eLife Assessment

The paper addresses the question of gene epistasis and asks what is the correct null model for which we should declare no epistasis. By reanalyzing synthetic gene array datasets regarding single and double-knockout yeast mutants, and considering two theoretical models of cell growth, the authors reach the valuable conclusion that the product function is a good null model. While the justification of some assumptions is incomplete, the results have the potential to be of value to the field of gene epistasis.

eLife Assessment

This paper highlights an important physiological function of PGAM in the differentiation and suppressive activity of Treg cells by regulating serine synthesis. This role is proposed to intersect with glycolysis and one-carbon metabolism. The study's conclusion is supported by solid evidence from in-vitro cellular and in-vivo mouse models.

eLife Assessment

This important study fills an gap in our knowledge of the evolution of GPCRs in holozoans, as well as the phylogeny of associated signaling pathway components such as G proteins, GRKs, and RIC8 proteins. The evidence supporting the conclusions is compelling, with the analysis of extensive new genomic data from choanoflagellates and other non-animal holozoans. Overall, the study is thorough and well-executed. It will be a resource for researchers interested in both the comparative genomics of multicellularity and GPCR biology more broadly, especially given the importance of GPCRs as highly druggable targets.

eLife Assessment

This important theoretical study examines the possibility of encoding genomic information in a collective of short overlapping strands (e.g., the Virtual Circular Genome (VCG) model). The study presents convincing theoretical arguments, simulations and comparisons to experimental data to point at potential features and limitations of such distributed collective encoding of information. The work should be of relevance to colleagues interested in molecular information processing and to those interested in pre-Central Dogma or prebiotic models of self-replication.

eLife Assessment

This is a valuable study that uses single-cell RNA sequencing to define tumor-intrinsic transcriptional programs that characterize distinct types of small intestine neuroendocrine tumors. The evidence supporting the claims of the authors is solid, but would benefit from a larger sample size. The work will be of interest to cancer biologists studying neuroendocrine tumors, as well as those studying tumor heterogeneity more broadly.

eLife Assessment

This study offers a valuable assessment of the impact of antibiotics on the human gut microbiota across diverse observational cohorts. The findings presented are convincing, despite the observational design and residual confounding that may still contribute to discrepancies between the cross-sectional and longitudinal data. The work is relevant for researchers and clinicians interested in antimicrobial resistance and the impact of antibiotics on the host.

eLife Assessment

This study provides important insights into the evolution of pesticide resistance, demonstrating that resistance can arise rapidly and repeatedly, which complements prior work on parallel evolution across species. The combination of extensive temporal sampling in the field, experimental evolution, and genomics makes for compelling findings. The authors are to be commended for acknowledging the main limitations of their study in the Discussion. Framing the work in a broader context of resistance beyond arthropod pests would further increase the appeal of the study, which is of relevance for both agronomic practitioners and evolutionary biologists.

eLife Assessment

This valuable study reports the first characterization of the CG14545 gene in Drosophila melanogaster, which the authors name "Sakura." Acting during germline stem cell fate and differentiation, Sakura is required for both oogenesis and female fertility, although some mechanistic details require further investigation. This solid study presents a wide-ranging and well-controlled characterization of Sakura, and accordingly the findings and associated reagents described will be of use to scientists interested in oogenesis and early development.

eLife Assessment

This valuable study identifies a population of CD81-positive fibroblasts showing senescence signatures that can activate neutrophils through the C3/C3aR1 axis, hence contributing to the inflammatory response in periodontitis. Solid evidence, combining in vitro and in vivo analyses and mouse and human data, supports these findings. The revised manuscript has addressed many concerns significantly. The work would be of interest to researchers working in the senescence and oral medicine fields.

eLife Assessment

This is a valuable study showing that differentiated cells of the zebrafish skin form membrane protrusions called cytonemes that contact and likely transmit Notch signals to cells of the undifferentiated layer below. The data are convincing that cytoneme like protrusions from the periderm are required for proper periderm structure, proliferation, gene expression, and Notch signaling. Evidence that inflammatory signaling through IL-17 affects epidermal differentiation, Notch and cytoneme formation is solid, but whether these are through a single common or two parallel pathways requires further investigation.

eLife Assessment

This fundamental manuscript presents a practical modification of the orthogonal hybridization chain reaction (HCR) technique, a promising yet underutilized method with broad potential for future applications across various fields. The authors advance this technique by integrating peptide ligation technology and nanobody-based antibody mimetics-cost-effective and scalable alternatives to conventional antibodies-into a DNA-immunoassay framework that merges oligonucleotide-based detection with immunoassay methodologies. Notably, they demonstrate with compelling evidence that this approach facilitates a modified ELISA platform capable of simultaneously quantifying multiple target protein expression levels within a single protein mixture sample.

eLife Assessment

With a computational analysis of a neuroanatomical network model in C. elegans, this valuable work investigates the synaptic mechanism for memory-dependent klinotaxis, i.e., salt concentration chemotaxis. By incorporating experimental data altering the ASER neuron's basal glutamate release into their model, the authors demonstrate the possibility of a transition between excitatory and inhibitory signaling at the ASER-AIY synapse, depending on environmental and cultivated salt concentrations. These solid findings offer a proposal for how synaptic plasticity plays a role in sensorimotor navigation, and will be of interest to worm biologists and theoretical neuroscientists.

eLife Assessment

This study presents a valuable finding on the molecular mechanisms that govern GABAergic inhibitory synapse function. The authors propose that Endophilin A1 serves as a novel regulator of GABAergic synapses by acting as a component of the inhibitory postsynaptic density. The authors have added substantial new analyses that take a wide range of approaches to provide solid support for their conclusions, although one of the reviewers concludes that the premise that gephyrin and endophilin A1 interact requires more robust analysis. The findings are likely to interest a broad audience of scientists focusing on inhibitory synaptic transmission, the excitation-inhibition balance, and its disruption in disorders such as epilepsy.

eLife Assessment

The manuscript by Ross, Miscik, and others describes an intriguing series of observations made when investigating the requirement for podxl during hepatic development in zebrafish. Understanding how genetic compensation pathways are involved in gene function is an important question. However, there is incomplete evidence provided in the manuscript at this point to conclude that discrepancies between observed phenotypes are due to genetic compensation.

