eLife assessment

The important study by Ding and colleagues identifies subpopulations of neurons recorded in the monkey subthalamic nucleus (STN) with distinct activity profiles and causal contributions during perceptual decision-making. The combination of neuronal recording, microstimulation, and computational methods provides convincing evidence for a heterogenous neural population that could support multifaceted roles in decision formation. This study should be of wide interest to computational and experimental neuroscientists interested in cognitive function.

eLife assessment

This important study uses calcium imaging to show an increase in the selectivity of the sensory-evoked response in the apical dendritic tuft of layer 5 barrel cortex neurons as mice learn a whisker-dependent discrimination task. The evidence supporting the conclusions is compelling, and this work will be of great interest to neuroscientists working on reward-based learning and sensory processing.

eLife assessment:

This study reported that cold exposure induced mRNA expression of genes related to lipid metabolism in the paraventricular nucleus of the hypothalamus (PVH). The authors provide useful data highlighting the potential role of lipid metabolism in the brain during cold exposure. However, the study is incomplete and would require specific experiments to solidify the claims being made.

eLife assessment

This is an important study to reveal local circuit mechanisms in the POA that control body temperature and also highlight how neurotransmitter GABA and neuropeptide NTS from the same neurons differentially modulate temperature. This study was carefully executed, providing convincing evidence for the conclusions in this paper. The findings have emphasized the importance of considering multiple diverse functions of the same neuron populations and will be of interest to neuroscientists working on central regulations of energy metabolism and temperature homeostasis.

eLife assessment

This technical study presents a novel sampling strategy for detecting synaptic coupling between neurons from dual pipette patch-clamp recordings in acute slices of mammalian brain tissue in vitro. The authors present solid evidence that this strategy, which incorporates automated patch clamp electrode positioning and cleaning for reuse with strategic neuron targeting, has the potential to substantially improve the efficiency of neuronal sampling with paired recordings. This technique and the extensions discussed will be useful for neuroscientists wanting to apply or already conducting automated multi-pipette patch clamp recording electrophysiology experiments in vitro for neuron connectivity analyses.

eLife assessment

In this work, the authors put forward a valuable methodological advancement for imaging deeper in the intact spinal cord of anaesthetized mice. The authors measured blood flow across different vessel types within the spinal cord and observed the cellular responses following venule occlusion. The demonstration is solid, although, a more quantitative comparison with state-of-the-art two-photon excited fluorescence microscopy and a discussion about applicability to functional imaging (e.g., calcium imaging) would have strengthened the study.

eLife assessment

This valuable study describes an apparatus, workflow, and proof-of-concept data for a system to study social cooperation in marmosets, an increasingly popular primate model for neuroscience. The apparatus and methodology have clear and convincing advantages over conventional methods based on manual approaches. However, the claims of faster social learning or of finer-grained behavioural analysis in their setup require further corroboration.

eLife assessment

The neurotrophic factor Neuritin can moderate T-cell tolerance and immunity through both regulatory T (Treg) and effector T cells, promoting Treg cell expansion and suppression while dampening effector T cells to mediate the inflammatory response. Neuritin expression influences the membrane potential, ion channels, and nutrient transporter expression patterns of CD4+ T cells, contributing to differential metabolic states in Treg and effector T cells. These findings are solid and important for understanding immune regulation involving Treg cells and effector T cells.

eLife assessment

This study presents a convincing analysis of the effects of covariates, such as age, sex, socio-economic status, or biomarker levels, on the predictive accuracy of polygenic scores for body mass index; The work is further supported by important approaches for improving prediction accuracy by accounting for such covariates across a variety of association studies. The authors did a commendable job addressing reviewer suggestions and comments. The work will be of interest to colleagues using and developing methods for phenotypic prediction based on polygenic scores.

eLife assessment

This study develops a new and important method for dissecting out two overlapping cell signaling pathways, phosphoinositide signaling and membrane protein trafficking. The combination of two state-of-the-art spectroscopic techniques provides compelling evidence for a reciprocal influence between an enzyme and a channel. The work will be of interest to the broader cell biology, biophysics and biochemistry communities.

eLife assessment

This important study demonstrates that the Pseudomonas aeruginosa-derived quorum sensing signal, 2-aminoacetophenone, induces immune tolerization in macrophages by perturbing metabolism, particularly in the context of mitochondrial respiration and bioenergetics. The authors present convincing evidence for 2-aminoacetophenone-mediated reduction of pyruvate transport into mitochondria, with downstream effects that result in reduced ATP production in tolerized macrophages. The work will be of interest to those studying host-pathogen interactions.

eLife assessment

This valuable work explores the utility of using analyte ratios for improved biological interpretation in a MALDI MSI workflow. The evidence supporting the conclusions is however incomplete, as relevant controls are missing and the novelty of the study has been exaggerated, omitting discussion of key relevant background. The work would be of interest to the mass spectrometry community.

eLife assessment

This valuable study uses convincing state-of-the-art neuroimaging analyses to characterise whole-brain networks during reward-based motor learning. This work motivates future research to dissociate why the observed changes in neural connectivity occur and how they support reward-based motor learning. The study is highly relevant for researchers at the intersection of decision-making and sensorimotor learning.

eLife assessment

This study represents a valuable step toward understanding how brain connectivity changes during reward-based motor learning. However, the evidence presented is incomplete. On one hand, the study leverages state-of-the-art techniques to examine brain connectivity; on the other hand, there are potential confounds in the experimental design, some omissions in statistical quantification, and at times, a lack of clarity about the methods used and the motor learning mechanisms being isolated.

eLife assessment

This study presents a rather valuable finding on the RBM7 function in spicing regulation and uncharacterized role of MFGE8 splicing alteration in breast cancer metastasis. The evidence supporting the claims of the authors is solid. The work will be of broad interest to clinicians, medical researchers and scientists working on breast cancer.

