eLife assessment

This manuscript aims to unravel the contribution of cholesterol to aquaporin-0 (AQP0) tetramer array formation within lens membranes. Compelling electron crystallography data are combined with solid molecular dynamics experiments to identify a specific cholesterol binding site of significance to protein clustering within lipid rafts. The important work advances our understanding of membrane biology and will be of broad interest to membrane transport biologists, biochemists, and structural biologists.

eLife assessment

This manuscript describes a deep mutational scanning study of the kinase domain of the MET receptor tyrosine kinase. The study yields an important catalog of essentially all possible deleterious mutations in this portion of the receptor., with convincing evidence. The manuscript will be of interest to researchers working in the field of receptor tyrosine kinases.

eLife assessment

This valuable study uses single-cell transcriptomics to explore the mouse vomeronasal organ and represents an advance that enhances our understanding of neural diversity within this sensory system. Findings suggest a unique endoplasmic reticulum (ER) structure in Gnao1 neurons and allow for the synthesis of a developmental trajectory from stem cells to mature vomeronasal sensory neurons. Convincing methods, data, and analyses broadly support the claims, although experiments supporting the main ER-related claim require additional quantification of co-expression and statistics on labeling intensity or coverage. Adding these data would greatly strengthen the conclusions of the paper.

eLife assessment

This study compiles a wide range of results on the connectivity, stimulus selectivity, and potential role of the claustrum in sensory behavior. While most of the connectivity results confirm earlier studies, this valuable work provides incomplete evidence that the claustrum responds to multimodal stimuli and that local connectivity is reduced across cells that have similar long-range connectivity. The conclusions drawn from the behavioral results are weakened by the animals' poor performance on the designed task.This study has the potential to be of interest to neuroscientists.

eLife assessment

This valuable study uses dynamic metabolic models to compare perturbation responses in a bacterial system, analyzing whether they return to their steady state or amplify beyond the initial perturbation. The evidence supporting the emergent properties of perturbed metabolic systems to network topology and sensitivity to specific metabolites is compelling. However, the mathematical explanation of the perturbation response is incomplete, and a more comprehensive metabolic and biosynthesis model would be beneficial.

eLife assessment

This important work offers a thorough exploration of the molecular features of different cell types within the mouse vomeronasal organ, including the expression of chemosensory receptors, using single-cell transcriptomics. The data are thoughtfully analyzed and presented, although the evidence is incomplete and only partially supports some of the claims made by the authors.

eLife assessment

This important study demonstrates a novel method for imaging glutamate receptors in situ via cryo-ET. The use of cutting-edge methods is well-described and is convincing, but there are minor concerns as to how generally this approach can be used in imaging cell surface receptors. This paper is broadly relevant to biophysicists and neuroscientists.

eLife assessment

This study provides the first analysis of vascular stabilization on the critical and evolutionarily conserved structure around the Circle of Willis in the brain, strengthened by using parallel in vivo and in vitro experimental approaches. The evidence supporting the claims is solid and the work will be valuable for scientists studying developmental and disease-related vascular stabilization.

eLife assessment

This important study demonstrates that combining AlphaFold2 with the author's sampling method AF2-RAVE improves protein-ligand docking for three protein kinases and their inhibitors. The evidence is compelling but would benefit from a more complete description of the methodology and a clear assessment of the method's range of applicability. The work will be of interest to researchers who work on computer-aided drug design.

eLife assessment

The mechanisms that ensure accurate chromosome segregation are key for genome integrity and defects therein can cause human disease. Although the involvement of MAP kinases in modulating mitosis is known, this manuscript makes a valuable contribution by going to some lengths to reveal links between Spindle Assembly Checkpoint dynamics and stress-responsive MAP-kinase pathways. The strength of the evidence is solid but there are minor weaknesses, which need to be addressed.

eLife assessment

The study is noteworthy for its effort to achieve a deeper understanding of PTH-1 Receptor signaling. This molecular pathway which underpins the control of calcium and phosphate metabolism throughout life in land-dwelling animals, can be targeted to the therapeutic benefit of people with osteoporosis. We consider the significance of the findings in this paper to be valuable to the community of investigators working on PTH receptor and PTH ligand signaling. The strength of the evidence is solid and it could become even stronger by addressing a few shortcomings.

eLife assessment

This valuable study uses neuroanatomical techniques to investigate somatosensory projections from the elephant trunk to the brainstem. Given its unique specializations, understanding how the elephant trunk is represented within the brain is of general interest to evolutionary and comparative neuroscientists. The authors present solid evidence for the existence of a novel isomorphism in which the folds of the trunk are mapped onto the trigeminal nucleus; however, due to their unusual structure, some uncertainty remains about the identification and anatomical organization of nuclei within the elephant brainstem.

eLife assessment

The authors further corroborated their model that Netrin signaling promotes survival and dissemination of non-proliferating ovarian cancer cells. These valuable results were found to be of significant potential interest to cancer biologists in as much as they address gaps in knowledge pertinent to the mechanisms underpinning ovarian cancer spread. In general, it was thought that solid experimental evidence was provided to support the role of Netrin signaling in fueling ovarian cancer progression.

eLife assessment

This is a useful study that used DEGAS, a deep transfer learning tool, to identify distinct pancreatic beta cell subpopulations that could be associated with type 2 diabetes (T2D) and/or obesity status. The data supporting the authors' findings is solid and demonstrates that DEGAS will be a helpful tool for analyzing cell-specific transcriptomic phenotypes. This study will be of interest to researchers studying the genetics of T2D.

eLife assessment

ProtSSN is a valuable approach that generates protein embeddings by integrating sequence and structural information, demonstrating improved prediction of mutation effects on thermostability compared to sequence-only models. The work is currently incomplete as it lacks a thorough comparison against other recent top-performing methods that also incorporate structural data, such as SaProt, EVE-based models, and GEMME. Providing a comprehensive analysis benchmarking ProtSSN against these state-of-the-art structure-based approaches would significantly strengthen the evidence supporting the utility of ProtSSN's joint sequence-structure representations.

