eLife Assessment

This manuscript provides a valuable in-depth biochemical analysis of p53 isoforms, highlighting their aggregation propensity, interaction with chaperones, and potential dominant-negative effects on p53 family members. The study presents solid evidence of isoform-specific properties, which may contribute to protein misfolding and impaired cellular function in cancer. While highly informative, the findings would benefit from further discussion of physiological relevance, given the high isoform expression levels used, and addressing prior evidence of isoform-specific transcriptional activity. Overall, this work significantly advances our understanding of p53 isoform biochemistry and its implications for cancer research.

eLife Assessment

This study examines age-related, sex-specific gene expression and alternative splicing in humans using the GTEx dataset. Solid evidence is provided to demonstrate that alternative splicing was affected by both sex and age across many tissues in this dataset. Although the authors performed comprehensive computational analyses with useful 'transcriptomic' changes with sex/age, they did not validate their findings with independent longitudinal datasets. This limits the wide impact of this study but can be used as a starting point to examine sex- and age differences in the transcriptome due to alternative splicing.

eLife Assessment

This useful study informs the transcriptional mechanisms that promote stem cell differentiation and prevent degeneration in the adult eye. Through inducible mouse mutagenesis, the authors uncover a dual role for a transcription factor (Sox9) in stem cell differentiation and prevention of retinal degeneration. The data at hand provide solid support to the main conclusions with several minor weaknesses identified as well. The study will be of general interest to the fields of neuronal development and neurodegeneration.

eLife Assessment

This study presents numerical results on a framework for understanding the dynamics of subthreshold waves in a network of electrical synapses modeled on the connectome data of the C elegans nematode. The strength of the evidence presented in favor of interference effects being a major component in subthreshold wave dynamics is inadequate and the approach is flawed. Substantial methodological issues are present, including altering the original network structure of the connectome without a clear justification and providing little motivation for the choice of numerical parameters values that were used.

eLife Assessment

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

eLife Assessment

The authors propose a new methodology to survey insects, using new sensors and analytical capabilities that could be valuable for addressing urgent conservation challenges. While the results of the optical sensors appear to be comparable to those obtained with classical survey methodologies, current analyses are considered incomplete.

eLife Assessment

This paper explores the important question of how two major inhibitory interneuron classes in the neocortex differentially affect cortical dynamics. Using a linearized fixed point approach, they provide convincing evidence that the existence of multiple interneuron classes can explain the counterintuitive finding that inhibitory modulation can increase the gain of the excitatory cell population while also increasing the stability of the circuit's state to minor perturbations. Support for the main conclusions is solid, but could be strengthened by additional analyses.

eLife Assessment

This useful manuscript presents findings on Tom1p's interaction with Spt6p and its role in chromatin dynamics, supported by structural analysis through CryoEM. The evidence for the conclusions is currently incomplete, lacking key experiments including continuation in vivo interaction and orthogonal binding assays (e.g., SPR, MST, ITC) to fully support the proposed mechanism. While the results are promising, further validation is needed to strengthen the evidence and improve the manuscript's overall cohesion.

eLife Assessment

By combining the 'pinging' technique with fMRI-based multivariate decoding, this important study examined the nature of the representation of the attentional template during preparation. While the findings are very interesting and the experimental evidence is solid, the methodological (e.g., the manipulation of attention, the potential cross-contamination between attention and working memory, and the representational distance analysis) and interpretation confounds (e.g., more thorough clarification of "pinging" and dual-format attentional templates) need to be addressed. The work will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife Assessment

What makes one member of the species behave differently from another? This is a core problem in behavioral neuroscience. This valuable study seeks an answer for the specific case of the fruit fly expressing preferences for one odor over another. By a combination of behavioral measurements, neurophysiology, and network modeling, the authors find solid evidence for at least one locus of individuality in the peripheral olfactory system.

eLife Assessment

This important study confirms the molecular function of putative components of the N-glycan-dependent endoplasmic reticulum protein quality control (ERQC) system in the pathogen Cryptococcus neoformans. The study demonstrates an involvement in fitness, virulence, and the secretion and composition of extracellular vesicles, albeit in ways that are not yet fully understood. The evidence provided is largely convincing, with rigorous well-controlled assays and the use of complemented strains.

eLife Assessment

This study provides valuable evidence for the mechanism underlying KCNC1-related developmental and epileptic encephalopathy. The authors have generated and characterized a new knock-in mouse with a pathogenic mutation found in patients to determine the synaptic and circuit mechanisms contributing to KCNC1-associated epilepsy. They provide convincing evidence for reduced excitability of parvalbumin-positive fast-spiking interneurons, but not in neighboring excitatory neurons, and suggest that this may contribute to seizures and premature death in the mice.

eLife Assessment

This important study by Bi and colleagues employed a clever genetics screen to uncover the role of the GidB rRNA methylase in translation fidelity, under certain conditions, in Mycobacterium smegmatis. The findings are solid, supporting the conclusions, but the structural analyses lack the necessary rigor and depth to provide a clear mechanism. The work will be of interest to microbiologists.

eLife Assessment

The study follows up on previous work suggesting that lower glucose concentrations are protective from sepsis but put the patient at risk for hypoglycemia. In this paper, the authors identify that a slightly higher dose of glucose is still protective but no longer puts the patients at risk for hypoglycemia. The study is important, supported by convincing data, and will be of interest to a broad audience.

eLife Assessment

In this important study, significant advancements are made in how cell division in Chlamydia trachomatis, lacking FtsZ, is mediated. With the careful use of fluorescence microscopy and genetic tools, the evidence identifying the DNA translocase, FtsK, as an early and essential component of the divisome, is convincing. As this role is distinct from what has been found in most other bacteria, this study will be of broad interest to microbiologists and molecular biologists.

