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    1. eLife Assessment

      This valuable study identifies a protein called adenosine deaminase-related growth factor (ADGF) as a key regulator of tip formation in the slime mold Dictyostelium discoideum. The authors convincingly show that ADGF catalyses the formation of ammonia from adenosine, allowing ammonia to initiate tip formation, and then elucidate pathways upstream and downstream from ADGF. The authors discuss the intriguing possibility that mammalian ADGF may also similarly regulate development.

    1. eLife Assessment

      This important study by Liu et al. presents a comprehensive structure-function analysis of the presynaptic protein UNC-13, leading to new insights into how its distinct domains control neurotransmitter release. The methods, data, and analyses are convincing, and the genetic and electrophysiological approaches support many of their conclusions. The work will be of interest to neuroscientists studying synaptic transmission, as it provides a foundation for future mechanistic studies of Munc13/UNC-13 family proteins.

    1. eLife Assessment

      This valuable work investigates the social interactions of mice living together in a system of multiple connected cages. It provides solid evidence for a statistical approach capturing changes in social interactions after manipulating prefrontal cortical plasticity. This research will be of broad interest to researchers studying animal social behaviour.

    1. eLife Assessment

      The study presents valuable insights into the role of periosteal stem cells in bone marrow regeneration. The evidence is convincing. The data broadly support their claims and in line with state-of-art methodology. Future study on their model will help to strengthen their discovery further.

    1. eLife Assessment

      This useful study introduces a deep learning-based algorithm that tracks animal postures with reduced drift by incorporating transformers for more robust keypoint detection. The efficacy of this new algorithm for single-animal pose estimation was demonstrated through comparisons with two popular algorithms. The strength of evidence is solid but would benefit from consideration of issues in multi-animal tracking. This work will be of interest to those interested in animal behavior tracking.

    1. eLife Assessment

      This useful manuscript reports on the crystal structures of two glycosaminoglycan (GAG) lyases from the PL35 family, along with in vitro enzyme activity assays and comprehensive structure-guided mutagenesis. The authors have addressed key concerns by incorporating additional docking analyses, validating the role of His188 in alginate degradation, and providing ICP-MS data to examine Mn²⁺ binding. While these improvements enhance the study, the study is incomplete due to the lack of enzyme-substrate complex structures and reliance on modeling which still limit mechanistic insight. Nonetheless, the revised manuscript presents a more complete analysis that will be of interest to specialists in carbohydrate-active enzymes.

    1. eLife Assessment

      This important work advances our understanding of how the SARS-CoV-2 Nsp16 protein is regulated by host E3 ligases to promote viral mRNA capping. Support for the overall claims in the revised manuscript is convincing . This work will be of interest to those working in host-viral interactions and the role of the ubiquitin-proteasome system in viral replication.

    1. eLife Assessment

      This study provides a valuable contribution to our understanding of causal inference in visual perception. The evidence provided through multiple well-designed psychophysical experiments is convincing. The current study targets very specific visual features of launch events, future work will be able to build on this to study the implementation of causal inference in general.

    1. eLife Assessment

      Cichlid fishes have attracted attention from a wide range of biologists because of their<br /> extensive species diversification at the ecological and phenotypic levels. In this important study, the authors have partially revealed the mechanism behind lip thickening in cichlid fishes, which has evolved independently across three lakes in Africa. To explore this phenomenon, the authors used histological comparison, proteomics, and transcriptomics, all of which are well suited for their objectives. With compelling evidence, this contribution provides insights into parallel evolution in polygenic traits and holds significant value for the field.

    1. eLife Assessment

      This important manuscript investigates the role of olfactory cues in Pieris brassicae larvae, focusing on their interactions with the host plant Brassica oleracea and the parasitoid wasp Cotesia glomerata. The authors' demonstration that impaired olfactory perception reduces caterpillar performance and increases susceptibility to parasitism is solid. These findings highlight the ecological significance of olfaction in mediating feeding behavior and predator avoidance in herbivorous insects.

    1. eLife Assessment

      This study presents a valuable open-source and cost-effective method for automating the quantification of male aggression and courtship in Drosophila melanogaster. The work as presented provides solid evidence that the use of the behavioral setup that the authors designed - using readily available laboratory equipment and standardised high-performing classifiers they developed using existing software packages - accurately and reliably characterises social behavior in Drosophila. The work will be of interest to Drosophila neurobiologists and particularly to those working on male social behaviors.

    1. eLife Assessment

      This study presents a valuable finding on predator threat detection in C. elegans and the role of neuropeptide systems in defensive behavioral strategies. The evidence supporting the conclusions is solid, although additional analyses and control experiments would strengthen the claims of the study. Overall, the work is of interest to the C. elegans community as well as neuroethologists and ecologists studying predator-prey interactions.

    1. eLife Assessment

      This useful study reports detailed molecular dynamics (MD) simulations of T-cell receptors (TCRs) in complex with a peptide/MHC complex, for a better understanding of the mechanism of T-cell activation. The MD simulations provide solid evidence supporting that different TCRs can respond mechanically in different ways upon binding to the same pMHC complex. The analyses are systematic and provide testable predictions that can be evaluated by future mutagenesis and force microscopy studies.

    1. eLife Assessment

      This important study shows a surprising scale-invariance of the covariance spectrum of large-scale recordings in the zebrafish brain in vivo. A convincing analysis demonstrates that a Euclidean random matrix model of the covariance matrix recapitulates these properties. The results provide several new and insightful approaches for probing large-scale neural recordings.

    1. eLife Assessment

      This study presents valuable insights into the involvement of miR-26b in the progression of metabolic dysfunction-associated steatohepatitis (MASH). The delivery of microRNA-containing nanoparticles to reduce MASH severity has practical implications as a therapeutic strategy. The authors use two sets of transgenic mouse models, conducted kinase activity profiling of mouse liver samples, and supplemented their findings with additional experiments on human liver and plasma, providing solid support for their findings.

    1. eLife Assessment

      This paper explores how diverse forms of inhibition impact firing rates in models for cortical circuits. In particular, the paper studies how the network operating point affects the balance of direct inhibition from SOM inhibitory neurons to pyramidal cells, and disinhibition from SOM inhibitory input to PV inhibitory neurons. This is an important issue as these two inhibitory pathways have largely been studied in isolation. A combination of analytical calculations and direct numerical simulations provides convincing evidence that the interplay of these inhibitory circuits can separately control network gain and stability.

    1. eLife Assessment

      This is an important study showing that people who are hungry (vs. sated) put more weight on taste (vs. health) in their food choices. The experiment is well-designed and includes choice behavior, eye-tracking, and state-of-the-art computational modeling, resulting in compelling evidence supporting the conclusions.

    1. eLife assessment

      Using intracellular in vitro and in vivo recordings and a deep learning approach, this study shows that mouse dentate gyrus mossy cells (MCs) and CA3 pyramidal cells process information from an important electrophysiological hall mark of hippocampus, sharp wave-ripples (SWRs). The innovative use of deep learning to predict SWR waveforms from MC membrane potentials represents an interesting methodological advance. While the key findings are potentially fundamental, some of the evidence is currently incomplete and should be revised to better support the findings.

    1. eLife Assessment

      The authors describe an approach to construct hybrid neuraminidase molecules that express epitopes (loops) of a specific neuraminidase grafted onto another neuraminidase. The loops (epitopes) are from low-expressing neuraminidases and the scaffold is derived from a high-expressing neuraminidase. This paper is an important contribution giving new insights into the structure, function, and immunogenicity of influenza virus neuraminidases. The paper presents convincing evidence supporting the conclusions arrived at by the authors.

    1. eLife Assessment

      This manuscript presents a potentially important strategy for stimulating mammalian Müller glia to proliferate in vivo by manipulating cell cycle components. The results are convincing that a large number of Müller glia can be induced to re-enter the cell cycle without a damage stimulus. These findings are likely to appeal to retinal biologists and neuroscientists in general.

    1. eLife Assessment

      This study provides valuable insight into the role of Meis2 in whisker hair follicle formation and confirms prior work that nerves are dispensable for this process. The solid imaging techniques support the authors' conclusions, however the data provides limited evidence to support the mechanism of Meis2 in whisker formation.

    1. eLife Assessment

      This valuable study presents a computational model that simulates walking motions in Drosophila and suggests that, if sensorimotor delays in the neural circuitry were any longer, the system would be easily destabilized by external perturbations. The hierarchical control model is sensible and the evidence supporting the conclusions convincing. The modular model, which has many interacting components with varying degrees of biological realism, will serve as a well-grounded starting point for future studies that incorporate richer or more complete empirical data.

    1. eLife Assessment

      This important study uses Mendelian Randomisation to show that early life phenotypes (i.e. onset of age at menarche and age at first birth) have an influence on a multitude of health outcomes later in life. The provided empirical evidence supporting the antagonistic pleiotropy theory is solid. However, some results seem improbable and need to be checked to make sure they are correct.

    1. eLife Assessment

      This valuable study presents a deep learning framework for predicting synergistic drug combinations for cancer treatment in the AstraZeneca-Sanger (AZS) DREAM Challenge dataset. However, the evidence on the generalizability of the model is incomplete, as part of the validation seems to be flawed by overfitting, and only a modest correlation between predictions and observations was observed in the second, more independent test set. The reported tool, DIPx, could be of use for personalized drug synergy prediction and exploring the activated pathways related to the effects of drug combinations.

    1. eLife Assessment

      The authors have generated important resources such as a reference dataset of early primate development by utilizing single-cell transcriptomic technology together with induced pluripotent stem cells (iPSCs) from four primate species: humans, orangutans, cynomolgus macaques, and rhesus macaques. By analyzing marker gene expression and cell types across species during undirected differentiation of iPSCs, the authors provide solid evidence that the transferability of marker genes decreases as the evolutionary distance between species increases. This work demonstrates the extended usage of iPSCs for broader fields, which will benefit several scientific communities including anthropology, comparative biology, and evolutionary biology.

    1. eLife Assessment

      This is an important study that establishes how anti-sense oligonucleotides degrading a specific target protein called EMC10 can rescue neuronal function in models of chromosome 22.11.2 deletions. The authors use human iPSC-derived neurons and a mouse model to provide compelling data for the rescue of cellular and cognitive features of 22.11.2 phenotypes upon ASO regulation of EMC10. These pre-clinical data are of interest because they support reduction of ECM10 as a promising therapeutic strategy.

    1. eLife Assessment

      This study presents an important finding on the involvement of a Caspase 3-dependent pathway in the elimination of synapses for retinogeniculate circuit refinement and eye-specific territory segregation. This work fits well with the concept of "synaptosis" which has been proposed in the past. The evidence supporting the claims of the authors is convincing, demonstrating that caspase-3 activation is essential for microglial elimination of synapses during both brain development and neurodegeneration. The work will be of interest to investigators studying cell death pathways, neurodevelopment, and neurodegenerative disease.