eLife assessment

This study provides important findings based on compelling evidence demonstrating that females and males have different strategies to regulate energy consumption in the brain in the context of low energy intake. While food deprivation reduces energy consumption and visual processing performance in the visual cortex of males, the female cortex is unaffected, likely at the expense of other functions. This study is relevant for scientists interested in body metabolism and neuroscience.

eLife assessment

This manuscript provides important information about the influence of TOR signaling pathway on development and aflatoxin production in the plant and human fungal pathogen Aspergillus flavus. Compared to an earlier version, the authors have addressed most of the concerns of the reviewers, including the convincing demonstration of the essential TOR pathway in this fungus by constructing a xylose promoter mutant strain.

eLife assessment

This important study contributes to the understanding of how parafoveal words are neurally processed during naturalistic sentence reading. Convincing evidence is provided that the MEG response to a word can be modulated by the semantic congruency of a parafoveal target word. The study addresses a classic question in reading using a new Rapid Invisible Frequency Tagging (RIFT) technique, which can separately monitor the neural processing of multiple words during sentence reading.

eLife assessment

The authors utilized scRNAseq profiling of NSCLC patient tumor samples to generate useful insights into the determinants of ICI responsiveness in NSCLC patients. While some of the findings add weight to the current literature, the analysis is incomplete due to the small cohort size and occasional departures from recognized subtype markers. This study would benefit from external cohorts to both validate the findings and to justify the statistical analysis undertaken.

eLife assessment

The current version of the study presents important findings on how the RelA/Stat3-dependent gene program in the liver influences intestinal homeostasis. The evidence supporting the conclusions is solid, with new data added compared to an earlier version of the study. The work will be of interest to scientists in gastrointestinal research fields.

eLife assessment

This work critically evaluates several widely-used assays of transcriptional responses to water limitation in Arabidopsis grown on defined agar-solidified media and, finding inconsistent responses in root transcriptome responses, introduces a new 'hard agar' assay with more consistent responses. The work is valuable as a simple and alternative experimental system that would enable high-throughput genetic screening (and GWAS) to assess the impacts of environmental perturbations on transcriptional responses in various genetic backgrounds. Within this scope, the work is solid, though the debate about whether field-level physiological inferences can be made from such assays remains.

eLife assessment

This useful study shows how genetic variation is associated with fecundity following a period of reproductive diapause in female Drosophila. The work identifies the olfactory system as central to successful diapause with associated changes in longevity and fecundity. While the genetic screening and methods used are solid, the approach to assessing diapause is incomplete and could benefit from additional orthogonal experiments.

eLife assessment

This important study presents findings of great practical value, offering fresh insights into natural species distributions across Japan. By combining multiple data sources (including those from non-academic sectors, aka citizen scientists), the manuscript also presents a compelling new tool that can be used to aid conservation agendas, detect species distribution changes, and testing of ecological theories.

eLife assessment

The paper illustrates a valuable approach to generating TCR transgenic mice specific for known epitopes. There is some solid evidence for the efficacy of this approach, although only limited evidence is provided that the TCR clone in question successfully recapitulates the functional features of the endogenous response to the same antigen, and the claim that this method is superior to more traditional clone selection methods is incompletely substantiated by the data presented.

eLife assessment

This manuscript uses public datasets of myelodysplastic syndrome (MDS) patients to undertake a multi-omics analysis of clinical, genomic, and transcriptomic datasets. Useful findings are provided by way of interesting correlations of specific mutations with inflammation and differing clinical outcomes. While the evidence is extensive and interesting, it remains incomplete in the absence of pipeline validation and addressing the potential confounding factors present in the datasets used. When these issues are addressed, this will be of substantive value to hematologists and clinical immunologists.

eLife assessment

This potentially useful study introduces an orthogonal approach for detecting RNA modification, without chemical modification of RNA, which often results in RNA degradation and therefore loss of RNA molecules. The approach might be of particular interest for sites where modifications are rare. However, the false positive and false negative rates are currently unclear, leaving the evidence for broad applicability of the method incomplete.

eLife assessment

In this manuscript, the authors describe a new AlphaFold2 pipeline called PabFold that can represent a useful tool for identifying linear antibody epitopes (B-cell epitopes) for different antigens. This information can be used in the selection of different reagents in competitive ELISA assays which can save time and reduce costs. Several questions, however, remain and the study is currently incomplete.

eLife assessment

This important study combines across multiple complementary neuroscientific methods to understand the neural response to visual stimulus complexity in the human brain across lifespan. Lalwani et al., provide solid evidence, drawing from appropriate and validated methodology. A weakness is that key information about methodological details and controls is still outstanding, as is a discussion on how generalizable the findings are. With these elements strengthened, the study would be of broad interest to neuroscientists and biologists interested in aging and sensory processing.

eLife assessment

This computational work represents a valuable and long overdue assessment of the potential mechanisms associating patterns of activity of entorhinal grid cells, recorded mostly in rodents, with the population property of hexasymmetry detected in non-invasive human studies. The methodic comparison of alternative hypotheses is compelling, and the conclusions are important for the future design of experiments assessing the neural correlates of human navigation across physical, virtual, or conceptual spaces.

eLife assessment

In this interesting study, the authors have used light-sensitive mGlu5 negative allosteric modulators to determine the role of these receptors in a chronic pain model. These findings could be useful to the pain field, but the evidence supporting these claims is incomplete.

eLife assessment

This study presents a useful examination of dense neuroanatomy in human postmortem medial entorhinal cortex, using a large number of small electron microscopy image volumes sampled from multiple cortical layers and individuals. The authors use solid experimental and annotation techniques, demonstrating the suitability of postmortem tissue reconstructions for analysis and presenting careful, detailed measurements of synapse properties and overall tissue composition. However, there is inadequate support connecting these findings to claims about general connectivity in medial entorhinal cortex, since factors affecting interpretability like noise, the spatial scales examined, and relationships between structural properties and connectivity are not characterized. With a more thorough contextualization, this work would be of interest for studies of cellular neuroanatomy or brain network organization.

