eLife Assessment

This important study reports on PI3KR mutations and a paradoxical mechanism of PI3KR signaling. The strength of evidence for the study is mostly convincing, as conclusions are supported by a variety of mutational strategies and cellular systems to look at interactions among signaling pathways.

eLife Assessment

This important study provides insights into the physiological role of RIPK1 in liver physiology, particularly during short-term fasting. The discovery that RIPK1 deficiency sensitizes the liver to acute injury and hepatocyte apoptosis is based on convincing evidence, highlighting the importance of RIPK1 in maintaining liver homeostasis under metabolic stress. The work will be of relevance to anyone studying liver pathologies.

eLife Assessment

This important collection of over 800 new cell type-specific driver lines will be an invaluable resource for researchers studying associative learning in Drosophila. Thoroughly characterized and well documented, this collection will permit researchers to selectively target neurons that deliver information to, or receive it from, the memory center of the fly brain called the Mushroom Body. Given the wealth of new drivers and the genetic access they provide to over 300 cell types, this compelling work will be of interest not only to researchers studying the mechanisms of associative learning but more generally to those dissecting sensorimotor circuits in the fly nervous system.

eLife Assessment

This paper presents useful results that extend our understanding of how the visual cortex encodes temporal structure, providing new information about sequence representations in the upper layers of the visual cortex. The evidence for prediction errors is solid, however, support for other claims regarding sparsification and simplification of activity following training is incomplete. The main concerns pertain to the confounds associated with restricted ordering within blocks that does not allow for separate plasticity mechanisms operating on different time scales.

eLife Assessment

This paper addresses an important topic (normative trajectory modelling), seeking to provide a method aiming to accurately reflect the individual deviation of longitudinal/temporal change compared to the normal temporal change characterized based on a pre-trained population normative model. The evidence provided for the new methods is solid.

eLife Assessment

Yonk and colleagues provide a valuable, timely, and in-depth study showcasing the role of thalamostriatal inputs in learning and action selection. After characterizing the synaptic properties of these inputs onto different striatal cell types in vitro, they provide solid evidence that posterior medial thalamic nucleus (POm) terminals in striatum are activated during reward expectation and arousal. The overall function of this pathway and the degree to which results are confounded by viral contamination of surrounding nuclei and movements remain open questions.

eLife Assessment

Somatostatin-expressing neurons of the entopeduncular nucleus (EPNSst+) provide a limbic output of the basal ganglia and co-release GABA and Glutamate in their projection to the lateral habenula, a structure that is key for reward-based learning. Combining fiber photometry and computational modeling, the authors provide compelling evidence that EPNSst+ neural activity represents movement, choice direction and reward outcomes in a probabilistic switching task but, surprisingly, neither chronic genetic silencing of these neurons nor selectively elimination glutamate release affected behavioral performance in well-trained animals. This valuable study shows that despite its representation of key task variables, EPNSst+ neurons are dispensable for ongoing performance in a task requiring outcome monitoring to optimize reward. This work will be of interest to those interested in neural circuits, learning, and/or decision making.

eLife Assessment

Cav2 voltage-gated calcium channels play key roles in regulating synaptic strength and plasticity. In contrast to mammals, invertebrates like Drosophila encode a single Cav2 channel, raising questions on how diversity in Cav2 is achieved from a single gene. Here, the authors present solid evidence that two alternatively spliced Cac isoforms enable important changes in Cav2 expression, localization, and function in synaptic transmission and plasticity at the Drosophila neuromuscular junction. How the isoforms affect synaptic calcium channel levels remains less clear. This study provides insights into the roles of voltage-gated calcium channel splice isoforms in synaptic transmission.

eLife Assessment

This important study presents an evaluation of several tools used for detecting Identity-By-Descent (IBD) segments in highly recombining genomes, using simulated data to replicate the high recombination and low marker density of Plasmodium falciparum, the parasite responsible for malaria. Most of the evidence presented by the authors is solid demonstrating that users should be cautious calling IBD when SNP density is low and recombination rate is high. This study will be of interest to scientists working in the field of genome evolution and infectious diseases.

eLife Assessment

This useful observational study was conducted in Dar es Salaam, Tanzania, to investigate potential associations between genetic variation in Mycobacterium tuberculosis and human host vs. disease severity. The authors conclude that human genetic ancestry did not contribute to tuberculosis severity, but the evidence for this conclusion is currently incomplete, as the analysis did not fully leverage the genome-wide data available in a human-strain association study, and there was no comparison group from the general population (or household controls), to which the ancestry findings could be compared. The findings have significance for the understanding of the influence of host / bacillary genetics on tuberculosis disease.

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, the determination of the range of applicability and of the errors is incomplete, leaving open some questions 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 a platform to implement closed-loop experiments in mice based on auditory feedback. The authors provide solid evidence that their platform enables a variety of closed-loop experiments using neural or movement signals, indicating that it will be a valuable resource to the neuroscience community. However, the demonstration experiments could be strengthened by increasing the sample size for several groups in the neurofeedback experiments, as well as a more thorough description of the results in the text.

eLife Assessment

This important study conducted experiments to quantify how changes in blood flow results in apparent fluorescence changes when imaging neural activity sensors using two-photon microscopy. While the study highlights the prevalence neural-activity independent artifacts in two-photon imaging, the evidence linking the observed signals to hemodynamic occlusion remains incomplete.