eLife assessment

This valuable manuscript provides an interesting account documenting the role of resident CD56(br) NK cells in driving interaction with dendritic cells that attract CD8+ T cells to the pancreas cancer tumor microenvironment (TME). The work convincingly illustrates how irradiation combined with CCR5i and PD1 blockade leads to a reduction in pancreatic cancer growth that correlates with a reduction in Treg cells and enhancement of NK and CD8 T cells in the TME. The correlation of NKC1 signature with survival in pancreatic cancer patients is indeed of broader interest regarding potential relevance to other types of cancer.

eLife assessment

The authors investigated the requirement and function of Blimp1/Prdm1 in murine natural killer (NK) cells and the ILC1 lineage of innate lymphoid cells, using a conditional knockout model. The single-cell mRNA-seq data provided here represent a valuable resource for the community, but the lack of mechanistic investigations leaves the study partially incomplete. The work will be of interest to the fields of innate lymphoid cell biology and tissue immunology.

eLife assessment

This important study demonstrates a link between an acute high fat diet, microglial metabolism and improved higher cognitive function. The evidence supporting the proposed mechanism in vivo is incomplete at this stage due to non-trivial technical limitations but the authors provide convincing in vitro metabolic characterization of primary microglia cultures to support the model. This work will be of interest to a broad audience in the field of neuroscience, metabolism, and immunology.

eLife assessment

Chang et al. provide glutamate co-expression profiles in the central noradrenergic system and test the requirement of Vglut2-based glutamatergic release in respiratory and metabolic activity under physiologically relevant gas challenges. Their experiments provide compelling evidence that conditional deletion of vesicular glutamate transporters from noradrenergic neurons does not impact steady-state breathing or metabolic activity in room air, hypercapnia, or hypoxia. This study provides an important contribution to our understanding of how noradrenergic neurons regulate respiratory homeostasis in conscious adult mice.

eLife assessment

This study presents solid evidence to support the effectiveness of the novel eIF2B activator DNL343 in mitigating the integrated stress response (ISR) and reducing neurodegeneration associated with ISR activation in two mouse models. These important findings offer promise for the potential use of DNL343 in treating vanishing white matter disease (VWMD), a rare condition resulting from eIF2B loss of function, and in addressing other neurodegenerative disorders characterized by ISR involvement. The study also identified potential VWMD biomarkers, which hold significance for assessing disease progression and evaluating treatment responses.

eLife assessment

This fundamental study addresses the question of how certain zooplankton achieve barotaxis, directed locomotion in response to changes in hydraulic pressure. The authors provide compelling evidence that the response involves ciliary photoreceptors interacting with motoneurons. This work should be of broad interest to scientists working on mechanosensation, cilia, locomotion, and photoreceptors.

eLife assessment

This valuable study elucidates the essential role of the chromatin regulator KDM6B in the establishment and maintenance of neural stem cells (NSCs) in the mouse hippocampus. While the evidence supporting the authors' claims is largely solid, a more comprehensive investigation into the cellular and molecular events underlying the loss of hippocampal NSCs would have further strengthened the study. Nonetheless, the findings will be of interest to biologists studying neural development and NSCs.

eLife assessment

This manuscript makes valuable contributions to our understanding of cell polarisation dynamics and its underlying mechanisms. Through the development of a computational pipeline, the authors provide solid evidence that compensatory actions, whether regulatory or spatial, are essential for the robustness of the polarisation pattern. However, a more comprehensive validation against experimental data and a proper estimation of model parameters are required for further characterization and predictions in natural systems, such as the C. elegans embryo.

eLife assessment

This valuable work advances our understanding of the foraging behaviour of aerial insectivorous birds. Its major strength is the large volume of tracking data and the accuracy of those data. However, the evidence supporting the main claim of optimal foraging is incomplete.

eLife assessment

Using multiparameter spectral flow cytometry and unbiased clustering analysis, this study provides useful insights into the heterogeneity of antigens-specific circulating T follicular helper cells from children and adults living in malaria-endemic areas of Kenya. Although the study is well-designed, the analysis and interpretation of the potential functional roles for PfSEA-1A- and PfGARP-specific subsets of circulating T follicular helper cells are incomplete.

eLife assessment

This study investigates the role of Caspar (Casp), an orthologue of human Fas-associated factor-1, in regulating the number of primordial germ cells that form during Drosophila embryogenesis. The findings are important in that they reveal an additional pathway involved in germ cell specification and maintenance. The evidence supporting the conclusions is solid, as the authors identify Casp and its binding partner Transitional endoplasmic reticulum 94 (TER94) as factors that influence germ cell numbers. Minor changes to the title, text, and experimental design are recommended.

eLife assessment

This important study investigates the influence of the cingulate cortex on the development of the social vocalizations of marmoset monkeys by making bilateral lesions of this brain area in neonatal animals. The evidence supporting the authors' claims is solid, although including longer-term effects and different social contexts would strengthen the manuscript. The work will be of broad interest to cognitive neuroscientists, speech and language researchers, and primate neuroscientists.

eLife assessment

This study provides an important re-evaluation of modality-specific information processing in the thalamus of trained mice. Using an elegant task design that probes competing tactile and visual stimuli, the authors present convincing evidence that behavioral training reshapes the sensitivity of higher-order thalamic nuclei. Despite the innovative methods and significant findings, the conclusions would be strengthened by deeper analyses of the sensory and non-sensory aspects of the modulation of the higher-order thalamic nuclei.

eLife assessment

This study presents convincing evidence of the role of an intestine-released neuropeptide, FLP-2, in the oxidative stress response of C. elegans, as well as for the neural circuit pathway that regulates its release in response to sensing reactive oxygen species (i.e., H2O2). These valuable results advance the understanding of gut-brain signaling and the neural circuit basis of behavioral responses to stress.