eLife Assessment

In this important study, the authors set out to determine the molecular interactions between the AQP2 from Trypanosoma brucei (TbAQP2) and the trypanocidal drugs pentamidine and melarsoprol in order to clarify the origins of clinically observed drug resistance and facilitate future drug design. Using cryo-EM, molecular dynamics simulations, and lysis assays, the authors present a solid theory for how drug resistance mutations in TbAQP2 prevent drug uptake. Overall, even though a few methodological issues still need minor clarification, this study will be of interest to those working on aquaporins and the development of drugs targeting aquaporins.

eLife assessment

This valuable manuscript presents findings supported by solid data to identify a surprising glia-exclusive function for betapix in vascular integrity and angiogenesis. The manuscript also describes the optimisation of a modified CRISPR-based Zwitch approach to generate conditional knockouts in zebrafish.

eLife Assessment

This useful study provides a spatial transcriptomic analysis of the mouse adrenal gland that could have implications for future research and applications. The authors present solid results that allow the dissection of the cell signalling pathways and cellular composition of different zones of the adrenal glands in the mouse model; they propose new zone-specific gene markers and specific intra- and inter-zonal signaling pathways based on receptor-ligand expression patterns. Their web tool is user-friendly and will be helpful for adrenal scientists; however, the validation of crucial results of the large dataset is necessary. There are also several contradictory results/interpretations, and the opportunity to dissect the sexually dimorphic gene expression pattern and mouse-human interspecies differences is a missed opportunity.

eLife Assessment

This valuable study asks how the neural representation of individual finger movements changes during the early periods of sequence learning. By combining a new method for extracting features from human magnetoencephalography data and decoding analyses, the authors provide solid evidence of an early, swift change in the brain regions correlated with sequence learning, including a set of previously unreported frontal cortical regions. The authors also show that offline contextualization during short rest periods is the basis for improved performance. Further confirmation of these results on multiple movement sequences would further strengthen the key claims.

eLife Assessment

The microbiome field is constantly providing insight on various health-related properties elicited by the commensals that inhabit their mammalian hosts. Harnessing the potential of these commensals for knowledge about host-microbe interactions, as well as properties with therapeutic implications, will likely remain a fruitful field for decades to come. In this valuable study, Wang et al use various methods, encompassing classic microbiology, genomics, chemical biology, and immunology, to identify a potent probiotic strain that protects nematode and murine hosts from Salmonella enterica infection. The authors provide compelling evidence identifying gut metabolites that are correlated with protection, and show that a single metabolite can recapitulate the effects of probiotic administration.

eLife Assessment

This valuable study identifies a novel bacteriophage that can use the exopolysaccharide Psl of Pseudomonas aeruginosa to infect and disrupt biofilms. The work is convincing and suggests a novel approach to control biofilms that is relevant to researchers working on biofilms, specifically in Pseudomonas, on phage physiology and discovery, and on alternatives to controlling bacterial pathogens.

eLife Assessment

This useful study analyzed 335 Mycobacterium tuberculosis Complex genomes and found that MTBC has a closed pangenome with few accessory genes. The research provides solid evidence for gene presence-absence patterns which support the appending conclusions.

eLife Assessment

This study presents potentially valuable insights into the role of climbing fibers in cerebellar learning. The main claim is that climbing fiber activity is necessary for optokinetic reflex adaptation, but is dispensable for its long-term consolidation. There is evidence to support the first part of this claim, though it requires a clearer demonstration of the penetrance and selectivity of the manipulation. However, support for the latter part of the claim is incomplete owing to methodological concerns, including the robustness of the CF marking and manipulation approach and the unclear efficacy of longer-duration climbing fiber activity suppression.

eLife Assessment

The study introduces new tools for measuring the intracellular calcium concentration close to transmitter release sites, which may be relevant for synaptic vesicle fusion and replenishment. This approach yields important new information about the spatial and temporal profile of calcium concentrations near the site of entry at the plasma membrane. This experimental work is complemented by a coherent, open-source, computational model that successfully describes changes in calcium domains. Some of the conclusions are strongly supported by the data, but a few gaps in the data presented mean that the evidence for other conclusions is incomplete.

eLife Assessment

The authors take a synthetic approach by introducing synaptic ribbon proteins into HEK cells to analyze how these assemblies cluster calcium channels at the active zone. Using a synapse-naive heterologous expression system and overexpression-based strategy is valuable, as it establishes a promising model for studying molecular interactions at the active zone. The study is built on a solid combination of super-resolution microscopy and electrophysiology, though it currently falls short of replicating the full functional properties of native ribbon synapses and instead resembles a multiprotein complex that partially mimics ribbon-type active zones.

eLife Assessment

The reported cryo-EM imaging of a pentameric ligand-gated ion channel in liposomes as opposed to nanodiscs has both broad implications and contributes valuable methodological advances to the structural investigation of membrane receptors. The comparison of structures assigned to distinct functional states in liposomes versus nanodiscs is convincing and will aid membrane protein structural biologists in selection of functionally relevant membrane reconstitution environments.

eLife Assessment

This study makes the valuable claim that people track, specifically, the elasticity of control (that is, the degree to which outcome depends on how many resources - such as money - are invested), and that control elasticity is impaired in certain types of psychopathology. A novel task is introduced that provides solid evidence that this learning process occurs and that human behavior is sensitive to changes in the elasticity of control. Evidence that elasticity inference is distinct from more general learning mechanisms and is related to psychopathology remains incomplete.

eLife Assessment

This study establishes bathy phytochromes, a unique class of bacterial photoreceptors that respond to near-infrared light (NIR), as important tools for bacterial optogenetics. NIR light is a key control signal in optogenetics due to its deep tissue penetration and the ability to combine with existing red- and blue-light sensitive systems, but thus far, NIR-activated proteins have been poorly characterized. The strength of the evidence is solid overall, with comprehensive in vitro characterization, modular design strategies, and validation across different hosts. There are some questions that remain – such as the rationale for linker choices, characterization of growth and performance relative to controls, and the physiological significance of color blind effects at alkaline pH – but overall, this study should advance the fields of optogenetics and photobiology and inspire future work.

eLife Assessment

This work models reinforcement-learning experiments using a recurrent neural network. It examines if the detailed credit assignment necessary for back-propagation through time can be replaced with random feedback. In this important study the authors show that it yields a satisfactory approximation and the evidence to support that it holds within relatively simple tasks is solid.