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 valuable study uses a novel method to record spine calcium responses without the confounds of backpropagating action potentials to study how the dendritic integration of large numbers of inputs generates the tuned output of cortical neurons. While the results are generally solid, the study would benefit from more details, characterizations, and quantifications, including better validation of the method to suppress backpropagating action potentials.

eLife Assessment

This study presents a valuable finding on a new role of glia in activity-dependent synaptic remodeling using the Drosophila NMJ as a model system. The evidence supporting the claims of the authors is solid. However, the unaddressed cell-type specific mechanisms of Shv secretion and regulation on the extracellular glutamate levels and lack of details on the methods for statistical analysis have hindered further evaluation of the claims. The work will be of interest to neuroscientists working on glia-neuron interaction and synaptic remodeling.

eLife Assessment

In this important manuscript, Ryan et al perform a genome-wide CRISPR based screen to identify genes that modulate TDP-43 levels in neurons. They identify a number of genes and pathways and highlight the BORC complex, which is required for anterograde lysosome transport as one such regulator of TDP-43 protein levels. Overall, this is a convincing study, which opens the door for additional future investigations on the regulation of TDP-43.

eLife Assessment

This valuable study by Cui et al. investigates mechanisms generating sighs, which are crucial for respiratory function and linked to emotional states. Utilizing advanced methods in mice, they provide solid evidence that increased excitability in specific preBötzinger complex neuronal subpopulations expressing Neuromedin B receptors, gastrin-releasing peptide receptors, or somatostatin can induce sigh-like large amplitude inspirations. With additional technical clarifications and further elaboration of the limitations in terms of how the results are interpreted in the revised manuscript, the study will interest neuroscientists studying respiratory neurobiology and rhythmic motor systems.

eLife Assessment

In this revised manuscript, Dong et al. investigate the role of the small Ras-like GTPase Rab10 in the exocytosis of DCVs in mouse hippocampal neurons, showing that Rab10 depletion hinders DCV exocytosis independently of its effects on neurite outgrowth. Upon revising their work, these findings provide compelling evidence that Rab10 depletion leads to altered ER morphology, impaired ER-based calcium buffering, and decreased ribosomal protein expression, which collectively contributes to defective DCV secretion. The study comes to the fundamental conclusion that Rab10 is critical for DCV release by ensuring ER calcium homeostasis.

eLife Assessment

This important study develops and exploits novel ideas in dendritic integration and implements these ideas in a neural network. Historically, dendritic plateau potentials were thought to exist primarily for maintaining neurons in a depolarized state for 100s of milliseconds, but this study presents a new perspective that dendritic plateau potentials are equally effective in much shorter integration windows. The computational evidence supporting the article's claims is compelling.

eLife Assessment

This study aggregates across five fMRI datasets and reports that a network of brain areas previously associated with response inhibition processes, including several in the basal ganglia, are more active on failed stop than successful stop trials. This study is valuable as a well-powered investigation of fMRI measures of stopping, and following revisions provides solid evidence for its conclusions.

eLife Assessment

In this fundamental study, the authors describe ELF3 as a candidate driver of luminal progenitor transformation, such that its up-regulation during replicative stress conditions and in BRCA1 deficient cells may permit cell proliferation by suppressing genome instability. While the work is certainly of interest, the supporting data remain incomplete as luminal progenitor cells could not be isolated, which would be needed in order to definitively determine whether ELF3 is a driver of transformation in these cells. Overall this paper may offer insight into mechanisms by which BRCA1 deficiency fuels breast tumorigenesis.

eLife Assessment

This important work advances our understanding of factors influencing efficacy assessments and biomarker viability for complement-directed gene therapy against age-related macular degeneration. The data presented is convincing and offers insights and teachings for the design of gene therapy and complement-targeted therapeutics in the eye and more broadly for future ocular biomarker studies.

eLife Assessment

In this valuable study, the authors propose a model wherein the bacterial redox state plays a crucial role in the differentiation of Chlamydia trachomatis into elementary and reticulate bodies. They provide solid evidence to argue that a highly oxidising environment favours the formation of elementary bodies while a reducing condition slows down development. Overall, the study convincingly demonstrates that Chlamydial redox states play a role in differentiation, an observation that may have implications for the study of other bacterial systems.

eLife Assessment

This is a valuable study on the efficacy of a live attenuated vaccine that was tested in different animal models and the evidence is convincing. The study has been strengthened after revisions.

eLife Assessment

In this important study, the authors investigate the biogenesis of extracellular vesicles in mycobacteria and provide several observations to link VirR with vesiculogenesis, peptidoglycan metabolism, lipid metabolism, and cell wall permeability. The authors have done a commendable job of comprehensively examining the phenotypes associated with the VirR mutant using various techniques. The evidence presented in the revised manuscript is convincing and creates several avenues for further research.

eLife Assessment

The authors performed extensive coarse-grained molecular dynamics simulations of 140 different prion-like domain variants to interrogate how specific amino acid substitutions determine the driving forces for phase separation. The analyses are solid, and the derived predictive scaling laws can aid in identifying potential phase-separating regions in uncharacterized proteins. Overall, this is a valuable contribution to the field of biomolecular condensates. It exemplifies how data-driven methodologies can uncover new insights into complex biological phenomena.

eLife Assessment

The authors propose that positive biodiversity-ecosystem functioning relationships found in experiments have been exaggerated because commonly used statistical analyses are flawed. To remedy this, a new type of analysis based on a concept of "partial density monoculture yield" is proposed. However, the presented concept and analysis methods are not reproducibly described (how can partial density monoculture yield experimentally be assessed?), do not appear to be complete, and are inadequate for hypothesis testing. The reviewers found that the authors misinterpret current research in the field and made limited efforts to understand or address the reviewer comments about this study.

eLife Assessment

This neuroimaging and electrophysiology study in a small cohort of congenital cataract patients with sight recovery aims to characterize the effects of early visual deprivation on excitatory and inhibitory balance in visual cortex. While contrasting sight-recovery with visually intact controls suggested the existence of persistent alterations in Glx/GABA ratio and aperiodic EEG signals, it provided only incomplete evidence supporting claims about the effects of early deprivation itself. The reported data were considered valuable, given the rare study population. However, the small sample sizes, lack of a specific control cohort and multiple methodological limitations will likely restrict usefulness to scientists working in this particular subfield.

eLife Assessment

This valuable study provides insights into the structure and function of bacterial contractile injection systems that are present in the cytoplasm of many Streptomyces strains. A convincing high-resolution model of the structure of extended forms of the cytoplasmic contractile injection system assembly from Streptomyces coelicolor is presented, with some investigation of the membrane protein CisA in attachment of the extended assembly to the inner face of the cytoplasmic membrane and the firing of the system. The work expands the current understanding of these diverse bacterial nanomachines.