eLife assessment

This important study by Franziska Auer and colleagues examines cerebellar Purkinje cells' role in controlling posture in larval zebrafish using the innovative chemogenetic tool TRPV1/capsaicin. This work will interest neuroscientists studying motor control and cerebellar function. Overall, solid evidence is presented showing that disrupting Purkinje cell function impairs balance in the pitch axis and that this cell population encodes tilt direction. At the same time, some conclusions require more data or better statistical analysis.

eLife assessment

In this valuable study, Li et al., set out to understand the mechanisms of audiovisual temporal recalibration - the brain's ability to adjust to the latency differences that emerge due to different (distance-dependent) transduction latencies of auditory and visual signals - through psychophysical measurements and modelling. The analysis supports a role for causal inference in recalibration, though the evidence is incomplete.

eLife assessment

This valuable study provides evidence that during learning of a simple detection task, the change in the rate of spike bursts is a signal that is distinct from the change in firing rate, and suggests that the change in bursting is more correlated with learning than other measures of change in activity. However, the evidence for the claim that bursting contributes to learning and attention is currently incomplete, because the authors did not take into account the potentially differential effects of learning-related changes in movement on bursting compared to non-burst spike events, and there is no meaningful way to measure attention in their task. Also, the study used an artificial microstimulation as the stimulus, which limits the generalization of these results to normal sensory-motor learning.

eLife assessment

This important study advances our understanding of how FGF13 variants confer seizure susceptibility. By acting in a set of inhibitory interneurons, FGF13 regulates synaptic transmission and excitability. The data presented here are convincing and combine cell type-specific knockouts and electrophysiology, complemented by histology/RNA studies. Collectively, this research will be of interest to a wide audience, particularly those involved in the study of epilepsy, inhibitory neurons, and ion channels.

eLife assessment

This study presented a valuable inventory in scoring a neuropsychological test, ROCFT. The level of evidence is compelling. The authors constructed large samples from multi-center international researchers and tested the model using internet data with excellent performance. Their deep learning method could potentially apply to neuropsychological tests as well as other related fields.

eLife assessment

This work identifies the molecular function of an orphan human transporter, SLC35G1, providing convincing but somewhat incomplete evidence that this protein is involved in intestinal citrate absorption. This work provides important insight into transporter function and human physiology.

eLife assessment

This is a valuable study on the diffusion rates of drug molecules in human-derived cells, highlighting that their diffusion behavior depends on their charged state. It proposes that blocking drug protonation enhances diffusion and fractional recovery, suggesting improved intracellular availability of weakly basic drugs. The correlation between pKa and intracellular diffusion is solid and well-supported, but the study would benefit from a more rigorous statistical treatment and a balanced comparison across different types of compounds. Despite these limitations, the findings are significant for drug design and understanding the biophysical behavior of small molecules in cells.

eLife assessment

This useful study draws on published single-cell and spatial transcriptomic data of colon cancer liver metastasis to clarify the pro- and anti-tumorigenic properties of NK cells. The authors discover increased GZMK+ resting NK cells in the tumor tissue and reduced abundance of KIR2DL4+ activated NK cells. However, the evidence is currently incomplete, as the models used to validate the hypothesis and claims are inadequate and lack necessary controls.

eLife assessment

This important study examines the relationship between expiratory airflow and vocal pitch in adult mice during the production of ultrasonic vocalizations and also identifies a molecularly defined population of brainstem neurons that regulates mouse vocal production across development. The evidence supporting the study's conclusions that expiratory airflow shapes vocal pitch and that these brainstem neurons preferentially regulate expiratory airflow is novel and compelling. This work will be of interest to neuroscientists working on mechanisms and brainstem circuits that regulate vocal production and vocal-respiratory coordination.

eLife assessment

This paper reports a valuable new method for creating localized damage to candidate brain regions for functional and behavioral studies. The authors present solid support for their ability to create long-term local lesions with mm spatial resolution. The paper is likely to be of broad interest to brain researchers working to establish causal links between neural circuits and behavior.

eLife assessment

This work describes a new software platform for machine-learning-based segmentation of and particle-picking in cryo-electron tomograms. The program and its corresponding online database of trained models will allow experimentalists to conveniently test different models and share their results with others. The paper provides solid evidence that the software will be valuable to the community.

eLife assessment

In this study, camera trapping and species distribution models are used to show that human disturbance in mountain forests in the eastern Himalayas pushes medium-sized and large mammal species into narrower habitat space, thus increasing their co-occurrence. While the collected data provide a useful basis for further work, the study presents incomplete evidence to support the claim that increased co-occurrence may indicate positive interactions between species.

eLife assessment

This study provides a valuable resource by thoroughly benchmarking multiple sequencing-based tRNA quantification methods. The suggested best practice is supported by solid evidence from in silico experiments in multiple scenarios. The major weakness of the manuscript is the incomplete validation of newly generated experimental datasets.

eLife assessment

The important study uses a new experimental method to provide compelling evidence on how sense- and anti-sense transcription is differentially regulated. The method described here can generally be used to study the alterations in transcription. This paper will be of interest to scientists working in the gene regulation community.

eLife assessment

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

eLife assessment

This work describes a novel affinity interactomics approach that allows investigators to identify networks of protein-protein interactions in cells. The important findings presented here describe the application of this technique to the SH3 domain of the membrane remodeling Bridging Integrator 1 (BIN1), the truncation of which leads to centronuclear myopathy. The authors present solid evidence that BIN1 SH3 engages with an unexpectedly high number of cellular proteins, many of which are linked to skeletal muscle disease, and evidence is presented to suggest that BIN1 may play a role in mitosis creating the potential for new avenues in drug development efforts. Some of the findings, however, remain rather preliminary, lack sufficient replicates and may require additional experiments to definitively support the conclusions.

eLife assessment

This useful manuscript extends prior work to identify OVO as a major transcriptional activator of the female germline gene expression program. Using a combination of solid genomic strategies, the authors demonstrate that OVO binds to the promoters of hundreds of genes in the female germline and promotes their expression.