    1. eLife Assessment

      This valuable study reports on the characteristics of premotor cortical population activity during the execution and observation of a moderately complex reaching and grasping task. By using new variants of well-established techniques to analyse neural population activity, the authors provide solid evidence that while the geometry of neural population activity changes between execution and observation, their dynamics are largely preserved. Although these findings are novel and robust, pending additional controls and analyses, the authors should further clarify the functional implications of their findings.

    1. eLife Assessment

      This important study provides solid evidence that glucosylceramide synthase (GlcT), a rate-limiting enzyme for glycosphingolipid (GSL) production, plays a role in the differentiation of intestinal cells. Mutations in GlcT compromise Notch signaling in the Drosophila intestinal stem cell lineage resulting in the formation of enteroendocrine tumors, and preliminary data suggests that a homolog of glucosylceramide synthase also influences Notch signaling in the mammalian intestine. While the outstanding strengths of the initial genetic and downstream pathway analyses are noted, there are weaknesses in the data regarding the potential role of this pathway in Delta trafficking. Nevertheless, this study opens the way for future mechanistic studies addressing how specific lipids modulate Notch signalling activity.

    1. eLife Assessment

      TrASPr is an important contribution that leverages transformer models focused on regulatory regions to enhance predictions of tissue-specific splicing events. The evidence supporting the authors' claims is convincing, with rigorous analyses demonstrating improved performance relative to existing models, although some aspects of the evaluation would benefit from further clarification. This work will be of particular interest to researchers in computational genomics and RNA biology, as it offers both a refined predictive model and a new tool to designing RNA sequences for targeted splicing outcomes.

    1. eLife Assessment

      Fleming et al sought to better understand DNAJC7's function in motor neurons as mutations in this gene have been associated with amyotrophic lateral sclerosis (ALS). Using iPSC-derived motor neurons, interactome, and transcriptomic data, they provide solid evidence that loss-of-function mutations in DNAJC7 disrupt RNA binding proteins and resistance to proteasomal stress. These important findings advance our understanding of DNAJC7 in motor neurons while providing clues to how its loss may be causal for ALS; nonetheless, the experiments were performed with a single iPSC line, while at least 3 are deemed to be required to validate the results. Furthermore, the mechanistic evidence is still incomplete with respect to how DNAJC7 mutations lead to HSF1 impaired activity, and whether it is direct or not.

    1. eLife assessment

      The authors made a useful finding that Zizyphi spinosi semen, a traditional Chinese medicine, has demonstrated excellent biological activity and potential therapeutic effects against Alzheimer's disease (AD). The researchers presented the effects, but the research evidence for the mechanism was incomplete. The main claims were only partially supported.

    1. eLife Assessment

      This useful study presents a possible solution for a significant problem - that of draining vein sensitivity in functional MRI, which complicates the interpretability of laminar-fMRI results. The addition of a low diffusion-weighted gradient is presented to remove the draining vein signal and obtain functional responses with higher spatial fidelity. However, the strength of the evidence is incomplete, and most tests appear to have been done only in a single subject. Significance thresholds in presented maps are very low and most cortical depth-dependent response profiles do not differ from baseline, even in the BOLD data shown as reference. Curiously, even BOLD group data fails to replicate the well-known pattern of draining towards the cortical surface.

    1. eLife Assessment

      In this useful study, Millard et al. assessed the effects of nicotine on pain sensitivity and peak alpha frequency (PAF). The evidence shown is incomplete to support the key claim that nicotine modulates PAF or pain sensitivity, considering the effect sizes observed. This raises the question of whether the chosen experimental intervention was the most suitable approach for investigating their research question. Nonetheless, the work can be incorporated into the literature investigating the relationship between nicotine and pain, and could be of broad interest to pain researchers.

    1. eLife Assessment

      This valuable study describes MerQuaCo, a computational and automatic quality control tool for spatial transcriptomics datasets. The authors have collected a remarkable number of tissues to construct the main algorithm. The exceptional strength of the evidence is demonstrated through a combination of empirical observations, automated computational approaches, and validation against existing software packages. MerQuaCo will interest researchers who routinely perform spatial transcriptomic imaging (especially MERSCOPE), as it provides an imperfection detector and quality control measures for reliable and reproducible downstream analysis.

    1. eLife Assessment

      This study presents important findings on the role of CXXC-finger protein 1 in regulatory T cell gene regulation and function. The evidence supporting the authors' claims is convincing, with mostly state-of-the-art technology. The work will be of relevance to immunologists interested in regulatory T cell biology and autoimmunity.

    1. eLife Assessment

      The authors use single molecule imaging and in vivo loop-capture genomic approaches to investigate estrogen mediated enhancer-target gene activation in human cancer cells. These potentially important results suggest that ER-alpha can, in a temporal delay, activate a non-target gene TFF3, which is in proximity to the main target gene TFF1, even though the estrogen responsive enhancer does not loop with the TFF3 promoter. To explain these results, the authors invoke a transcriptional condensate model. The claim of a temporal delay and effects of the target gene transcription on the non-target gene expression are supported by solid evidence but there is no direct evidence of the role of a condensate in mediating this effect. The reviewers appreciate that the authors have done a lot of work to strengthen the study. This work will be of interest to those studying transcriptional gene regulation and hormone-aggravated cancers.

    1. eLife Assessment

      This important study developed a mathematical model to predict biological age by leveraging physiological traits across multiple organ systems. The results presented are convincing, utilizing comprehensive data-driven approaches. However, additional external validation could further strengthen its generalizability. The model provides a way to identify environmental and genetic factors impacting aging and lifespan, revealing new factors potentially affecting aging. It also shows promise for evaluating therapeutics aimed at prolonging a healthy lifespan.

    1. 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 information. Compared to previous versions, the most recent one is improved and sufficiently aligned with the standards of the field to merit consideration by the research community, making the evidence solid according to said standards. Nevertheless, uncertainty regarding false positive and false negative rates remains, as it does for some of the alternative approaches. With more rigorous validation, the approach might be of particular interest for sites in RNA molecules where modifications are rare.

    1. eLife Assessment

      The research presents valuable findings on the impact of FRMD8 loss on tumor progression and resistance to tamoxifen therapy. Through a series of convincing and systematic experiments, the author thoroughly investigates the role of FRMD8 in breast cancer and its underlying regulatory mechanisms. The study confirms that FRMD8 holds potential as a therapeutic target for reversing tamoxifen resistance, offering helpful insights for future treatment strategies.

    1. eLife Assessment

      This study shows that a peptide called galanin can decrease or increase seizure activity in experimental models of seizures depending on the model. The authors use zebrafish and several methods to address the effects of galanin. The study will be useful to researchers who use zebrafish as experimental animals and who are interested in how peptides like galanin regulate seizures. However, the strength of evidence was considered incomplete at the present time due to several limitations of the results.

    1. eLife Assessment

      This study presents valuable findings on the control of survival and maintenance of a specific set of brain resident immune cells. The authors generate a new animal model to enable sophisticated analysis of cell function in vivo. The sophisticated knock-in/knock-out alleles are compelling, although the work would ultimately be strengthened with further mechanistic analyses.

    1. eLife Assessment

      Du et al. present a valuable study on neural activation in medial prefrontal cortex (mPFC) subpopulations projecting to the basolateral amygdala (BLA) and nucleus accumbens (NAc) during behavioral tasks assessing anxiety, social preference, and social dominance. The study has innovative approaches and solid in vivo calcium imaging data, but the evidence linking neural physiology to behavioral outcomes is incomplete. Addressing these gaps would significantly enhance the understanding of how distinct mPFC→BLA and mPFC→NAc pathways influence anxiety, exploration, and social behaviors.

    1. eLife Assessment

      The authors of this important study investigate how telomere length regulates hTERT expression via non-telomeric binding of the telomere-associated protein TRF2. They conclusively show that TRF2 binding to long telomeres results in a reduction in its binding to the hTERT promoter, while short telomeres restore TRF2 binding in the hTERT promoter, recruiting repressor complexes like PRC2, and suppressing hTERT expression. There is convincing support for the claims and the findings should be of broad interest for cell biologists and those working in fields where telomeres alter function, such as cancer and aging.

    1. eLife Assessment

      This study provides an important method to model the statistical biases of hypermutations during the affinity maturation of antibodies. The authors show convincingly that their model outperforms previous methods with fewer parameters; this is made possible by the use of machine learning to expand the context dependence of the mutation bias. They also show that models learned from nonsynonymous mutations and from out-of-frame sequences are different, prompting new questions about germinal center function. Strengths of the study include an open-access tool for using the model, a careful curation of existing datasets, and a rigorous benchmark; it is also shown that current machine-learning methods are currently limited by the availability of data, which explains the only modest gain in model performance afforded by modern machine learning.

    1. eLife Assessment

      Using an unbiased approach, this important study discovered a role of Ezh2 in the differentiation of granule neuron precursors, the cell of origin for Shh group of medulloblastoma. Furthermore, the authors also provided solid evidence that combined inhibition of Ezh2 and CDK4/6 likely represents a promising strategy for the treatment of this subgroup of MB. Validation of these findings using the FDA-approved Ezh2 inhibitor is needed to further strengthen this preclinical study.

    1. Editors Assessment:

      The Visayan spotted deer (Rusa alfredi), is a small, endangered, primarily nocturnal species of deer found in the rainforests of the Visayan Islands in the Philippines. The present study reports the first draft genome assembly for the species, addressing a critical gap in genomic data for this IUCN-redlisted cervid. Using Illumina sequencing, the resulting genome assembly spans 2.52 Gb in size with a BUSCO completeness score of 95.5% and encompasses 24,531 annotated genes. Phylogenetic analysis suggests a close evolutionary relationship between R. alfredi and Cervus species suggesting that the genus Rusa is sister to Cervus. Peer-review teased out more benchmarking results and the annotation files, demonstrating this genomic resource is useful and usable for advancing population genetics and evolutionary studies, thereby informing conservation strategies and enhancing breeding programs for the critically threatened species. Providing whole genome sequences for other native species of Rusa could further provide genomic resources for detecting hybrids, which will also help the management and monitoring of these species, especially for the reintroduction of captive populations in the wild.

      This evaluation refers to version 1 of the preprint

    1. eLife Assessment

      This serostudy of blood donors in Bolivia (a country with very high COVID death rates in 2020-21) provides useful insights on the successive viral variants of SARS-CoV-2 over 2021 and 2022. Using compelling antibody and neutralization assays, the authors describe variant specific distributions in the different parts of Bolivia. The main methodological advance is to use serology to understand variant diversity, which in turn helps deepen understanding of "hybrid" immunity from widespread infection (and vaccination).

    1. eLife Assessment

      This study presents a valuable finding on the role of secretory leukocyte protease inhibitors (SLPI) in developing Lyme disease in mice infected with Borrelia burgdorferi. The evidence supporting the claims of the authors is solid. This paper will be of interest to scientists in the infectious inflammatory disease field.