eLife assessment

This study presents a valuable finding on prognostic values of serum CA125, CEA, and AFP for predicting patient outcomes of endometrial cancer. The evidence supporting the claims of the authors is solid, although inclusion of detailed discussion of present results with prior documented findings would have strengthened the study. The work will be of interest to scientists working on endometrial cancer.

eLife assessment

This important manuscript used state-of-the-art techniques and employed relevant animal models to provide both convincing and solid evidence supporting the regulatory role of microRNA cluster 221/222 in rheumatoid arthritis synovial fibroblast. The findings of this work offer significant advances to current knowledge which will be interesting to a wide range audience in the rheumatology and bone research fields. However, whereas models, techniques, and analyses are solid, certain concepts related to the role of immune and bone cells are limited.

eLife assessment

How and why nutritional requirements change over development and differ between species are significant questions with wide-ranging implications spanning ecology to health. In this manuscript, Talal et al. set out to address these questions in laboratory and field experiments with grasshoppers and in a comparative analysis of different species. The laboratory experiments are convincing but the field and comparative aspects are not sufficiently well developed. In general, the study offers some evidence of a universal shift from high protein to high carbohydrate intake during ontogeny in animals, but the methods are not clear and/or appropriate to support the goals and conclusions of the manuscript as it is.

eLife assessment

This is a valuable investigation of how type 5 metabotropic receptor signaling contributes to regulation of striatal circuit dynamics, that focuses on its role in direct pathway striatal projection neurons. The range of methods deployed and levels of analysis undertaken are key strengths but concerns remain that make the conclusions incomplete at present. This study will be of great interest for its unique demonstration of metabotropic receptor regulation of striatal circuit dynamics, physiology and behavior.

eLife assessment

This study provides valuable insights into the mechanistic basis of neurological manifestations of RNA polymerase III-related disease by creating a mutant mouse to dissect transcriptional changes. The data are solid and provide compelling evidence for disease progression initiated by a global reduction in tRNA levels leading to integrated stress and innate immune responses and neuronal loss. These observations notwithstanding, additional studies will be necessary to separate the direct and indirect effects of diminished RNA polymerase III transcription on cellular function and neurodegeneration in this valuable mouse model. The work will be of interest to those engaged in the study of chromosome biology, developmental biology and neurodegeneration.

eLife assessment

This study presents a valuable new behavioral apparatus aimed at differentiating the strategies animals use to orient themselves in an environment. The evidence supporting the claims is solid, with statistical modeling of animal behavior. Overall, this study will attract the interest of researchers exploring spatial learning and memory.

eLife assessment

This important manuscript describes experimental evolution experiments using a novel genetic system in yeast, showing that solute carrier transporters can incorporate additional functionality through the introduction of point mutations to either the ligand binding site or gating helices. These findings provide convincing evidence to establish that for Amino Acid transporters of the APC-type family, evolution to recognize new substrates passes through generalist intermediates that can transport most amino acids.

eLife assessment

The manuscript examined the potential modulatory effects of nitric oxide (NO) on the response properties of mouse retinal ganglion cells (RGCs) using two-photon calcium imaging and multi-electrode arrays (MEA). The data identifying a group of RGCs affected by NO are solid but fall short on the precise nature of the effects and their physiological implications. The findings that there can be cell-specific adaptation effects provide useful new information for the field, and more experiments and MEA analysis are encouraged.

eLife assessment

This important study describes a new mathematical method to analyze clonal composition of tissues using fluorescent reporters and to estimate the number of precursor cells contributing to tissue homeostasis and regeneration based on statistical variance. The evidence provided is convincing, with rigorous measurement of hematopoietic cell labeling during steady state and regenerative hematopoiesis following insult. It could be further strengthened by exploring the limitations of the binomial assumption, using tools to measure clonality and considering the possible effects of the inducing agent (tamoxifen) on precursor cells. The manuscript not only presents a compelling approach to better understand tissue dynamics, it also challenges some ideas in pathological hematopoiesis, opens new research directions and is thus of broad interest to stem cell and developmental biologists.

eLife assessment

This important work substantially advances our understanding of nocturnal animal navigation and the ways that animals use polarized light. The evidence supporting the conclusions is convincing, with elegant behavioural experiments in actively navigating ants. The work will be of interest to biologists working on animal navigation or sensory ecology.

eLife assessment

The microRNA lin-4, originally discovered in C. elegans, has a key role in controlling developmental timing across species, but how its expression is developmentally regulated is poorly understood. Here, the authors provide convincing evidence that two MYRF transcription factors are essential positive regulators of lin-4 during early C. elegans larval development. These results provide important insight into the molecular control of developmental timing that could have significant implications for understanding these processes in more complex systems.

eLife assessment

This important manuscript uses a machine-learning approach to predict and annotate cis-regulatory elements across insect genomes, helping to address a much-needed gap in comparative genomics. This method does not rely on sequence alignments, thereby allowing functional genomics studies of more distant species, including emerging model organisms. There are nuanced views on the strength of the evidence from the predictions: the pipeline appears to be based on solid evidence, but the methods could be better described. We suggest the manuscript would be much more robust if the code used was accessible for review and validated further.

eLife assessment

Hartman et al.'s important research examines six commonly utilized imaging-based multiplexed transcriptomic techniques and introduces a novel specificity metric, "MECR," to streamline platform evaluations. The authors highlight the crucial influence of cell segmentation methodologies on outcomes, offering insight into the field. Nonetheless, the substantiation for the principal assertions remains incomplete, as the comparisons across platforms seem uneven due to variations in gene panels.

