

This study examined how multidimensional social relationships influence social attention in rhesus macaques, linking individual and group-level behaviors to attentional processes. The findings that oxytocin altered social attention and its relationship to both social tendencies and dyadic relationships are important, as recent technological advances allow for the exploration of neuronal activities and mechanisms in free-moving macaques. This work is convincing and will be of interest to those studying the interplay between social dynamics and information processing in primates.

eLife Assessment

This study reveals a novel mechanism of glutamine synthetase (GS) regulation in Methanosarcina mazei, demonstrating that 2-oxoglutarate (2-OG) directly promotes GS activity by stabilizing its dodecameric assembly. Using mass photometry, activity assays, and cryo-electron microscopy, the authors show that GS transitions from a dimeric, inactive form at low 2-OG concentrations to a fully active dodecameric complex at saturating 2-OG levels, highlighting 2-OG as a key effector in C/N sensing. The findings are valuable, supported by solid data, and provide new insights into archaeal GS regulation, though further clarification of interactions with known partners like Glnk1 and sp26 is needed.

eLife Assessment

This important paper reports functional interactions between L1TD1, an RNA binding protein (RBP), and its ancestral LINE-1 retrotransposon which is not modulated at the translational level. The evidence for the association between L1TD1 and LINE-1 ORF1p is solid. The work implies that the transposon-derived RNA binding protein in the human genome can interact with the ancestral transposable element from which this protein was initially derived. This work spurs interesting questions for cancer types, where LINE1 and L1TD1 are aberrantly expressed.

eLife Assessment

The study reports valuable findings from a very rich EEG-fMRI dataset including 107 participants, which was collected during nocturnal naps. The authors link activity in memory-related brain regions (e.g., hippocampus, thalamus, and medial prefrontal cortex), and their functional connectivity, to the occurrence of canonical sleep rhythms, namely spindles and slow oscillations in non-rapid eye movement sleep. This work could contribute to further understanding of sleep neural dynamics, although the evidence for some of the main claims is incomplete at present.

eLife Assessment

The authors use deep mutational scanning to assess the effect of ~6,600 protein-coding variants in MC4R, a G protein coupled receptor associated with obesity. They develop new, more precise approaches to deep mutational scanning, enabling them to probe molecular phenotypes directly relevant to the development of drugs that target this receptor. In this important work, the authors provide compelling evidence that variants impact signaling through MC4R in different ways, that some defective variants are amenable to a corrector drug and that deep mutational scanning data could guide compound optimization.

eLife Assessment

This manuscript describes an important study of the giant virus Jyvaskylavirus. The characterisation presented is compelling. The work will be of interest to virologists working on giant viruses as well as those working with other members of the PRD1/Adenoviridae lineage.

eLife Assessment

This manuscript presents solid evidence suggesting that the loss of ZNRF3 and RNF43, two E3 ubiquitin ligases, leads to dysregulation of EGFR signaling in cancer. The authors propose that EGFR is a direct substrate of ZNRF3/RNF43. While the authors provide immunoprecipitation data showing increased detection of ubiquitinated species, this evidence does not definitively establish that EGFR itself is ubiquitinated by RNF43/ZNRF3. The absence of direct evidence for EGFR ubiquitination is a major limitation, although the findings are useful as they may provide novel insights into the mechanisms underlying EGFR-driven cancers and open new therapeutic avenues.

eLife Assessment

This manuscript presents a clever and powerful approach to examining differential roles of Nav1.2 and Nav1.6 channels in excitability of neocortical pyramidal neurons, by engineering mice in which a sulfonamide inhibitor of both channels has reduced affinity for one or the other channels. Overall, the results in the manuscript are compelling and give important information about differential roles of Nav1.6 and Nav1.2 channels. Activity-dependent inactivation of NaV1.6 was also found to attenuate seizure-like activity in cells, demonstrating the promise of activity-dependent NaV1.6-specific pharmacotherapy for epilepsy.

eLife Assessment

This valuable study provides a novel framework for leveraging longitudinal field observations to examine the effects of aging on stone tool use behaviour in wild chimpanzees. However, the analysis and interpretation are currently incomplete and would benefit from a more robust consideration of additional sources of variance for the data (e.g., foraging ecology, nut and tool properties, etc.). Despite the low sample size of five individuals, this study is of broad interest to ethologists, primatologists, archaeologists, and psychologists.