eLife Assessment

This valuable study uses steered molecular dynamics simulations to interrogate force transmission in the mechanosensitive NOMPC channel, which plays roles including soft-touch perception, auditory function, and locomotion. The finding that the ankyrin spring transmits force through torsional rather than compression forces may help understand the entire TRP channel family. The evidence is, however, considered to be still incomplete. It could be strengthened by testing how the channel responds to different twisting and compressional force magnitudes over longer simulation times to see a full gating motion, or to prove that the partial or initial motion observed relates to physiological gating. Experimental validation of reduced mechano-sensitivity through mutagenesis of proposed ankyrin/TRP domain coupling interactions would be best to enhance the manuscript.

eLife Assessment

Maloney et al. offer an important contribution to understanding the potential ecological mechanisms behind individual behavioral variation. By providing compelling theoretical data and convincing experimental data, the study bridges the gap between individual, apparently stochastic behavior with its evolutionary purpose and consequences. The work further provides a testable and generalizable model framework to explore behavioral drift in other behaviors.

eLife Assessment

The results by Zhu et al provide valuable insights into the representation of border ownership in area V1. They used neuropixel recording to demonstrate the clustering of border ownership, and compared cross-correlation functions between neurons in different layers to demonstrate that they depend on the type of stimulus. The strength of the evidence is solid but can be improved by performing additional analyses and accounting for the differences in classical and non-classical receptive field stimulation conditions.

eLife Assessment

This study provides valuable insights into the differential impact of intrinsic and synaptic conductances on circuit robustness, emphasizing intrinsic plasticity as a crucial but often overlooked factor in neural dynamics. Although the findings are solid and underscore the significance of intrinsic factors, they are limited by the simplified model and the potential confounding effects of drastic intrinsic perturbations on single-neuron activity. Further refinements would help validate the generality of these conclusions across diverse networks and functions.

eLife Assessment

This important study highlights a critical challenge to a great many studies of the neural correlates of consciousness that were based on post hoc sorting of reported awareness experience. The evidence supporting this criticism is convincing, based on simulations and decoding analysis of EEG data. The results will be of interest not only to psychologists and neuroscientists but also to philosophers who work on addressing mind-body relationships.

eLife Assessment

In this important study, Li et al. identify estrogen receptor 1-expressing neurons (ESR1+) in Barrington's nucleus as key regulators coordinating both bladder contraction and the relaxation of the external urethral sphincter. Using appropriate and validated methodologies aligned with the current state of the art, the data are convincing and of generally high quality.

eLife Assessment

This work presents important findings regarding the interaction of the monkeypox virus (MPXV) attachment H3 protein with the cellular receptor heparan sulfate and the use of this information to develop antivirals potentially effective against all orthopoxviruses. Using a combination of state-of-the art computational and wet experiments the authors present convincing evidence to sustain their claims. These results will interest those working on basic orthopoxviruses biology and antiviral development.

eLife Assessment

This fundamental work provides evidence that glutamate and GABA are released from different synaptic vesicles at supramammillary axon terminals onto granule cells of the dentate gyrus. The study uses complementary electrophysiological and anatomical experimental approaches. Together, these provide convincing evidence that the co-release of glutamate and GABA from different vesicles within the same terminal could modulate granule cell firing in a frequency-dependent manner, although thorough elimination of alternative mechanisms would have strengthened the study. The work will be of interest to neuroscientists investigating co-release of neurotransmitters in various synapses in the brain and those interested in subcortical control of hippocampal function.

eLife Assessment

The presented soft tissue data of pterosaur tail vanes represent a valuable contribution to ongoing research efforts to decipher the flight abilities of pterosaurs in the fields of paleontology, comparative biomechanics, and bioinspired design. The new methods are compelling and give new detail on tail morphology, with a potential to resolve how pterosaurs were able to control and maintain tail stiffness to furnish flight control.

eLife Assessment

In this important work, Lodhiya et al. provide evidence that excessive ATP underlies the killing of the model organism Mycobacterium smegmatis by two mechanistically-distinct antibiotics. The data are generally solid as the authors deploy multiple, orthogonal readouts and methods for manipulating reactive oxygen species and ATP. The work will be of interest to those studying antibiotic mechanisms of action.

eLife Assessment

In this important study the authors develop an elegant lung metastasis mouse model that closely mimics the events in human patients. They provide convincing evidence for the effectiveness of IL-15/12-conditioned NK cells in this design, which was also critical for the authors being able to conclusively reveal the T cell-dependency of NK-cell-mediated long-term control of experimental metastasis. Of note, an investigator-initiated clinical trial demonstrated that similar NK cell infusions in cancer patients after resections were safe and showed signs of efficacy, which is of promising clinical application value.

eLife Assessment

This important study presents work on the molecular mechanism driving asymmetric cell division and fate decisions during embryonic development of echinoids. The evidence supporting the claims of the authors is convincing. The work will be of interest to developmental biologists and cell biologists working in the field of self-renewal.

eLife Assessment

This manuscript offers valuable insights by identifying two distinct liver cancer subtypes through multi-omics integration and developing a robust prognostic model, validated across various datasets, including single-cell RNA sequencing. The evidence is solid, with comprehensive validation in both internal and independent cohorts; however, the reliance on computational methods highlights the necessity for further experimental validation to fully confirm the mechanistic insights.

eLife Assessment

The paper illustrates a valuable approach to generating TCR transgenic mice specific for known epitopes. Solid evidence validates the described pipeline for identification of TCRs from single-cell datasets for the generation of TCR transgenic mice, while obviating the need for generation of T-cell lines and hybridomas.