    1. Editors Assessment:

      Teinturier grapes produce berries with pigmented skin and flesh, and are used in red wine blends, as they provide a deeper colour. This paper presents the genomes of two popular teinturier varieties (Dakapo and Rubired); sequenced, assembled, and annotated to provide additional resources for their use in breeding. Combining Nanopore and Illumina sequencing for Dakapo, scaffolding to the existing grapevine assembly to generate a final assembly of 508.5 Mbp and 36,940 gene annotations. For Rubired PacBio HiFi reads were assembled, scaffolded, and phased to generate a diploid assembly with two haplotypes 474.7-476.0 Mbp long and 56,681 genes annotated. Peer review has helped validate their high quality, these genomes hopefully enabling more insight into the genetics of grapevine berry colour and their other traits like frost and mildew-resistance.

      This evaluation refers to version 1 of the preprint

    1. eLife Assessment

      This study presents valuable findings with practical and theoretical implications for drug discovery, particularly in the context of repurposing cipargamin CIP for the treatment of Babesia spp. The evidence is solid with the methods, data and analyses broadly supporting the claims. The paper will be of great interest to scientists in drug discovery, computational biology, and microbiology

    1. eLife Assessment

      This important study utilizes humanized mice, in which human immune cells are introduced into immune-deficient mice, to provide convincing evidence that two helper CD4 T-cell subsets, T-follicular helper (Tfh) and T-peripheral helper (Tph) cells, are able to drive both autoantibody production and induction of autoimmunity. The work will be of broad interest to medical scientists engaged in deciphering how human immune cells mediate immune responses and contribute to the development of autoimmune diseases.

    1. eLife Assessment

      This important paper on measuring molecular connectivity using combined serotonin PET and resting-state fMRI provides both novel methods for studying the brain as well as insights into the effects of ecstasy administration. The methods are convincing, with the high anaesthetic dose used likely limiting network activity.

    1. eLife Assessment

      This important work provides another layer of regulatory mechanism for TGF-beta signaling activity. The evidence convincingly supports the involvement of microtubules as a reservoir of Smad2/3, and association of Rudhira with microtubules is critical for this process. The work will be of board interest to developmental biologists in general and molecular biologists in the field of growth factor signaling.

    1. eLife Assessment

      The authors provide a compelling method for characterizing communication within brain networks. The study engages important, biologically pertinent, concerns related to the balance of dynamics and structure in assessing the focal points of brain communication. It will be of interest to researchers trying to dissect structure of complex interaction networks across scales, from cells to regions.

    1. eLife Assessment

      The paper addresses the problem of optimising the mapping of serum antibody responses against a known antigen. The manuscript describes a method using EM polyclonal epitope mapping to help elucidate endogenous antibodies. The work is interesting and valuable to the fields of immunology and serology, and the strength of evidence to support its findings is considered solid.

    1. eLife Assessment

      This valuable study presents an interesting analysis of the role of the polyamine precursor putrescine in the pili-dependent surface motility of a laboratory strain of Escherichia coli. The overall data convincingly demonstrate a role in this case. This study presents interesting findings for those studying uropathogenic bacteria, and those studying bacterial polyamine function.

    1. eLife Assessment

      This important study analyzes the effect of heat treatment on phage-bacterial interactions and convincingly shows that prior heat exposure alters the bacterial cell envelope, enhancing persistence and bacterial survival when exposed to lytic phages. The study will interest researchers working on antibiotic resistance, tolerance, and phage therapy.

    1. eLife Assessment

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

    1. eLife Assessment

      This study reports that the RNA binding and cardiomyopathy-associated protein RBM20 is expressed in specific populations of neurons in the CNS, where it binds to and regulates the expression of synapse-related RNAs. This is an important finding because it reveals a new mechanism for gene regulation in neurons by an RNA binding protein previously studied in the heart; the authors also provide data to suggest that the mechanism by which RBM20 acts in neurons may be distinct from the splicing regulation studied in cardiac tissue. The data in support of the binding and regulation of RNAs by RBM20 is compelling, using leading edge sequencing methods to determine RNA binding profiles, and cell type specific genetics for evaluation of function.

    1. eLife Assessment

      This study presents a useful method based on flow cytometry to study partitioning noise during cell division. The evidence supporting the claims of the authors is incomplete, as the method neglects other sources of noise present in cells. With the theoretical part extended, this paper would be of interest to cell biologists and biophysicists working on asymmetric partitioning during cell division.

    1. eLife Assessment

      This study presents valuable findings suggesting that the late maturation of prefrontal cortex-based control processes enhances conceptual learning by allowing a period of less-constrained knowledge acquisition. The authors provide convincing computational evidence that delayed semantic control promotes learning without compromising representation integrity, with the strongest benefits emerging when control connections target intermediate layers of the model. However, the model's narrow scope raises concerns about scalability to more complex, real-world learning environments, and the meta-analysis, while supporting the developmental trajectory, does not directly test the model's specific predictions regarding task outcomes or error patterns.

    1. eLife Assessment

      The study presents valuable findings regarding the incidence and clinical impact of a mutation in a cardiac muscle protein and its association with the development of atrial fibrillation. The authors provide some convincing evidence of electrophysiological disturbances in cells with this mutation which would be of interest to cellular electrophysiologists. However, evidence supporting the conclusion that this mutation causes atrial fibrillation would benefit from more rigorous electrophysiologic approaches.

    1. eLife Assessment

      Studying the biological roles of polyphosphates in metazoans has been a longstanding challenge to the field given that the polyP synthase has yet to be discovered in metazoans. This important study capitalizes on the sophisticated genetics available in the Drosophila system and uses a combination of methodologies to start to tease apart how polyphosphate participates in Drosophila development and in the clotting of Drosophila hemolymph. The data validating the tools are solid and well-documented and they will open up a field of research into the functional roles of polyP in a metazoan model.

    1. eLife Assessment

      This is an important study that examines the impact of Streptococcus pneumoniae genetics on its in vitro growth kinetics, aiming to identify potential targets for vaccines and therapeutics. The study identified significant variations in growth characteristics among capsular serotypes and lineages, linked to phylogeny and high heritability, but genome-wide association studies did not reveal specific genomic loci associated with growth features independent of the genetic background. The evidence supporting these findings is solid.

    1. eLife Assessment

      This important study examines the relationship between cognition and mental health and investigates how brain, genetics, and environmental measures mediate that relationship. The methods and results are compelling and well-executed. Overall, this study will be of interest in the field of population neuroscience and in studies of mental health.

    1. eLife Assessment

      This study establishes the methodology (machine vision and gaze pose estimation) and behavioral apparatus for examining social interactions between pairs of marmoset monkeys. Their results enable unrestrained social interactions under more rigorous conditions with detailed quantification of position and gaze. It has been difficult to study social interactions using artificial stimuli, as opposed to genuine interactions between unrestrained animals. This study makes an important contribution to studying social neuroscience within a laboratory setting; the approach is novel and well-executed, backed by convincing evidence.

  2. Mar 2025
    1. Editors Assessment:

      The accuracy of basecalling of nanopore sequencing still needs to be improved. With recent advances in deep learning this paper introduces SqueezeCall, a novel end-to-end tool for accurate basecalling. This uses Squeezeformer-achitecture which integrates local context extraction through convolutional layers and long-range dependency modeling via global context acquisition. Testing and peer review demonstrated that SqueezeCall outperformed traditional RNN and Transformer-based basecallers across multiple datasets, indicating its potential to refine genomic assembly and facilitate direct detection of modified bases in future genomic analytics. Future work is ongoing that will focus on training on highly curated datasets, including known modifications, to further increase research value. SqueezeCall is MIT licensed and available from GitHub here: https://github.com/labcbb/SqueezeCall

      This evaluation refers to version 1 of the preprint

    1. eLife Assessment

      The study describes a useful tool for assessing microglia morphology in a variety of experimental conditions. The MorphoCellSorter provides a solid platform for ranking microglia to reflect their morphology continuum and may offer new insight into changes in morphology associated with injury or disease. While the study provides an alternative approach to existing methods for measuring microglia morphology, the functional significance of the measured morphological changes were not determined.

    1. Evaluation Statement (30 January 2025)

      Kay and Aminzare discuss a claim made in a prior publication that macromolecular condensation acts as a water buffering mechanism in cells to compensate for the effects of osmotic shock. The authors argue that, although such a buffer could temporarily maintain a transmembrane osmolality differential, this differential would drive water across the membrane to reach a steady-state in which osmolality within the cell equals osmolality outside the cell. Using the well-established pump-leak model for osmotic water transport, they further show that the timescale at which a water buffer could maintain a modest 10% osmolality differential across the membrane is at most one minute for a typical animal cell.

      Biophysics Colab recommends this study to researchers working on membrane transport, intracellular water buffering, and condensate biology.

      Biophysics Colab has evaluated this study as one that meets the following criteria:

      • Rigorous methodology
      • Transparent reporting
      • Appropriate interpretation

      (This evaluation refers to version 3 of this preprint, which has been revised in response to peer review of versions 1 and 2.)

    1. eLife Assessment

      This manuscript represents a fundamental contribution demonstrating that fentanyl-induced respiratory depression can be reversed with a peripherally-restricted mu opioid receptor antagonist. The paper reports compelling and rigorous physiological, pharmacokinetic, and behavioral evidence supporting this major claim, and furthers mechanistic understanding of how peripheral opioid receptors contribute to respiratory depression. These findings reshape our understanding of opioid-related effects on respiration and have significant therapeutic implications given that medications currently used to reverse opioid overdose (such as naloxone) produce severe aversive and withdrawal effects via actions within the central nervous system.

    1. eLife Assessment

      In this revised work, Barzó et al. assessed the electrophysiological and anatomical properties of a large number of layer 2/3 pyramidal neurons in brain slices of human neocortex across a wide range of ages, from infancy to elderly individuals, using whole-cell patch clamp recordings and anatomical reconstructions. This large data set represents an important contribution to our understanding of how these properties change across the human lifespan, supported by convincing data and analyses. The authors have addressed the concerns raised in previous reviews. Overall, this study strengthens our understanding of how the neural properties of human cortical neurons change with age and will contribute to building more realistic models of human cortical function.

    1. eLife assessment:

      This study describes a new set of genetic tools for optimized Cre-mediated gene deletion in mice. The advances are substantial and will facilitate biomedical research. Although the tools have been validated using solid methodologies, the quantitative assessment of their recombination efficiency is not yet sufficiently described. Evaluating their ability to mediate the deletion of multiple alleles in a mosaic setting would also be a highly valuable addition.