eLife Assessment

The conclusions of this work are based on valuable simulations of a detailed model of striatal dopamine dynamics. Establishing that a lower dopamine uptake rate can lead to a 'tonic' level of dopamine in the ventral but not dorsal striatum, and that dopamine concentration changes at short delays can be tracked by D1 but not D2 receptor activation, is of value and will be of interest to dopamine aficionados. However, the simulations are incomplete, providing only partial support for the key claims. Several things can be done to strengthen the conclusions, including, for example, but not exclusively, a demonstration of how the results would change as a function of changes in D2 affinity.

eLife Assessment

This valuable study provides convincing evidence that specific proteins on the surface of cancer cells undergo a particular form of recycling and are redirected toward the cell-cell contact with T cells, a type of immune cell. However, the characterization of the consequences of T cell activation resulting from perturbing the recycling pathway is incomplete. Furthermore, relevant literature has not been sufficiently cited.

eLife Assessment

This study presents valuable insights into the role of two proteins, Rab27A and SYTL5, which control vesicle transport and delivery. While the data is clear, the overall evidence is somewhat incomplete. Strengthening the mechanistic aspect would enhance the study, making it of greater interest to cell biologists studying membrane trafficking and mitochondria.

eLife Assessment

This important study characterizes the mechanics and stability of bolalipids from archaeal membranes using molecular dynamics simulations. A mesoscale model of bolalipids is presented and evaluated across a series of membrane configurations. The evidence supporting the conclusions is convincing, demonstrating that mixtures of bolalipids and regular bilayer lipids in archaeal membranes enhance fluidity and stability.

eLife Assessment

This important study explores the commander-independent function of COMMD3-Arf1 in endosomal recycling. The evidence supporting the authors' claims is solid; however, the inclusion of additional validation experiments and control conditions would have further strengthened the study. The findings will be of significant interest to cell biologists working on membrane trafficking.

eLife Assessment

This manuscript makes a valuable contribution to the field by uncovering a molecular mechanism for miRNA intracellular retention, mediated by the interaction of PCBP2, SYNCRIP, and specific miRNA motifs. These findings advance our understanding of RNA-binding protein-mediated miRNA sorting and provide deeper insights into miRNA dynamics. While the conclusions are supported by solid experimental evidence, additional controls and clarification of the precise intracellular interactions would further strengthen the study.

eLife Assessment

This important study explores the conserved role of IgM in both systemic and mucosal antiviral immunity in teleosts, challenging established views on the differential roles of IgT and IgM. The findings have theoretical and practical implications for immunology and aquaculture. However, the strength of the evidence is incomplete due to insufficient validation of the monoclonal antibodies used to deplete IgM, which limits confidence in the main claims. Addressing these methodological weaknesses would significantly enhance the study's impact.

eLife Assessment

This study reveals that PRMT1 overexpression drives tumorigenesis of acute megakaryocytic leukemia (AMKL) and that targeting PRMT1 is a viable approach for treating AMKL. While the evidence, based largely on one cell line, is convincing, further validations in additional experiment settings will solidify the conclusion. These findings have important implications for the treatment of AMKL with PRMT1 over expression in the future.

eLife Assessment

This useful study reports analyses of Neuropixel recordings in the medial prefrontal cortex and hippocampus of rats in a spatial navigation trial, focusing on classifying prefrontal neurons based on SWR modulation and anatomical location. However, the evidence for claims of a clear link between SWR modulation and neuronal encoding, and the evidence for anatomical organization, is currently incomplete. Further analyses might strengthen the evidence for some conclusions, and some of the strong claims of the paper should likely be moderated.

eLife Assessment

Using electrophysiological recordings in freely moving rats, this valuable study investigates the role of different gamma frequency bands in the development of spatial representations in the hippocampus. Solid evidence supports the idea that gamma-modulated neurons are crucial for generating specific neuronal sequences. These findings will be of interest to neuroscientists studying spatial navigation and neuronal dynamics.