eLife assessment

This is an important study that brings insight into mechanisms that underlie regulation of GABAergic transmission in response to changes in activity. The authors present solid data supporting the premise that action potential firing rather than excitatory synaptic strength is a key determinant of GABAergic synaptic inputs.

eLife assessment

This study demonstrates that neurons receiving inputs from auditory cortex in the inferior colliculus widely encode the outcome of a sound detection task independant of the presence of auditory cortex. This valuable study based on imaging of transynaptically labelled neurons provides convincing evidence that auditory cortex is necessary neither for sound detection, nor to channel information related to behavioral outcome to the subcortical auditory system. This study will be of wide interest for sensory neuroscientists.

eLife assessment

This important study discovered DBT as a novel gene implicated in the resistance to MG132-mediated cytotoxicity and potentially also in the pathogenesis of ALS and FTD, two fatal neurodegenerative diseases. The authors provided convincing evidence to support a mechanism by which loss of DBT suppresses MG132-mediated toxicity via promoting autophagy. This work will be of interest to cell biologists and biochemists, especially in the FTD/ALS field.

eLife assessment

Building on previous toolboxes to distinguish 1/f noise from oscillatory activity, this study introduces an important advancement in neural signal analysis to identify oscillatory activity in electrophysiological data that refines the accuracy of identifying non-sinusoidal neural oscillations. Extensive validation, using synthetic and various empirical data, provides convincing evidence for the accuracy of the method and outlines practical implications for relevant scientific problems in the field.

eLife assessment

This study presents valuable findings regarding the microstructural basis of brain development in the cerebellum and thalamus of rat neonates using diffusion-weighted MRS. The authors present solid evidence of differential development trajectories in the thalamus and the cerebellum through analytical and morphometric biophysical modelling of the diffusion-weighted MRS data, though some aspects such as the validation of the findings against gold-standard techniques and a detailed discussion of methodological choices require further elaboration. The work will be of interest to developmental biologists and neuroscientists seeking noninvasive approaches to probe in vivo neuronal and glial development in the brain.

eLife assessment

This valuable study marks a significant advancement in brain aging research by centering on Asian populations (Chinese, Malay, and Indian Singaporeans), a group frequently underrepresented in such studies. It unveils solid evidence for anatomical differences in brain aging predictors between the young and old age groups. Overall, this study broadens our understanding of brain aging across diverse ethnicities.

eLife assessment

The authors use a synthetic approach to introduce synaptic ribbon proteins into HEK cells and analyze the ability of the resulting assemblies to cluster calcium channels at the active zone. The use of this ground-up approach is valuable as it establishes a system to study molecular interactions at the active zone. The work relies on a solid combination of super-resolution microscopy and electrophysiology, but would benefit from: (i) additional ultrastructural analysis to establish ribbon formation (in the absence of which the claim of these being synthetic ribbons might not be supported; (ii) data quantification (to confirm colocalization of different proteins); (iii) stronger validation of impact on Ca2+ function; (iv) in depth discussion of problems derived from the use of an over-expression approach.

eLife assessment

The authors provide an important step forward in understanding how brain-derived hormones modulate behavior, using medaka fish as a model system. Knockout lines present convincing evidence from multiple mutant lines, showing that estrogens play a significant role in male social behavior, and that lacking aromatase changes brain gene expression. The conclusions for females are less substantiated, and the conclusions regarding sexual differentiation should be considered carefully.

eLife assessment

This important study reports that glutamate signaling in LepRb PMv neurons is necessary for leptin-dependent fertility. The data supporting the conclusion is solid. This work will be of interest to researchers in the fields of both reproductive and metabolic biology.

eLife assessment

This work describes important updates to qFit, the state-of-the art tool for modeling alternative conformations of protein molecules based on high resolution X-ray diffraction or Cryo-EM data. The authors provide some convincing analyses of qFit's performance in selected test cases. This manuscript will be of interest to structural biologists and protein biochemists, since the adoption of qFit in structural refinement may lead to new mechanistic insights into protein function.

eLife assessment

Urofacial syndrome is a rare early-onset lower urinary tract disorder characterized by variants in HPSE2, the gene encoding heparanase-2. This study provides a useful proof-of-principle demonstration that AAV9-based gene therapy for urofacial syndrome is feasible and safe at least over the time frame evaluated, with restoration of HPSE2 expression leading to re-establishment of evoked contraction and relaxation of bladder and outflow tract tissue, respectively, in organ bath studies. The evidence is, however, still incomplete. The work would benefit from evaluation of additional replicates for several endpoints, quantitative assessment of HPSE2 expression, inclusion of in vivo analyses such as void spot assays or cystometry, single-cell analysis of the urinary tract in mutants versus controls, and addressing concerns regarding the discrepancy in HPSE2 expression between bladder tissue and liver in humans and mice.

eLife assessment

This important study develops a machine learning method to reveal hidden unknown functions and behavior in gene regulatory networks by searching parameter space in an efficient way. The evidence for some parts of the paper is still incomplete, needing systematic comparison to other methods and to the ground truth, but the work will nevertheless be of broad interest to anyone working in biology of all stripes, since the ideas put forward by the authors extend beyond gene regulatory networks to revealing hidden functions in any complex system with many interacting parts.

eLife assessment

Despite the importance of long-lived plasma cells (LLPCs), particularly for the infection and vaccination field, it is still unclear how they acquire their longevity. With a solid genetic approach, the authors demonstrate quite convincingly a requirement for chemokine/chemokine receptor-mediated interaction in LLPC longevity. The data are very valuable for the development of new types of vaccines.