eLife Assessment

This is a valuable study and a promising development for the field of open-source microscopy for educational purposes. The strengths include the low cost of constructing the microscope, impressive performance and detailed resources including a dedicated website and YouTube channel. The claims are generally supported by solid evidence, however, the manuscript would be strengthened by inclusion of further details on standard performance metrics (e.g. signal to noise ratio etc.) compared to existing systems and further details and clarification on the microscope, construction and operation.

eLife Assessment

The work presented in this paper provides an important insight into how early life experience shapes adult behavior in fruit bats. The authors raised juvenile bats either in an impoverished or enriched environment and studied their foraging behaviors. The evidence is convincing that bats raised in enriched environments are more active, bold, and exploratory, although further exploration of the data and clarification of the analysis would strengthened the evidence. The work will be of interest to ethologists and developmental psychologists.

eLife Assessment

This valuable study presents findings linking prophage carriage to lifestyle regulation in the marine bacterium Shewanella fidelis, with potential implications for niche occupation within a host (Ciona robusta) and mediation of host immune responses. The study leverages a unique animal model system that offers distinct advantages in identifying select phenotypes to present generally solid evidence that supports findings relating to the impact of a prophage on host-microbe interaction. Understanding the role of integrated lysogenic phages in bacterial fitness, both within a host and in the environment, is a significant concept in bacterial eco-physiology, potentially contributing to the success of certain strains.

eLife Assessment

This fundamental study examines infection of the liver and hepatocytes during Mycobacterium tuberculosis infection using different systems including aerosol infection of mice and guinea pigs to demonstrate appreciable infection of the liver as well as the lung. The authors present convincing evidence that hepatocyte infection leads to metabolic dysfunction that promotes M. tuberculosis growth, in part potentially mediated by a nuclear receptor called PPARg. Overall, this is an interesting paper on an area of tuberculosis research which has been understudied, representing a significant advancement in the field.

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 solid 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

Using a TN-seq based approach, the authors identified the genetic determinants of drug tolerance in M. abscessus. Since M. abscessus is resistant to multiple antibiotics, the study is valuable in generating new knowledge linking antibiotic tolerance with ROS in this non-tuberculosis mycobacterial (NTM) species. However, the study is incomplete due to a need for more validation of the Tn-seq data, inconsistency with the clinical strains, and insufficient experiments confirming the role of ROS detoxification in drug tolerance.

eLife Assessment

This work describes a valuable method, SICKO, for real-time longitudinal quantification of bacterial colonization in the gut of individual C. elegans. The authors present convincing evidence to support the validity of the approach. SICKO provides an experimental framework that will enable progress in our understanding of host-microbe interactions.

eLife Assessment

This useful paper systematically evaluates B-cell receptor (BCR) repertoires across tumors, tumor-draining lymph nodes, and peripheral blood in patients with melanoma, lung adenocarcinoma, and colorectal cancer. It investigates the interplay between the tumor microenvironment and immune responses, revealing differences in BCR clonotype maturity, hypermutation, and spatial distribution. The study highlights the heterogeneity in immune responses and provides solid insights into the potential of tumor-infiltrating B cells for therapeutic applications, despite limitations in patient cohort size and sequencing methodology.

eLife Assessment

The paper presents a streamlined new approach for functional validation of genes known to underlie fragile bone disorders in a relatively high throughput, using CRISPR-mediated knockouts and a number of phenotypic assessments in zebrafish. Convincing data demonstrate the feasibility and validity of this approach, which presents an important tool for rapid functional validation of candidate gene(s) associated with heritable bone diseases identified from genetic studies.

eLife Assessment

This manuscript describes important findings on a rhizobial effector, its cleavage, and legume receptors involved in symbiosis. The evidence supporting the main claims is solid, though some conclusions would benefit from additional investigation. The findings have potential implications beyond bacterial interactions with plants.

eLife Assessment

Given a great need for novel human model systems to study small cell lung cancer (SCLC), the authors describe an important pre-clinical model with broad potential for the study of how genetic perturbations or drug treatments alter SCLC tumor growth, metastasis, and response to therapy. For the major finding, the authors provide convincing evidence that RB/TP53 suppression coupled with MYC overexpression in an ES cell-derived model system results in aggressive and metastatic SCLC. However, the impact of the work would have been increased with the inclusion of a broader set of genetic perturbations, such as over-expression of MYCL, to better model major SCLC phenotypes. The new model described will be of significant interest to researchers studying lung cancer.

eLife Assessment

This study reports valuable insights into the interactome of the RNA-binding protein SERBP1 and possible links through PARylation to diverse processes, including splicing, cell division, and ribosome biogenesis. The diversity of processes SERBP1 may regulate means this work would be of very broad interest to the cell biology community. The proteomics data are solid, but the functional connection to downstream processes and the link to Alzheimer's disease, while compelling, still require further examination. These latter data currently rely on a very limited set of experiments and patient samples with questionable quality of preservation and methodology.

eLife Assessment

This work is a valuable study that presents a detailed analysis of translation, driven by the untranslated regions of the Japanese encephalitis virus. It reports a role for the RNA helicase DDX3 in promoting a cap-independent translation mechanism. The conclusions are based on generally solid evidence, although there are some weaknesses in the overall model based on suboptimal experimental approaches and over-interpretation of some of the data. Addressing deficiencies noted in peer review could elevate the impact of the study.

eLife Assessment

The authors demonstrated cellular heterogeneity of companion cells (CCs) and also suggested the CC subpopulation that highly expressed the florigen gene FT. Based on this finding, they further identified flowering time regulators acting in CCs, including small proteins and NITRATE-INDUCIBLE GARP-TYPE TRANSCRIPTIONAL REPRESSOR1 type proteins (NIGT1s). In particular, the authors propose the NIGT1-FT regulatory module, which may be involved in the response to nitrogen status. This important study advances our understanding of flowering time control at high spatial resolution. While we believe this work will be of broad interest to plant biologists, the supporting evidence remains in parts incomplete. In particular, the quality of the single-cell and bulk RNA-seq data needs to be addressed to solidify the conclusions.