    1. eLife Assessment

      This is an important study that characterizes a surprising interaction between two different cytokine/hormone receptors using nanoscale resolution (dSTORM) microscopy. The study provides solid evidence that the interaction is ligand-dependent, and is mediated by the receptor-associated intracellular signalling molecule JAK2. While at present limited to growth hormone and prolactin receptors in a limited number of cell lines, there are potentially broad implications for cytokine signalling, as such JAK2-mediated interactions could occur between a range of different cytokines. Moreover, the specific hormone interactions shown in the manuscript may have significant implications for understanding how these hormones can have differential effects in breast cancer, under different conditions.

    1. eLife Assessment

      In their valuable study, Lee et al. explore a role for the Hippo signaling pathway, specifically wts-1/LATS and the downstream regulator yap, in age-dependent neurodegeneration and microtubule dynamics using C. elegans mechanosensory neurons as a model. The authors demonstrate that disruption of wts-1/LATS leads to age-associated morphological and functional neuronal abnormalities, linked to enhanced microtubule stabilization, and show a genetic connection between yap and microtubule stability. Overall, the study employs robust genetic and molecular approaches to reveal a convincing link between the Hippo pathway, microtubule dynamics, and neurodegeneration.

    1. eLife Assessment

      This important study aims to understand the function of ProSAP-interacting protein 1 (Prosapip1) in the brain. Using a conditional Prosapip1 KO mouse (floxed prosapip1 crossed with Syn1-Cre line), the authors performed analysis including protein biochemistry, synaptic physiology, and behavioral learning. Convincing evidence from this study supports a role of Prosapip 1 in synaptic protein composition, synaptic NMDA responses, LTP, and spatial memory.

    1. eLife Assessment

      This valuable study investigates how the neural representation of individual finger movements changes during the early period of sequence learning. By combining a new method for extracting features from human magnetoencephalography data and decoding analyses, the authors provide incomplete evidence of an early, swift change in the brain regions correlated with sequence learning, including a set of previously unreported frontal cortical regions. The addition of more control analyses to rule out that head movement artefacts influence the findings, and to further explain the proposal of offline contextualization during short rest periods as the basis for improvement performance would strengthen the manuscript.

    1. eLife Assessment

      This work investigates the functional difference between the most commonly expressed form of PTH, and a mutant form of PTH, identified in a patient with chronic hypocalcemia and hyperphosphatemia which characterizes hypoparathyroidism. The authors investigate the hypothesis that this mutant PTH assumes a dimeric form in vivo and serves anabolic functions in the bone. The data are compelling and the translational aspects are fundamental in understanding PTH-1 Receptor activation.

    1. eLife Assessment

      Catani and colleagues provide data on antigenic properties of neuraminidase proteins of pandemic H1N1 and show that antigenic diversity of the neuraminidase from 2009 to 2020 largely falls into two groups. These antigenic groups map to two phylogenetic groups, and substitutions at positions 432 and 321 are likely associated with the antigenic change. These data and results allow useful insights into the antigenic properties of N1 influenza and the evidence supporting the conclusions is solid.

    1. eLife Assessment

      The study by Chi and colleagues presents important new tools for precise genetic manipulation and lineage tracing in mice. The characterization of these new models was conducted using validated, state-of-the-art methodologies and convincingly demonstrates their ability to enhance the precision of genetic manipulation in distinct cell types. This work will be of great interest to many laboratories worldwide and will facilitate future research across various biomedical disciplines.

    1. eLife Assessment

      This important study examined orientation representations along the visual hierarchy during perception and working memory. The authors provide results suggesting that during working memory there is a gradient where representations are more categorical in nature later in the visual hierarchy. The evidence presented is solid, most notably a match between behavioral data, though minor weakness can be attributed to the tasks and behaviors not being designed to address this question. The findings should be of interest to a relatively broad audience, namely those interested in the relationship between sensory coding and memory.

    1. eLife Assessment

      The songbird vocal motor nucleus HVC contains cells that project to the basal ganglia, the auditory system, or downstream vocal motor structures. In this fundamental study, the authors conduct optogenetic circuit mapping to clarify how four distinct inputs to HVC act on these distinct HVC cell types. They provide compelling evidence that all long-range projections engage inhibitory circuits in HVC and can also exhibit cell-type specific preferences in monosynaptic input strength. Understanding the HVC microcircuit at this microcircuit level is critical for informing models of song learning and production.

    1. eLife Assessment

      This work presents important findings that the human frontal cortex is involved in a flexible, dual role in both maintaining information in short-term memory, and controlling this memory content to guide adaptive behavior and decisions. The evidence supporting the conclusions is compelling, with a well-designed task, best-practice decoding methods, and careful control analyses. The work will be of broad interest to cognitive neuroscience researchers working on working memory and cognitive control.

    1. eLife Assessment

      This study presents a fundamental finding on how levels of m6A levels are controlled, invoking a consolidated model where degradation of modified RNAs in the cytoplasm plays a primary role in shaping m6A patterns and dynamics, rather than needing active regulation by m6A erasers and other related processes. The evidence is compelling through its use of transcriptome-wide data and mechanistic modeling. Relevant for any reader with an interest in RNA metabolism, this new framework consolidates previous observations and highlights the importance of careful experimentation for evaluation m6A levels.

    1. eLife Assessment

      This valuable study builds on previous work by the authors by presenting a potentially key method for correcting optical aberrations in GRIN lens-based microendoscopes used for imaging deep brain regions. By combining simulations and experiments, the authors provide convincing evidence showing that the obtained field of view is significantly increased with corrected, versus uncorrected microendoscopes. Because the approach described in this paper does not require any microscope or software modifications, it can be readily adopted by neuroscientists who wish to image neuronal activity deep in the brain.

    1. eLife Assessment

      This paper represents an important contribution to the field. Summarizing results from neural recording experiments in mice across ten labs, the work provides compelling evidence that basic electrophysiology features, single-neuron functional properties, and population-level decoding are fairly reproducible across labs with proper preprocessing. The results and suggestions regarding preprocessing and quality metrics may be of significant interest to investigators carrying out such experiments in their own labs.

    1. eLife Assessment

      This study provides valuable insights into the evolutionary histories and cellular infection responses of two Salmonella Dublin genotypes. While the evidence is compelling, a more phylogenetically diverse bacterial collection would enhance the findings. This research is relevant to scientists studying Salmonella and gastroenteritis-related pathogens.

    1. eLife Assessment

      This valuable study reports that epididymal proteins are required for embryogenesis after fertilization. The data presented are generally supportive of the conclusion and considered solid. This work will be of interest to reproductive biologists and andrologists.

    1. eLife Assessment

      This study provides valuable information on a novel gene that regulates meiotic progression in both male and female meiosis. The evidence supporting the conclusions of the authors is solid. This study will be of interest to developmental and reproductive biologists.

    1. eLife Assessment

      This important study shows that a very slow (infraslow) oscillation occurs in voltage recordings from the dentate gyrus of the adult mouse. The authors suggest that it is related to sleep stage and serotonin acting at one type of serotonin receptor in the dentate gyrus. The results are significant because they suggest new insight into how a slow oscillation affects memory through serotonin receptors in the dentate gyrus. Convincing data are provided to support the claims.

    1. eLife Assessment

      This important manuscript proposes a dual behavioral/computational approach to assess emotional regulation in humans. The authors present solid evidence for the idea that emotional distancing (as routinely used in clinical interventions for e.g. mood and anxiety disorders) enhances emotional control.

    1. eLife Assessment

      This important study has modified ChIP-seq and 4C-seq procedures with a urea step and shows that this drastically changes the pattern of chromatin interactions observed for SATB1 but not other proteins (CTCF, Jarid2, Suz12, Ezh2). Multiple controls make the data convincing. The findings shed new light on the role of SATB1 in genome organization and will be of interest to those who study chromosome structure and nuclear organization.

    1. eLife Assessment

      This important study investigates the different mechanisms that provide instructions for a missing body part to regenerate its appropriate identity. The authors use two species of planarians to identify a key role for bodywide canonical Wnt gradients in controlling the outcome of regeneration. The study provides convincing evidence for variable regeneration efficiency among planarian species that will be of interest to developmental biologists interested in regeneration. However, some of the results are over-interpreted and the additional experiments could provide better support for the authors' claims.

    1. eLife Assessment

      This valuable study reports a potential connection between the seminal microbiome and sperm quality/male fertility. The data are generally convincing. This study will be of interest to clinicians and biomedical researchers who work on microbiome and male fertility.

    1. eLife Assessment

      This compelling study introduces a set of novel genetically encoded tools for the selective and reversible ablation of excitatory and inhibitory synapses. These new tools enable selective and efficient ablation of excitatory synapses, and photoactivatable and chemically inducible methods for inhibitory synapse ablation in specific cell types, providing valuable methods for disrupting neural circuits. This approach holds broad potential for investigating the roles of specific synaptic input onto genetically determined cells.

    1. eLife Assessment

      The paper describes a novel approach for inferring features of synaptic networks from recordings of individual cells within the network. The paper will be a valuable contribution to those studying central pattern generators, including those involved in respiration. However, the theoretical approach to drawing inferences regarding the underlying synaptic currents is incomplete as it relies on unsupported simplifying assumptions.

    1. eLife Assessment

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

    1. eLife Assessment

      van Vliet and colleagues show a useful correlation between internal states of a convolutional neural network (CNN) trained on visual word stimuli with three specific components of evoked MEG potentials during reading in humans. The findings are solid, though quantitative evidence that model can produce any of the phenomena that the human visual system is known to have (e.g., feedback connections, sensitivity to word frequency), or that it has comparable performance to human behaviour (i.e., similar task accuracy with a comparable pattern of mistakes) would make the conclusions much stronger.

    1. eLife Assessment

      Hardly anything is known about the genetic basis and mechanism of male-killing. Recently, a gene called oscar, in the bacterium Wolbachia, was implicated in killing male corn borer moths by interfering with moth genes that control sex determination and proper dosage of sex-specific genes. In this paper, the authors show that a distantly related oscar gene in another strain of Wolbachia kills male tea tortrix moths in a similar mechanism. This valuable study cements our understanding of the sophisticated way that Wolbachia kills male moths and butterflies (Lepidoptera) so early in their development. The conclusions are supported by solid evidence.

    1. eLife Assessment

      The authors have developed a biosensor for programmed cell death. They use this biosensor to provide cell death measurements in a specific early development time. The findings useful in a specific context; however, the application of this biosensor is incomplete as it does not take into account existing literature and is missing controls.

    1. eLife Assessment

      It is known from model organisms that genes' effects on traits are often modulated by environmental variables, but similar gene-by-environment (GxE) interactions have been difficult to detect using statistical analyses of genomic data, e.g., in humans. This study introduces a new framework to estimate gene-by-environment effects, treating it as a bias-variance tradeoff problem. The authors convincingly show that greater statistical power can be achieved in detecting GxE if an underlying model of polygenic GxE is assumed. This polygenic amplification model is a truly novel view with fundamental promise for the detection of GxE in genomic datasets, especially with continued development to detect more complex signals of amplification.