eLife assessment

This study presents an important finding on the molecular mechanism for transduction of environmentally induced polyphenism. The evidence supporting the claims of the author is incomplete due to limited sample sizes and inadequate analysis. This paper would be of interest to those studying aphids wing dimorphism.

eLife assessment

This important study presents a new quantitative imaging pipeline that describes with high temporal precision and throughput the movements of late-stage Drosophila embryos, a critical moment when motion first appears. A new approach is used to explore the role of miRNAs in motion onset and presents solid evidence that shows a role for miR-2b-1 and its target Motor in embryonic motion. The data are well supported even if the mechanistic insight into the emergence of movement remains to be explored.

eLife assessment

The study makes a valuable empirical contribution to our understanding of visual processing in primates and deep neural networks, with a specific focus on the concept of factorization. The analyses provide convincing evidence that high factorization scores are correlated with neural predictivity. This work will be of interest to systems neuroscientists studying vision and could inspire further research that ultimately may lead to better models of or a better understanding of the brain.

eLife assessment

This important study assesses a novel in silico neoantigen prediction algorithm combined with in vivo validation to determine important parameters of neoantigen immunogenicity and tumor control. The strength of evidence is compelling. This study contributes to the field and will aid in the development of improved personalized cancer vaccines.

eLife assessment

This study presents a valuable finding on sperm flagellum and HTCA stabilization. The evidence supporting the authors' claims is incomplete. The work will be of broad interest to cell and reproductive biologists working on cilium and sperm biology.

eLife assessment

This manuscript highlights single-stranded DNA exo- and endo-nuclease activities of ExoIII as a potential caveat and an underestimated source of decreased efficiency in its use in biosensor assays. The data present solid evidence for the ssDNA nuclease activity of ExoIII and identifies residues that contribute to it. The findings are useful, but some aspects in the study remain incomplete.

eLife assessment

The study offers a compelling molecular model for the organization of rootlets, a critical organelle that links cilia to the basal body, ensuring proper anchoring. While previous research has explored rootlet structure and organization, this study delivers an unprecedented level of resolution, valuable to the centrosome and cilia field. This research marks a significant step forward in our understanding of rootlets' molecular organization.

eLife assessment

Hepatocellular carcinoma (HCC) is a particularly aggressive form of cancer, with an increasing number of treatment options approved for use in patients over the past decade. However, the biology of HCC and identifiable therapeutic targets have not been as clear, even in the era of molecular oncology. Likewise, the cellular biology of HCC, including the role of intercellular communication, has not been well elucidated. In this compelling study, Dantzer et al. provide fundamental insight into the role of beta-catenin on intercellular communication occurring via extracellular vesicles, with implications for immune evasion in a cancer increasingly being treated using immuno-oncologic agents.

eLife assessment

The study elucidates a detailed molecular mechanism of the initial stages of transport in the medically relevant Na+-coupled GABA neurotransmitter transporter GAT1 and thus generates useful new insights into this protein family. In particular, it presents convincing evidence for the presence of a "staging binding site" that locally concentrates Na+ ions to increase transport activity, whilst solid evidence for how Na+ binding influences larger scale dynamics.

eLife assessment

In this potentially important study, the authors report results of QM/MM simulations and kinetic measurements for the phosphoryl-transfer step in adenylate kinase. The results point to the mechanistic proposal that the transition state ensemble is broader in the most efficient form of the enzyme (i.e., in the presence of Mg2+ in the active site) and thus a different activation entropy. With a broad set of computations and experimental analyses, the level of evidence is considered solid by some reviewers. On the other hand, there remain limitations in the computational analyses, especially regarding free energy profiles using different methodologies and the activation entropy, leading some reviewers to the evaluation that the level of evidence is incomplete.

eLife assessment

This study provides valuable new insights on how a prevailing model of hippocampal sequence formation can account for recent data, including forward and backward sweeps, as well as constant cycling of sweeps across different arms of a T-maze. The convincing evidence presented in support of this work relies on classical analytical and computational techniques about continuous attractor networks.

eLife assessment

This solid study assesses a novel mitochondrial inhibitor in combination with the BCL-2 inhibitor venetoclax, with the aim to increase its activity in acute myeloid leukemia. It provides valuable findings of combinatorial efficacy using preclinical models, confirming the overall importance of targeting oxidative phosphorylation to overcome venetoclax resistance in acute myeloid leukemia, and could be strengthened through mechanistic studies demonstrating drug specificity, pharmacodynamic efficacy studies in vivo to test clinical utility and extended statistical analyses of the results. The study is of interest to hematologists because it addresses a key biomedical issue in acute myeloid leukemia (venetoclax resistance) and provides data regarding the safety and activity of a novel inhibitor of the mitochondrial polymerase addressed in combination with venetoclax.

eLife assessment

This valuable study aims to present a mathematical theory for why the periodicity of the hexagonal pattern of grid cell firing would be helpful for encoding 2D spatial trajectories. The idea is supported by solid evidence, but some of the comparisons of theory to the experimental data seem incomplete, and the reasoning supporting some of the assumptions made should be strengthened. The work would be of interest to neuroscientists studying neural mechanisms of spatial navigation.

eLife assessment

Notch1 is expressed uniformly throughout the mouse endocardium during the initial stages of heart valve formation, yet it remains unclear how Notch signaling is activated in specific regions to induce valve formation. To answer this question, the authors used a combination of in vivo and ex vivo experiments in mice to demonstrate ligand-independent activation of Notch1 by circulation induced-mechanical stress and provide partially convincing evidence for stimulation of a novel mechanotransduction pathway involving post-translational modification of mTORC2 and Protein Kinase C (PKC) upstream of Notch1. While these findings represent an important advance in our understanding of Notch1-mediated valve formation, data supporting the main claims are incomplete.

eLife assessment

In this fundamental work, the authors demonstrated that maternal choline supplementation improved spatial memory, reduced hyperexcitability, and restored NeuN expression in a familial Alzheimer's disease mouse model. Interestingly, choline deficiency increased mortality, while paradoxically reduced hyperexcitability. Through behavioral, electrophysiological, and histological measures, the authors present convincing evidence supporting the significant role of maternal choline supplementation in protecting hippocampal functions vulnerable to Alzheimer's disease.

eLife assessment

In this important work, a quantitative analysis method for three-dimensional morphogenetic processes during embryonic development is introduced. The proposed method is a pipeline combining several methods, allowing quantitative analysis of developmental processes without cell segmentation and tracking. Upon application of their method, the authors obtain convincing evidence that ascidian gastrulation is a two-step process. This work should be of interest to a broad range of developmental biologists who aim to obtain a quantitative understanding of morphogenesis.