eLife Assessment

This useful study examines how deletion of a major DNA repair gene in bacteria may facilitate the rise of mutations that confer resistance against a range of different antibiotics. Although the phenotypic evidence is intriguing, the interpretation of the phenotypic data presented and the proposed mechanism by which these mutations are generated are incomplete, relying on untested assumptions and methodology that merits optimization. For instance, the authors cannot fully rule out the possibility that the resistance mutations are the result of selection. Nevertheless, this work could be of interest to microbiologists studying antibiotic resistance, genome integrity, and evolution, but the significance remains uncertain.

eLife Assessment

The authors analyze the relationship between human mobility and genomic data of SARS-CoV-2 using mobile phone mobility data and sequence data and present a solid proof of concept. This useful work was conducted on a fine spatial scale and provides suggestions on how mobility-derived surveillance could be conducted, although these results are mixed. The primary significance of this work is the strong use of large datasets that were highly granular. The authors provide a rigorous study, but with less clear predictive power of mobility to inform transmission patterns.

eLife Assessment

In their important manuscript, Costa et al. establish an in vitro model for dorsal root ganglion (DRG) axonal asymmetry, revealing that central and peripheral axon branches have distinct patterns of microtubule populations that are linked to their differential regenerative capacities. The authors employ creative tissue culture methods to demonstrate how these branches develop uniquely in vitro, offering a potential explanation for long-observed regeneration disparities. The evidence provides a solid contribution to our understanding of the neuronal cytoskeleton and axonal regeneration, but the paper would benefit from additional methodology details and controls.

eLife Assessment

This important study reports new insights into the roles of a long noncoding RNA, lnc-FANCI-2, in the progression of cervical cancer induced by a type of human papillomavirus. Through a blend of cell biological, biochemical, and genetic analyses of RNA and protein expression, protein-protein interaction, cell signaling, and cell morphology, the authors provide convincing evidence that lnc-FANCI-2 affects cervical cancer outcome by regulating the RAG signaling pathway. These findings will be of interest to scientists in the fields of cervical cancer, long noncoding RNA, and cell signaling.

eLife Assessment

This valuable study proposes a novel rapid-entry mechanism of S. aureus that involves the rapid release of calcium from lysosomes. The strength of the paper lies in a very interesting hypothesis; what diminishes enthusiasm is the lack of appropriate methodology, thus making the study incomplete. The methods used are deficient: they are largely reliant on the use of chemical inhibitors and do not adequately support the conclusions.

eLife Assessment

In this potentially important study, the authors employed advanced computational techniques to explore a detailed atomistic description of the mechanism and energetics of substrate translocation in the MelB transporter. The overall approach is solid and reveals the coupling between sodium binding and melibiose transport through a series of conformational transitions, and the results for a mutant are also in qualitative agreement with the experiment, providing further support to the computational analyses. Nevertheless, the level of evidence is considered incomplete since there are concerns regarding the convergence and initial guess of the string calculations, leaving doubts that the computed pathway does not reflect the most energetically favorable mechanism.

eLife Assessment

This fundamental work provides new mechanistic insight in regulation of PDGF signaling through splicing controls. The evidence is compelling to demonstrate functional involvement of Srsf3, an RNA binding protein to this new and interesting mechanism. The work will be of broad interest to developmental biologists in general and molecular biologists/biochemists in the field of growth factor signaling and RNA processing.

eLife Assessment

This valuable manuscript presents a spatiotemporal genetic analysis of malaria-infected individuals from four villages in The Gambia, covering the period between December 2014 and May 2017. Overall, laboratory and data analyses are solid, although details of the methods are lacking. This study offers evidence to advance the understanding of malaria epidemiology in sub-Saharan Africa, but would benefit from additional analysis to strengthen the findings.

eLife Assessment

This manuscript describes a novel magnetic steering technique to target human adipose derived mesenchymal stem cells (hAMSC) or induce pluripotent stem cells to the TM (iPSC-TM). The authors demonstrate the valuable findings that delivery of the stem cells compared to baseline lowered IOP, increased outflow facility, and increased TM cellularity. Although the methods, data, and analysis are solid, there is an overall weakness in the experimental controls, and questions around the transgenic mouse model. If these issues are addressed, the manuscript will be significantly improved.

eLife Assessment

In this potentially valuable study, the authors employed in vivo experiments and theoretical modeling to study the growth dynamics of nuclear condensates. They observed that condensates can exhibit distinct growth modes, as dictated by the competition between condensate surface tension and local elasticity of chromatin. While the theoretical model appears to capture the experimental observations, the level of evidence supporting the proposed growth mechanism is incomplete due to, among other limitations, the multiple fitting parameters and poorly justified Neo-Hookean elasticity.

eLife Assessment

This study presents important advances in the discovery and assessment of microcins that improve our understanding of their prevalence and roles. The bioinformatics analysis, expression, and antimicrobial assays are solid, although the diverging evaluations also indicated the need for additional support regarding the sequence analysis and validation to fully back some of the claims and conclusions. This study will appeal to researchers working on the discovery and analysis of novel peptide natural products.

eLife Assessment

Ulcerative colitis (UC) is a chronic gut inflammatory condition affecting the colon in humans. This study uses human samples as well as a mouse model of colitis induced by a chemical, DSS, to investigate the role of an immune marker, CD131, in UC pathogenesis. The study, as presented, is incomplete, as experimental details are lacking, the statistical analyses are deficient, and there is not yet direct evidence for a CD131-mediated mechanism of gut inflammation.