eLife Assessment

This important manuscript presents a thorough analysis of trans-specific polymorphism (TSP) in Major Histocompatibility Complex gene families across primates. The analysis makes the most of currently available genomic data and methods to substantially increase the amount and evolutionary time that TSPs can be observed. Both false negative TSPs due to missing genes at the assembly and/or annotation level, as well as false positives due to read mismapping with missing paralogs, are well assessed and discussed. Overall the evidence provided is compelling, and the manuscript clearly delineates the path for future progress on the topic.

eLife Assessment

This study reports valuable findings on the role of Layilin in the motility and suppressive capacity of clonal expanded regulatory T cells (Tregs) in the skin. Although the strength of the study is utilizing conditional knock-out mice and human skin samples, the analysis of the molecular mechanism by which Layilin affects Treg function is incomplete. The study will be of interest to medical scientists working on skin immunology.

eLife Assessment

This revised study describes an important new model for in vivo manipulation of microglia, exploring how mutations in the Adar1 gene within microglia contribute to Aicardi-Goutières Syndome. The methodology is validated with exceptional data, supporting the authors' conclusions. The paper underscores both the advantages and limitations of using transplanted cells as a surrogate for microglia, making it a resource that is of value for biologists studying macrophages and microglia.

eLife Assessment

This valuable work proposes a novel, rapid S. aureus entry mechanism via Ca²⁺-dependent lysosomal exocytosis and acid sphingomyelinase release, which influences bacterial sub-cellular fate. However, reliance on chemical inhibitors and the absence of a knockout phenotype weakens the overall impact, making the study incomplete.

eLife Assessment

The authors modified a common method to induce epilepsy in mice to provide an improved approach to screen new drugs for epilepsy. This is important because of the need to develop new drugs for patients who are refractory to current medications. The authors' method evokes seizures to circumvent a low rate of spontaneous seizures and the approach was validated using two common anti-seizure medications. The strength of evidence was solid, making the study invaluable, but there were some limitations to the approach and methods.

eLife Assessment

This useful manuscript reports on a new mouse model for LAMA2-MD, a rare but very severe congenital muscular dystrophy. The knockout mice were generated by removing exon3 in the Lama2 gene, which results in a frameshift in exon4 and a premature stop codon. These animals lack any laminin-alpha2 protein and confirm results from previous Lama2 knockout models. Additionally, this study includes weak transcriptomics data that might be a good resource for the field. However, experimental evidence, methods, and data analyses supporting the main claims of the manuscript are incomplete.

eLife Assessment

The authors present useful findings on the use of a single-fly behavioral paradigm for assessing different Drosophila genetic models of neurodegeneration. The experimental design and analyses are solid and can be used for quick behavioral assessment in fly models of various neurodegenerative diseases, especially those having an impact on locomotion. The work will be of interest to Drosophila biologists using behavior as a readout for their studies.

eLife Assessment

This is an important study that combines replications of findings and novel detailed MRI investigations to assess the impact of environmental enrichment and maternal behavior on mice brain structure at different stages of development. The results and evidence supporting the conclusions are convincing, but in detail, the interpretation is challenging, in particular due to inter-individual and inter-litter variability. The extent to which maternal care mediates the impact of enrichment on brain development during the perinatal period also remains unclear because behavior was observed only during short periods, and the performed analyses are still incomplete. This study will nevertheless be of significant interest to neuroscientists and researchers interested in neurodevelopment in relation to environmental factors because of its in-depth use of MRI to study brain plasticity in mice.

eLife Assessment

This manuscript aims to identify the pacemaker cells in the lymphatic collecting vessels - the cells that initiate the autonomous action potentials and contractions needed to drive lymphatic pumping. Through the exemplary use of existing approaches (genetic deletions and cytosolic calcium detection in multiple cell types), the authors convincingly determine that lymphatic muscle cells are the origin of the action potential that triggers lymphatic contraction. The inclusion of scRNAseq and membrane potential data enhances a tremendous study. This fundamental discovery establishes a new standard for the field of lymphatic physiology.

eLife Assessment

This important work advances our understanding of the impact of malnutrition on hematopoiesis and subsequently infection susceptibility. Support for the overall claims is convincing in some respects and incomplete in terms of identifying mechanism as highlighted by reviewers. This work will be of general interest to those in the fields of hematopoiesis, malnutrition, and dietary influence on immunity.

eLife Assessment

This important study explores the role of SIRT2 in regulating Japanese encephalitis virus replication and disease progression in rodent models. The findings presented are novel as sirtuins are known for their roles in aging, metabolism, and cell survival, but have not been studied in the context of viral infections until recently. The evidence supporting the claims is solid, although additional experiments to further characterize the clinical outcomes and directly test the link between acetylated NF-kB and SIRT2 expression would have strengthened the study. The work will be of interest to biologists studying viruses, sirtuins, and inflammation.

eLife Assessment

This valuable study tested whether several months of dolutegravir intensification alters the size of the HIV reservoir as well as immune activation in individuals already on suppressive ART. While the general study approach is appropriate and the paper is well written, the evidence supporting the claims of the authors is incomplete. The title of the paper is only partially supported by the data, based on specific issues with the study design and analysis plan highlighted by Reviewer 1. Specifically, the primary study outcomes were not clearly described a priori, the plausibility of a biologic effect is uncertain based on lack of a consistent effect across participants, and sample size is small. Given a possible observed partial effect and relevant hypothesis, this approach warrants study in a larger trial.

eLife Assessment

Tropical single-island endemic bird populations are particularly vulnerable to climate change. The authors investigate genetic evidence of how such species dealt with climate changes in the past as a possible predictor for how they will respond to change in the future, which could provide an important example for the fields of conservation genetics and island biogeography. The authors' integration of genomics and habitat modeling is commendable, but we find that the support for their conclusions is incomplete: at times, the results presented appear to contradict each other, the authors do not fully account for key variables, and the limited taxonomic scope may cause problematic biases for the conclusions.

eLife Assessment

This study presents important findings that enhance our understanding of immune cell interactions in the context of chronic HIV-1 infection. The evidence supporting the conclusions is convincing. The authors have employed appropriate and validated methodologies, including detailed data reprocessing and batch correction to account for inter-donor variability. The inclusion of supplementary figures and analyses, such as cell communication inference, further substantiates the robustness of the findings. Overall, this work contributes to our understanding of HIV-1 immune evasion and highlights potential therapeutic targets for reservoir eradication.