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 potentially useful study involves neuro-imaging and electrophysiology in a small cohort of congenital cataract patients after sight recovery and age-matched control participants with normal sight. It aims to characterize the effects of early visual deprivation on excitatory and inhibitory balance in the visual cortex. While the findings are taken to suggest the existence of persistent alterations in Glx/GABA ratio and aperiodic EEG signals, the evidence supporting these claims is incomplete. Specifically, small sample sizes, lack of a specific control cohort, and other methodological limitations will likely restrict the usefulness of the work, with relevance limited to scientists working in this particular subfield.

eLife assessment

This study by Cuaya et al. reveals and characterizes two distinct forms of spike timing-dependent long-term depression (t-LTD) at the synapses between excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways to granule cells (GC) of the dentate gyrus (DG) in mice. The findings are valuable for the field of synaptic physiology and are based on solid electrophysiological data. The study extends current knowledge by elucidating additional plasticity mechanisms at PP-GC synapses, complementing existing literature.

eLife assessment

In this important study, the authors use a genetically engineered mouse model to reveal a tumor suppressive role for focal adhesion kinase in right-sided colon cancer. The evidence in support of the authors' claims is generally solid, although the data supporting the mechanism through which FAK deletion promotes tumorigenesis are incomplete. This work will be of interest to cancer researchers and others studying the biological consequences of tuning signal transduction pathways.

eLife assessment

The findings of this study are valuable as they challenge the dogma regarding the link between lowered bacterial metabolism and tolerance to aminoglycosides. The authors propose that the well-known tolerance to AG of mutants such as those of complexes I and II is not due to a decrease in the proton motive force and thus antibiotic uptake. The results presented here are convincing.

eLife assessment

In this useful study, Wang and colleagues investigate the potential probiotic effects of Bacillus velezensis in a murine model. They provide solid evidence that B. velezensis limits the growth of Salmonella typhimurium in lab culture and in mice, together with beneficial effects on the microbiota. The overall presentation of the manuscript and logical flow requires improvement and the work will be of interest to infectious disease researchers.

eLife assessment

Duan et al analyzed brain imaging data in UKBK and divided structural brain aging into two groups, revealing that one group is more vulnerable to aging and brain-related diseases compared to the other group. Such subtyping could be valuable and utilized in predicting and diagnosing cognitive decline and neurodegenerative brain disorders in the future. This discovery, supported by solid evidence, harbors a substantial impacts in aging and brain structure and function.

eLife assessment

This study presents an important dataset that captures the transition from epiblast to amnion using a novel in vitro model of human amnion formation. The supporting evidence for the authors' claims is convincing. Key strengths of the study include the efficiency and purity of the cell populations produced, a high degree of synchrony in the differentiation process, comprehensive benchmarking with single-cell data and immunocytochemistry from primate embryos, and the identification of critical markers for specific differentiation phases. A notable limitation, however, is the model's exclusion of other embryonic tissues.

eLife assessment

This study investigates plant-microbe interactions for an invasive plant, Ageratina adenophora. The findings are valuable in advancing our understanding of how leaf and soil microbes separately affect its performance, with solid experimental evidence revealing the importance of litter microbes in shaping A. adenophora populations. The work will be of interest to invasion biologists.

eLife assessment

Through a genome-wide screen for functional alternative transcription start sites (TSS) in Arabidopsis, the authors provide evidence for widespread transcription of potential microproteins from previously annotated protein-coding genes. Functional analysis of AtHB2-miP, derived from the C-terminal region of transcription factor AtHB2 and predicted to form non-productive dimers with ATHB2, suggested that this microprotein could affect AtHB2 functions in shade responses, root growth, and iron homeostasis. The work is valuable as a case study of how new microproteins could act to modulate gene regulation in response to environmental change, but the focus on a single gene, the lack of precision in AtHB2-miP measurement and missing controls, and the relatively minor phenotypic effects mean that data supporting microprotein production as a vital regulatory strategy are incomplete.

eLife assessment

This valuable study reports a novel function of ATG14 in preventing pyroptosis and inflammation in oviduct cells, thus allowing smooth transport of the early embryo to the uterus and implantation. However, the data supporting the main conclusion remain incomplete. This work will be of interest to reproductive biologists and physicians practicing reproductive medicine.

eLife assessment

This study is a computational analysis using publicly available deep sequencing datasets and the findings support the models that propose widespread gene transfer amongst DNA viruses. The evidence supporting the claims of the authors is solid, but reproducing the analysis based only on the information as presented in the Materials and Methods would be difficult as the data are currently presented. A Flow chart that details the process would help. This is an almost entirely computational study without experimental evidence but one that has the potential to become a fundamental resource for virus hunters - an activity of increasing importance.

eLife assessment

This study investigates the role of queuosine (Q) tRNA modification in aminoglycoside tolerance in Vibrio cholerae and presents convincing evidence to conclude that Q is essential for the efficient translation of TAT codons, although this depends on the context. The absence of Q reduces aminoglycoside tolerance potentially by reprogramming the translation of an oxidative stress response gene, rxsA. Overall, the findings point to an important mechanism whereby changes in Q modification levels control the decoding of mRNAs enriched in TAT codons under antibiotic stress.