eLife assessment

This valuable work investigates the role of boundary elements in the formation of 3D genome architecture. The authors established a specific model system that allowed them to manipulate boundary elements and examine the resulting genome topology. The work yielded the first demonstration of the existence of stem and circle loops in a genome and confirms a model which had been posited based on extensive prior genetic work, providing insights into how 3D genome topologies affect enhancer-promoter communication. The evidence is solid, although the degree of generalization remains uncertain.

eLife assessment

This study presents important findings on the different polymorphs of alpha-synuclein filaments that form at various pH's during in vitro assembly reactions with purified recombinant protein. Of particular note is the discovery of two new polymorphs (1M and 5A) that form in PBS buffer at pH 7. The strength of the evidence presented is convincing. The work will be of interest to biochemists and biophysicists working on protein aggregation and amyloids.

eLife assessment

This study presents a valuable strategy to co-deliver peptides and adjuvants to antigen-presenting cells by engineering the Virus-like particle (VLP). The evidence supporting the claims of the authors is convincing, but the antitumour efficacy is unimpressive and would benefit from more antitumor experiments. The work will be of broad interest to bioengineers and medical biologists focusing on cancer vaccines.

eLife assessment

This study presents fundamental findings that could redefine the specificity and mechanism of action of the well-studied Ser/Thr kinase IKK2 (a subunit of inhibitor of nuclear factor kappa-B kinase (IkB) that propagates cellular response to inflammation). Solid evidence supports the claim that IKK2 exhibits dual specificity that allows tyrosine autophosphorylation and the authors further show that auto-phosphorylated IKK2 is involved in an unanticipated relay mechanism that transfers phosphate from an IKK2 tyrosine onto the IkBa substrate. These are potentially provocative results but open questions remain due to the nature of the in vitro assays and questions about protein purity and identity. Nevertheless, the findings are a starting point for follow-up studies to confirm the unexpected mechanism and further pursue functional significance.

eLife assessment

This important study investigates the sensitivity to endogenous cosolvents of three families of intrinsically disordered proteins involved with desiccation. The findings, drawn from well-designed experiments and calculations, suggest a functional synergy between sensitivity to small molecule solutes and convergent desiccation protection strategy. While the evidence is found to be convincing, the study's conclusions cannot be generalized due to the small number of proteins investigated. This work will be of interest to biochemists and biophysicists interested in the conformation-function relationship of intrinsically disordered proteins.

eLife assessment

Based on largely indirect evidence, this study proposes that genomic integration of HIV targets DNA/RNA hybrids called R-loops. The evidence is indirect because the authors do not use relevant models systems to show integration and because they artificially induce R-loops in the critical experiments. There are two interrelated findings: 1) VSVg-pseudotyped HIV-1 induces R-loops in various cell types, and 2) VSVg-pseudotyped HIV-1 targets R-loops for integration in an artificial Hela cell model in which R-loops are exogenously induced. The induction of R-loops by a pseudotyped HIV-1 is a potentially valuable finding. Critically, however, because of the caveats above, the evidence is inadequate to support the primary claims in the title, abstract, and manuscript. Furthermore, if these claims were true, the authors do not provide context for how they could be reconciled with well-established structural data showing that HIV-1 integrase catalyzes the integration of viral DNA into dsDNA as a substrate.

eLife assessment

The authors study how inflammatory priming and exposure to irradiated Mycobacterium tuberculosis or the bacterial endotoxin LPS impact the metabolism of primary human airway macrophages and monocyte-derived macrophages. The work shows that metabolic plasticity is greater in monocyte-derived macrophages than alveolar macrophages. The experimental methods and evidence are solid, and the results and findings are useful for the field of immunometabolism.

eLife assessment

This fundamental study analyzes the roles of post-translational modifications of tubulin by generating a large panel of tubulin mutants and describing their effects on morphogenesis and function of sensory neurons in C. elegans. The work, which is of interest to all cell biologists, in particular researchers with an interest in the microtubule cytoskeleton and neurobiology, presents conclusions that are supported by solid evidence. Demonstrating that all introduced mutations have the intended consequences and exploring their direct effect on microtubules would further increase the impact of the work.

eLife assessment

This study presents a valuable syngeneic zebrafish model for studying glioblastoma and will be of interest to neuro-oncologists and cancer biologists. Using a feasible in vivo model to study the tumour microenvironment, cell/cell interaction, and immunity, the data are compelling, and opens up new lines of inquiries for future investigation on the impact of efferocytosis on tumor progression and cell of origin in this model as well as assessments of drug resistance mechanisms, using inhibitors to MAPK , Akt and/or mTOR pathway.

eLife assessment

Building on on the observation of an increase in miR-182-5p in diabetic patients, the authors investigated the role of miR-182-5p and its target gene LRP6 in dysregulated glucose tolerance and fatty acid metabolism in obese type 2 diabetics. The use of human livers complemented by supporting data in mice and cells are strengths, but the evidence presented remains incomplete. The findings provide valuable insights into the role of miRNAs in the regulation of liver metabolism and insulin sensitivity in individuals with diabetes and fatty liver disease.

eLife assessment

This study provides a fundamental advance in palaeontology by reporting the fossils of a new invertebrate, Beretella spinosa, and inferring its relationship with already described species. The analysis placed the newly described species in the earliest branch of moulting invertebrates. The study, supported by convincing fossil observation, hypothesizes that early moulting invertebrate animals were not vermiform.

eLife assessment

The authors report that the neurohormone, bursicon, and its receptor, play a role in regulating aspects of the seasonal polyphenism of the bug, Cacopsylla chinensis. This important study shows that low temperature activates the bursicon signaling pathway during the transition from the summer to the winter form and that it affects cuticle pigment and chitin content, and cuticle thickness. In addition, the authors show that the microRNA miR-6012 targets the bursicon receptor, thereby modulating the function of the bursicon signaling pathway. The study's solid set of experiments and results reveal a role of bursicon signaling in regulating features of polyphenism related to the exoskeleton. Nevertheless, they only incompletely substantiate the authors' claims about the regulation of polyphenism itself.