eLife Assessment

This important paper reports functional interactions between L1TD1, an RNA binding protein (RBP), and its ancestral LINE-1 retrotransposon which is not modulated at the translational level. The evidence for the association between L1TD1 and LINE-1 ORF1p is solid. The work implies that the a transposon-derived RNA binding protein in the human genome can interact with the ancestral transposable element from which this protein was initially derived. This work spurs interesting questions for cancer types, where LINE1 and L1TD1 are aberrantly expressed.

eLife Assessment

This study presents a valuable methodological advancement in quantifying thoughts over time. A novel multi-dimensional experience-sampling approach is presented, identifying data-driven patterns that the authors use to interrogate fMRI data collected during naturalistic movie-watching. The experimentation is inventive and the analyses carried out and results presented are convincing.

eLife Assessment

Rachubinski and colleagues provide an important manuscript that includes two major advances in understanding immune dysregulation in a large cohort of individuals with Down syndrome. The work comprises compelling, comprehensive, and state-of-the-art clinical, immunological, and autoantibody assessment of autoimmune/inflammatory manifestations. Additionally, the authors report promising results from a clinical trial with the JAK inhibitor tofacitinib for individuals with dermatological autoimmune disease.

eLife Assessment

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

eLife Assessment

This important study offers insights into the function and connectivity patterns of a relatively unknown afferent input from the endopiriform to the CA1 subfield of the ventral hippocampus, suggesting a neural mechanism that suppresses the processing of familiar stimuli in favor of detecting memory guided novelty. The strength of evidence is solid, with careful anatomical and electrophysiological circuit characterization. The work will be of broad interest to researchers studying the neural circuitry of behavior.

eLife Assessment

This important work presents two studies on predictive processes in subjects with and without tinnitus. The evidence supporting the authors' claims is compelling, as their second study serves as an independent replication of the first. Rigorous matching between study groups was performed, especially in the second study, increasing the probability that the identified differences in predictive processing can truly be attributed to the presence of tinnitus. This work will be of interest to researchers, especially neuroscientists, in the tinnitus field.

eLife Assessment

This is a potentially important study on interpretation of protein coding genetic variation in CDKN2A. The presentation of the data has improved, revealing that the experimental design is flawed and concerns that the data that are not robust enough to support the major claim of supporting clinical variant interpretation for CDKN2A. This work, while incomplete, will serve as a resource for diagnostic labs as well as cancer geneticists.

eLife Assessment

This work presents a valuable exploration of AI-assisted protein engineering, particularly in designing a VHH antibody with enhanced resistance and stability to extreme environments. However, the approach is weakened by incomplete support, with computational methods and experimental design appearing somewhat arbitrary and lacking clear justification. Further justification of the chosen methods and clearer exposition would strengthen the study's support and conclusions.

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 include the use of formaldehyde crosslinking and tagged H1.8 which might affect the structures obtained; and the NPM2 work could be better incorporated into the main findings. Overall this is an important new tool in the arsenal of single molecule biologists, permitting a deep dive into structure of native complexes. This work will be of high interest to a broad swathe of scientists studying native macromolecules present at low concentrations in cells.

eLife Assessment

This interesting study presents valuable information on how human cytomegalovirus (HCMV) infection disrupts the activity of the TEAD1 transcription factor, leading to widespread chromatin alterations. However, the precise mechanisms underlying this disruption and the extent to which these chromatin changes influence HCMV replication remain unclear. The study is supported by solid evidence, which would be made stronger by including functional analyses. This work will be of interest to virology, chromosome biology and transcriptional co-regulation fields.

eLife Assessment

This study examines the impact of DNA methylation on CTCF binding in two cancer cell lines. Increased CTCF binding sites are enriched in gene bodies, and associate with nuclear speckles, indicating a potential role in increased transcription. However, the association with nuclear speckles needs to be more diligently demonstrated. Thus the strength of the evidence is considered incomplete. This work would be made more valuable to the community if these claims were buttressed by additional evidence and a deeper discussion of new findings in the light of previous relevant literature. This work will be of interest to the chromosome biology/epigenetics field.

eLife Assessment

This is an important study that reports the mechanism by which Ankle2 (LEM4 in humans) interacts with and recruits PP2A and the ER protein Vap33 to promote BAF dephosphorylation and mediate nuclear membrane reformation, using Drosophila as their model. Using Ankle2 mutants, they find that the ER protein Vap33 is key for the normal interphase localisation of Ankle2/LEM4 and also impacts on the function of Ankle2/LEM4 during mitosis. The authors use a variety of complementary techniques and provide convincing evidence to support the claims. The conclusions about the subcellular localization of Ankle2 might be incomplete since they are drawn from overexpression experiments.

eLife Assessment

This valuable study reports the first characterization of the CG14545 gene in Drosophila melanogaster, which the authors name "Sakura." Acting during germline stem cell fate and differentiation, Sakura is required for both oogenesis and female fertility. The evidence supporting the claims of the authors is solid, but the manuscript would be strengthened by a more in-depth investigation into the cause-and-effect relationships for the different defects observed.

eLife Assessment

This useful study presents findings on how some antibiotics, which inhibit protein synthesis in bacteria, affect the translation in mitochondrial ribosomes. The authors provide solid evidence that most tested antibiotics act similarly on bacterial and mitochondrial translation. Additionally, this work shows that alternative translation initiation events might exist in two specific mt-mRNAs (MT-ND1 and MT-ND5). The conclusions of this manuscript are of broad interest to the antibiotic and the mitochondrial fields.

eLife Assessment

The authors studied the relationship between structural and functional lateralization in the planum temporale region of the brain, whilst also considering the morphological presentation of a single or duplicated Heschl's gyrus. The analyses are compelling due to a large sample size, inter-rater reliability, and corrections for multiple comparisons. The associations in this important work might serve as a reference for future targeted-studies on brain lateralization.