eLife assessment

This study provides valuable new insights into insect cognition and problem-solving in bumblebees. The authors present convincing evidence that bumblebees lack causal understanding in a string-pulling task, although evidence that bumblebees instead use image-matching for this task, which would benefit from further experiments, is currently incomplete.

eLife assessment

This study provides a single-cell atlas for syngnathid fishes (seahorses, pipefishes, and seadragons), a valuable new resource to investigate the molecular basis of the many unique characters that define the pipefish embryo. The findings are generally supported by solid arguments, but whereas the single-cell RNA-sequencing analysis appears to be of good quality, the spatiotemporal expression data only incompletely support the authors' arguments. Additional computational analyses on cell identity and developmental trajectories would allow a deeper examination of the current data from these unconventional model organisms, to provide new insights into understanding the extraordinary adaptations of the Syngnathidae family. If appropriately improved, the work could be of broad interest for evolutionary developmental biology, particularly for fishes.

eLife assessment

This valuable study proposes that protein secreted by colon cancer cells induces cells with Paneth-like properties that favor colon cancer metastasis. The evidence supporting the conclusions is incomplete and would benefit from more direct experiments to test the functional role of Paneth-like cells and to monitor metastasis from colon tumors. The work will be of interest to researchers studying colon cancer metastasis.

eLife assessment

This study makes a connection between cellular metabolism and proteostasis through MAGIC, a previously proposed protein quality control pathway of clearance of cytosolic misfolded and aggregated proteins by importing into mitochondria. The authors reveal the role of Snf1, a yeast AMPK, in preventing the import of misfolded proteins to mitochondria for MAGIC controlled by the transcription factor Hap4, depending on the cellular metabolic status. The key message is important, although the evidence for physiological relevance of MAGIC for overall cellular proteostasis and its molecular regulation by Snf1 remains incomplete.

eLife assessment

This useful paper addresses a novel exercise mimetic agent on muscle exercise and performance. While the data provided are interesting, the evidence is incomplete, as much of it is correlative.

eLife assessment

The paper presents valuable insights into the success of the parasitoid Trichopria drosophilae on Drosophila suzukii, elucidating the importance of both molecular adaptations, such as specialized venom proteins and unique cell types, ecological strategies, including tolerance of intraspecific competition and avoidance of interspecific competition. Through convincing methodological approaches, the authors demonstrate how these adaptations optimize nutrient uptake and enhance parasitic success, highlighting the intricate coordination between molecular and ecological factors in driving parasitization success.

eLife assessment

The authors discuss an effect, "diffusive lensing", by which particles would accumulate in high-viscosity regions – for instance in the intracellular medium. To obtain these results, the authors rely on agent-based simulations using custom rules performed with the Ito stochastic calculus convention. The "lensing effect" discussed is a direct consequence of the choice of the Ito convention without spurious drift which has been discussed before and its adequacy for the intracellular medium is insufficiently discussed and relatively doubtful. Consequently, the relevance of the presented results for biology remain unclear and based on incomplete evidence.

eLife assessment

This important study provides deep insight into a ubiquitous, but poorly understood, phenomenon: synaptic noise (primarily due to failures). Through a combination of theoretical analysis, simulations, and comparison to existing experimental data, this paper makes a compelling case that synapses are noisy because reducing noise is expensive. It touches on probably the most significant feature of living organisms -- their ability to learn -- and will be of broad interest to the neuroscience community.

eLife assessment

This important study reveals the use of an allocentric spatial reference frame in the updating perception of the location of a dimly lit target during locomotion. The evidence supporting this claim is compelling, based on a series of cleverly and carefully designed behavioral experiments. The results will be of interest not only to scientists who study perception, action and cognition but also to engineers who work on developing visually guided robots and self-driving vehicles.

eLife assessment

This valuable study presents a novel analysis of a large human intracranial electrophysiological recording dataset. The study challenges the traditional view that neural responses to word lists exhibit smoothly drifting contexts over time, showing that items just after a boundary have a characteristic response that occurs repeatedly. The evidence is incomplete, however, leaving open the possibility for alternative explanations.

eLife assessment

This study presents valuable intracranial findings on how two types of natural auditory stimuli - speech and music - are processed in the human brain, and demonstrates that speech and music largely share network-level brain activities, thus challenging the domain-specific processing view. The evidence supporting the claims of the authors is solid. The work will be of broad interest to speech and music researchers as well as cognitive scientists in general.

eLife assessment

This important work substantially advances our understanding of episodic memory in individuals with aphantasia, and sheds light on the neural underpinnings of episodic memory and mental imagery. The evidence supporting the conclusions is convincing, including evidence from a well-established interview paradigm complemented with fMRI to assess neural activation during memory recall. The work will be of broad interest to memory researchers and mental imagery researchers alike.

eLife assessment

This manuscript is useful to researchers with an interest in cervical cancers because it provides scRNA-seq data from a diverse cohort of 15 early-stage cervical cancer patients. While the dataset could be of use to the research community, the key claims of the paper around the immunosuppressive microenvironment associated with specific tumour cell clusters (and the properties/importance of those clusters) are incomplete. Additional experiments will be required to substantiate these claims.

eLife assessment

This important work illuminates the dynamics of BRAF in both its monomeric and dimeric forms, with or without inhibitors, combining traditional techniques and sophisticated computational analyses. The evidence presented is convincing and suggests a potential allosteric effect, though substantiating the exact mechanism will require further studies. The work has implications for understanding kinase signaling and the development of potential drug candidates. This study will be of interest to structural biologists, medicinal chemists, and pharmacologists.