eLife assessment

This paper addresses a question regarding the low overlap between genetic variants linked to human complex diseases and variants linked to differences in gene expression. Some of the analyses supporting the main claims are convincing, and the key conclusions are valuable and of interest to readers in the fields of human genetics and functional genomics. However, chromatin accessibility QTL (caQTL) also carry the limitation of not identifying the genes that directly mediate the influence on disease phenotypes.

eLife assessment

This valuable work presents elegant experimental data from the Drosophila embryo supporting the notion that interactions among specific loci, called boundary elements, contribute to topologically associated domain (TAD) formation and gene regulation. The evidence supporting boundary:boundary pairing as a determinant of 3D structures is compelling; however, an inability to deplete loop extruders formally leaves open a possible contribution of loop extrusion. This study will be of interest to the nuclear structure community, particularly those using Drosophila as a model.

eLife assessment

This useful work investigates the social interactions of mice living together in a system of multiple connected cages. The approach is interesting as it uses some of the tools developed in physics to investigate animal behaviour. However, , some of the analyses require further scrutiny, leaving the evidence supporting the main claim currently incomplete.

eLife assessment

This important and novel study addresses the challenge of antimicrobial resistance by targeting plasmid proteins that interfere with plasmid transfer as a strategy to limit the spread of antibiotic-resistance genes. The evidence presented and the integration of two approaches to tackle antimicrobial resistance is convincing. This work will interest those working on plasmid transfer and antimicrobial resistance.

eLife assessment

How the triplicate interaction between chemokines with both GAGs and G protein-coupled receptors (GPCR) works and how gradients are created and potentially maintained in vivo are poorly understood. The authors provide solid evidence to show phase separation can drive chemotactic gradient formation. The paper is a useful advance in the field of chemokine biology.

eLife assessment

This valuable study uses a novel experimental design to elegantly demonstrate how we exploit stimulus structure to overcome working memory capacity limits. The presented behavioural and neural evidence are solid and in line with the proposed information compression mechanism. This study will be of interest to cognitive neuroscientists studying structure learning and memory.

eLife assessment

This study focuses on the regulation of GLP-1 in enteroendocrine L cells and how this may be stimulated by the mechanogated ion channel Piezo1. The work is innovative and the hypothesis that is being tested may have important mechanistic and translational implications. The data remains incomplete at present and needs a substantial amount of supporting evidence and corrections to be a stronger manuscript and publication.

eLife assessment

Efforts to increase the representation of women in academia have focussed on efforts to recruit more women and to reduce the attrition of women. This study - which is based on analyses of data on more than 250,000 tenured and tenure-track faculty from the period 2011-2020, and the predictions of counterfactual models - shows that hiring more women has a bigger impact than reducing attrition. The study is an important contribution to work on gender representation in academia, and the evidence in support of the findings is convincing.

eLife assessment

This valuable study describes mice with a knock out of the IQ motif-containing H (IQCH) gene, to model a human loss-of-function mutation in IQCH associated with male sterility. The infertility is reproduced in the mouse, making it a compelling model, but the mechanistic experiments provide only incomplete evidence for interaction between IQCH and potential RNA binding proteins, which are prominently mentioned in the title. The paper, which has undergone multiple rounds of review, could be of interest to cell biologists and male reproductive biologists working on the sperm flagellar cytoskeleton and mitochondrial structure.

eLife assessment

This study presents an important finding on the function of PLP1+ enteric glia. The evidence supporting the claims of the authors is solid, although the inclusion of additional data showing the mechanisms by which PLP1+ enteric glia acts on Paneth cells would have strengthened the study. The work will be of interest to researchers working on intestinal biology.

eLife assessment

This valuable study provides solid in vivo data that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promotes long-term survival of mice with low metastatic burden from breast cancer. Also, the authors conducted an investigator-initiated clinical trial that demonstrated that similar NK cell infusions in cancer patients after resections were safe and showed signs of efficacy. Therefore, this study is of interest and value to oncologists in the field of breast cancer research.

eLife assessment

This valuable study adopted a multi-omics approach to elucidate the regulatory mechanism underlying parturition and myometrial quiescence. The data presented to support the main conclusion remains incomplete. This work will be of interest to both basic researchers who work on reproductive biology and clinicians who practice reproductive medicine.

eLife assessment

In this valuable study, the authors sought to investigate the associations of age at breast cancer onset with the incidence of myocardial infarction and heart failure. Based on results from a series of solid statistical analyses, the authors conclude that a younger onset age of breast cancer is associated with myocardial infarction and heart failure, highlighting the need to carefully monitor the cardiovascular status of women who have been diagnosed with breast cancer.

eLife assessment

This study combines genetic, cell biological, and interaction data to propose a model of meiotic double-strand break regulation in C. elegans. Comprehensive cataloging of their interactions (physical and genetic) would be valuable information for the field. However, the analyses used in the manuscript are not consistent or comprehensive, and therefore the evidence to support their model is currently incomplete.

eLife assessment

Using experiments in the white fly, this manuscript provides evidence that the bacterial symbiont Wolbachia can be transmitted from parasitoid wasps to their insect hosts. Characterizing the transfer of Wolbachia between insect species is a valuable attempt to explain the widespread of this intracellular bacterium. This paper is incomplete as it does not furnish sufficient data to support several of its claims for which additional methods and data are necessary.

eLife assessment

This manuscript presents experiments that address the question of whether the lateral parafacial area (pFL) is active in controlling active expiration, which is particularly significant in patient populations that rely on active exhalation to maintain breathing (eg, COPD, ALS, muscular dystrophy). This study presents solid evidence for a valuable finding of pharmacological mapping of the core medullary region that contributes to active expiration and addresses the question of where these regions lie anatomically. Results from these experiments will be of value to those interested in the neural control of breathing and other neuroscientists as a framework for how to perform pharmacological mapping experiments in the future.

