eLife Assessment

This study presents important information about the role of mu opioid receptors in synaptic communication between the medial habenula and the interpeduncular nucleus. The authors provide solid evidence that mu opioid receptor activation has differential effects on glutamate release from substance P neurons and cholinergic neurons, with a canonical reduction in release from the former but a novel increase in release from the latter. They also show that blocking potassium channels can unmask a nicotinic cholinergic synaptic response that is also facilitated by mu opioid receptor activation. This work will be of interest to those studying the interpeduncular nucleus, as well as the larger neuroscience community studying opioids and motivated behavior.

eLife Assessment

This study provides proof-of-principle data for the use of trained immunity to modulate macrophage interactions with tumours. The study makes a valuable contribution to the field of trained immunity. However, the study is incomplete without vivo data, which would have made the claims in the paper stronger by providing meaningful context for the in vitro experiments that were conducted.

eLife Assessment

Using fMRI-based pRF mapping, this important study presents a novel method to estimate visual field (VF) and VF loss/or potential restoration, through analysis of contrast sensitivity patterns in the early visual cortex. While the approach is very interesting and the evidence supporting the claims of the authors is solid, some methodological concerns need to be addressed. The work will be of interest to researchers in vision/clinical vision, neuroscience, and brain imaging.

eLife Assessment

The medicinal leech preparation is an amenable system in which to understand the neural basis of locomotion. Here a previously identified non-spiking neuron was studied in leech and found to alter the mean firing frequency of a crawl-related motoneuron, which fires during the contraction phase of crawling. The findings are valuable and the experiments were diligently done and generally solid; however, the presentation could improve. The work could be taken to the next level by further experiments, and by providing more overall context for the study.

eLife assessment

The work is interesting in its characterization of a large number of antibiotic persisters from a wild-type strain. Previous work was typically limited to directly observe either high persister strains or a smaller number of wt persisters. Therefore, it sheds new light on the elusive non-dormant persisters present in exponentially growing cultures and should help resolve previous conflicting observations.

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 compelling and the conclusions are supported by rigorous analyses.

eLife Assessment

This study aims to identify the proteins that compose the electrical synapse, which are much less understood than those of the chemical synapse. The study is useful in terms of both method development and biological advances, as the authors identified more than 50 new proteins and used immunoprecipitation and immunostaining to validate their interaction. However, the current experimental data are considered incomplete, as many key experimental details are missing.

eLife Assessment

This study presents a valuable finding on the importance of the plasma metabolome in glaucoma risk prediction. The evidence supporting the claims of the authors is solid and the work offers insights for the design of protective therapeutic strategies for glaucoma. The authors have addressed the concerns of the reviewers and reported on the limitations of the study.

eLife Assessment

The authors examine the role of Numb, a Notch inhibitor, in intestinal stem cell self-renewal in Drosophila during homeostasis and regeneration. The significance is important as the authors demonstrate the ISC maintenance is reduced when both BMP signaling and Numb expression is reduced. The strength of evidence is convincing as large sample sizes and statistical analyses are provided.

eLife Assessment

This valuable study shows that an odorant that is typically thought of as a repellant actually activates both attractant and repellant olfactory neurons in C. elegans. Solid evidence is provided that nematode worms can integrate signals using different pathways to drive different behavioral responses to the same cue. These findings will be of interest to scientists interested in combinatorial coding in sensory systems.

eLife Assessment

This valuable study sets new standards in analyzing the ultrastructure of insect eyes, which have long served as models for understanding how vision works. The way it describes an entire eye with the resolution of electron microscopy is convincing. On top of this, a miniaturized visual system provides additional, remarkable insights towards understanding optimized solutions.

eLife Assessment

This valuable study sets new standards in analyzing the ultrastructure of insect eyes, which have long served as models for understanding how vision works. The way it describes an entire eye with the resolution of electron microscopy is convincing. On top of this, a miniaturized visual system provides additional, remarkable insights towards understanding optimized solutions.

eLife Assessment

This study presents useful data on sex differences in gene expression across organs of four mice taxa. While the methods and analysis are largely sound, the strength of evidence is solid only in parts and the conclusions drawn from the results are not always appropriate.

eLife Assessment

This valuable study unravels the mechanisms underlying mammalian sperm-oocyte recognition and penetration, shedding light on cross-species interactions. It provides solid evidence that exposure of sperm to oviductal fluid or OVGP1 proteins from bovine, murine, or human sources imparts species-specific zona pellucida (ZP) recognition, ensuring that only sperm from the corresponding species can penetrate the ZP, regardless of its origin. These findings hold significant potential for reproductive biology, offering insights to enhance porcine in vitro fertilization (IVF), which frequently suffers from polyspermy, as well as advancing human IVF through improved intrinsic sperm selection.