eLife Assessment

This study presents valuable findings on the relationship between nutrient availability and NAD/NADH levels, which in turn regulate biomass production in cancer cells. The authors provide solid evidence to support their claims, offering insight into why it is difficult to predict which nutrients limit cancer cell growth: both cell type and nutrient availability together determine the oxidative capacity that constrains the synthesis of various metabolic intermediates. The manuscript will be of interest to researchers working in cancer and cell metabolism.

eLife Assessment

Weiss et al. provide important new insights and convincing evidence to further our mechanistic understanding of how antigen presentation shapes skin persistence of CD8+ TRM. Using a mouse model for inducible genetic ablation of transforming growth factor beta receptor 3 (TGFBR3) in CD8+ T cells, they demonstrate TGFBR3's role in regulating CD8+ TRM persistence in skin. Furthermore, they show that the strength of T cell receptor (TCR) engagement upon initial CD8+ TRM skin seeding has a positive influence on subsequent TRM expansion following a secondary antigen-reencounter. Together, these mechanisms add to our understanding of how the skin CD8+ T cell repertoire is dynamically responsive to topical antigen.

eLife Assessment

This study presents a useful framework to extract the individuality index to predict subjects' behavior in the target tasks. However, the evidence supporting such a framework is somewhat incomplete and would benefit from overall framing and clarity on its approaches. Overall, this study would be of interest to cognitive and AI researchers who work on cognitive models in general.

eLife Assessment

This manuscript makes important contributions to the methodology commonly used to assess representational structures in human and animal brain activity recorded using various techniques (especially fMRI). The evidence in the form of mathematical analysis and simulations is solid. The impact of this contribution could be improved by extending the simulations to assess the effects of violations of explicit and implicit assumptions.

eLife Assessment

This study makes an important contribution by showing that humans adapt learning rates rationally to environmental volatility yet systematically misattribute noise as volatility, demonstrating approximate rationality with simplified internal models. The evidence is compelling, encompassing a cleverly designed volatility-versus-noise paradigm, innovative lesion-based comparisons between reinforcement-learning and degraded Bayesian Observer Models, and convergent behavioural and pupillometric data. Expanding formal model comparisons (e.g., BIC/AIC) and directly contrasting RL and Bayesian fits to physiological markers would further enhance the work, but these are minor limitations that do not detract from the core findings.

eLife Assessment

This study, from the group that pioneered migrasome, describes a novel vaccine platform of engineered migrosomes that behave like natural migrasomes. Importantly, this platform has the potential to overcome obstacles associated with cold chain issues for vaccines such as mRNA. In the revised version, the authors have addressed previous concerns and the results from additional experiments provide compelling evidence that features methods, data, and analyses more rigorous than the current state-of-the-art. Although the findings are important with practical implications for the vaccine technology, results from additional experiments would make this an outstanding study.

eLife Assessment

The authors provide compelling evidence that a chloride ion stabilizes the protonated Schiff base chromophore linkage in the animal rhodopsin Antho2a. This important finding is novel and of major interest to a broad audience, including optogenetics researchers, protein engineers, spectroscopists, and environmental biologists. The study combines state-of-the-art research methods, such as spectroscopic and mutational analyses, which are complemented by QM/MM calculations, and was further improved based on the comments from the reviewers.

eLife Assessment

This valuable study employs transition-metal FRET (tmFRET) and time-correlated single-photon counting to investigate allosteric conformational changes in both isolated cyclic nucleotide-binding domains (CNBDs) and full-length bacterial CNG channels, demonstrating that transmembrane domains stabilize CNBDs in their active state. By comparing isolated CNBD constructs with full-length channels, the authors reveal how allosteric networks couple domain movements to gating energetics, providing insights into ion channel regulation mechanisms. The rigorous methodology and compelling quantitative analysis establish a framework for applying tmFRET to study conformational dynamics in diverse protein systems.

eLife Assessment

The authors provide a convincing summary of ten years of Brain Initiative funding including the historical development, the specific funding mechanisms, and examples of grants funded and work produced. It is particularly valuable at this moment in history, given the cataclysmic changes in the US government structure and function occurring in early 2025.

eLife Assessment

This manuscript provides valuable insights into the heterogeneity of hematopoietic stem cells and age-associated myeloid-biased hematopoiesis. While several aspects of the study are intriguing and merit further investigation, the current results remain incomplete and additional data are necessary to substantiate the conclusions. Some of the methods and data analyses partially support the claims.

eLife Assessment

In this valuable study, Taber et al used a battery of biophysical and structural approaches to characterize the impact of erythrocytosis-related mutations in prolyl hydroxylase domain protein 2 (PHD2). The authors show that PHD2 mutant proteins are destabilized, thus supporting the tenet that dysregulation of PHD2/hypoxia induced factor (HIF) axis underpins erythrocytosis, while providing incomplete evidence that N-terminal ODD prolyl hydroxylation of HIF is indispensable for these phenotypes. Notwithstanding that this study was found to be of broad interest for a variety of fields focusing on oxygen sensing in homeostasis and pathological states, resolving inconsistencies in the biophysical analysis (e.g., NMR, SEC, and BLI/MST) was thought to be warranted to further corroborate the proposed model.

eLife Assessment

Based on several lines of interesting data, the authors conclude that FMRP, though associated with stalled ribosomes, does not determine the position on the mRNAs at which ribosomes stall. Although this conclusion would be valuable if clearly established, the current set of data are incomplete and it is unclear if the methodologies applied in this paper are fully adequate to address this gap.

eLife Assessment

In this study, the authors investigate the role of ZMAT3, a p53 target gene, in tumor suppression and RNA splicing regulation. Using quantitative proteomics, the authors uncover that ZMAT3 knockout leads to upregulation of HKDC1, a gene linked to mitochondrial respiration, and that ZMAT3 suppresses HKDC1 expression by inhibiting c-JUN-mediated transcription. This set of convincing evidence reveals a fundamental mechanism by which ZMAT3 contributes to p53-driven tumor suppression by regulating mitochondrial respiration.

eLife Assessment

In their study, Neiswender et al. provide important insights into how BicD2 variants linked to spinal muscular atrophy alter dynein activity and cargo specificity. While the findings suggest disease-relevant changes in BicD2's binding partners, the evidence connecting these changes to disease mechanisms remains incomplete and would benefit from further experimental validation. The work lays a strong foundation for future research, but could be strengthened by deeper functional analysis of key interactions, such as the BicD2/HOPS complex.