eLife Assessment

The manuscript provides an important assessment of the number and distribution of different retrovirus env genes present in primate genomes in the form of ancient endogenous retroviruses (ERV loci) and the potential role that viral recombination played in the diversification of retrovirus env genes and their propagation in the primate germline over millions of years. The exploration of this process in this study is considered solid, ultimately representing a conceptual advance with potentially broad implications. However, issues of clarity in the text and figures of the current version of the manuscript, as noted by multiple reviewers, may limit the ultimate impact of the work if insufficiently unaddressed.

eLife Assessment

This study provides a valuable and timely analysis of invasive and non-invasive Streptococcus pyogenes emm89 isolates, which have become a dominant serotype in the past decade. Using genome sequencing of 311 strains from Japan and comparing them with 666 global strains, the authors present compelling evidence in support of the identification of genetic factors linked to the invasive phenotype of emm89. The findings are both theoretically and practically significant in medical microbiology.

eLife Assessment

This study presents a valuable finding regarding the role of Arp2/3 and the actin nucleators N-WASP and WAVE complexes in myoblast fusion. The data presented is convincing, but it is suggested to perform validation of the knock-down efficiency of the mouse model and making adjustments to some of the data interpretation. The work will be of interest to biologists studying skeletal muscle stem cell biology in the context of skeletal muscle regeneration.

eLife Assessment

This study provides important insights into how cryptic pockets play a role in shaping binding preferences of protein-nucleic acid interactions. By combining biochemical assays and state-of-the-art molecular dynamics simulations, mechanism underlying viral protein 35 (VP35) homologs to bind the backbone of double stranded RNA is presented. The evidence is compelling for molecular determinants that suggest two different dsRNA binding modes for VP35 and also underscores the evolutionary importance of these pockets.

eLife Assessment

This important work substantially advances our understanding of reactive oxygen species (ROS) as a regenerative signal during postnatal cerebellum repair by activating adaptive progenitor reprogramming. The evidence supporting the conclusions is generally compelling, although addressing reviewers' comments would further strengthen the study. This work will be of broad interest to biologists working on stem cells, neurodevelopment and regenerative medicine.

eLife Assessment

The study provides a valuable analysis of escape from X-inactivation based on three rare female GTEX-donors with non-mosaic X-inactivation. The methods and analyses broadly support the author's claims, although some additional explanation could be helpful. Their data are more comprehensive than those presented previously and add significant weight to evidence for which genes are inactivated or escape from X inactivation in humans. However, without further experimentation the overall study unfortunately remains incomplete in its current form.

eLife Assessment

This important study reveals a critical role of the transcription factor NR2F2 in mouse fetal Leydig cell (FLC) differentiation. With elegantly carried out experiments, the authors provide compelling evidence that NR2F2 helps to initiate the differentiation of certain interstitial cells into FLC until these cells mature into functional secretory cells that produce androgen and insulin-like peptide 3 (INSL3). The particular importance of the work comes from the fact that NR2F2 affects FLCs without altering paracrine signals known to be involved in FLC differentiation. The work will be of interest to colleagues studying reproductive development in mammals including humans or the biological functions of the nuclear receptor family.

eLife Assessment

This useful study provides the first assessment of potentially interactive effects of seasonality and blood source on mosquito fitness, together in one study. During revision, the manuscript has been improved, providing additional solid data to support the robustness of observations. However, the discussion still requires further refinement to present the conclusions in manner that is consistent with the data presented. Overall, this interesting study will advance our current understanding of mosquito biology.

eLife Assessment

This useful study presents a genetically encoded barcoding system that could advance transcriptomic studies and that has the potential for further applications, such as in high-throughput population-scale behavioral measurements. The evidence supporting the claims of the authors is solid and highlights both the usefulness and the limitations of the approach.

eLife Assessment

Modulation of BMP signalling affects body size in the nematode Caenorhabditis elegans, and this paper examines the effects on C. elegans body size brought about by the modulation of BMP signalling. Thw study provides valuable analyses of ChIP-seq and RNA-Seq data to understand the function of SMA-3 (Smad) and SMA-9 (Schnurri) in this model. The authors provide compelling evidence that the BMP-dependent body size effect could be due to defects in cuticle collagen secretion, a finding of interest to those studying organismal growth and epidermal function.

eLife Assessment

This valuable paper describes a comprehensive quantitative phospho-proteomic analysis of Xenopus oocytes during meiosis. Using time-resolved proteomic analyses, the authors provide insights into changes in protein levels and phosphorylation states to an unprecedented depth, quality, and quantitative detail. The key findings are solid and offer a helpful resource for the scientific community.

eLife Assessment

In this important study, the authors combine innovative experimental approaches, including direct compressibility measurements and traction force analyses, with theoretical modeling to propose that wild-type cells exert compressive forces on softer HRasV12-transformed cells, influencing competition outcomes. The data generally provide solid evidence that transformed epithelial cells exhibit higher compressibility than wild-type cells, a property linked to their compaction during mechanical cell competition. However, the study would benefit from further characterization of how compression affects the behavior of HRasV12 cells and clearer causal links between compressibility and competition outcomes.

eLife Assessment

In this important study, the authors combine innovative experimental approaches, including direct compressibility measurements and traction force analyses, with theoretical modeling to propose that wild-type cells exert compressive forces on softer HRasV12-transformed cells, influencing competition outcomes. The data generally provide solid evidence that transformed epithelial cells exhibit higher compressibility than wild-type cells, a property linked to their compaction during mechanical cell competition. However, the study would benefit from further characterization of how compression affects the behavior of HRasV12 cells and clearer causal links between compressibility and competition outcomes.

eLife Assessment

This manuscript presents a valuable study utilizing an in vitro organoid system to recapitulate the developmental process of the olfactory epithelium. The authors provided solid evidence indicating that a combination of niche factors can induce organoid development and give rise to multiple cell types. However, the calcium imaging part of the study could be seen as a limitation.