eLife Assessment

This is a convincing study of the morphological properties of Purkinje cell dendrites and dendritic spines in adult humans and mice, and the anatomical determinants of multi-innervation by climbing fibers. The data will provide an important resource for the field of cerebellar computation.

eLife Assessment

This important study shows that the Nora virus, a natural Drosophila pathogen that also persistently infects many laboratory fly stocks, infects intestinal stem cells (ISCs), leading to a shorter life span and increased sensitivity to intestinal infection with the Pseudomonas bacterium. The authors provide convincing data to support their conclusions. The paper provides new insights into virus-host interactions in the Drosophila gut and serves as a warning for scientists who use the fruit fly as a model to study gut physiology.

eLife Assessment

This important research addresses the effects of subjective control and task difficulty on experienced stress using a novel behavioral task in two, large online samples. Convincing evidence is provided, establishing internal and external task validity and a relationship with individual differences in relevant mental health constructs. Evidence for the core claims could be strengthened by disentangling the effects of controllability from those of reward rate and adjusting data parcellation for computing internal consistency. This work will be of interest to psychologists and clinicians studying controllability, stress, and psychopathology.

eLife Assessment

This study offers valuable insights into the conformational dynamics of the nucleic acid recognition lobe of GeoCas9, a thermophilic Cas9 from Geobacillus stearothermophilus. The authors investigate the influence of local dynamics and allosteric regulation on guide RNA binding affinity and DNA cleavage specificity through advanced NMR techniques and mutagenesis. The revised manuscript incorporates new experimental data, including molecular dynamics simulations and additional RNA binding studies, which provide convincing support for the findings. While the mutations studied do not lead to significant changes in GeoCas9 cleavage activity, the study contributes to a better understanding of the allosteric mechanisms and interdomain communication in Cas9 enzymes, and will be of great interest to biochemists and biophysicists exploring these complex systems.

eLife Assessment

This important study aims to understand the role of endothelial cell differentiation into pericytes in the restoration of blood-brain barrier function after ischemic stroke. Identification of pericytes derived from endothelial cells and the involvement of myeloid cell-derived TGFβ1 signaling are compelling new findings, but the evidence supporting the origin and nature of these pericytes is incomplete and would benefit from more rigorous approaches demonstrating reproducibility. The work will be of interest to researchers whose work focuses on the blood-brain barrier and basic and translational stroke.

eLife Assessment

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

eLife Assessment

The manuscript provides valuable findings in the field for understanding the RNAi regulation in plants at the molecular level with a model of how DRB7.2 and DRB4 form a heterodimer and protect dsRNA from DICER activity. The presented data provide a solid basis for the model, but certain measurements could benefit from replicates for robust statistics.

eLife Assessment

In this manuscript, Franco and colleagues describe valuable findings about the chemotactic response of Salmonella to serine and indole, conflicting chemotactic signals. Although the evidence presented is solid, concerns were raised about the novelty of the chemotactic phenomena observed with these two compounds. Also, although the induction of invasion by feces is a novel and interesting finding, the lack of follow-up to this observation was also noted.

eLife Assessment

This solid work, a Research Advance linked to Buchwalter et al., 2019, demonstrates that epitope tagging influences protein fate, serving as a cautionary example of how different tagging and imaging strategies may alter the pattern of endogenous protein trafficking. The information presented will be useful for researchers in the field of membrane trafficking, particularly in guiding their experimental designs. That being said, the study offers limited new insights into the biogenesis or disposal of endogenous Emerin.

eLife Assessment

This potentially important model-based study seeks to mimic bat echolocation behavior and flight under high-density conditions. The simulations convincingly suggest that the problem of acoustic jamming in these situations may be less severe than previously thought, a finding that would be of broad interest to scientists working in the fields of bat biology and collective behaviour. However, some aspects of the manuscript were found to lack clarity and concerns were raised about some of the assumptions underlying the parameters used for the simulations, which impact both the modeling results and the conclusions that can be made from the data.