eLife Assessment

The Twin Domain model proposed by Lui and Wang proposing that twin supercoiling domains of DNA emerge during transcription were first described decades ago, but direct experimental evidence has been challenging to obtain. Here, the authors make a fundamental contribution by directly measuring DNA torsion in cells using a photoactivatable intrastrand cross-linker compared to controls. They gather compelling data using this clever method, which provides direct evidence in support of the twin-supercoiled domain model, for torsional effects at transcription start and end sites, and thereby uncover novel features of higher order structure of chromatin in yeast. These data are exciting, and the tools will be of interest to anyone studying chromosome structure and gene regulation.

eLife Assessment

This useful paper uses a quantitative modeling approach to explore a putative mechanism underlying a well-studied behavioral transition in the nematode C. elegans. The premise, that what has been considered a two-state behavior can instead be described as a process whose parameters are smoothly modulated within a single state, is intriguing. However, in the paper's current state, concerns about the model and its fit to empirical data make the support for this idea inadequate.

eLife Assessment

The study presents valuable findings on the molecular mechanisms of glucose-stimulated insulin secretion from pancreatic islets, focusing on the main regulatory elements of the signaling pathway in physiological conditions. While the evidence supporting the conclusions is solid, the study can be strengthened by the use of a beta cell line or knockout mice. The work will be of interest to cell biologists and biochemists working on diabetes.

eLife Assessment

This paper presents miniML, an AI-based framework for the detection of synaptic events. Benchmark results presented in the paper are compelling, demonstrating the superiority of miniML over current state-of-the-art alternatives. The performance of miniML is demonstrated across various experimental paradigms, showing that miniML has the potential to become a valuable tool for the analysis of synaptic signals.

eLife Assessment

This manuscript describes a novel approach for assessing cognitive function in freely moving mice in their home-cage, without human involvement. The authors provide convincing evidence in support of the tasks they developed to capture a variety of complex behaviors and demonstrate the utility of a machine learning approach to expedite the acquisition of task demands. This work is important given its potential utility for other investigators interested in studying mouse cognition. However, additional information (e.g., detailed construction manual, code) is needed to allow other investigators to implement this system independently and use it widely.

eLife Assessment

The authors have undertaken a useful study to update an existing niche model of highly pathogenic avian influenza. However, there are issues regarding the conceptualisation of the ecological niche of highly pathogenic avian influenza transmission that the modelling aims to capture, raising concerns about the strength of evidence used to support the findings. There are a number of modelling assumptions that are incompletely justified. Combined with shortcomings in the communication, this dilutes the strength of the key findings of this work.

eLife Assessment

This study provides valuable findings on the effects of mating experience on sweet taste perception. The data as presented provide solid evidence that the dopaminergic signaling-mediated reward system underlies this mating state-dependent behavioral modulation. The work will interest neuroscientists, particularly those working on neuromodulation and the effects of internal states on behavior.

eLife Assessment

This useful study presents a virtual reality-based contextual fear conditioning paradigm for head-fixed mice. The approach provides a way to perform multiphoton imaging of neural circuits during behaviors that have traditionally been studied in freely moving animals. However, evidence supporting key claims is currently incomplete, particularly regarding elicitation and detection of freezing behaviors, and the impact of the study would be increased by articulating what this initial exploration of parameters offers over existing approaches.

eLife Assessment

This study presents a valuable finding regarding how partner preference formation and pair bonding behavior are related to the oxytocin receptor gene expression in the NAc and paraventricular nucleus of the hypothalamus in prairie voles. The evidence supporting this claim is solid but could benefit from clarity in the framing, approach, and results. This study will be of interest to social scientists and neuroscientists who work on pair bonding and oxytocin.

eLife Assessment

This multimodal neuroimaging study leverages fMRI, PET, and deep learning to predict memory performance. The authors introduce the brain-cognition gap to link these different imaging modalities to cognition and evaluate their results in two independent cohorts. The results are a valuable addition to the literature and will be of interest to neuroscientists working at the interface of cognition, neuroimaging, and computational modeling. However, the evidence supporting the conclusions remains incomplete.

