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.

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.

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

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).

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).]

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.]

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.