eLife Assessment

In this article, García-Vázquez et al. report valuable findings demonstrating that G2 and S phases expressed protein 1 (GTSE1), is a previously unappreciated non-pocket substrate of the cyclin D/cyclin-dependent kinase (CDK) 4/6 axis. The authors provide convincing evidence showing that this mechanism is triggered in pathological states in which cyclin D levels are elevated (e.g., cancer). Overall, this study holds a promise to improve understanding of the mechanisms underpinning cell cycle progression including its dysregulation in neoplasia and may thus be of broad interest to researchers belonging to diverse biomedical disciplines ranging from cancer research to cell biology.

eLife Assessment

This is an important study demonstrating the importance of S100A4+ alveolar macrophages in the earlier stages of tumour development and suggesting a role in angiogenesis. As such this convincing study is of interest to cancer biologists focused on early tumour development and those interested in the development of therapeutics that may specifically target early cancers.

eLife Assessment

How misfolded proteins are segregated and cleared is a significant question in cell biology, since clearance of these aggregates can protect against pathologies that may otherwise arise. The authors discover a cell cycle stage-dependent clearing mechanism that involves the ER chaperone BiP, the proteosome, and CDK inactivation, but is curiously independent of the anaphase promoting complex (APC). These are valuable and interesting new observations, but the evidence supporting these claims is partially incomplete. New experiments and/or toning down the conclusions and highlighting what has not been learned may be appropriate and can then spur more work in the field.

eLife Assessment

Cardiolipin is known to play an important role in modulating the assembly and function of membrane proteins in bacterial and mitochondrial membranes. Here, authors convincingly define the molecular determinants of cardiolipin binding on de novo-designed and native membrane proteins combining the coarse-grained molecular dynamics simulation with the state-of-the-art experimental approaches such as native mass spectrometry and cryogenic electron microscopy. The major findings in this study, which are the identification of degenerate cardiolipin binding motifs, the characterization of their dynamic features, and the role in membrane protein stability and activity, will provide much needed insight into the still poorly understood nature of protein-cardiolipin interactions.

eLife Assessment

This important study provides insights into the role of maternal behavior in the learning and ontogeny of vocalization. It finds evidence that the maternal behavior of sac-winged bats (Saccopteryx bilineata) can influence the learned territorial songs of their pups. The behavioral analyses are convincing, using longitudinal acoustic recordings and behavioral monitoring of individual mother-pup pairs across development and multiple wild bat colonies. The work will be relevant to a broad audience interested in the evolution and development of social behavior as well as sensory-motor learning.

eLife Assessment

This valuable contribution to the field evaluated the function of the cytoskeletal protein ABBA in mediating key aspects of mitosis of neuronal precursor cells. The authors provide compelling evidence that ABBA interactions with its signaling partners is related to the development of at least some cases of microcephaly — a developmental anomaly associated with intellectual disability and other neurological findings.

eLife Assessment

This important Research Advance presents compelling evidence on the neuroprotective effects of reserpine in a well-established model of retinitis pigmentosa (P23H-1). This study builds on previous work establishing reserpine as a neuroprotectant in models of Leber congenital amaurosis. Here authors show reserpine's disease gene-independent influence on photoreceptor survival and emphasizes the importance of considering biological sex in understanding inherited retinal degeneration and the impact of drug treatments on mutant retinas. The work will be of interest to vision researchers as well as a broad audience in translational research.

eLife Assessment

In this valuable study, the authors integrate several datasets to describe how the genome interacts with nuclear bodies across distinct cell types and in Lamin A and LBR knockout cells. They provide convincing evidence to support their claims and particularly find that specific genomic regions segregate relative to the equatorial plane of the cell when considering their interaction with various nuclear bodies.

eLife Assessment

Using multiple techniques previously validated by the authors, this study identified INTS12, a component of the Integrator complex involved in 3' processing of small nuclear RNAs U1 and U2, as a factor promoting HIV-1 latency. The work is valuable, based on a sound strategy for screening targets to activate HIV latency and the solid mechanistic insights it provides on INTS12 repression of transcriptional elongation. Future studies are needed to explore INTS12 as a drug target against HIV/AIDS.

eLife Assessment

This valuable study investigates both online responses to, and offline replay of, visual motion sequences. Sophisticated EEG analyses provide convincing evidence for both feature-specific and non-specific sequence representations. These intriguing findings will be of interest to perception and learning researchers alike.