eLife Assessment

This study investigates the molecular mechanisms underlying chronic pain-related memory impairment by focusing on S1P/S1PR1 signaling in the dentate gyrus (DG) of the hippocampus. Through behavioral tests (Y-maze and Morris water maze) and RNA-seq analysis, the researchers discovered that S1P/S1PR1 signaling is crucial for determining susceptibility to memory impairment, with decreased S1PR1 expression linked to structural plasticity changes and memory deficits. This work has important significance and a convincing level of evidence, thus offering new insights into the mechanisms underlying chronic pain-related memory impairment.

eLife Assessment

This important work investigates how orientation signals detected in higher brain areas may be transformed into motor responses in behaving animals. The authors characterize two types of descending neurons (DNs) that connect the brain to motor units and are involved in different aspects of turning control. They further show that orientation signals act by preferentially increasing relative stimulation onto left- or right-turn-inducing DNs. These convincing results, together with the independent work that they have inspired, represent significant progress in our understanding of mechanisms of animal navigation.

eLife Assessment

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

eLife Assessment

This valuable study investigates the oscillatory activity of gonadotropin-releasing hormone (GnRH) neurones in mice using GCaMP fiber photometry. It demonstrates three distinct patterns of oscillatory activity that occur in GnRH neurons comprising low-level rapid baseline activity, abrupt short-duration oscillations that drive pulsatile gonadotropin secretion, and, in females, a gradual and prolonged oscillating increase in activity responsible for the relatively short-lived preovulatory LH surge. The evidence presented in the study is solid, offering theoretical implications for understanding the behaviour of GnRH neurones in the context of reproductive physiology, and will be of interest to researchers in neuroendocrinology and reproductive biology.

eLife Assessment

This important study presents genome-wide high-resolution chromatin-based 3D genomic interaction maps for over 50 diverse human cell types and integrates these data with pediatric obesity GWAS. The work provides convincing evidence that multiple pancreatic islet cell types are key effector cell types. The authors also perform variant-to-gene mapping to nominate genes underlying several GWAS hits. Overall, the results will be of interest to both the fields of 3D genome architecture and pediatric obesity.

eLife Assessment

This study's findings substantially advance our understanding of an important aspect of mitochondrial metabolism. The data are compelling and the study is well executed. The work is relevant to all who are interested in the biogenesis of mitochondria.

eLife Assessment

This valuable study investigates the signaling pathways regulating retina regeneration. Solid evidence shows that the sphingosine-1-phosphate (S1P) signaling pathway is inhibited following retinal injury. Small-molecule activators and inhibitors support a model in which S1P signaling must be inhibited to generate Müller glia progenitor cells-a key step in retinal regeneration. The presented results support the major conclusions. However, the methodology concerning drug treatments is unclear, and the conceptual innovation is, to some extent, incremental.

eLife Assessment

This is a useful contribution to our understanding of taste perception. The idea that specific receptors function in the pharynx to mediate responses to carboxylic acids is interesting, although the expression analysis is incomplete. Reviewers also have a number of other suggestions for improvement, including the request that authors provide more details about the methodology used. In general, the claims are supported by solid evidence and add to a growing body of literature on this topic.

eLife Assessment

This important work advances our understanding of the impact of malnutrition on hematopoiesis and subsequently infection susceptibility. Support for the overall claims is convincing in some respects and incomplete in others as highlighted by reviewers. This work will be of general interest to those in the fields of hematopoiesis, malnutrition, and dietary influence on immunity.

eLife Assessment

Through cellular, developmental, and physiological analysis, this valuable study identifies a gene that regulates the relative growth of roots and shoots under salt stress. The holistic approach taken provides solid evidence that this member of a larger tandemly duplicated gene family together with an upstream regulator contributes to salt tolerance, although the statistical or biological support for some conclusions could be more robust. The manuscript will be of interest to plant biologists studying mechanisms of abiotic stress tolerance and gene family evolution.

eLife Assessment

This study provides a valuable new resource to investigate the molecular basis of the particular features characterizing the pipefish embryo. The authors found both unique and shared gene expression patterns in pipefish organs compared with other teleost fishes. The solid data collected in this unconventional model organism will give new insights into understanding the extraordinary adaptations of the Syngnathidae family and will be of interest in the domain of evolution of fish development.

eLife Assessment

This important study investigates how working memory load influences the Stroop effect from a temporal dynamics perspective. Solid evidence is provided that the working memory load influences the Stroop effect in the late-stage stimulus-response mapping instead of the early sensory stage. This study will be of interest to both neuroscientists and psychologists who work on cognitive control.

eLife Assessment

This study presents useful albeit preliminary findings on transcriptome changes in cardiac lymphatic cells after myocardial infarction in mice. Despite revision, the conclusions of the authors remain uncertain as sample sizes in general are very low, and even sometimes too low to allow for valid statistical comparisons. Accordingly, there are concerns regarding statistical robustness, raised by both the editors and the reviewers. While the single-cell transcriptomic data were analyzed using solid advanced methodology, too few cells were included in the scRNA-seq data set and the spatial transcriptomics analyses. Thus, this study rather represents more a collection of preliminary transcriptomic data than a full scientific report that would definitively advance the field.

eLife Assessment

This important study presents a series of results aimed at uncovering the involvement of the endosomal sorting protein SNX4 in neurotransmitter release. While the evidence supporting the conclusions is solid, the molecular mechanisms remain unclear. This paper will be of interest to cell biologists and neurobiologists.