    1. eLife Assessment

      This important study reports numerous attempts to replicate reports on transgenerational inheritance of a learned behavior – pathogen avoidance – in C. elegans. While the authors observe parental effects that are limited to a single generation (also called intergenerational inheritance), the authors failed to find evidence for transmission over multiple generations, or transgenerational inheritance. The experiments presented are meticulously described, making for compelling evidence that in the authors' hands transgenerational inheritance cannot be observed. There remains the possibility that different assay setups explain the failure to reproduce previous observations, although the authors present data suggesting that details of the assay are not that significant. There also remains the possibility that differences in culture conditions or lab environment explain the failure to reproduce previous observations, with updates to the paper having further reduced the probability that this applies here. Even if this were the case, it would imply that the original experimental paradigm was dependent on a very specific context. Given the prominence of the original reports of transgenerational inheritance, the present study is of broad interest to anyone studying genetics, epigenetics, or learned behavior.

      [As also pointed out by the authors of this study, the authors of the original reports have provided a response on bioRxiv (DOI: https://doi.org/10.1101/2025.01.21.634111).]

    1. eLife Assessment

      This work investigates ZC3H11A as a cause of high myopia through the analysis of human data and experiments with genetic knockout of Zc3h11a in mouse, providing a useful model of myopia. The evidence supporting the conclusion is still incomplete in the revised manuscript as the concerns raised in the previous review were not fully addressed. The article will benefit from further strengthening the genetic analysis, full presentation of human phenotypic data, and explaining the reasons why there was no increased axial length in mice with myopia. The work will be of interest to ophthalmologists and researchers working on myopia.

    1. eLife Assessment

      This study follows up on Arimura et al's powerful new method MagIC-Cryo-EM for imaging native complexes at high resolution. Using a clever design embedding protein spacers between the antibody and the nucleosomes purified, thereby minimizing interference from the beads, the authors concentrate linker histone variant H1.8 containing nucleosomes. From these samples, the authors obtain convincing atomic structures of the H1.8 bound chromatosome purified from interphase and metaphase cells, finding a NPM2 chaperone bound form exists as well. Caveats previously noted have been addressed nicely in the revision, strengthening the overall conclusions. This is an important new tool in the arsenal of single molecule biologists, permitting a deep dive into structure of native complexes, and will be of high interest to a broad swathe of scientists studying native macromolecules present at low concentrations in cells.

    1. eLife Assessment

      The formation of the Z-ring at the time of bacterial cell division interests researchers working towards understanding cell division across all domains of life. The manuscript by Jasnin et al reports the cryoET structure of toroid assembly formation of FtsZ filaments driven by ZapD as the cross linker. The findings are important and have the potential to open a new dimension in the field, but the evidence to support these exciting claims is currently incomplete, mostly because of the suboptimal "resolution of the toroids", so in the absence of additional experiments, the interpretations would need to be toned down.

    1. eLife Assessment

      Combining experimental and computation approaches, this manuscript provides convincing evidence for a post-transcriptional mechanism that provides robust control over the protein expression level of RecB in E. coli. In addition to uncovering how DNA damage drives higher levels of RecB protein, this work also reveals important tenets for how broader mechanisms that suppress noise and underlie responsive tuning of protein levels can be achieved.

    1. eLife Assessment

      In this detailed study, Cohen and Ben-Shaul characterized Accessory Olfactory Bulb (AOB) cell responses to various conspecific urine samples in female mice across the estrous cycle. The authors found that AOB cell responses varied depending on the strain and sex of the sample, but no clear differences were observed between estrous and non-estrous females. These findings provide convincing evidence that the AOB functions as a stable sensory relay, without directly modulating responses based on reproductive state, which supports the role of downstream brain regions in integrating reproductive state. Overall, this study provides valuable insights for researchers in the fields of olfaction and social neuroscience.

    1. eLife Assessment

      Pinho et al use in vivo calcium imaging and chemogenetic approaches to examine the involvement of hippocampal sub-regions across the different stages of a sensory preconditioning task in mice. They find convincing evidence for sensory preconditioning in male mice. They also find that, in these mice, CaMKII-positive neurons in the dorsal hippocampus: (1) encode the audio-visual association that forms in stage 1 of the task, and (2) retrieve/express sensory preconditioned fear to the auditory stimulus at test. These findings are supported by evidence that ranges from incomplete to convincing. The study will be valuable to researchers in the field of learning and memory.

    1. eLife Assessment

      In this paper, the authors report important structural and functional findings on the interaction of how the group A streptococci (GAS) M3 protein (expressed on GAS strains emm3, which are associated with invasive disease) binds to human collagens. They demonstrate an unusual T-shaped structure within the N-terminal hypervariable region of M3 protein that can bind two copies of collagen triple helix in parallel. These solid data advance understanding of how GAS M3 interacts with human collagen, information relevant to understanding and developing treatments for GAS infection. A major limitation of the work is the lack of mutational work to test if the T-shaped structure is necessary for binding collagen.

    1. eLife Assessment

      This important theoretical study introduces an extension to the commonly used SIR model for infectious disease dynamics, to explicitly consider the role of larger group sizes. Instead of the commonly used individual-based network models, the authors developed a simplified approach based on group sampling, with discrete high- and low-risk groups, which makes the results easier to produce and interpret, at the cost of less detail in the model. The evidence is convincing in terms of the soundness of the theoretical projections and the impact that accounting for group sizes may have on inferences from surveillance data. However, it has not yet been demonstrated that the predictions provide more realistic projections when based on real-world data.

    1. eLife Assessment

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

    1. eLife Assessment

      This study presents valuable findings on the increased prevalence of pain in women with polycystic ovary syndrome and its relationship to health outcomes. The evidence supporting the conclusions is compelling with a large number of patients and sound methodology, and can be used as a starting point for studies of etiology and mechanisms of pain in women with polycystic ovary syndrome and comorbidities. The work will be of interest to medical biologists working on polycystic ovary syndrome pathophysiology and clinicians.

    1. eLife Assessment

      This valuable study characterises the activity of motor units from two of the three anatomical subdivisions ("heads") of the triceps muscle while mice walked on a treadmill at various speeds. Although this is the most thorough characterisation of motor unit activity in walking mice to date, the evidence supporting some of the claims, especially pertaining to probabilistic recruitment of motor units, is incomplete. Further investigating whether the differences in motor unit recruitment across muscle heads go beyond their different mechanical functions would also strengthen the paper.

    1. eLife Assessment

      This important study identifies a novel role for Hes5+ astrocytes in modulating the activity of descending pain-inhibitory noradrenergic neurons from the locus coeruleus during stress-induced pain facilitation. The role of glia in modulating neurological circuits including pain is poorly understood, and in that light, the role of Hes5+ astrocytes in this circuit is a key finding with broader potential impacts. However, the impact of this work is limited by incomplete evidence, notably the fact that acute restraint stress is generally anti-nociceptive rather than pro-nociceptive, and a lack of specificity in defining this novel circuit.

    1. eLife Assessment

      This is a useful follow-up on previous work on the same LGI1-ADAM22 complex using cross-linking to stabilize a trimeric state that the authors had previously observed by SEC-MALS and small-angle X-ray scattering (the previous crystal structure was determined in a dimeric form). A strength of this solid work is that oligomeric states do not affect the critical interaction between LGI1 and ADAM23, so the previous conclusions are still valid. A weakness is that the physiological relevance of the trimeric assembly is unclear.

    1. eLife Assessment

      This paper presents the important finding that BNIP3/NIX, a mitophagy receptor, and its binding to ATG18 are required for mitophagy during muscle cell reorganization in Drosophila. Although the involvement of the BNIP3-ATG18/WIPI axis in mitophagy induction has been reported in mammalian cell culture systems, this study provides the first compelling evidence for this pathway in vivo in animals. The physiological significance of this BNIP3-dependent mitophagy will require further investigation.

    1. eLife Assessment

      This paper provides a compelling and rigorous quantitative analysis of the turnover and maintenance of CD4+ tissue-resident memory T cell clones, in the skin and the lamina propria. It provides a fundamental advance in our understanding of CD4 T cell regulation. Interestingly, in both tissues, maintenance involves an influx from progenitors on the time scale of months. The evidence that is based on fate mapping and mathematical inference is strong, although open questions on the interpretation of the Ki67-based fate mapping remain.

    1. eLife Assessment

      This study approaches an important topic providing insight into the neuronal circuitry that interconnects memory consolidation and sleep. The data were collected and analysed using a solid methodology, contributing new findings for neurobiologists working on how memories are stored and the roles of sleep. However, the data is incomplete to support the proposed role of the PAM-DPM circuits as the link between sleep state and long-term memory consolidation.

    1. eLife Assessment

      Lu and colleagues developed an important imaging protocol that combines expansion microscopy, light-sheet microscopy, and image segmentation for use with the planarian Schmidtea mediterranea, a powerful model system for regeneration. This represents a substantial improvement on current standards and enables more rapid data acquisition. The utility of this solid protocol is demonstrated by quantifying several aspects of this flatworm's neural anatomy and musculature during homeostasis and regeneration. This work will be of interest to researchers looking to implement more systematic approaches towards imaging and quantifying intact specimens.

    1. eLife Assessment

      This study makes the fundamental discovery of the first natural animal rhodopsin that uses a chloride ion instead of an amino acid side chain as a counterion. Using a combination of biochemical and spectroscopic experiments together with QM/MM simulations, the authors identify the spectral tuning mechanism in the dark state and in the photoproduct state. The methods are sound and the results are convincing. This work will be of interest to biologists working on visual proteins and it also raises new questions about how environmental factors might affect coral opsins.

    1. eLife Assessment

      This paper reports the analysis of coevolutionary patterns and dynamical information for identifying functionally relevant sites. These findings are considered important due to the broad utility of the unified framework and network analysis capable of revealing communities of key residues that go beyond the residue-pair concept. The data are solid and the results are clearly presented.

    1. eLife Assessment

      CellDetective is a useful software package for segmentation, tracking, and analysis of time‐lapse microscopy datasets, specifically designed to be accessible to researchers without coding expertise. The authors provide solid evidence of its capabilities through comprehensive validations and well‐executed comparisons across immunological assays. However, the current implementation is limited to 2D widefield imaging and presents technical challenges - including occasional crashes, restricted flexibility in defining multiple cell populations, and some interface issues that hinder the full user experience. Overall, this work will be of significant interest to the bioimaging community, especially those in immunology and cell biology, and promises to evolve into a more robust tool with further development.

    1. eLife Assessment

      This manuscript describes the characterization of the conformational dynamics of two chemokine receptors at the single-molecule level using FRET. The authors make a convincing case for attributing the distinct interaction and pharmacology of the two receptors to differences in their conformational energy landscape. These important findings will be of interest to scientists working on activation mechanisms of GPCRs and signal transduction.