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.

eLife Assessment

In this important and compelling study, Sánchez-León et al. investigate the effects of tDCS on the firing of single cerebellar neurons in awake and anesthetized mice. They find heterogeneous responses depending on the orientation of the recorded Purkinje cell. The paper may well explain part of the controversial and ambiguous outcomes of various clinical trials.

eLife Assessment

This important study provides significant insights into the dynamics of attentional re-orienting within visual working memory, demonstrating how expected and unexpected memory tests influence attention focus and re-focus. The evidence supporting these conclusions is convincing, with the use of state-of-the-art methodologies. This work will be of interest to cognitive neuroscientists studying attention and memory.

eLife Assessment

This study by Li et al. presents important findings on the metabolism-independent role of nuclear IDH1 in chromatin regulation during erythropoiesis. The authors provide convincing evidence that IDH1 deficiency disrupts H3K79 methylation and nuclear architecture, contributing to dyserythropoiesis. Their findings offer invaluable mechanistic insights with potential therapeutic implications for erythroid disorders and hematologic malignancies.

eLife Assessment

This study provides a potentially useful investigation into the positive role of BDNF/TrkB signaling in implanted dental pulp stem cells to enhance dentin regeneration in the context of dental caries. Some of the key methods used need to be much better documented, and the data should be strengthened and added to in support of several of the claims of functional benefit, which are inadequately supported at present. Additional details for the validation of the reagents and techniques are needed to support the interpretation of the results.

eLife Assessment

The authors propose that the kinase MARK2 regulates the Golgi's reorientation towards the cell's leading edge through the regulation of microtubule binding protein CAMSAP2 and its binding to USO1. While the model is interesting and the study is useful, the quantification of an insufficient number of cells and insufficient description of the methods and biological replicates mean the results are inadequate to support the model.

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

eLife Assessment

This manuscript offers an exploration of the immune cells in the oyster Crassostrea gigas, by correlating distinct hemocyte morphotypes with specific single-cell transcriptional profiles. The evidence supporting the conclusion is convincing, deriving from the comprehensive dataset that not only captures unicellular diversity but also associates these cells with distinct immune roles, making it an important resource for the broader research community. There are some concerns on the data presentation that leave some questions.

eLife Assessment

Kin selection and inclusive fitness have generated significant controversy. While not entirely new, this paper reconsiders the general form of Hamilton's rule in which benefits and costs are defined as regression coefficients, with higher-order coefficients being added to accommodate non-linear interactions. The paper is a valuable contribution to the field with convincing, systematic analysis, giving clarity to long-standing debates.

eLife Assessment

This useful study employs AlphaFold2 to predict interactions among 20 nuage proteins, identifying five novel interaction candidates, three of which are validated experimentally through co-immunoprecipitation. Expanding the analysis to 430 oogenesis-related proteins and screening ~12,000 Drosophila proteins for interactions with Piwi, the study identifies 164 potential binding partners, demonstrating how computational predictions can streamline experimental validation. This study provides a solid basis for further investigations into eukaryotic protein interaction networks.

eLife Assessment

This study explores how complement protein C3 and its signalling may modulate immune training in alveolar macrophages. The findings are an important contribution to the field of trained immunity. The data presented is mainly solid, but incomplete in parts.

eLife Assessment

This study provides compelling evidence that kinesin's stepping mechanism is governed by strain-induced conformational changes in its nucleotide-binding pockets. Using pre-steady state kinetics and single-molecule assays, the authors demonstrate that the neck linker's conformation differentially modulates nucleotide affinity and detachment rates, establishing an asynchronous chemo-mechanical cycle that prevents simultaneous detachment. Supported by cryo-EM structural data, the work presents an important advance in our understanding of kinesin's hand-over-hand movement.

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

eLife Assessment

This valuable study tackles the well-established overflow metabolism issue by applying a coarse-grained metabolic flux model to predict how individual cells execute various energy strategies, such as respiration versus fermentation. The model's population average is convincing enough to align with experimental observations on overflow metabolism. The potential source of metabolic or proteomic heterogeneity of individual cells remains an open question to be studied. How individual cells adjust their metabolic strategies also requires future study of the underlying mechanisms. Overall, this work provides a key aspect on cell-to-cell variability on general metabolic response.

eLife Assessment

This valuable study uses state-of-the-art neural encoding and video reconstruction methods to achieve a substantial improvement in video reconstruction quality from mouse neural data, providing a convincing demonstration of how reconstruction performance can be improved by combining these methods. The findings showed that model ensembling and the number of neurons used for reconstruction were key determinants of reconstruction accuracy, but the theoretical contribution to understanding neural encoding was less clear. The treatment of how image masking improved reconstruction performance was also incomplete.

eLife Assessment

This manuscript provides valuable novel insights into the role of interpersonal guilt in social decision-making by showing that responsibility for a partner's bad lottery outcomes influences happiness. Through the integration of neuroimaging and computational modelling methods, and by combining findings from two studies, the authors provide solid support for their claims.