eLife Assessment

This is a well-written important paper on the recovery of fauna and flora following the end-Permian extinction event in several continental sites in northern China. The convincing conclusion, a rapid recovery in tropical riparian ecosystems following a short phase of hostile environments and depauperate biota, is supported by an impressive amount of data from sedimentology, body fossils of animals and plants, and especially trace fossils.

eLife Assessment

The manuscript addresses the 3D chromatin architecture in monocytes from patients with alcohol-associated hepatitis and its relationship to enhanced transcription of innate immune genes. While the concept and methodological approach are appealing, the evidence is incomplete as a result of insufficient sample sizes as well as other significant analytical concerns.

eLife Assessment

This valuable study combined whole-head magnetoencephalography (MEG) and subthalamic (STN) local field potential (LFP) recordings in patients with Parkinson's disease undergoing deep brain stimulation surgery. The paper provides convincing evidence that cortical and STN beta oscillations are sensitive to movement context.

eLife Assessment

This important study by Wong et al. addresses a longstanding question in the field of associative learning regarding how a motivationally relevant event can be inferred from prior learning based on neutral stimulus-stimulus associations. The research provides convincing behavioral and neurophysiological evidence to address this question. The manuscript will be interesting for researchers in behavioral and cognitive neuroscience.

eLife Assessment

This important work investigates the mechanism that underlies the switch between feeding and mating behaviors in the oriental fruit fly, Bactrocera dorsalis. Using a variety of approaches, the authors show that this switch is mediated by the neuropeptide, sulfakinin, acting peripherally through the sulfakinin receptor 1 to regulate the expression of antennal odorant receptors. The evidence is solid in support of the hypothesis that sulfakinin signaling mediates changes in the periphery, although additional sites of action may also contribute to these changes.

eLife Assessment

This important work combines molecular genetics and behavioral analyses to identify inhibitory neurons in the female medial preoptic area as a neural locus that is activated following male ejaculation and whose prolonged activity plays a key role in the regulation of female sexual motivation. These experiments are rigorous and well-performed. The data are compelling and demonstrate that a subpopulation of neurons in the medial preoptic area are selectively activated following the completion of mating in females. The medial preoptic area has long been implicated as critical to sexual behavior in both sexes; however the use of a self-paced mating assay for females provides fine control over manipulating and monitoring cellular activity in this region during more naturalistic behavior. In addition, this study may act to inspire others to further explore the additional brain regions found to show upregulation of neural activity (Fos) during mating completion in females using the datasets generated here.

eLife Assessment

Yamamoto and Matano provide convincing evidence that a G63E/R CD8+ T-cell escape mutation in the accessory viral protein Nef promote the induction of neutralizing antibody (nAb) responses in rhesus macaques infected with SIVmac239, which is usually largely resistant to neutralization. Functional analyses support that this mutation specifically impairs Nef`s ability to stimulate PI3K/Akt/mTORC2 signalling. This important study suggests that the accessory viral protein Nef impairs B cell function and effective humoral immune responses and is of interest for researchers and physicians interested in HIV/AIDS and vaccine development.

eLife Assessment

This valuable study presents data suggesting the critical roles of two ancient proteins, XAP5 and XAP5L, in regulating the transcriptional program of ciliogenesis during mouse spermatogenesis. The supporting data are solid, and this work will be of interest to biomedical researchers studying ciliogenesis and reproduction.

eLife Assessment

This important study employed multiple orthogonal techniques and tissue samples to investigate the interaction between the NRL transcription factor and RNA-binding proteins in the retina. The findings are convincing to support an interaction between NRL and the DHX9 helicase. The significance of the study could be enhanced with functional experiments of NRL-R-loop interactions in the developing retina and their potential role in photoreceptor health and gene regulation.

eLife Assessment

This study is a valuable contribution to the field of neuronal modeling by way of providing a method for rapidly obtaining neuronal physiology parameters from electrophysiological recordings. While the approach seems promising, in its current form it is incomplete since the generated models often diverge from the data and the comparison with existing methods has concerns.

eLife Assessment

This study presents valuable findings on the role of the small GTPase Rab3A in homeostatic plasticity. While the study demonstrates that Rab3A is required for homeostatic scaling, the evidence supporting the model put forward by the authors is incomplete. The work will be of interest to researchers in the field of synaptic transmission and plasticity.