eLife Assessment

This manuscript reports on an FLIM-based calcium biosensor, G-CaFLITS. It represents an important contribution to the field of genetically-encoded fluorescent biosensors, and will serve as a practical tool for the FLIM imaging community. The paper provides convincing evidence of G-CaFLITS's photophysical properties and its advantages over previous biosensors such as Tq-Ca-FLITS. Although the benefits of G-Ca-FLITS over Tq-Ca-FLITS are limited by the relatively small wavelength shift, it presents some advantages in terms of compatibility with available instrumentation and brightness consistency.

eLife Assessment

This paper presents useful findings that misfolded proteins in the nucleus can impair proteasomal degradation and activate p53. The results supporting the findings are largely solid, but incomplete. The manuscript could be strengthened by including more quantitative data analyses and additional experimentation/discussions on the mechanism of p53 activation by misfolded nuclear proteins. The work will be interesting primarily to scientists studying protein homeostasis.

eLife Assessment

This is a valuable polymer model that provides insight into the origin of macromolecular mixed and demixed states within transcription clusters. The well-performed and clearly presented simulations will be of interest to those studying gene expression in the context of chromatin. While the study is generally solid, it could benefit from a more direct comparison with existing experimental data sets as well as further discussion of the limits of the underlying model assumptions.

eLife Assessment

The role of ACVR2A is potentially of importance to both the biology of trophoblast cells and to the pathogenesis of preeclampsia. In this manuscript, the authors have taken a useful first step towards better understanding this protein using a loss of function model in trophoblast cell lines and then examining invasion, proliferation, and transcription in these cells. At present, the results of this study are only based on the observation of in vitro phenotypes, and the strength of the invasion data is somewhat weak, given the confounding effect on proliferation. The study is currently incomplete as there is a lack of direct evidence on how target factors participate in the occurrence of placental structural disorders and diseases through potential downstream pathways.

eLife Assessment

This important study introduces a biologically constrained model of telencephalic area of adult zebrafish to highlight the significance of precisely balanced memory networks in olfactory processing. The authors provide compelling evidence that their model performs better in multiple situations (for e.g. in terms of network stability and shaping the geometry of representations), compared to traditional attractor networks and persistent activity. The work supports recent studies reporting functional E/I subnetworks in several sensory cortexes, and will be of interest to both theoretical and experimental neuroscientists studying network dynamics based on structured excitatory and inhibitory interactions.

eLife Assessment

This work is important because it elucidates how immune cells migrate across the blood brain barrier. In the revised version of this study, the authors present a convincing framework to visualize, recognize and track the movement of different immune cells across primary human and mouse brain microvascular endothelial cells without the need for fluorescence-based imaging using microfluidic devices. This work will be of broad interest to the cancer biology, immunology and medical therapeutics fields.

eLife Assessment

This study presents a valuable conceptual approach that cell lineage can be determined using methylation data. However, the evidence supporting the claims of the author remains incomplete after revision. If clarified further as described in the reviews, this approach could be of broad interest to neuroscientists and developmental biologists.

eLife Assessment

This study presents a valuable finding on the mechanism of self-prioritization by revealing the influence of self-associations on early attentional selection. The evidence supporting the claims of the authors is solid, although inclusion of a discussion about the generalization and limitation would have strengthened the study. The work will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife Assessment

This study describes a valuable 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 solid 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 provocative manuscript presents important comparisons of the morphologies of Archaean bacterial microfossils to those of microbes transformed under environmental conditions that mimic those present on Earth during the same Eon. The evidence in support of the conclusions is solid. The authors' environmental condition selection for their experiment is justified.

eLife Assessment

Previous studies in mammals and other vertebrates have shown that a noninvasive measure of cochlear tuning, based on the latency derived from stimulus-frequency otoacoustic emissions, provides a reasonable, and non-invasive, estimate of cochlear tuning. This valuable study confirms that finding in a new species, the budgerigar, and provides convincing support for the utility of otoacoustic estimates of cochlear tuning, a methodology previously explored primarily in mammals. The study's remaining claims of a mismatch between behavioral frequency selectivity and cochlear tuning are based on old behavioral data, and collected in an extreme frequency region at the edge of the limits of hearing. Hearing abilities are hard to measure accurately on the upper frequency edge of the hearing range, and the evidence for these claims is weak.

eLife Assessment

This is an important study using a combination of optogenetics and calcium imaging to provide insight into the function of the cholinergic input to the prelimbic cortex in probabilistic spatial learning as it relates to threat. These data are timely in contributing to an ongoing discussion in the field about the role of phasic cholinergic signaling to the cortex, about which relatively little is known. The strength of the evidence is incomplete and could be improved by changes in task design and analyses, cross-validation of the conditions in calcium imaging, as well as the incorporation of control experiments to more definitively show it is indeed acetylcholine working in this circuit.

eLife Assessment

This important study leverages the power of Drosophila genetics and sparsely-labeled neurons to propose a new model for neuronal injury signaling. The authors present convincing evidence to support that the somatic response to axonal injury is suppressed if the injury is not complete, suggesting the presence of an integration of axonal injury-related signaling. While the underlying mechanism of this fascinating observation is unknown, the phenomenon itself will be of broad significance in the field.

eLife Assessment

This important study describes a neural circuit contributing to two behavioral processes affecting pathogen avoidance in the nematode C. elegans. The method used to identify specific contributing neurons is innovative and the experimental evidence supporting the major claims is solid. This study will be of interest to neuroscientists studying behavior, in particular in C. elegans.

eLife Assessment

This study presents important analyses of the impacts of microexon deletions and loss-of-function in microexon regulators on zebrafish neurite outgrowth and gene expression, as well as adult and larval behavior. While microexons have been mapped in many genes several years ago, information on their functions - in particular with regard to individual gene isoforms - is limited. The authors provide convincing evidence that individual microexon deletions, only in a few cases, produce subtle cellular and behavioural phenotypes, while transcriptomic analysis reveals gene expression alterations that are suggestive of compensatory mechanisms that buffer against microexon disruption.

eLife Assessment

This important study provides new insights into the plasticity mechanisms underlying the formation of spatial maps in the hippocampus. Supported by a large and comprehensive dataset, the evidence is solid. However, certain aspects of the statistical analysis and data presentation may seem incomplete and warrant improvement. This study will be of interest to neuroscientists focusing on spatial navigation, learning, and memory.