    1. eLife Assessment

      This manuscript focuses on understanding if and how the glycosylation of SARS-CoV2 spike protein affects a putative allosteric network of interactions controlled by the binding of a fatty acid. The main conclusion is that glycans do not significantly affect the network of allosteric interactions. This valuable information - albeit mainly consisting of negative results - is based on convincing evidence. It will be of interest to scientists focusing on SARS CoV2 protein structure and dynamics.

    1. eLife Assessment

      In this manuscript, Abd El Hay and colleagues use an innovative behavioral assay and analysis method, together with standard calcium imaging experiments on cultured dorsal root ganglion (DRG) neurons, to evaluate the consequences of global knockout of TRPV1 and TRPM2, and overexpression of TRPV1, on warmth detection. Compelling evidence is provided for a role of TRPM2 channels in warmth avoidance behavior, but it remains unclear whether this involves channel activity in the periphery or in the brain. In contrast, TRPV1 is clearly implicated at the cellular level in warmth detection. These findings are important because there is substantial ongoing discussion regarding the contribution of TRP channels to different aspects of thermo-sensation.

    1. eLife Assessment

      This is an important study that generates an inventory of accessible genomic regions bound by a transcription factor ZFHX3 within the suprachiasmatic nucleus in the hypothalamus and details the impact of its depletion on daily rhythms in behavior and gene expression patterns. Analysis using circadian phase-estimation algorithms makes the argument that gene regulatory networks are at play and changes in gene expression of a few clock genes cannot account for the observed animal behaviour. While the transcriptome analysis is compelling, the data on the activity of the TF in rhythmic gene expression is solid, and interpretations that allow for direct and/or indirect roles have been incorporated.

    1. eLife Assessment

      This work presents a useful resource combining scRNA-seq and spatial transcriptomics studies to map mouse pre-clinical models of colorectal cancer, identifying distinct cellular programs and microenvironments that could enhance patient stratification and therapeutic approaches in colorectal cancer. While the novelty of the biological findings remains limited and incompletely supported by the evidence provided in the manuscript, the data were collected and analyzed using a validated methodology that will be of interest to the community in future studies.

    1. eLife Assessment

      This is an important study linking olfactory bulb activity not only to sniffing parameters but also to movement and place. The evidence for odor sampling is mostly solid, but the analysis supporting the potentially exciting result on the encoding of place is currently incomplete.

    1. eLife Assessment

      This valuable manuscript presents a potentially novel mechanism by which the phospholipid scramblase, PLSCR1, defends against influenza A virus infection. The paper was based on solid findings involving knockout and lung-specific over-expressing Plscr1 mice, airway tissue expression, and mechanistic studies to show Plscr1 enhances type III interferon-mediated viral clearance. The study is extensive and overall well performed.

    1. eLife Assessment

      It is well established cellulose synthesis in higher plants requires three different but related catalytic subunits known as CESA proteins. Here the authors provide cryo electron microscopy structural information on soybean CESA1, CESA3, and CESA6 and find substantial differences between the structure of these CESA homotrimers and the previously-resolved secondary cell wall CESAs. They present an important model with convincing evidence in which the multi-subunit cellulose synthase complexes are made of multiple homotrimers.

    1. eLife Assessment

      This study investigates the conditions under which abstract knowledge transfers to new learning. It presents convincing evidence across a number of behavioral experiments that when explicit awareness of learned statistical structure is present, knowledge can transfer immediately, but that otherwise similar transfer requires sleep-dependent consolidation. The valuable results provide new constraints on theories of transfer learning and consolidation.

    1. eLife Assessment

      This important study demonstrates that screening by artificial intelligence can identify relevant novel compounds for interacting with KATP channels. The experimental work is compelling. The broader significance of this work relates to the possibility that KATP channel mutations linked to congenital hyperinsulinism may be effectively rescued to the cell surface with a drug, which could normalize insulin secretion or enhance the effectiveness of existing KATP channel activators such as diazoxide.

    1. eLife Assessment

      This valuable manuscript uses mathematical modeling to address the synchrony of the vertebrate segmentation clock with the developmental processes. The authors use convincing arguments to support the idea that this would allow the evolution of flexible body plans and a variable number of segments. This manuscript could be of interest to developmental biologists and systems biologists.

      [Editors' note: this paper was reviewed by Review Commons.]

    1. eLife Assessment

      This useful study presents a comparative investigation of category selectivity in dogs and humans. The study compares brain representations of animate and inanimate objects, replicating and extending previous reports in this nascent field of dog FMRI. The methods and results seem to lack sufficient detail, appropriate controls, or statistical evidence, so at this stage of the review process, the strength of evidence is deemed incomplete.

    1. eLife Assessment

      This valuable study provides new insights into the synchronization of ripple oscillations in the hippocampus, both within and across hemispheres. Using carefully designed statistical methods, it presents convincing evidence that synchrony is significantly higher within a hemisphere than across. However, further controlling for potential confounds related to differences in animal behavior will help clarify whether this effect is influenced by memory processing. This study will be of interest to neuroscientists studying the hippocampus and memory.

    1. eLife Assessment

      In this important study, the authors employed state-of-the-art biochemistry, cryo-EM, and HDX mass spec approaches to study the formation of the binary Uba7-UBE2L6 and ternary UBA7-UBE2L6-ISG15 complexes. The results established mechanisms by which UBA7 and UBE2L6 form disulfide bonds, disrupting the ISG15 transfer cascade. While the biochemical and structural experiments are largely convincing, the mechanism under in vivo conditions remains unclear, due to the limited use of a single E2 enzyme. The authors need to repeat their experiments with a representative panel of human E2 enzymes.

    1. eLife Assessment

      In this important quantitative study of HIV-1 evolution in humans and rhesus macaques, selection coefficients are inferred at scale over the HIV genome. Selection coefficients are similar in humans and macaques, providing convincing evidence that these coefficients are representative of the fitness landscapes of these viruses within hosts. This work should be of interest to the community working on quantitative evolution and fitness landscape inference, and the finding that rapid fitness gains in the HIV population predict bNAb emergence has implications for HIV vaccine design.

    1. eLife Assessment

      The authors attempt to identify which patients with benign lesions will progress to cancer using a liquid biomarker. Although the study is valuable, the evidence provided for the liquid biopsy EV miRNA signature developed based on radiomics features is incomplete. This is because the data are derived from discrepant sample sets and the description of the clinical characteristics of the samples enrolled in the study needs to be improved.

    1. eLife Assessment

      This is a valuable study that explores the function of CCP5 in mouse ependymal cells. The methods, data, and analyses broadly support the claims. However, the study is incomplete as it stands. Minor weaknesses remain and the authors may wish to address them.

    1. BANKSY offers a practical approach to spatial omics analysis by combining cell typing and tissue domain segmentation, which could aid researchers in mapping tissue organization and microenvironment interactions more efficiently. Its scalability for large datasets may streamline workflows in studies of development, disease, or tissue heterogeneity.

    1. eLife Assessment

      This study provides an important first look at the influence of vertical transmission in the establishment of the amphibian microbiome, with a specific focus on the potential role of parental care. Through a combination of cross-fostering experimental work, comparative analysis across species that show variable levels of care, and developmental time series, the authors provide convincing evidence that vertical transmission through care is possible, but incomplete evidence that it plays a significant role in shaping frog skin microbiomes in nature or across time. This work will be of interest to researchers studying the evolution of parental care and microbiomes in vertebrates.

    1. eLife Assessment

      The valuable findings in this study reveal an intricate pattern of memory expression following retrieval extinction at different intervals from retrieval-extinction to test. They document that immediately after extinction there is a nonselective impairment in memory, which leads to no impairment at a 6-hour interval. At a 24-hour interval, there is a selective impairment. The evidence supporting the claims is incomplete and there are inconsistencies in the analyses reported that obscure the interpretation.

    1. eLife Assessment

      This study provides a valuable structural analysis of the Sedoheptulose-1,7-Bisphosphatase (SBPase) from Chlamydomonas reinhardtii. The data presented are solid and based on X-ray structures of the CrSBPase in an oxidized and reduced state, the authors identify a disulfide bond in close proximity to the dimer interface. They show that the redox-state of the CrSBPase impacts its oligomeric state and might also influence the activity of the protein.

    1. eLife Assessment

      The study presents important findings on inositol-requiring enzyme (IRE1α) inhibition on diet-induced obesity (overnutrition) and insulin resistance where IRE1α inhibition enhances thermogenesis and reduces the metabolically active and M1-like macrophages in adipose tissue. The evidence supporting the conclusions is convincing. The work will be of interest to cell biologists and biochemists working in metabolism, insulin resistance and inflammation with a broad eLife readership.

    1. eLife Assessment

      This manuscript presents important findings on a bacterial effector involved in plant symbiotic signaling. The effector proteolytically targets a key receptor while its activity is counteracted by host-mediated phosphorylation, revealing a dynamic interplay that fine-tunes symbiotic interactions. The evidence supporting these claims is solid, and the findings have potential signaling implications beyond bacterial interactions with plants.

    1. eLife Assessment

      This study leverages an impressive and comprehensive longitudinal 16S rRNA gut microbiome dataset from baboons to provide important insight regarding the use of a microbiome-based clock to predict biological age. The evidence for age-associated microbiome features and environmental and social variables that impact microbiome aging is convincing. This study of microbiomes as markers of host age will fuel inquiries and studies and interest a broad range of researchers, especially those interested in alternatives to measuring biological aging.

    1. eLife Assessment

      This research is valuable as it investigates metabolic shuttling between photoreceptors and retinal pigment epithelium (RPE) using in vivo infusion techniques and mouse models. The authors find that the retina significantly relies on circulating glucose, with photoreceptors being the primary consumers of glucose, which is convincing. However, the study has incomplete evidence to support the claims that photoreceptors can use lactate as a fuel source, that lactate exported from photoreceptors is utilized by the RPE, and that lactate contributes to the TCA cycle in the RPE. These claims need substantial revision to include potential alternative explanations or perform key experiments.

    1. eLife Assessment

      This potentially valuable study presents claims of evidence for coordinated membrane potential oscillations in E. coli biofilms that can be linked to a putative K+ channel and that may serve to enhance photo-protection. The finding of waves of membrane potential would be of interest to a wide audience from molecular biology to microbiology and physical biology. Unfortunately, a major issue is that it is unclear whether the dye used can act as a Nernstian membrane potential dye in E. coli. The arguments of the authors, who largely ignore previously published contradictory evidence, are not adequate in that they do not engage with the fact that the dye behaves in their hands differently than in the hands of others. In addition, the lack of proper validation of the experimental method including key control experiments leaves the evidence incomplete.

    1. eLife Assessment

      This study presents an important contribution to the understanding of neural speech tracking, demonstrating how minimal background noise can enhance the neural tracking of the amplitude-onset envelope. The evidence, through a well-designed series of EEG experiments, is convincing. This work will be of interest to auditory scientists, particularly those investigating biological markers of speech processing.