eLife assessment

This article reports an important bioluminescence-based reporter system to evaluate kinase conformations. This assay is applied to four different kinases that have unique, very special regulatory features, thereby indicating that the assay can be used to provide convincing evidence on the conformational state of a large number of kinases. This paper will be of interest to researchers working on kinases and their conformational states.

eLife assessment

This study presents a predictive scoring system in DLBCL based on the expression of three tumour microenvironment-related genes. Such a scoring system seems useful for predicting tumour purity levels in DLBCL. The provided evidence showing an association between worse DLBLC prognosis and high-risk score is solid, but it is incomplete to draw a clear conclusion about the links between risk score and drug sensitivity.

eLife assessment

This paper describes an important software framework for the curation, retrieval, and analysis of ancient human genomic data and their associated metadata, overcoming long-standing coordination and harmonization issues in ancient human genomics. The resource is built on compelling and sometimes exceptional principles of software engineering and reproducibility, and the authors make an excellent case that their resource will be of practical use to many researchers studying human history using DNA. The main issues include natural uncertainties regarding future funding and maintenance of this resource, as well as deviation from established standards in other areas of genomics.

eLife assessment

The study presents valuable findings on the role of RIPK1 in maintaining liver homeostasis under metabolic stress. Strengths include the intriguing findings that RIPK1 deficiency sensitizes the liver to acute liver injury and apoptosis, but because the conclusions require additional experimental support, the evidence is incomplete.

eLife assessment

Brain inflammation is a hallmark of multiple sclerosis. Using novel spatial transcriptomics methods, the authors provide solid evidence for a gradient of immune genes and inflammatory markers from the meninges toward the adjacent brain parenchyma in a mouse model. This important study advances our understanding of the mechanisms of brain damage in this autoimmune disease. However, the control mouse groups are not well designed to rule out confounding effects, a limitation that needs to be acknowledged and addressed.

eLife assessment

This study provides important insight into the mechanisms of proton-coupled oligopeptide transporters. It uses enhanced-sampling molecular dynamics (MD), backed by cell-based assays, revealing the importance of protonation of selected residues for PepT2 function. The simulation approaches are convincing, using long MD simulations, constant-pH MD and free energy calculations. Overall, the work has led to findings that will appeal to structural biologists, biochemists, and biophysicists studying membrane transporters.

eLife assessment

This fundamental study investigates the transcriptional changes in neurons that underlie loss of learning and memory with age in C. elegans, and how cognition is maintained in insulin/IGF-1-like signaling mutants. The presented evidence is compelling, utilizing a cutting-edge method to isolate neurons from worms for genomics that is clearly conveyed with a rigorous experimental approach. Overall, this study supports that older daf-2 worms maintain cognitive function via mechanisms that are unique from younger wild type worms, which will be of great interest to neuroscientists and researchers studying ageing.

eLife assessment

This valuable study combines massively parallel reporter assays and regression analysis to identify sequence features in untranslated regions that contribute to mRNA stability. The strength of evidence presented is generally solid, but providing more details about how half lives are calculated and explaining some aspects of the subsequent choices made for analysis would clarify and strengthen the overall approach. Taken together, this study will be of interest to researchers broadly studying post-transcriptional gene regulation and also to scientists using massively parallel reporter assays.

eLife assessment

This important study reports a novel mechanism linking DHODH inhibition and subsequent pyrimidine nucleotide depletion with upregulation of cell surface MHC I in cancer cells. The in vitro mechanistic data are compelling, with rigorous methodology and validation across multiple cell lines. The authors also provide in vivo evidence for additive effects of DHODH inhibitors and immune checkpoint blockade. However, the in vivo assessments of the functional relevance of this mechanism remain incomplete, requiring additional analyses to fully substantiate the conclusions made.

eLife assessment

This valuable study presents the design of a new device to use high-density electrophysiological probes ("Neuropixels") in freely moving rodents. The evidence showing that the system is versatile and capable of recording high-quality extracellular data in both mice and rats is compelling. This study will be of interest to neuroscientists performing chronic electrophysiological recordings.

eLife assessment

This study is a detailed investigation of how chromatin structure influences replication origin function in yeast ribosomal DNA, with focus on the role of the histone deacetylase Sir2 and the chromatin remodeler Fun30. Convincing evidence shows that Sir2 does not affect origin licensing but rather affects local transcription and nucleosome positioning which correlates with increased origin firing. However, the evidence remains incomplete as the methods employed do not rigorously establish a key aspect of the mechanism, fully address some alternative models, or sufficiently relate to prior results. Overall, this is a valuable advance for the field that could be improved to establish a more robust paradigm.

eLife assessment

The authors report that optogenetic inhibition of hippocampal axon terminals in retrosplenial cortex impairs the performance of a delayed non-match to place task. Elucidating the role of hippocampal projections to the retrosplenial cortex in memory and decision-making behaviors is important. However, the strength of evidence for the paper's claims is incomplete.

eLife assessment

The paper reports the important discovery that the mouse dorsal inferior colliculus, an auditory midbrain area, encodes sound location. The evidence supporting the claims is solid, although how the encoding of sound source position in this area relates to localization behaviors in engaged mice remains unclear. The observations described should be of interest to auditory researchers studying the neural mechanisms of sound localization.

eLife assessment

This valuable study provides convincing evidence that mutant hair cells with abnormal, reversed polarity of their hair bundles in mouse otolith organs retain wild-type localization, mechanoelectrical transduction and receptor field of their afferent innervation, leading to mild behavioral dysfunction. It thus demonstrates that the bimodal pattern of afferent nerve projections in this organ is not causally related to the bimodal distribution of hair-bundle orientations, as also confirmed in the zebrafish lateral line. The work will be of interest to scientists interested in the development and function of the vestibular system as well as in planar-cell polarity.

eLife assessment:

This important study investigates the contribution of cytosolic S100A/8 to neutrophil migration to inflamed tissues. The authors provide convincing evidence for how the loss of cytosolic S100A/8 specifically affects the ability of neutrophils to crawl and subsequently adhere under shear stress. This study will be of interest in fields where inflammation is implicated, such as autoimmunity or sepsis.