eLife Assessment

This cleverly-designed and potentially important work supports our understanding regarding how and whether social behaviours promoting egalitarianism can be learned, even when implementing these norms entails a cost for oneself. However, the evidence supporting the major claims is currently incomplete, with major limitations being the statistical approach, the modelling, and over-interpretation. With a strengthening of the supporting evidence, this work will be of interest to a wide range of fields, including cognitive psychology/neuroscience, neuroeconomics, and social psychology, as well as policy making.

eLife Assessment

This paper shows convincingly that the human visual system can recalibrate itself to compensate for phase alterations in an image induced by optical blur. This phenomenon is studied using state-of-the-art adaptive optics approaches that allow the manipulation of the eye's optics while making concurrent psychophysical measurements. The findings are broadly important because they highlight a neural mechanism by which flawed information is used to create seemingly accurate perceptions of the visual environment.

eLife Assessment

The study presents some useful findings on Mendelian randomization-phenome-wide association, with BMI associated with health outcomes, and there is a focus on sex differences. Although there are some solid phenotype and genotype data, some of the data are incomplete and could be better presented, perhaps benefiting from more rigorous approaches. Confirmation and further assessment of the observed sex differences will add further value.

eLife Assessment

This important study explores the power of computational methods to predict lifespan-extending small molecules, demonstrating that while these methods significantly increase hit rates, experimental validation remains essential. The study uses all-trans retinoic acid in Caenorhabditis elegans as a model, providing genetic and transcriptomic insights into its longevity effects. The data are compelling in describing a robust, computationally informed screening process for discovering compounds that extend lifespan in this species.

eLife Assessment

This study reveals that female moths utilize ultrasonic sounds emitted by dehydrated plants to inform their oviposition decisions, highlighting sound as a potential sensory cue for optimal host plant selection. By investigating this novel acoustic interaction, the research adds an important piece to our understanding of plant-insect interactions. While the authors employed an overall solid experimental approach, weaknesses include the lack of raw data and individual data point visualization, inconsistencies in moth responses to sound cues with and without plants, and the use of a click frequency higher than what plants typically produce, which may limit the ecological applicability and broader generalization of the findings.

eLife Assessment

This descriptive manuscript builds on prior research showing that the elimination of Origin Recognition Complex (ORC) subunits does not halt DNA replication. The authors use various methods to genetically remove one or two ORC subunits from specific tissues and observe continued replication, though it may be incomplete. The replication appears to be primarily endoreduplication, indicating that ORC-independent replication may promote genome reduplication without mitosis. Despite similar findings in previous studies, the paper provides convincing genetic evidence in mice that liver cells can replicate and undergo endoreduplication even with severely depleted ORC levels. While the mechanism behind this ORC-independent replication remains unclear, the study lays the groundwork for future research to explore how cells compensate for the absence of ORC and to develop functional approaches to investigate this process. The reviewers agree that this valuable paper would be strengthened significantly if the authors could delve a bit deeper into the nature of replication initiation, potentially using an origin mapping experiment. Such an exciting contribution would help explain the nature of the proposed new type of Mcm loading, thereby increasing the impact of this study for the field at large.

eLife Assessment

In this useful manuscript, the authors performed scRNA-seq on a diverse cohort of 15 early-stage cervical cancer patients. Correlative data is provided to support the possible establishment of an immunosuppressive microenvironment near SCL26A3+ cells, and an association of these cells with upstaging at time of surgery. However without more extensive validation, the evidence supporting the conclusions remains incomplete. Overall, this paper will provide a potentially helpful dataset for researchers studying cervical cancer.

eLife Assessment

This valuable study shows previously unappreciated binding of the eukaryotic translation initiation factor 3 (eIF3) to the poly(A) tail proximal portion of 3' untranslated regions (UTRs) of mRNAs that are efficiently translated in neuronal progenitors. The authors' conclusions are supported by solid experimental evidence which is based on several orthogonal systems biology approaches. This article is of considerable interest to the broad spectrum of biomedical researchers interested in studying post-transcriptional regulation of gene expression.

eLife Assessment

Yu and colleagues used two-sample MR to test the effect of PUFA on cerebral aneurysms. They found that genetically predicted omega-3 and DHA decreased the risk for Intracranial Aneurysm and Subarachnoid Haemorrhage. This work is useful and the revised version provides solid evidence to support the claims.

eLife Assessment

This work provides important findings characterizing potential synaptic mechanisms supporting the role of midline thalamus-hippocampal projections in fear memory extinction in mice. The methods and approaches were considered solid, though some evidence is incomplete as there are some concerns with the analytical approaches used for some aspects of the study. This work will be of interest to those in the field of thalamic regulation and fear memory.

eLife Assessment

The important study established a large-scale objective and integrated multiple optical microscopy systems to demonstrate their potential for long-term imaging of the developmental process. The convincing imaging data cover a wide range of biological applications, such as organoids, mouse brains, and quail embryos, but enhancing image quality can further enhance the method's effectiveness. This work will appeal to biologists and imaging technologists focused on long-term imaging of large fields.

eLife Assessment

Wang et al. presented visual (dot) motion and/or the sound of a walking person and found solid evidence that EEG activity tracks the step rhythm, as well as the gait (2-step cycle) rhythm, with some demonstration that the gait rhythm is tracked superadditively (power for A+V condition is higher than the sum of the A-only and V-only condition). The valuable findings will be of wide interest to those examining biological motion perception and oscillatory processes more broadly. Some of the theoretical interpretations concerning entrainment must remain speculative when the authors cannot dissociate evoked responses from entrained oscillatory effects

eLife Assessment

In this manuscript, Griesius et al analyze the dendritic integration properties of NDNF and OLM interneurons, and suggest that the supralinear NMDA receptor-dependent synaptic integration may be associated with dendritic calcium transients only in NDNF interneurons. These findings are important because they suggest there might be functional heterogeneities in the mechanisms underlying synaptic integration in different classes of interneurons of the mouse neocortex and hippocampus. The revised work remains incomplete due to remaining concerns about experimental methodology, cell health, and lack of dendritic Na-spikes which have been recorded in previous works.