eLife Assessment

This manuscript provides fundamental studies to help us better understand the effects of mutations in the presenilin-1 (PSEN1) gene on proteolytic processing of the amyloid precursor protein (APP). The authors provide compelling evidence using mutations in PSEN to understand what drives alternative substrate turnover with conclusive data and rigorous analysis. This deep mechanistic study provides a framework towards the development of small molecule inhibitors to treat Alzheimer's disease.

eLife Assessment

This valuable study provides a novel method to detect sleep cycles based on variations in the slope of the power spectrum from electroencephalography signals. The method, dispensing with time-consuming and potentially subjective manual identification of sleep cycles, is supported by solid evidence and analyses. This study will be of interest to researchers and clinicians working on sleep and brain dynamics.

eLife Assessment

This important study investigates how working memory load influences the Stroop effect from a temporal dynamics perspective. Convincing evidence is provided that the working memory load influences the Stroop effect in the late-stage stimulus-response mapping instead of the early sensory stage. This study will be of interest to both neuroscientists and psychologists who work on cognitive control.

eLife Assessment

This study uses carefully designed experiments to generate a useful behavioural and neuroimaging dataset on visual cognition. The results provide solid evidence for the involvement of higher-order visual cortex in processing visual oddballs and asymmetry. However, the evidence provided for the very strong claims of homogeneity as a novel concept in vision science, separable from existing concepts such as target saliency, is incomplete. The authors and the reviewers do not agree on several points, which are explained in the reviews and author response.

eLife Assessment

This important study enhances our understanding of ephaptic interactions by utilizing earthworm recordings to refine a general model and use it to predict ephaptic influences across various synaptic configurations. The integration of experimental evidence, a robust mathematical framework and computer simulations convincingly demonstrates the effects of action potential propagation and collision properties on nearby membranes. The study will interest both computational neuroscientists and physiologists.

eLife Assessment

This paper represents a "classic" approach towards evaluating a novel taste stimulus in an animal model, including standard behavioral tests (some with nerve transections), taste nerve physiology and immunocytochemistry of the tongue. The stimulus being tested is ornithine, from a class of stimuli called "kokumi", which enhance other canonical tastes, increasing their hedonic attributes; the mechanism for ornithine detection is thought to be GPRC6A receptors expressed in taste cells. The authors showed evidence for this in an earlier paper with mice; this paper evaluates ornithine taste in a rat model. This work is valuable but incomplete.

eLife Assessment

This study proposes an important new approach to analyzing cell-count data that are often undersampled and cannot be correctly assessed with traditional statistical analyses. The presented case studies provide convincing evidence of the superiority of the proposed methodology to existing approaches, which could promote the use of Bayesian statistics among neuroscientists. However, the generalizability of the methodology to other data types is not fully evidenced.

eLife Assessment

This study utilizes an elegant approach to examine valence encoding of the mesolimbic dopamine system. The findings are valuable, demonstrating differential responses of dopamine to the same taste stimulus according to its valence (i.e., appetitive or aversive) and in alignment with distinct behavioral responses. The evidence supporting the claims is convincing, resulting from a well-controlled experimental design with minimal confounds and thorough reporting of the data.

eLife Assessment

In this paper, the authors use single-cell RNA sequencing to understand post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastoma genesis. The work is important and the evidence is generally convincing. The findings of rod/cone fate determination at a very early stage are intriguing.

eLife Assessment

This important study addresses how DNA replication restarts in Escherichia coli in the absence of a functional replication initiator protein DnaA. The authors show that helicase DnaB loading at the replication origin oriC can be executed by PriC under sub-optimal initiation conditions. While the genetic and biochemical evidence is solid, there is so far no direct evidence for PriC acting at oriC in vivo.

eLife Assessment

This is a useful report of a spatially-extended model to study the complex interactions between immune cells, fibroblasts, and cancer cells, providing insights into how fibroblast activation can influence tumor progression. The model opens up new possibilities for studying fibroblast-driven effects in diverse settings, which is crucial for understanding potential tumor microenvironment manipulations that could enhance immunotherapy efficacy. While the results presented are solid and follow logically from the model's assumptions, some of these assumptions may require further validation, as they appear to oversimplify certain aspects in light of complex experimental findings, system geometry, and general principles of active matter research.

eLife Assessment

This study provides valuable advances in our understanding of how inputs from multiple sources can impact the physiology of motor neurons during the process of multisensory integration. Specifically, the authors show how streams of auditory and principally visual information modulate the physiology of Mauthner neurons in goldfish, thus allowing the different senses to influence escape behavior. Supporting evidence is generally convincing, although material reporting the direct control of behavior is less representative of the data.

eLife Assessment

This study provides an important advancement of knowledge by showing neural functional compensation in the brains of healthy older adults completing a fluid-intelligence task. Validated whole-brain voxel-wide analyses and multivariate Bayesian approaches provide compelling evidence that supports the claims of the authors. The work delivers methods for quantifying reserve and compensation in future studies and will be of interest to researchers in the field of the neuroscience of healthy aging.

eLife Assessment

This manuscript reports a detailed model of juvenile rat somatosensory cortex, consisting of 4.2 million morphologically and biophysically detailed neuron models, arranged in space and connected according to diverse experimental data - a valuable tool for the field. The construction of the model is based on a methodology with solid supporting evidence. It should be noted that, by necessity, such a large-scale model development involves many assumptions, interpolations, and decisions that could have compounding downstream effects on further analyses that may be difficult to disambiguate.

eLife Assessment

This work is potentially important and largely convincing given the state-of-the-art approaches used to unravel the mechanism underlying the release of Claudins via Rho-mediated activation of Matriptase during tight junction formation. However, there are a few concerns. Addressing the following two major concerns a) showing Matriptase is indeed activated and b) Matriptase inhibition does not interfere with keratinocyte specification, would significantly improve the strength of the evidence. In addition, including quantifications, missing methods, and improving the rigor of the analyses would be helpful.