eLife assessment

This study presents valuable findings on the ligand- and ion-dependent structural dynamics of a transcriptional riboswitch. The single-molecule data presented are solid and prompts intriguing hypotheses and models, which will undoubtedly stimulate future structural analyses. These findings are of considerable interest to biochemists and biophysicists engaged in the study of RNA structure and riboswitch mechanisms.

eLife assessment

This study presents a valuable finding on the relationship between brain activity related to sustained attention and substance use in adolescence/early adulthood with a large longitudinal dataset. The evidence supporting the claims of the authors is solid, although the inclusion of more details of methods, results, and data analyses would have strengthened the study. The work will be of interest to cognitive neuroscientists, psychologists, and clinicians working on substance use or addiction.

eLife assessment

This interesting study reports that muscle contains fibro-adipogenic progenitor cells (FAPs) that promote regeneration following injury of peripheral neurons. These novel results indicate that several known growth factors are involved in the process of regeneration. This is an important contribution, however the analysis is incomplete since additional experimental data is needed to support the main conclusions.

eLife assessment

Cancer treatments are not just about the tumor - there is an ever-increasing need for treating pain, fatigue, and anhedonia resulting from the disease. Using an implantable oral tumor model in the mouse, the authors provide valuable information showing that nerve fibers are transmitting sensory signals to the brain that reduce pleasure and motivation. These findings are in part supported by anatomical and transcript changes in the tumor that suggest sensory innervation, neural tracing, and neural activity measurements; however, the study is incomplete in its current form.

eLife assessment

The authors show that short bouts of chemical ischemia lead to presynaptic changes in glutamate release and long-term potentiation, whereas longer bouts of chemical ischemia lead to synaptic failure and presumably cell death (which could be confirmed experimentally). This solid work relies on rigorous electrophysiology/imaging experiments and data analysis. It is valuable as it provides new mechanistic details on chemical ischemia, though its implications for ischemic stroke in vivo remain to be determined.

eLife assessment

This important study sheds new light on cargo movement within the Golgi apparatus, challenging the cisternal progression model by providing convincing evidence for a velocity decrease from cis to trans Golgi and variable speeds within cisternae, suggesting a more stable compartmental nature. While these findings propose refinements to the classic model, they prompt further exploration of recent models like rapid partitioning and rim progression, necessitating additional experimental approaches to account for cargo expression variations and HeLa cell-specific effects.

eLife assessment

This important work provides interesting datasets of myofiber differentiation. The evidence supporting the involvement of SRF2 in selected biological processes is convincing, however, additional evidence to pin-point the major action of SRF2 during muscle differentiation is appreciated. The work will be of broad interest to developmental biologists in general and molecular biologists in the field of gene regulation.

eLife assessment

This study describes the application of machine learning and Markov state models to characterize the binding mechanism of alpha-Synuclein to the small molecule Fasudil. The results suggest that entropic expansion can explain such binding. However, the simulations and analyses in their present form are inadequate.

eLife assessment

This valuable study establishes a method for live-cell imaging, tracking, and quantification of Alu elements marking euchromatic regions of the nucleus. The method will help characterize the relationship between chromatin dynamics and transcriptional activity. While the findings are largely consistent with previous reports, characterization of the technique is incomplete and could benefit from additional controls.

eLife assessment

This study provides valuable initial characterization of a verterbrate embryonic system that demonstrates aspects of an optogenetically inducible hyperplasia model. Although the evidence provided is incomplete to conclude that the system is demonstrating tumor initiation from a single cell that is metastasizing that can be quantitatively assessed, the authors propose a mechanism whereby reactivation of re-programming factors correlates with the increased likelihood of a mutant cell undergoing malignant transformation. This work will be of interest to developmental and cancer biologists mainly for the novel genetic tools described.

eLife assessment

The authors show in vitro that TAK1 overexpression reduces tumor cell migration and invasion, while TAK1 knockdown promotes a mesenchymal phenotype and enhances migration and invasion. The work is a valuable addition to the field of tumor biology of esophageal squamous cell carcinoma. Although minor limitations exist, the overall evidence is solid. The data aligns with previous findings by the same researchers and others.

eLife assessment

In the current study, the authors describe how sex and age affect the consequence of traumatic brain injury in Drosophila. They find that females are more sensitive than males, and mated females are sensitive whereas virgin females are not. This fundamental work substantially advances our understanding of how sex-dependent response to traumatic brain injury occurs, by identifying the Sex Peptide and the immune system as modulators of sex differences. The authors provide a compelling set of results, showing that female Sex Peptide signaling in Drosophila adversely affects late-life neurodegeneration after early-life exposure to repetitive mild head injury.

eLife assessment

This manuscript describes an AI-automated microscopy-based approach to characterize both bacterial and host cell responses associated with Shigella infection of epithelial cells. The methodology is compelling and should be helpful for investigators studying a variety of intracellular pathogens. The authors have acquired valuable findings regarding host and bacterial responses in the context of infection, which should be followed up with further mechanistic-based studies.

eLife assessment

This valuable work characterized a new set of small molecules targeting the interaction between ELF3-MED23, with one of the reported compounds representing a promising novel therapeutic strategy, The evidence supporting the conclusions is solid, although including characterization with breast and lung cancer cell models would strengthen the study. This article will be of interest to medical and cell biologists working on cancer and, particularly, on HER2-overexpression cancers.

eLife assessment

This manuscript describes a method for genetic manipulation of Leishmania species which should be sufficiently efficient to enable genome-wide genetic screens. The authors improved numerous aspects of their previously described method, which is based on sequence-specific genome editing to introduce premature stop codons using a CAS9-cytidine deaminase variant. The work is thoroughly described, with convincing data, and will be very important for Leishmania researchers, as well as perhaps suggesting the use of similar approaches in other organisms in which genetic manipulation is challenging.