eLife assessment

This valuable study reports that actin-related proteins may be involved in transcriptional regulation during spermatogenesis. The supporting data remain incomplete, and more extensive disentanglement from the canonical role of these actin-related proteins and the experimental validation of in silico predictions are required. This work will be of interest to reproductive biologists and other researchers working on non-canonical roles of actin and actin-related proteins.

eLife assessment

This study presents an important finding on the influence of visual uncertainty and Bayesian cue combination on implicit motor adaptation in young healthy participants, hereby linking perception and action during implicit adaptation. The evidence supporting the claims of the authors is convincing. The normative approach of the proposed PEA model, which combines ideas from separate lines of research, including vision research and motor learning, opens avenues for future developments. This work will be of interest to researchers in sensory cue integration and motor learning.

eLife assessment

This important study provides insights into how the brain constructs categorical neural representations during a difficult auditory target detection task. Through recordings of simultaneous single-unit activity in primary and secondary auditory areas, compelling evidence is provided that categorical neural representations emerge in a secondary auditory area, i.e., PEG. The study is of interest to neuroscientists and can also potentially shed light on human psychological studies.

eLife assessment

In this study, the authors found that a species of aphid that is a known agricultural pest salivated longer and produced more honeydew when feeding at night. The authors identified aphid genes with diurnal expression patterns, including potential saliva-related genes. Silencing these genes reduced aphid performance only on real plants, suggesting a specific role in plant feeding. While this study is valuable for understanding plant-insect interactions in agriculture, it is currently incomplete, as further research is needed to elucidate the function of the identified genes.

eLife assessment

This fundamental study investigates the transcriptional changes in neurons that underlie loss of learning and memory with age in C. elegans, and how cognition is maintained in insulin/IGF-1-like signaling mutants. The presented evidence is compelling, utilizing a cutting-edge method to isolate neurons from worms for genomics that is clearly conveyed with a rigorous experimental approach. Overall, this study supports that older daf-2 worms maintain cognitive function via mechanisms that are unique from younger wild type worms, which will be of great interest to neuroscientists and researchers studying ageing.

eLife assessment

This computational modeling study builds on multiple previous lines of experimental and theoretical research to investigate how a single neuron can solve a nonlinear pattern classification task. The study presents valuable insights that the location of synapses on dendritic branches, as well as synaptic plasticity of excitatory and inhibitory synapses, influences the ability of a neuron to discriminate combinations of sensory stimuli. However, the evidence presented is incomplete - the major conclusions are only partially supported by the data presented, and there are identified gaps between the supporting evidence and the major conclusions.

eLife assessment

The authors study how cells with lower levels of the conserved steroid hormone signaling component Taiman (tai) are out-competed by neighboring wild-type cells with higher fitness in Drosophila imaginal discs. The findings are useful since they uncover an unexpected link between tai and Wingless signaling in cell competition. The evidence however is incomplete, since the tai loss-of-clone phenotype is based on one allele and the mechanism involved in cell competition through Dlp and Wg lacks adequate supporting data.

eLife assessment

The findings are valuable and supported by compelling evidence from deep sequencing and bioinformatics analyses. The strength of this work lies in the comprehensive analysis of different cells representing various life stages, exposing vulnerabilities to EDCs and relating epimutations to specific genomic regulatory regions. Despite the small sample size, the results make a major contribution to the field and provide novel insight into the emergence and correction of epimutations during epigenetic programming and into the processes underlying multigenerational effects of EDCs.

eLife assessment

This manuscript reports an important finding that the transcription factor Scleraxis regulates regenerative myogenesis by controlling the proliferation and differentiation of muscle stem cells. The evidence presented is compelling and supports the conclusions and the mechanisms by which this gene regulates satellite cell function. These data will be of interest to developmental, transcriptional, and stem cell biologists.

eLife assessment

This article describes a novel mechanism allowing the insect Drosophila to combat pathogenic enteric pathogens while preserving the beneficial indigenous microbiota. The authors provide compelling evidence that oral infection of Drosophila larvae by pathogenic bacteria activate a valve that traps the intruders in the anterior midgut, allowing them to be killed by antimicrobial peptides. This important work substantially advances our understanding of pathogen clearance in the insect gut.

eLife assessment

This study represents valuable findings on the asymmetric connectivity pattern of two different types of CA3 pyramidal cell types showing that while athorny cells receive strong inputs from all other cell types, thorny cells receive weaker inputs from athorny neurons. Computational modeling is used to evaluate the impact of this connectivity scheme on the sequential activation of different cell types during sharp wave ripples. The experimental evidence supporting the authors' claims is solid, although improvements to the modelling aspect of the study would strengthen the study.

eLife assessment

This important work describes the activation of astrocytes via the nuclear translocation of PKM2 in an animal model of multiple sclerosis. This study provides solid evidence of the interaction between TRIM21 and PKM2 as the crucial molecular event leading to the translocation of PKM2 and a metabolic shift towards glycolysis dominance, fostering proliferation in stimulated astrocytes. This finding is significant as it underscores the potential of targeting glycolytic metabolism to mitigate neurological diseases mediated by astrocytes, offering a strong rationale for potential therapeutic interventions. However, control experiments and imaging analyses with higher magnification images should be performed to better support the main claims of the study.

eLife assessment

This study reports an important discovery highlighting the essential role of the putative ion channel, TMC7, in acrosome formation during sperm development and thus male fertility. The evidence for the requirement of TMC7 in acrosome biogenesis and sperm function is convincing, although its function as an ion channel remains to be further determined. Overall, this work will be of great interest to developmental biologists and ion channel physiologist alike.

eLife assessment

This manuscript reports valuable findings on the role of the Srs2 protein in turning off the DNA damage signaling response initiated by Mec1 (human ATR) kinase. The data provide solid evidence that Srs2 interaction with PCNA and ensuing SUMO modification is required for checkpoint downregulation. However, experimental evidence with regard to the model that Srs2 acts at gaps after camptothecin-induced DNA damage is currently lacking. The work will be of interest to cell biologists studying genome integrity but would be strengthened by considering the possible role of Rad51 and its removal.