eLife Assessment

The ingenious design in this study achieved the observation of 3D cell spheroids from additional lateral view and gained more comprehensive information than the traditional one angle of imaging. This extended the methods to investigate cell behaviors in the growth or migration of tumor organoids in a time-lapse manner and these extensions should be valuable to the field. The authors provide solid evidence that the methods work as described.

eLife Assessment

In this valuable study, the authors used an elegant genetic approach to delete EED at the post-neural crest induction stage. The usage of the single-cell RNA-seq analysis method is extremely suitable to determine changes in the cell type-specific gene expression during development. Results backed by solid evidence demonstrate that Eed is required for craniofacial osteoblast differentiation and mesenchymal proliferation after the induction of the neural crest.

eLife Assessment

This study introduces an important approach using selection linked integration (SLI) to generate Plasmodium falciparum lines expressing single, specific surface adhesins PfEMP1 variants, enabling precise study of PfEMP1 trafficking, receptor binding, and cytoadhesion. By moving the system to different parasite strains and introducing an advanced SLI2 system for additional genomic edits, this work provides compelling evidence for an innovative and rigorous platform to explore PfEMP1 biology and identify novel proteins essential for malaria pathogenesis including immune evasion.

eLife Assessment

This is a study that makes the important finding that pleiotropy is positively associated with parallelism of evolutionary responses in gene expression, while theory would predict the opposite. The analysis uses a state-of-the-art experimental evolution approach to study the genetic basis of adaptation of Drosophila simulans to a hot environment. The experimental data is relevant and its analysis is robust, however, this paper appears to conflate gene expression variation and its underlying causative variation, in both its data interpretation and theoretical framework. This leads to incomplete conclusions on the causal link between pleiotropy and genetic variation and their role during adaptation.

eLife Assessment

Liang et al. have conducted a small pilot study investigating the feasibility and tolerability of a regimen of neoadjuvant chemo-immunotherapy for non-small cell lung cancer; with lower cumulative dose of chemotherapy and with the immunotherapy delivered on D8 of each cycle. The clinical data are interesting and novel, and overall the findings of the study are valuable. However, the translational data and analyses are incomplete and do not support key claims in the title.

eLife Assessment

This valuable study is a detailed investigation of how chromatin structure influences replication origin function in yeast ribosomal DNA, with a focus on the role of the histone deacetylase Sir2 and the chromatin remodeler Fun30. The paper shows that Sir2 does not affect origin licensing but rather affects local transcription and nucleosome positioning which correlates with increased origin firing. Overall, the evidence is convincing and the model is plausible.

eLife Assessment

This paper aims to understand why prostate cancer with CDK12 loss does not respond to HRd-based therapeutics, such as PARP inhibitors. The work is felt to be fundamental given a thorough computational and genomic analysis, the generation of CDK12-adapted cell lines, and potential synthetic vulnerability to CDK13 loss with genetic knockdown or co-inhibition with a CDK12/13 inhibitor. The evidence is compelling given the authors' systematic testing of components of the CDK12/13 pathways in a number of prostate cancer models. Some weaknesses focused on the functional effect of the various mutations found at different CDK12 sites (loss vs. altered), more comprehensive characterization of CDK12 KO lines, and specificity of the CDK12/13 inhibitor and in vivo experimental schema.

eLife Assessment

This is an important study showing that age-related gut microbiota modulate uric acid metabolism through the NLRP3 inflammasome pathway and thereby regulate susceptibility to age-related gout. Several experimental approaches (mechanistic insights) and methods (data quality) remain incomplete. This paper should be of interest to researchers working on gout and microbiota.

eLife Assessment

The aim of this important study is to identify novel genes involved in sleep regulation and memory consolidation. It combines transcriptomic approaches following memory induction with measurements of sleep and memory to discover molecular pathways underlying these interlinked behaviors. The authors explore transcriptional changes in specific mushroom body neurons and suggest roles for two genes involved in RNA processing, Polr1F and Regnase-1, in the regulation of sleep and memory. Their findings offer convincing evidence that the expression of RNA processing genes is modulated during sleep-dependent memory, with Polr1F potentially contributing to increased sleep.

eLife Assessment

This is a fundamental study into human spinal neurulation, which substantially advances our understanding of human neural tube closure. Crucial unanswered questions in the field currently rely on model systems, not faithful to human development. The evidence provided is compelling, with a large number of specimens and the rigorous use of state-of-the-art methodology providing robustness. The work will be of broad interest to developmental biologists, embryologists, and medical professionals working on neural tube defects, and will act as a precious reference resource for future studies.

eLife Assessment

This article uncovers a new important role of STAMBPL1 in promoting angiogenesis in triple-negative breast cancer (TNBC) and elucidates the specific mechanisms by which it activates the GRHL3/HIF1α/VEGFA axis through interaction with FOXO1. The finding that STAMBPL1 mediates GRHL3 transcription through the interaction with FOXO1 is novel. These experimental results corroborate each other, forming a solid foundation of evidence that supports the main findings of the article.

eLife Assessment

This valuable study investigates the development of high-level visual responses in infants, finding that neural responses specific to faces are present by 4-6 months but not earlier. The study is methodologically convincing, using state-of-the-art experimental design and analysis approaches. The findings would be of broad interest to the cognitive neuroscience and developmental psychology research communities.

eLife Assessment

The authors provide convincing data that identify a novel, non-opioid biologic from human birth tissue products with anti-nociceptive properties in a preclinical mouse model of surgical pain. This important study highlights the potential use of naturally derived biologics from human birth tissues as safe and sustainable pain treatment options that do not possess the adverse side effects associated with opioids and synthetic pharmaceuticals. Whether these results will translate to the clinic remains to be seen, nevertheless, these preclinical findings are promising.