eLife Assessment

This valuable study identifies asymmetric dimethylarginine (ADMA) histones as potential determinants of the initial genomic binding of Rhino, a Drosophila-specific chromatin protein essential for piRNA cluster specification. The authors provide correlative genomic and imaging data to support their model, although functional validation of the proposed mechanism remains incomplete. The authors could revise the manuscript to reflect that they have uncovered a small subset of piRNA clusters dependent on ADMA-histones, which may not be the general rule.

eLife Assessment

This is a useful study in the role of CHI3L1 in Kupffer cells, the macrophages of the liver, showing that CHI3L1 alters glucose regulation in obesity. Specifically, Chi3l1 protects glucose-dependent Kupffer cells during Metabolic dysfunction-associated steatotic liver disease (MASLD) by inhibiting glucose uptake, preventing metabolic stress and death. These data are compelling, yet require further validation.

eLife Assessment

This valuable manuscript provides convincing evidence that BK and CaV1.3 channels can co-localize as ensembles early in the biosynthetic pathway, including in the ER and Golgi. The findings, supported by a range of imaging and proximity assays, offer insights into channel organization in both heterologous and endogenous systems. However, mechanistic questions remain unresolved, particularly regarding the specificity of mRNA co-localization, the dynamics of ensemble trafficking, and the functional significance of pre-assembly at the plasma membrane. While the data broadly support the central claims, certain conclusions would benefit from more restrained interpretation and additional clarification to enhance the manuscript's impact and rigor.

eLife Assessment

This study provides valuable insights into a new toxin-antidote element in C. elegans, the first naturally occurring unlinked toxin-antidote system where endogenous small RNA pathways post-transcriptionally suppress the toxin. The strength of evidence is solid, using a combination of genomic and experimental methods. Enthusiasm, however, is tempered by its reliance on meta-analysis of existing data sets and limited experimental evaluation.

eLife Assessment

This important study uses long-term behavioural observations to understand the factors that influence female-on-female aggression in gorilla social groups. The evidence supporting the claims is convincing, as it includes novel methods of assessing aggression and considers other potential factors. The work will be of interest to broad biologists working on the social interactions of animals.

eLife Assessment

This important work by Malita et al. describes a mechanism by which an intestinal infection causes an increase in daytime sleep through signaling from the gut to the blood-brain barrier. Their findings suggest that cytokines upd3 and upd2 produced by the intestine following infection act on glia of the blood brain barrier to regulate sleep by modulating Allatostatin A signaling. The evidence is compelling and elegantly performed using the ample Drosophila genetic toolbox, making this work appealing for a broad group of neuroscience researchers interested in sleep and gut-brain interactions.

eLife Assessment

This valuable study investigates the selectivity of neuronal responses in the neocortex and thalamus to visual stimuli presented far outside their receptive fields. The study shows convincing evidence for a long-latency surround-induced response in primary visual cortex that is absent in the dorsal lateral geniculate nucleus and does not depend strongly on the visual characteristics of the surround stimulus. The paper should be of interest to neurophysiologists interested in vision and contextual modulations.

eLife Assessment

This important study addresses how wing morphology and kinematics change across hoverflies of different body sizes. The authors provide convincing evidence that there is no significant correlation between body size and wing kinematics across 28 species and instead argue that non-trivial changes in wing size and shape evolved to support flight across the size range. Overall, this paper illustrates the power and beauty of an integrative approach to animal biomechanics and will be of broad interest to biologists, physicists and engineers.

eLife Assessment

This is an overall valuable set of findings on the role of centrally produced estrogens in the control of behaviors in male and female medaka. The significance of the findings rests on the revealed potential mechanism between brain derived estrogens modulating social behaviors in males as well as females. The results are supported by the analysis of multiple transgenic lines although the evidence is incomplete, and further validation would be necessary to fully validate the conclusions on the role of brain-derived estrogens. Nonetheless, the findings have led to helpful hypotheses on the hormonal control of behaviors in teleosts that can be tested further.

eLife Assessment

This important study combines imaginative experiments to demonstrate the relevance of poroelasticity in the mechanical properties of cells across physiologically relevant time and length scales. Through innovative experiments and a finite element model, the authors present solid evidence that cytosolic flows and pressure gradients can persist in cells with permeable membranes, generating spatially segregated influx and outflux zones. These findings will be of interest to the cell biology and biophysics communities. Nevertheless, a more in depth discussion of why other possible explanations for the long time scales associated to mechanical propagation are less effective could further strengthen their message.

eLife Assessment

This study makes a novel and valuable contribution by adapting step selection functions, traditionally used in animal ecology, to explore human movement and environmental risk exposure in urban slums, offering a promising framework for spatial epidemiology, particularly regarding leptospirosis. The integration of GPS telemetry with environmental data and the stratification by gender and serostatus are notable strengths that enhance the study's relevance for public health applications. The strength of evidence is compelling.

eLife Assessment

Alignment and sequencing errors are a major concern in molecular evolution, and this valuable study represents a welcome improvement for genome-wide scans of positive selection. This new method seems to perform well and is generally convincing, although the evidence could be made more direct and more complete through additional simulations to determine the extent to which alignment errors are being properly captured.

eLife Assessment

In this valuable study, the authors provide a simple yet elegant approach to identifying therapeutic targets that synergize to prevent therapeutic resistance in ovarian cancer using cell lines, data-independent acquisition proteomics, and bioinformatic analysis. The authors convincingly identify several combinations of pharmaceuticals that were able to overcome or prevent therapeutic resistance in culture models of ovarian cancer, a disease with an unmet diagnostic and therapeutic need. However, the extent to which these findings may extend to more complex models of ovarian cancer remains unclear.

eLife Assessment

This is a valuable study that suggests that HPV-human DNA junctions can be identified from cfDNA in women with cervical cancer and that detection of these junctions is indicative of recurrence. The evidence supporting the conclusions is incomplete, in part because the numbers of reads identifying breakpoints in tumor samples or in circulating cell-free serum samples are not provided. More quantitative analysis will be required to confirm that the breakpoints represented in cell-free DNA can be used as a surrogate to monitor the recurrence of cervical cancer cells, and additional patient studies would also be needed to strengthen the study. This work will be of interest to those who study and treat cervical cancer as well as other HPV-related malignancies.