    1. eLife Assessment

      Saijilafu et al. describe valuable findings suggesting that MLCK and MLCP bidirectionally regulate NMII phosphorylation ultimately impinging on axonal growth during regeneration in the central and peripheral nervous systems. Solid evidence is collected from culture and in vivo models, and through pharmacologic and genetic loss-of-function approaches. However, how MLCK and MLCP regulates NMII activity is not fully addressed or discussed. In sum, this knowledge is of potential interest for the field due to the relevance of identifying mechanistic details that regulate axonal regeneration

    1. eLife Assessment

      This useful study identifies new monoclonal antibodies produced by cystic fibrosis patients against the Pseudomonas aeruginosa type three secretion system. The evidence supporting the authors' claim is solid. However, in the current version of the manuscript, it is unclear what the benefits of the newly isolated antibodies are with respect to antibodies previously identified using a similar approach. The study will be of interest to those working on developing mAbs against Pseudomonas aeruginosa and also against other pathogens that harbor the T3SS.

    1. eLife Assessment

      In this valuable study, the authors show the physiological response and molecular pathway mediating the effect of quinofumelin, a developed fungicide with an unknown mechanism. The authors present convincing data suggesting the involvement of the uridine/uracil biosynthesis pathway, by combining in vivo microbiology characterization as well as in vitro biochemical binding results.

    1. eLife Assessment

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

    1. eLife Assessment

      This valuable manuscript by Jia et al. investigates the role of cartilage intermediate layer protein (CILP) and moderate exercise in maintaining hyaline cartilage integrity following anterior cruciate ligament transection (ACLt) in rats. Solid data support the downregulation of CILP in human OA cartilage and its potential role in regulating Keap1/Nrf2 interaction and chondrocyte ferroptosis. However, the data supporting a role for CILP in exercise-mediated inhibition of hyaline cartilage fibrosis in early OA are incomplete.

    1. eLife Assessment

      This study describes a useful technique to improve imaging depth using confocal microscopy for imaging large, cleared samples. The work is supported by solid findings and will be of broad interest to many microscopical researchers in different fields who want a cost effective way to image deep into samples.

    1. eLife Assessment

      This important 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. The data supporting the main conclusion are convincing. This work will be of interest to reproductive biologists and physicians practicing reproductive medicine.

    1. eLife Assessment

      This fundamental study provides a comprehensive analysis of the EmrE efflux pump and the role of the C-terminal domain in preventing uncoupled proton leak in the absence of substrate. The evidence supporting the conclusions is solid, although incomplete analyses limit some of the conclusions.

    1. eLife Assessment

      This valuable descriptive manuscript builds on prior research showing that the elimination of Origin Recognition Complex (ORC) subunits does not halt DNA replication. The authors obtain solid data using various methods to genetically remove one or two ORC subunits from specific tissues and still observe replication. The replication appears to be primarily endoreduplication, indicating that ORC-independent replication may promote genome reduplication without mitosis. The mechanism behind this ORC-independent replication remains to be elucidated. The study and mutants described herein lay the groundwork for future research to explore how cells compensate for the absence of ORC and to develop functional approaches to investigate this process. The reviewers suggested the observations could be supported by additional experiments. This work will be of interest to those studying genome duplication and replication.

    1. eLife Assessment

      This valuable study reports the critical role of two cyclin-dependent kinases, CDK8 and CDK19, in spermatogenesis. The data presented are generally supportive of the main conclusion and are considered solid. This work may be of interest to reproductive biologists and physicians working on male fertility.

    1. eLife Assessment

      This manuscript presents a detailed characterization of male and female wildtype and Ctrp10 knockout mice, and reveals that knockout mice develop female-specific obesity that is largely uncoupled from metabolic dysfunction. The data are convincing, and the work will be an important contribution to understanding how obesity is coupled to metabolic dysfunction, and how this can occur in a sex-specific manner.

    1. eLife Assessment

      This paper provides a valuable contribution to our understanding of how adenosine acts as a signal of nutrient insufficiency and extends this idea to suggest that adenosine is released by metabolically active cells in proportion to the activity of methylation events. Convincing data supports this idea. The authors use metabolic tracing approaches to identify the biochemical pathways that contribute to the regulation of adenosine levels and the S-adenosylmethionine cycle in Drosophila larval hemocytes in response to wasp egg infection.

    1. eLife Assessment

      This is an important study that describes the development of optical biosensors for various Rab GTPases and explores the contributions of Rab10 and Rab4 to structural and functional plasticity at hippocampal synapses during glutamate uncaging. The evidence supporting the conclusions of the paper is solid, and several improvements were noted by the reviewers upon revision, although some persisting inconsistencies would benefit from further clarification.

    1. eLife Assessment

      This study presents important findings on the role of pyramidal cells driving vasoconstriction in brain arteries through a COX-2/PGE2 pathway, with additional contributions from NPY (interneurons) and 20-HETE (astrocytes). Optogenetic stimulation of cortical pyramidal neurons induces vasoconstriction, potentially leading to oxygen and nutrient undersupply in regions with sustained activation - a mechanism potentially relevant under pathological conditions. The authors provide convincing evidence from brain slice experiments and some in vivo data from anesthetized animals, carefully discussing the strengths and limitations of both approaches.

    1. eLife Assessment

      This study presents a useful demonstration that a specific protein fragment may induce the loss of synapses in Alzheimer's disease. The evidence supporting the data is solid but only partially supports the conclusion and would benefit from additional discussion indicated by the literature from reviewer #1. The application of the findings is limited because blocking the formation of the protein fragment has not benefited patients in several clinical trials.

    1. eLife Assessment

      NAD deficiency perturbs embryonic development resulting in multiple congenital malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD). The authors report fundamental findings demonstrating that extra-embryonic visceral yolk sac endoderm is critical for NAD de novo synthesis during early organogenesis and perturbations of this pathway may underlie CNDD. The authors combine gene expression with metabolic assays to provide solid evidence of an essential role of the extra-embryonic visceral yolk sac in both mouse and human embryos.

    1. eLife Assessment

      This manuscript addresses the role of alpha oscillations in sensory gain control. The authors use an attention-cuing task in an initial EEG study followed by a separate MEG replication study to demonstrate that whilst (occipital) alpha oscillations are increased when anticipating an auditory target, so is visual responsiveness as assessed with frequency tagging. The authors propose their results demonstrate a general vigilance effect on sensory processing and offer a re-interpretation of the inhibitory role of the alpha rhythm. While these results are valuable, the provided evidence is incomplete.

    1. eLife Assessment

      This study presents a valuable finding on the importance of the plasma metabolome in glaucoma risk prediction. The authors have used the UK Biobank data to interrogate the association between plasma metabolites and glaucoma. The evidence supporting the claims of the authors is solid and the work offers insights into the design of protective therapeutic strategies for glaucoma.

    1. eLife Assessment

      This important study examines the neuronal mechanisms underlying visual perception of integrated face and body cues. The innovative paradigm, which employs monkey avatars in combination with electrophysiological recordings from fMRI-defined brain areas, is a compelling approach. These results should be of wide interest to system and cognitive neuroscientists, psychologists, and behavioural biologists working on visual and social cognition.

    1. eLife Assessment

      This study presents SegPore, a valuable new method for processing direct RNA nanopore sequencing data, which improves the segmentation of raw signals into individual bases and boosts the accuracy of modified base detection. The evidence presented to benchmark SegPore is solid and the authors provide a fully documented implementation of the method. If updated to process newer RNA nanopore sequencing data types, SegPore will be of great interest to researchers studying RNA modifications.

    1. eLife Assessment

      The study is a valuable contribution to the question of evolutionary shifts in neuronal proliferation patterns and the timing of developmental progressions. The authors present convincing data which confirm the presence of type-II NB lineages in beetle with the same molecular characteristics as the Drosophila counterparts but differing in lineage size and number. The data lay the foundation for future analysis of the role and molecular characteristics of individual lineages and of whether differences in the identity, proliferation pattern and timing of developmental progression can be linked to differences in the development of functionality of the central complex.

    1. eLife Assessment

      This important study employs an optogenetics approach aimed at activating oncogene (KRASG12V) expression in a single somatic cell, with a focus on following the progression of activated cell to examine tumourigenesis probabilities under altered tissue environments. Although the description of the methodologies applied is incomplete, 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, especially in relation to the genetic tools described.

    1. eLife Assessment

      This study makes the important finding that pleiotropy is positively associated with parallelism of evolutionary responses in gene expression. This finding, if true, runs counter to current expectations in the field. The analysis uses state-of-the art experimental evolution approach to study the genetic basis of adaptation of Drosophila simulans to a hot environment. Although the experimental results are convincing, the theoretical model is incomplete, due to several unusual assumptions. It remains to be seen whether the main conclusion can be replicated in other contexts.

    1. eLife Assessment

      This study provides important findings that during credit assignment, the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) encode causal choice representations, while the frontopolar cortex (FPl) mediates HC -lOFC interactions when the causality needs to be maintained over longer distractions. This research offers compelling evidence and employs sophisticated multivariate pattern analysis. However, while the task design captures the delayed component, it lacks the full complexity and ambiguity of the credit assignment process observed in real-world scenarios. Moreover, the data indicated that other frontal regions beyond just lOFC were involved in delayed credit assignment. This work will be of interest to cognitive and computational neuroscientists who work on value-based decision-making and fronto-hippocampal circuits.

    1. eLife Assessment

      This work attempts to demonstrate an ATP-independent non-canonical role of proteasomal component PA28y in the promotion of oral squamous cell carcinoma growth, migration, and invasion. Although the authors have addressed some concerns, uncertainties regarding the PA28g-C1QBP direct interaction still exist. The overall findings of the manuscript are useful, but the validation evidence is incomplete.

    1. eLife Assessment

      This valuable study leverages innovative high-dimensional imaging strategies to interrogate pancreatic immune cell profiles and distributions throughout stages of type 1 diabetes (T1D). Despite a notable limitation in the number of donor samples analyzed, the authors identify a series of intriguing "immune signatures" and histopathological features that collectively constitute a solid foundation for future investigations into immunological processes underpinning the pathogenesis of T1D. Accordingly, the work will be of considerable interest to the community of T1D researchers and clinicians.

    1. eLife Assessment

      The authors demonstrate the valuable discovery that human CD29+/CD56+ myogenic progenitors can differentiate into tendon through the TGFβ pathway, addressing mouse and human interspecies differences in regard to the potential of muscle stem cells. The in vivo transplantation experiments provide convincing evidence for the conclusion, as human CD29+/CD56+ myogenic progenitors contribute to tendon regeneration, resulting in functional recovery in mouse model. The authors' approach can be used for the development of cell therapy for tendon-injured patients.