eLife assessment

The authors use point light displays to measure biological motion (BM) perception in children (mean = 9 years) with and without ADHD, and relate it to IQ, social responsiveness scale (SRS) scores and age. They report that children with ADHD were worse at all three BM tasks, but that those tasks loading more heavily on local processing relate to social interaction skills and those loading on global processing relate to age. There are still some elements of the results that need clarification with future work, but nevertheless, the important and solid findings extend our limited knowledge of BM perception in ADHD, as well as biological motion processing mechanisms in general.

eLife assessment

This valuable paper explores the role of translational regulation in the establishment of differential gene expression between neurons and glia in Drosophila. The paper uses Ribo-seq to show extensive variation in the translation efficiency of specific transcripts between neurons and glia. The evidence supporting the model is solid, although only one example (that exhibits very strong differential transcriptional expression between one class of neurons and glia) is studied in detail for translation efficiency.

eLife assessment

The manuscript presents a valuable model for the field of endosome maturation, providing perspective on the role of the deubiquitinating enzyme UPS-50/USP8 in the process. The evidence presented in the paper is clear, incorporating well-designed experiments that suggest the dual actions of UPS-50 and USP8 in the conversion of early endosomes into late endosomes. Overall, the work is convincing and centers on an intriguing subject.

eLife assessment

This study reveals an important mechanism, a polyunsaturated fatty acid increases a K+ channel conductance by helping its K+ selectivity filter form a conductive state. Overall, this mechanism is supported by convincing single channel recordings, macroscopic current recordings and mutational analyses, though further clarification of some results seems warranted. These findings are expected to be of interest to researchers studying ion channel gating.

eLife assessment

In this useful study, the authors investigate the regulatory mechanisms related to toxin production and pathogenicity in Aspergillus flavus. Their observations indicate that the SntB protein regulates morphogenesis, aflatoxin biosynthesis, and the oxidative stress response. In general, the data supporting the conclusions are solid but could be strengthened further through additional analyses of CHIP-seq data.

eLife assessment

The manuscript makes an important contribution to antimalarial drug discovery, utilizing diverse systems biology methodologies. It focuses on an improved M1 metalloprotease inhibitor and provides compelling evidence for the utility of chemoproteomics in pinpointing PfA-M1 targeting. Additionally, metabolomic analysis reveals specific alterations in the final steps of hemoglobin breakdown. These findings highlight the potential of the developed methodology not only for PfA-M1 targeting but also for other inhibitors targeting various malarial proteins or pathways.

eLife assessment

Sulphur atoms derived from cysteine are thought to play significant roles in maintaining redox homeostasis in Mycobacterium tuberculosis, which encounters stresses associated with immune cell interactions. In this valuable manuscript, the authors provide solid evidence that the genes encoding cysteine biosynthetic enzymes (cysM and cysK2) are required to maintain full viability of M. tuberculosis under in vitro stress conditions, macrophage infections, and within the lung tissues of mice. The manuscript presents transcriptomic and metabolomic evidence to support the hypothesis that CysM and CysK2 play distinct roles in maintaining cysteine-derived metabolite pools under stress conditions. The work will be of interest to microbiologists in general.

eLife assessment

This study advances our understanding of the allosteric regulation of anaerobic ribonucleotide reductases (RNRs) by nucleotides, providing valuable new structural insight into class III RNRs containing ATP cones. The cryo-EM structural characterization of the system is solid, but some open questions remain about the interpretation of activity/binding assays and the HDX-MS results that have been newly incorporated compared to a previous version. The work will be of interest to biochemists and structural biologists working on ribonucleotide reductases and other allosterically regulated enzymes.

eLife assessment

This important work examines the potential utility of socio-emotional and socio-cognitive mental training on hippocampal subfield structure and function, and cortisol levels. The authors provide convincing evidence that CA1-3 volume is sensitive to socio-emotional training, with changes related to function plasticity and cortisol levels. Further, the authors provide evidence of change across all subfields and training modules related to stress.

eLife assessment

This manuscript provides an important advance in our understanding of the molecular events that promote osteoclast fusion. Compelling data support the conclusion that an oxidized form of the ubiquitous protein La promotes osteoclast fusion following enrichment at the cell surface of osteoclast progenitors. These data improve our understanding of the processes that regulate bone resorption and will be of broad interest to researchers in the fields of cell biology and musculoskeletal physiology.

eLife assessment

This important study employs an innovative genetic selection-based approach to identify short peptide sequences that target bacterial proteins for degradation. Using random mutagenesis they identified 5 amino acid long "degrons" that target the toxin VapC for degradation permitting survival. They provide compelling data that degrons ending in Ala-Ala are selectively recognized by the ClpXP protease and identify the sequence FKLVA as a particularly significant target. As a whole, there is enthusiasm about the author's findings, although there are also some improvements that could be made to increase the clarity and impact, mostly in the form of revisions to the text.

eLife assessment

This study provides valuable scRNA-seq and scATAC-seq data for testicular tissues from patients with spermatogenesis disorders. By examining the transcriptomic and epigenetic changes in Sertoli cells, the authors uncovered key regulatory mechanisms underlying male infertility and identified potential therapeutic targets. While some of the cellular profiling results are convincing, the analyses for differential profiling of NOA cases and epigenomics data remain incomplete in their current form.

eLife assessment

This study reports that the timing of 'brain-to-gut' signaling influences the lifespan of the C. elegans model. The main finding, that modulating the same neurotransmitter, Acetylcholine, at different ages elicits lifespan shortening - or extending - effects utilizing different receptors, is important and of broad interest to the longevity field as recognized by all the reviewers. The data is largely consistent with the authors' model, but the strength of the evidence is incomplete. The study requires several rigorous experiments detailed by the reviewers to substantiate the main conclusions.