eLife Assessment

This manuscript reports an important finding for understanding the molecular mechanisms of mutagenesis, carcinogenesis, and senescence. It follows a previous report showing that the Werner syndrome protein WRN and its interacting protein WRNIP1 are indispensable for translesion DNA synthesis (TLS) by Y-family DNA polymerases (Pols). The manuscript provides convincing evidence that WRN and WRNIP1 ATPases, in addition to the previously reported role of the WRN 3'>5' exonuclease activity, are essential for promoting the fidelity of replication through DNA lesions by Y-family Pols in human cells.

eLife Assessment

This study presents important findings on increased ground beetle diversity in strip cropping compared with crop monocultures. Solid methods are used to analyze data from multiple sites with heterogeneous systems of mixed crops, allowing broad conclusions, albeit at the expense of lacking taxonomic specificity. The work will be of interest to all those applying plant diversity treatments to improve the diversity of associated animals in agricultural fields.

eLife Assessment

This important study investigates how hummingbird hawkmoths integrate stimuli from across their visual field to guide flight behavior. Cue conflict experiments provide solid evidence for an integration hierarchy within the visual field: hawkmoths prioritize the avoidance of dorsal visual stimuli, potentially to avoid crashing into foliage, while they use ventrolateral optic flow to guide flight control. These findings will be of broad interest to enthusiasts of visual neuroscience and flight behavior.

eLife Assessment

By combining the 'pinging' technique with fMRI-based multivariate pattern analysis, this important study provides convincing evidence for a dual-format of attentional representation during preparatory period. The result reconciles the competing views between the sensory-like versus non-sensory accounts of attentional template and advances our understanding of how the brain flexibly utilizes different versions of template to guide attention. This work will be of interest to researchers in psychology, vision science, and cognitive science.

eLife Assessment

This study aims to clarify the effects of cochlear neural degeneration on auditory processing in listeners with normal audiograms (sometimes referred to as 'hidden hearing loss'). The authors provide important new data demonstrating associations between cochlear neural degeneration, non-invasive assays of auditory processing, and speech perception. Based on a cross-species comparison, the findings pose compelling evidence that cochlear synaptopathy is associated with a significant part of hearing difficulties in complex environments.

eLife Assessment

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

eLife Assessment

The authors examine the effect of cell-free chromatin particles (cfChPs) derived from human serum or from dying human cells on mouse cells in culture and propose that these cfChPs can serve as vehicles for cell-to-cell active transfer of foreign genetic elements. The work presented in this paper is intriguing and potentially important, but it is incomplete. At this stage, the claim that horizontal gene transfer can occur via cfChPs is not well supported because it is only based on evidence from one type of methodological approach (immunofluorescence and fluorescent in situ hybridization (FISH)) and is not validated by whole genome sequencing.

eLife Assessment

Fallah et al carefully dissect projections from substantia nigra pars reticulata (SNr) and the globus pallidus externa (GPe) - two key basal ganglia nuclei - to the pedunculopontine nucleus (PPN), a brainstem nucleus that has a central role in motor control. They consider inputs from these two areas onto three types of downstream PPN neurons - GABAergic, glutamatergic, and cholinergic neurons - and carefully map connectivity along the rostrocaudal axis of the PPN. Overall, this important study provides convincing data on PPN connectivity with two key input structures that will provide a basis for further understanding PPN function.

eLife Assessment

This useful modeling study shows how spatial representations similar to experiment emerge in a recurrent neural network trained on a navigation task by requiring path integration and decodability, but without relying on grid cells. The network modeling results are solid, although the link to experimental data may benefit from further development.

eLife Assessment

This important work by Diallo et al. substantially advances our understanding of the chemosensory system of a non-hymenopteran eusocial insect by identifying the first olfactory receptor for the trail pheromone in termites. The evidence supporting the conclusions that the receptor PsimOR14 is very narrowly tuned for the pheromone neocembrene is compelling. The work will be of broad interest to entomologists, chemical ecologists, neuroscientists, and molecular biologists.

eLife Assessment

This manuscript reports effects of a single dose of methamphetamine vs placebo on a probabilistic reversal learning task with different levels of noise, in a large group of young healthy volunteers. The paper is well written and the methods are rigorous. The findings are important and have theoretical or practical implications beyond a single a subfield. The strength of the evidence is convincing, with the methods, data, and analyses broadly supporting the claims in the paper, which are sufficiently qualified given the lack of a significant effect of the binary baseline performance variable, and the nonlinear effect of individual differences in baseline performance.

eLife Assessment

Bonnifet et al. present data on the expression and interacting partners of the transposable element L1 in the mammalian brain. The work includes important findings addressing the potential role of L1 in aging and neurodegenerative disease. The reviewers conclude that several aspects of the study are well done. However, the experimental evidence presented supporting the L1 increase with aging is not fully conclusive and this finding remains incomplete in its current form.

eLife Assessment

This fundamental study describes patterns of anatomical connectivity between the cortex and the thalamus using magnetic resonance imaging data in humans and non-human primates. The measures are related to numerous other modalities to develop a robust understanding of the organisation of the system. The authors provide convincing evidence that there is a difference between sensory and association cortices in terms of their connectivity with the thalamus, which may have downstream effects on brain function. This work will be of interest to neuroscientists interested in the organization and dynamics of cortico-thalamic circuits.

eLife Assessment

The manuscript reports fundamental findings supported by convincing data that supports the biological mechanism for optimal nodulation in soybean. The results are of relevance to understanding the signaling pathways (specifically those dependent on RIN4/RPM1-interacting protein 4) underpinning beneficial rhizobia symbiosis, while repressing the immune response.

eLife Assessment

This paper shows that it is possible to optogenetically activate single retinal ganglion cells in vivo in monkeys. This is an important step towards towards causal tests of the role of specific ganglion cell types in visual perception. The paper presents convincing evidence for the promise of the approach but further work will be needed to full explore its limitations and specificity.

eLife Assessment

The study reports an important finding on the role of the global metabolic regulator Crp/cAMP in the formation of antibiotic persister Escherichia coli. The evidence supporting the claims is solid including metabolomic analysis and characterization of many mutant strains.