    1. eLife Assessment

      This study presents a useful theoretical model of molecular evolution of multi-copy gene systems by extending the classic Haldane model and applies the model to explain the surprisingly rapid evolution of rRNA genes. Although the conceptual model is intuitive and provides a new perspective for contextualizing this problem, the model presented does not adequately consider plausible biological constraints on the molecular and genetic processes. The lack of such constraints in the model, along with technical issues in the data analysis, provide incomplete support for the conclusion that the genetic variation patterns of rRNA genes in mouse is compatible with neutral evolution.

    1. eLife Assessment

      This study presents a useful model of genetic drift by incorporating variance in reproductive success, aiming to address several apparent paradoxes in molecular evolution. However, some of the apparent paradoxes only arise in the most basic version of standard models and have been reconciled in more advanced models. Nonetheless, this paper offers intuitive explanations for these apparent paradoxes, by adopting a new perspective and solid modeling and analysis. More broadly, the proposed model provides an alternative framework to address puzzling observations in molecular evolution, which will be of interest to evolutionary and population geneticists.

    1. eLife Assessment

      This important study presents a method to visualize the location of the cell types discovered through single-cell RNA sequencing. The data allowed the authors to build spatial tissue atlases of the fly head and body, and to identify the location of previously unknown cell types. The data are convincing and appropriate, and the authors validate the methodology in line with the current state-of-the-art.

    1. eLife Assessment

      In this valuable study, Seidel et al. identify and characterize a novel subset of hepatocellular carcinoma patient-derived xenograft models defined by active Jagged 1-Notch2 signaling and a distinctive progenitor-like gene expression profile. Within the limitations of the PDX system they used, their methods are state-of-the-art, their data are strong and believable, and their conclusions are convincing. However, the ability to identify HCC patients that might respond is limited, and the mechanistic assessment downstream of JAG1/NOTCH2 is relatively descriptive. Some additional clarifications and experiments would strengthen the paper.

    1. eLife Assessment

      The manuscript contains important findings regarding inflammatory macrophage subsets that have theoretical and/or practical applications beyond the field of rheumatology. The authors demonstrate with convincing evidence the effects of PGE2 on TNF signaling in a well-written manuscript that features methods, data, and analyses in line with current state-of-the-art technologies. This work will be of broad interest to immunologists and cell biologists.

    1. eLife Assessment

      This important study presents novel data on variation in sperm whale communication, contributing to a richer understanding of the social transmission of vocal styles across neighbouring clans. The evidence is solid but could have been further improved with clarification of the specialized metrics and terminology used, particularly for comparisons to other taxa. This research will be of interest for bioacoustics and animal communication specialists, particularly those working on social learning and culture.

    1. eLife Assessment

      This important study compares the cortical projections to primary motor and sensory areas originating from the ipsilateral and contralateral hemispheres. Results show that, while there is substantial symmetry between the two hemispheres regarding the areas sending projections to these primary cortical areas, contra-hemispheric projections had more inputs from layer 6 neurons than ipsi-projecting ones. The evidence is convincing and the conclusions are supported by rigorous analyses.

    1. eLife Assessment

      This fundamental study highlights potential mechanisms underlying the sex-dependent bias in susceptibility to gut colonization by Methicillin-resistant Staphylococcus aureus (MRSA). The evidence supporting the conclusion is compelling. The work will interest biologists who study intestinal infection and immunity.

    1. eLife Assessment

      This important study uses reinforcement learning to study how turbulent odor stimuli should be processed to yield successful navigation. The authors find that there is an optimal memory length over which an agent should ignore blanks in the odor to discriminate whether the agent is still inside the plume or outside of it, complementing recent studies using recurrent neural networks and finite state controllers to identify optimal strategies for navigating a turbulent plume. The strength of evidence is compelling, presenting a novel approach to understanding optimal representations for navigation in stochastic sensory environments.

    1. eLife Assessment

      This important study identifies one way in which episodic heat exposure can result in negative changes in motivated and affective behaviors. This work positively expands the field of thermoregulation. The data were collected using a myriad of next-generation approaches, including extensive behavior testing, thermal monitoring, electrophysiology, circuit mapping, and manipulations. There is convincing evidence that neurons of the paraventricular thalamus change plastically over three weeks of episodic heat stimulation this affects behavioral outputs such as social interactions and anxiety-related behavior. Conclusions regarding the specificity of the POA-pPVT pathway compared to other inputs to the PVT in the control of observed effects would benefit from further validation. The study will be of interest to behavioral neuroscientists, climate/environmental biologists, and pre-clinical neuropsychiatrists.

    1. eLife Assessment

      The results from this study, which investigates the mechanisms necessary for initiating tissue invagination using a cellular Potts modelling approach, suggest that apical constriction is not sufficient to drive the process by itself. The study highlights how choices inherent to modelling - such as permitting straight or curved cell edges - may affect the outcome of simulations and, consequently, their biophysical interpretation. Despite incomplete evidence supporting their major claims due to a rather coarse-grained exploration of the model, this work is useful for biophysicists investigating complex tissue deformation through computational frameworks.

    1. eLife Assessment

      This important study combines single nucleus transcriptional profiling with spatial transcriptomics to identify and map heterogeneity among dopamine neurons in the mouse ventral midbrain. The compelling results separate dopamine neurons into three broad families that have unique (yet overlapping) spatial distribution within the ventral tegmental area and substantia nigra, and also identify population-specific changes in a LRRK2 mouse model of Parkinson's Disease. The creation of a public-facing app where the snRNA-seq data can be investigated by anyone is a major strength.

    1. eLife Assessment

      This important and unique study proposes a framework to understand and predict generalization in visual perceptual learning in humans based on form invariants. Using behavioral experiments in humans and by training deep networks, the authors offer evidence that the presence of stable invariants in a task leads to faster learning. However, this interpretation is promising but counter-intuitive and incomplete, since there could be possible other confounds such as differing attentional demands that lead to differing patterns of generalization. It can be strengthened through additional experiments and by rejecting alternate explanations.

    1. eLife Assessment

      This is a valuable paper that might contribute new insight into the role of GABA in semantic memory, which is a significant question in higher cognition. However, the empirical support for the main claims is incomplete. These results, once further strengthened and more appropriately discussed, will be of interest to broad readers of the neuroscience and cognitive neuroscience community.

    1. eLife Assessment

      This valuable study investigates the immune system's role in pre-eclampsia. The authors map the immune cell landscape of the human placenta and find an increase in macrophages and Th17 cells in patients with pre-eclampsia. Following mouse studies, the authors suggest that the IGF1-IGF1R pathway might play a role in how macrophages influence T cells, potentially driving the pathology of pre-eclampsia. There is convincing evidence in this study that will be of interest to immunologists and developmental biologists.

    1. eLife Assessment

      This study makes the important claims that people track, specifically, the elasticity of control (rather than the more general parameter of controllability) and that control elasticity is specifically impaired in certain types of psychopathology. These claims will have implications for the fields of computational psychiatry and computational cognitive neuroscience. However the evidence for the claim that people infer control elasticity is incomplete, given that it is not clear that the task allows the elasticity construct to be distinguished from more general learning processes, the chosen models aren't well justified, and it is unclear that the findings generalize to tasks that aren't biased to find overestimates of elasticity. Moreover, the claim about psychopathology relies on an invalid interpretation of CCA; a more straightforward analysis of the correlation between the model parameters and the psychopathology measures would provide stronger evidence.

    1. eLife Assessment

      This valuable retrospective analysis identified three independent components of glucose dynamics - "value," "variability," and "autocorrelation" - which may be used in predicting coronary plaque vulnerability. The study is solid and of interest to a wide range of investigators in the medical field who are interested in the role of glycemia on cardiometabolic health. However, the generalizability of the results needs further confirmation through experimental and prospective validation.

    1. eLife Assessment

      The authors have demonstrated the use of adenine base editors delivered via adeno-associated viruses to introduce edits in the mitochondrial genome. The manuscript describes the methodology well, and the conclusions are convincingly supported by the results. The valuable results highlight the potential of these base editors to model mtDNA variations in somatic tissues in animal models.

    1. eLife Assessment

      This manuscript offers important insights into how polyphosphate (polyP) influences protein phase separation differently from DNA. The authors present compelling evidence that polyP distinguishes between protein conformational states, leading to diverse condensate behaviors. However, differences in charge density between polyP and DNA complicate direct comparisons, and the extent to which polyP-driven phase transitions reveal initial protein states remains unclear. Addressing these concerns would strengthen the manuscript's impact for researchers interested in biomolecular condensates, protein dynamics, and stress response mechanisms.

    1. eLife Assessment

      Shah and colleagues take advantage of the presence of maternal and somatic ribosomes in zebrafish and confirm their differential expression during development. The authors convincingly show that ribosomes previously found expressed during oogenesis are also expressed in primordial germ cells and that hybrid maternal and somatic ribosomes are formed during development. The question of ribosome heterogeneity, the expression and function of maternal versus somatically provided ribosomes are of broad interest and this fundamental work sets new directions for future functional studies of this interesting phenomenon.

    1. eLife Assessment

      The manuscript presents a useful analysis of the relationship between climate variables and malaria incidence, for local temperature and rainfall and the global climate driver of ENSO from 2008 to 2019 in a lowland region of East Africa, with wavelet analyses and linear regressions after time series decomposition. The paper is convincing albeit not novel in its application of wavelets to the analysis of this type of time series data for a vector-borne infection. It is less persuasive on what is learned about the role of climate variability (non-seasonal climate effects), and it is also unclear how the analysis informs climate change and malaria, and this motivation for the work is not warranted as it pertains to longer time scales than those considered. The work should be better placed in the context of what is known for malaria in East Africa and in different transmission settings.

    1. eLife Assessment

      This work derives a valuable general theory unifying theories of efficient information transmission in the brain with population homeostasis. The general theory provides an explanation for firing rate homeostasis at the level of neural clusters with firing rate heterogeneity within clusters. Applying this theory to the primary visual cortex, the authors present solid evidence that accounts for stimulus-specific and neuron-specific adaptation.

    1. eLife Assessment

      This fundamental study provides compelling evidence that TRPV4 plays a crucial role in mechanical sensing during cancer cell transition from non-invasive to invasive states, and offers novel insights into metastasis. By employing multiple experimental approaches, including pharmacological and genetic manipulation, as well as advanced imaging techniques, the authors demonstrate a strong correlation between TRPV4 dynamics, calcium homeostasis, and cell volume plasticity. The findings significantly enhance our understanding of mechanotransduction in cancer and present TRPV4 as a promising therapeutic target for inhibiting metastasis.

    1. eLife Assessment

      This important study explores the interplay between gene dosage and gene mutations in the evolution of antibiotic resistance. The authors provide compelling evidence connecting proteostasis with gene duplication during experimental evolution in a model system. This paper is likely to be of interest to researchers studying antibiotic resistance, proteostasis, and bacterial evolution.