eLife assessment

This manuscript provides valuable information about the genesis of CPSF6 condensates due to HIV-1 infection. However, the evidence is incomplete as it is missing more functional assays. Furthermore, some data on the fusion between CPSF6 Aggregates and SC35 speckles are not novel.

eLife Assessment

This fundamental work demonstrates that compartmentalized cellular metabolism is a dominant input into cell size control in a variety of mammalian cell types and in Drosophila. The authors show that increased pyruvate import into the mitochondria in liver-like cells and in primary hepatocytes drives gluconeogenesis but reduces cellular amino acid production, suppressing protein synthesis. The evidence supporting the conclusions is compelling, with a variety of genetic and pharmacologic assays rigorously testing each step of the proposed mechanism. This work will be of interest to cell biologists, physiologists, and researchers interested in cell metabolism, and is significant because stem cells and many cancers exhibit metabolic rewiring of pyruvate metabolism.

eLife Assessment

This work is of fundamental significance and has a compelling level of evidence for the role of mutant p53 in regulation of tumorigenesis using an in vivo mouse model. The study is well-conducted and will be of interest to a broad audience including those interested in p53, transcription factors and cancer biology.

eLife Assessment

This manuscript provides potentially important findings examining in 2D and 3D models in MYC liver cancer cells changes in DNA repair genes and programs in response to hypoxia. The authors use convincing methodology in most cases, but there is some concern that the analysis is incomplete.

eLife Assessment

Overall, this fundamental study identified a novel role of NOLC1 in regulating p53 nuclear transcriptional activity and p53-mediated ferroptosis in gastric cancer. The evidence supporting the conclusions is solid, although some new evidence is needed to make it more robust. The work will be of broad interest to cancer biologists and oncologists.

eLife Assessment

This important work advances our understanding of how the SARS-CoV-2 Nsp16 protein is regulated by host E3 ligases to promote viral mRNA capping. However, support for the overall claims is incomplete as the authors need to demonstrate Nsp16 ubiquitination and the role of E3 ligases in a more biologically relevant context (ie. infection). This work will be of interest to those working in host-viral interactions and the role of the ubiquitin-proteasome system in viral replication.

eLife Assessment

In the field of early detection of disease and recurrence and monitoring of treatment efficacy by cfDNA analysis, this study presents a useful finding that HPV cfDNA level monitoring provides advantages over serum levels of squamous cell carcinoma antigen (SCC-Ag), specifically for HPV+ cervical cancer. The data were collected and analysed using solid and validated methodology but the sample number was limited.

eLife Assessment

This work presents a valuable self-supervised method for the segmentation of 3D cells in microscopy images, alongside an implementation as a Napari plugin and an annotated dataset. While the Napari plugin is readily applicable and promises to eliminate time consuming data labeling to speed up quantitative analysis, there is incomplete evidence to support the claim that the segmentation method generalizes to other light-sheet microscopy image datasets beyond the four specific ones used here.

eLife Assessment

This important study uses optogenetics in combination with single cell recordings to selectively activate sensory input channels within the olfactory bulb, providing direct evidence for activity-dependent and distance-independent enhancement of stimulus-evoked gamma oscillations via lateral interactions between input channels, most likely via granule cells. The article presents solid evidence to support the main conclusions.

eLife Assessment

The findings of this study are potentially valuable, offering insights into the neural representation of reversal probability in decision-making tasks, with potential implications for understanding flexible behavior in changing environments. The evidence presented is incomplete, with interesting comparisons between neural data and models, but the analyses do not yet provide clear evidence against line attractor dynamics for the accumulation of evidence of a reversal in this probabilistic reversal learning task.

eLife Assessment

This important work examines how microexons contribute to brain activity, structure, and behavior. The authors find that loss of microexon sequences generally has subtle impacts on these metrics in larval zebrafish, with few exceptions. The evidence is still partially incomplete and needs to be strengthened by key experiments or more precise data descriptions. Overall, this work will be of interest to neuroscientists and generate further studies of interest to the field.

eLife Assessment

This study demonstrates the potential role of 17α-estradiol in modulating neuronal gene expression in the aged hypothalamus of male rats, identifying key pathways and neuron subtypes affected by the drug. While the findings are useful and provide a foundation for future research, the strength of supporting evidence is incomplete due to the lack of female comparison, a young male control group, unclear link to 17α-estradiol lifespan extension in rats, and insufficient analysis of glial cells and cellular stress in CRH neurons.

eLife Assessment

This valuable study suggests that Naa10, an N-α-acetyltransferase with known mutations that disrupt neurodevelopment, acetylates Btbd3, which has been implicated in neurite outgrowth and obsessive-compulsive disorder, in a manner that regulates F-actin dynamics to facilitate neurite outgrowth. While the study provides promising insights and biochemical, co-immunoprecipitation, and proteomic data that enhance our understanding of protein N-acetylation in neuronal development, the evidence supporting larger claims is incomplete. Nonetheless, the implications of these findings are noteworthy, particularly regarding neurodevelopmental and psychiatric conditions tied to altered expression of Naa10 or Btbd3.

eLife Assessment

This study uncovers and characterizes a role for Pfdn5 in stabilizing axonal microtubules and synaptic morphology in the Drosophila peripheral nervous system. Although the mechanisms remain unresolved, the phenotypic characterization is an important contribution with solid evidence. The work also aims to address a potential interaction between Pfdn5/6 and Tau-mediated mechanisms of neurodegeneration; here, the evidence is partially incomplete.

eLife Assessment

This valuable study explores the role of spatial genome organization in oncogenic transformation, addressing an ambitious and significant topic. The authors have assembled comprehensive datasets from various subtypes of localized and lung-metastatic breast cancer cells, as well as from healthy and cancerous lung cells. They identified switching patterns in the 3D genome organization of lung-metastatic breast cancer cells, revealing a reconfiguration of genome architecture that resembles that of lung cells. If validated, this study could be critical for the field; however, at this stage, it is incomplete, as the main claims are only partially substantiated.