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. The manuscript could be further improved through appropriate revisions to data analysis and interpretation.

eLife Assessment

The manuscript by Mancl et al. provides valuable mechanistic insights into the conformational dynamics of Insulin Degrading Enzyme (IDE), a zinc metalloprotease involved in the clearance of various bioactive peptides. Supported by a convincing combination of cryo-EM, SEC-SAXS, enzymatic assays, and molecular dynamics simulations, the study characterizes the dynamic transitions between IDE's open and closed states in the presence of a sub-saturating concentration of insulin. This work contributes to a refined model of IDE's functional cycle, enhancing our understanding of its role in proteolysis.

eLife Assessment

The macromolecular organization of photosynthetic complexes within the thylakoids of higher plant chloroplasts has been a topic of significant debate. Using in situ cryo-electron tomography, this study reveals the native thylakoid architecture of spinach thylakoid membranes with single-molecule precision. The experimental methods are unique and compelling, providing important information for understanding the structural features that impact photosynthetic regulation in vascular plants and addressing several long-standing questions about the organization and regulation of photosynthesis.

eLife Assessment

This paper provides an important proposal for why learning can be much faster and more accurate if synapses have a fast component that immediately corrects errors, as well as a slower component that corrects behavior averaged over a longer timescale. It is convincingly shown that integrating these two learning timescales improves performance compared to classical strategies, particularly in terms of robustness and generalization when learning new target signals. However, the biological plausibility and justification for the proposed rapid learning mechanism require further elaboration and supporting mechanistic examples.

eLife Assessment

This work presents an important genetic toolkit for Drosophila neurobiologists to access and manipulate neuronal lineages during development and adulthood. The evidence supporting the fidelity of this toolkit is convincing. This work will interest Drosophila neurobiologists in general, and some of the genetic tools may be used outside the nervous system. The conceptual approaches used in this paper are likely transferable to other fields as comparable data and genomic methods are obtained.

eLife Assessment

This study introduces a useful toolkit for zebrafish transgenesis, significantly enhancing the flexibility and efficiency of transgene generation for immunological applications. The authors provide supporting evidence through well-designed experiments, demonstrating the toolkit's utility in generating diverse and functional transgenic lines. While the findings are solid, additional functional validation and broader comparisons to existing systems would strengthen the overall evidence base and ensure broader relevance to the zebrafish field, thereby increasing the significance of the study.

eLife Assessment

This manuscript introduces Opto-PKCε, an optogenetic tool that enabled important findings derived from interactome and phosphoproteome studies. Light-dependent recruitment of Opto-PKCε to the plasma membrane revealed the specific phosphorylation of the insulin receptor at Thr 1160. In turn, recruitment to mitochondria led to phosphorylation of the complex I subunit NDUFS4, correlating with reduced spare respiratory capacity. The evidence supporting these conclusions is solid, although additional clarification on data analysis would further enhance readability.

eLife Assessment

The study reports valuable findings on the nature of genotype-by-climate interaction, parameterised in a framework that allows integrating genetics and ecophysiological variation in switchgrass. The evidence provided is solid overall but the analysis could be improved to better support some of the claims.

eLife Assessment

This paper reports the fundamental finding of how Raman spectral patterns correlate with proteome profiles. The authors then go further to show that this can be used to infer global stochiometric regulation of the proteomes. These findings are likely general and the authors provide compelling evidence by analyzing bacterial and human cells but there are some suggestions provided below to make the work clearer and more accessible for it to reach a broader audience.

Editors Assessment:

As volumes of viral and bacterial sequence data grow exponentially, the field of computational phylogenetics now demands resources to manage the burgeoning scale of this input data. This study introduces CompactTree, a C++ library designed for ultra-large phylogenetic trees with millions of tips. To address these scalability issues while maintaining ease of incorporation into external code bases, CompactTree is a header-only library with enhanced performance utilizing minimal dependencies, optimized node representation, and memory-efficient tree structure schemes. Resulting in significantly reduced memory footprints and improved processing times. Peer review requested some more detail on the functionality and some real-world examples, demonstrating the current utility of the tool. Although primarily supporting the (text-based) Newick format, the increased and extensibility scalability holds promise for multiple biological and epidemiological applications supporting more complex formats such as Nexus and NeXML. The tool is open source (GPLv3 licensed) and available in GitHub: https://niema.net/CompactTree

This evaluation refers to version 1 of the preprint

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.