eLife Assessment

This study introduces a valuable spring-bead model for epithelial cell layers, designed to improve previous cell-resolved approaches and to understand the connection between the biophysics of cell-cell contacts and the tissue mechanics. While the model is not entirely new and does not fully settle open questions such as the role of adhesion in tissue fluidity, it provides solid evidence and stands out as simple and efficient. A more comprehensive comparison with previous cell-revolved approaches and, in particular, with experimental data, would further strengthen the proposed model as a conceptual and practical tool.

eLife Assessment

This important study utilizes the nematode C. elegans and mammalian cell culture to investigate the role of MML-1/Mondo in conserved regulation of metabolism and aging. The evidence supporting the conclusions is convincing and covers a range of areas including localization, upstream pathways, and conservation. The paper will be of interest to a broad range of biologists studying aging, metabolism, and transcriptional regulation.

eLife Assessment

This Research Advance manuscript further elucidates the roles of SMC5/6 loader proteins and associated factors in the silencing of extrachromosomal circular DNA by the SMC5/6 complex. While the findings are largely in line with expectations, they are useful, representing a meaningful advance beyond the recent study (reference 33), contributing to a growing foundation for further comparative and mechanistic investigations. Solid evidence is presented for a role for SIMC1/SLF2 in the localization of the SMC5/6 complex to plasmid DNA, and the distinct requirements, as compared to the recruitment of SMC5/6 to chromosomal DNA lesions.

eLife Assessment

This study provides an important understanding of the contribution of different striatal subregions, the anterior Dorsal Lateral Striatum (aDLS) and the posterior Ventrolateral Striatum (pVLS), to auditory discrimination learning. The authors have included robust behavior combined with multiple observational and perturbation techniques. The data provided are convincing of the relevance of task-related activity in these two subregions during learning.

eLife Assessment

This valuable paper used a longitudinal cohort of individuals initiating ART to suggest that CD8+ T cells may contribute to the clearance of intact HIV DNA during long-term antiretroviral therapy (ART) for HIV, which is relevant to our understanding of the mechanisms driving reservoir persistence in people living with HIV. The reviewers concluded that the evidence presented is incomplete to fully support these claims, as the cohort sampling is relatively infrequent, and the association direction could be bi-directional or due to other confounding variables.

eLife Assessment

This paper examines selection on induced epigenetic variation ("Lamarckian evolution") in response to herbivory in Arabidopsis thaliana. The authors find weak evidence for such adaptation, which contrasts with a recently published study that reported extensive heritable variation induced by the environment. The authors convincingly demonstrate that the findings of the previous study were confounded by mix-ups of genetically distinct material, so that standing genetic variation was mistaken for acquired (epigenetic) variation. Given the controversy surrounding the influence of heritable epigenetic variation on phenotypic variation and adaptation, this study is an important, clarifying contribution; it serves as a timely reminder that sequence-based verification of genetic material should be prioritized when either genetic identity or divergence is of importance to the conclusions.

eLife Assessment

Using a combination of connectomics, optogenetics, behavioral analysis, and modeling, this study provides important findings on the role of two populations of inhibitory neurons in the generation of leg grooming movements in Drosophila. The data as presented provide incomplete evidence that the identified neuronal populations contribute to the alternation of flexion and extension by inhibiting specific sets of motor neurons while disinhibiting their counterparts. While the manuscript provides comprehensive details about the 13A/B neuronal populations involved in grooming control, updates on statistics, and explicit mentioning of experimental/modeling caveats would strengthen the study. The work will interest neuroscientists, and particularly those working on motor control.

eLife Assessment

This study presents a valuable finding on the perturbed pyruvate metabolism in models of repetitive traumatic brain injury. The evidence supporting the main claims of the authors is solid, but much of the accompanying analysis and interpretation relies on incomplete evidence. The work will be of interest to those working on the imaging of traumatic brain injury.

eLife Assessment

This is a valuable and rigorous study that addresses the question of what determines the spatial organization of endocytic zones at synapses. The authors use compelling approaches, in both Drosophila and rodent model systems, to define the role of activity and active zone structure on the organization of the peri-active zone. While the findings are primarily negative, they are carefully executed and contribute to the field by refining existing models of presynaptic organization.

eLife Assessment

The authors conducted a valuable study that investigates a molecular pathway mediating the transformation of a cell aggregate into a sheet known as the nucleus laminaris, a crucial site for auditory processing. While the study offers a comprehensive view of the sequence of developmental events and suggests possible roles for FGF signaling, the transcription factor Mafb, and the cell surface adhesive molecule Cadherin-23 in this process, the current data were considered incomplete.

eLife Assessment

This manuscript provides valuable information on the neurodynamics of emotional processing while participants were watching movie clips. The methods and results were solid in deciphering the temporal-spatial dynamics of emotional processing. This work will be of interest to affective neuroscientists.

eLife Assessment

This important study looks into the effect of exogenous CoA on the response of TLR4-activated macrophages. Specifically, CoA enhances the LPS response by examining metabolomics, 13C tracing, and assessments of transcription and acetylation. Together, these provide a compelling series of findings that show exogenous CoA is taken up by macrophages, and this facilitates histone acetylation and transcription associated with activation and antimicrobial activity.

eLife Assessment

Karimian et al. present a valuable new model to explain how gamma-band synchrony (30-80 Hz) can support human visual feature binding by selectively grouping image elements, countering recent criticisms that the stimulus dependence of gamma oscillations limits their functional role. Grounded in the theory of weakly coupled oscillators and informed by primate electrophysiology, the model captures behavioural patterns observed in human psychophysics, offering support for the potential role of synchrony-based mechanisms, but incomplete evidence for a specific role of gamma oscillations. This work could be strengthened by more direct evidence for the proposed mechanism, and expanding beyond figure-only model inputs with limited ecological validity.

eLife Assessment

The authors present an important multi-scale computational platform, which aims to automate the workflow for coarse-grained simulations of biomolecules in the framework of the popular MARTINI model. The capability of the platform has been convincingly demonstrated by the application to a large number of proteins as well as macrocycles and polymers. This work will be of interest to both computational biophysicists and chemists.

eLife Assessment

This study provides a fundamental analysis of the EmrE efflux pump, highlighting the role of the C-terminal domain in influencing uncoupled proton leak. The integration of biophysical techniques with molecular dynamics simulations offers solid support for the key findings and adds substantial evidence toward a definitive understanding of EmrE transport mechanism.