eLife Assessment

This study presents the state-dependent role of serotonin for the protein and sugar intake of Drosophila by expressing a dominant-negative serotonin transporter in subsets of serotoninergic neurons. This paper is valuable for neuroscientists working on neuromodulation and the effects of internal states such as hunger, however the characterization of behavioral and neuroanatomical data is incomplete.

eLife Assessment

This study reports important findings about the nature of feedback to primary visual cortex (V1) during object recognition. The state-of-the-art functional MRI evidence for the main claims is solid, although currently alternative explanations of the findings cannot be fully ruled out. The findings presented here are relevant to a number of scientific fields such as object recognition, categorisation and predictive coding.

eLife Assessment

This valuable study relating brain anatomy to reading ability in children studied longitudinally finds that a difference in sulcal anatomy is more predictive of reading ability than cognitive measures. The evidence that this anatomical difference is predictive and confers some benefit in the connectivity between brain areas is based on careful analyses and is solid. The findings would be of interest to researchers studying brain and cognitive development.

eLife Assessment

This valuable study combines evolution experiments with molecular and genetic techniques to study how a genetic lesion in MreB that causes rod-shape cells to become spherical, with concomitant deleterious fitness effects, can be rescued by natural selection. The results are convincing, although further improvement of the statistical analyses and figure presentation, and further clarification of the concrete contribution of the paper and how it relates to previous literature, would be welcome.

eLife Assessment

Gil Ávila et al. evaluated the aperiodic component in the medial prefrontal cortex using resting-state EEG recordings from 149 individuals with chronic pain and 115 healthy participants. The authors present compelling evidence that the aperiodic component of the EEG does not differentiate between those with chronic pain and healthy individuals. The study was well-designed and rigorously conducted, and the clear and conclusive results provide important insights that can guide future research in the field of pain neuroscience.

eLife Assessment

This important study enhances our understanding of the foraging behaviour of aerial insectivorous birds. Using solid methodology, the authors have collected extensive data on bird movements and prey availability, which in turn provide support for the main claim of the study. The work will be of broad interest to behavioural ecologists.

eLife Assessment

This important study describes two findings: first, that TEAD is subject to turnover by the ubiquitin-proteasome system involving RNF146 and Parylation, and second, the development of a pan-TEAD heterobifunctional degrader that is used to inhibit growth of a YAP-dependent cancer cell line and to characterize TEAD binding sites in the genome. Convincing evidence supports the development and specificity of the degrader. This article will be of relevance to cancer biologists and scientists interested in proteostasis, cellular signaling, and post-translation modification of proteins.

eLife Assessment

This study presents a useful model of genetic drift by incorporating variance in reproductive success, claiming to address several paradoxes in molecular evolution. However, some of the claimed "paradoxes" seem to be overstatements, as previous literature has pointed out the limitations of the standard model and proposed more advanced models to address those limitations. While the proposed new model presented in this paper yields some intriguing theoretical predictions, the analysis and simulations presented are incomplete to support the authors' strong claims, and it is unclear how much the model helps explain empirical observations.

eLife Assessment

In this important study, the authors employed three types of theoretical/computational models (coarse-grained molecular dynamics, analytical theory and field-theoretical simulations) to analyze the impact of salt on protein liquid-liquid phase separation. These different models reinforce each other and together provide convincing evidence to explain distinct salt effects on ATP mediated phase separation of different variants of caprin1. The insights and general approach are broadly applicable to the analysis of protein phase separation. Still, modeling at the coarse-grained level misses key effects that have been revealed by all-atom simulations, including salt-backbone coordination and strengthening of pi-type interactions by salt.

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 valuable study presents new observations on white matter organisation at the micron scale, using a combination of synchrotron imaging and diffusion MRI across two species. Notably, the authors provide solid evidence for the fasciculation of axons within major fibre bundles into laminar structures, though these structures are not consistently observed across modalities or species. The study will be of general interest to neuroanatomists and those interested in white matter imaging.

eLife Assessment

This valuable study extends the previous interesting work of this group to address the potentially different control of movement and posture. Through experiments in which stroke participants used a robotic manipulandum, the authors provide solid evidence supporting a lack of a relation between the resting force postural bias they measure (closely related to the flexor synergy in stroke) and kinematic deficits during movement. Based on these results, the authors propose a conceptual framework that differentially weights the two main descending pathways (corticospinal tract and reticulospinal tract) for neurologically intact and stroke patients. Discussing the potential impact of differences on muscle/spinal circuit state and their responses between holding a posture and movement, as well as the assumptions of their statistical comparisons, would further improve the paper.

eLife Assessment

This study provides important insights into the regulation of a retained intron in the mRNA coding for OGT, a process known to be regulated by the O-GlcNAc cycling system, and highlights the functional role of the splicing regulator SFSWAP. The evidence supporting the claims of the authors is convincing: the authors performed an elegant state-of-the-art CRISPR knockout strategy and sophisticated bioinformatic analysis to identify SFSWAP as a negative regulator of alternative splicing. The work will be of interest to researchers in the fields of splicing and glycobiology.

eLife Assessment

This study provides useful findings about the effects of heterozygosity for Trio variants linked to neurodevelopmental and psychiatric disorders in mice. However, the strength of the evidence is limited and incomplete mainly because the experimental flow is difficult to follow, raising concerns about the conclusions' robustness. Clearer connections between variables, such as sex, age, behavior, brain regions, and synaptic measures, and more methodological detail on breeding strategies, test timelines, electrophysiology, and analysis, are needed to support their claims.

eLife Assessment

This study investigates the fundamental role of polyunsaturated fatty acids (PUFAs) in membrane biology, using a unique model to perform a thorough genetic screen that highlights that PUFA synthesis defects cannot be compensated for by mutations in other pathways. While the data are solid and generally support the claims, additional experimental validation or more detailed descriptions of their results would strengthen the broader conclusions. This study will appeal to researchers in membrane biology, lipid metabolism, and C. elegans genetics.