eLife Assessment

This fundamental study investigates the role of polyunsaturated fatty acids (PUFAs) in physiology and membrane biology, using a unique model to perform a thorough genetic screen that demonstrates that PUFA synthesis defects cannot be compensated for by mutations in other pathways. These findings are supported by compelling evidence from a high quality genetic screen, functional validation of their hits, and lipid analyses. This study will appeal to researchers in membrane biology, lipid metabolism, and C. elegans genetics.

eLife Assessment

The authors design and implement an elegant strategy to delete genomic sequences encoding the dopamine receptor dop1R2 from specific subsets of mushroom body neurons (ab, a'b' and gamma) and show that while none of these manipulations affect short term appetitive or aversive memory, loss of dop1R2 from ab or a'b' block the ability of flies to display measurable forms of longer forms of memory. These findings are important in confirming and extending prior observations, and well supported by convincing evidence that build on precise techniques for genetic perturbation.

eLife Assessment

This important study presents an alternative platform for nanobody discovery using phage-displayed synthetic libraries. The evidence supporting the platform, which is used to isolate and validate nanobodies targeting Drosophila secreted proteins, is compelling. By making the library openly accessible, this provides an excellent resource to the wider scientific community. The paper presents a detailed protocol for nanobody screening; as this protocol is refined and optimized over time, this will increase the success rate for discovering nanobodies with improved properties using this alternative platform.

eLife Assessment

This study reveals a neural signature of a common behavioural phenomenon: serial dependence, whereby estimates of a visual feature (here motion direction) are attracted towards the recent history of encoded and reported stimuli. The study provides solid evidence that this phenomenon arises primarily during working memory maintenance. The pervasiveness of serial dependencies across modalities and species makes these findings important for researchers interested in perceptual decision-making across subfields.

eLife Assessment

In this valuable study, Nold et al. examined exercise-induced pain modulation in a pharmacological within-subject fMRI study using the opioid-antagonist naloxone and different levels of aerobic exercise intensity and pain. This investigation provides solid evidence to show that the intensity of exercise does not seem to impact the hypoalgesic effect. Moreover, exploratory analysis identified that fitness level and sex may potentially play a role in exercise-induced hypoalgesia, and that further confirmatory studies are required in order to verify these findings.

eLife Assessment

This valuable manuscript investigates the localisation of nutrient receptors in bloodstream stage trypanosomes, with implications for both nutrient uptake and immune evasion. Results after direct fixation of the cells in culture medium provide convincing evidence that the amounts of receptors on the surface of the cell, as opposed to the flagellar pocket, have previously been severely underestimated. Some results were essentially confirmatory, and there are questions regarding the quantitation of ligand binding by transferring receptors.

eLife Assessment

The study is a timely and important contribution to our knowledge of the circuit mechanisms of fear analgesia. The novel cue-induced analgesia paradigm allowed a compelling identification of a brainstem circuit element, i.e., somatostatin-expressing neurons within the ventrolateral periaqueductal grey that project to the rostroventral medulla, in mediating fear analgesia. The vlPAG is a known region of pain modulation, and this study adds key insight to the circuit involved in fear-associated analgesia. This work will be of interest to systems and behavioral neuroscientists, especially those interested in emotional behavior, pain, and/or brainstem function.

eLife Assessment

This valuable study addresses the structural basis of voltage-activation of BK channels using atomistic simulations of several microseconds, to assess conformational changes that underlie both voltage-sensing and gating of the pore. The findings, including movement of specific charged residues, combined with the degree to which these movements are coupled to pore movements, provide a solid basis for understanding voltage-gating mechanisms in this class of channels. This paper will likely be of interest to ion channel biologists and biophysicists focused on voltage-dependent channel gating mechanisms.

eLife Assessment

Sanchez-Vasquez et al establish an innovative approach to induce aneuploidy in preimplantation embryos. This important study extends the author's previous publications evaluating the consequences of aneuploidy in the mammalian embryo. In this work, the authors investigate the developmental potential of aneuploid embryos and characterize changes in gene expression profiles under normoxic and hypoxic culture conditions. Using a solid methodology they identify sensitivity to Hif1alpha loss in aneuploid embryos, and in further convincing experiments they assess how levels of DNA damage and DNA repair are altered under hypoxic and normoxic conditions.

eLife Assessment

This study provides a comprehensive analysis of gene expression and bioinformatics data, offering important insights into the roles of fibroblasts in cardiac development. The large and well-analyzed single-cell RNA sequencing (scRNA-seq) dataset is compelling and a significant contribution to the field, and will be of broad interest to the scientific community.

eLife Assessment

This paper identifies a crucial step in the regulation of tight junction formation by identifying Rho-ROCK activity-dependent activation of the serine protease Matriptase, making Claudins available for tight junction formation. The reviewers were satisfied with the revisions and found the work important and the approach convincing.

eLife Assessment

This valuable study by Wu et al presents data on bacterial cell organization, demonstrating that the two structures that account for bacterial motility - the chemotaxis complex and the flagella - colocalize to the same pole in Pseudomonas aeruginosa cells. The work provides convincing results for the regulation underlying this spatial organization and its functioning.

eLife Assessment

This important study demonstrates that slow fluctuations in serotonin release during wakefulness and non-REM sleep correspond to periods of heightened arousal or enhanced offline information processing. The evidence supporting this claim is convincing, and the methodology is robust and broadly applicable, likely to benefit many researchers in the field. This work will be of significant interest to neuroscientists studying sleep, memory, and neuromodulation.

eLife Assessment

This important study by Lee et al. explores the heterogeneous response of non-growing bacteria to the antimicrobial peptide (AMP) tachyplesin. The authors identify a subpopulation of cells that evade lethal damage by limiting the intracellular accumulation of a fluorescently labeled tachyplesin analog. The study provides compelling evidence that reduced drug accumulation underlies the decreased susceptibility of this subpopulation to the AMP. The molecular basis of this phenotype is well supported by the data.

eLife Assessment

This valuable study reports the development of a novel organoid system for studying the emergence of autorhythmic gut peristaltic contractions through the interaction between interstitial cells of Cajal and smooth muscle cells. The authors further utilized the system to provide convincing evidence for a previously unappreciated potential role for smooth muscle cells in regulating the firing rate of interstitial cells of Cajal. The work will be of interest to those studying development and physiology of the gut.