eLife Assessment

The work presented is important for our understanding of the development of the cardiac conduction system and its regulation by T-box transcription factors. The conclusions are supported by convincing data. Overall this is an excellent study that advances our understanding of cardiac biology and has implications beyond the immediate field of study.

eLife Assessment

Sanchez-Vasquez et al establish an innovative approach to induce aneuploidy in preimplantation embryos. This important study extends the author's previous publications evaluating the consequences of aneuploidy in the mammalian embryo. In this work, the authors investigate the developmental potential of aneuploid embryos and characterize changes in gene expression profiles under normoxic and hypoxic culture conditions. Using a solid methodology they identify sensitivity to Hif1alpha loss in aneuploid embryos, and in further convincing experiments they assess how levels of DNA damage and DNA repair are altered under hypoxic and normoxic conditions.

eLife Assessment

This study provides important findings in characterizing dopamine neuron heterogeneity in the ventral midbrain. The strength of evidence is strong for a convincing classification, but claims related to the effects of G2019S-LRRK2 expression were considered more preliminary. The creation of an snRNA-seq exploration tool for these datasets should interest groups interested in understanding dopamine neuron subclass dynamics in behavior and diseases.

eLife Assessment

This potentially valuable study investigates the interaction of two integral membrane proteins (Cdhr1a and Pcdh15b) and their roles in cone-rod dystrophy. Convincing evidence using loss-of-function mutants demonstrates that both proteins are required for cone maintenance and survival. There is insufficient evidence to support the subcellular localization and the proposed heterodimeric interaction of the two proteins from distinct subcellular compartments. The methodologies are unclear, and the statistical methods and analysis are improperly applied.

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 deep mechanistic insights it provides on INTS12 repression of transcriptional elongation. While the work is solid, authors must address minor weaknesses, including assessing knockdown efficiency and validating the target by examining the impact on cell viability and latency-reversing activity in combination with LRAs other than AZD5582 & I-BET151.

Editors Assessment:

Due to them being found in the landlocked, isolated habitat of Lake Baikal makes the Baikal Seal (Pusa sibirica) unique among all pinnipeds as the only freshwater seal. This paper presents reference-based assemblies of six newly sequenced Baikal seal individuals, one individual of the ringed seal, as well as the first short-read data of the harbor seal and the Caspian seal . This data aiding the study of the genomic diversity of the Baikal seal and to contribute baseline data to the limited genomic data available for seals. Peer review extended the description of the used tools and parameters in the revised manuscript, and provided some more information on the methods..This newly generated sequencing data hopefully now helps to extend the phylogeny of the Phoca/Pusa group on genome-wide data and can also broaden the view into the genetic structure and diversity of the Baikal seal

This evaluation refers to version 1 of the preprint

Editors Assessment:

The article presents strategies for accelerating sequence alignment using multithreading and SIMD (Single Instruction, Multiple Data) techniques, and introduces a new algorithm called TSTA (Thread and SIMD-Based Trapezoidal Pairwise/Multiple Sequence-Alignment). The Technical Release write-up presenting a detailed description of TSTA's performance in pairwise sequence alignment (PSA) and multiple sequence alignment (MSA), and compares it with various existing alignment algorithms. Demonstrating the performance gains achieved by vectorized SIMD technology and the application of threading. Testing and debugging a few errors, and adding some more background detail, demonstrating it can achieve faster comparison speed. Demonstrating TSTA's efficacy in pairwise sequence alignment and multiple sequence alignment, particularly with long reads, and showcasing considerable speed enhancements compared to existing tools.

This evaluation refers to version 1 of the preprint

eLife Assessment

This is a convincing paper that addresses topics important in our understanding of how inflammatory markers are modulated in both obesity and type 2 diabetes and their effects on Wnt signaling mediators in human bone. There are changes in bone at the tissue level in these 2 common metabolic disorders that ultimately lead to compromised bone strength. These data will be critical to our understanding of the pathophysiology of skeletal fragility in obesity and diabetes.

eLife Assessment

This valuable study examines the effects of side-wall confinement on the chemotaxis of swimming bacteria in a shallow microfluidic channel. The authors present solid experimental evidence, combined with geometric analysis and numerical simulations of simplified models, showing that chemotaxis is enhanced when the distance between the side walls is comparable to the intrinsic radius of circular swimming near open surfaces. This study should be of interest to scientists specializing in bacteria-surface interactions.

Editors Assessment:

The crested gecko (Correlophus ciliatus), is a lizard species endemic to New Caledonia, and a potentially interesting model organism due to its unusual (for a gecko) inability to regenerate amputated tails. With that in mind here is presented a new reference genome for the species, assembled using PacBio Sequel II platform and Dovetail Omni-C libraries. Producing a genome with a total size of 1.65 Gb, 152 scaffolds, a L50 of 6, and N50 of 109 Mb. Peer review making sure more detail was added on data acquisition and processing to enhance reproducibility. In the end producing potentially useful data for studying the genetic mechanisms involved in loss of tail regeneration.

This evaluation refers to version 1 of the preprint

Editors Assessment:

This paper presents the SMARTER database, a collection of tools and scripts to gather, standardize, and share with the scientific community a comprehensive dataset of genomic data and metadata information on worldwide small ruminant populations. Which has come out of the EU multi-actor (12 country) H2020 project called SMARTER: SMAll RuminanTs breeding for Efficiency and Resilience. This bringing together genotypes for about 12,000 sheep and 6,000 goats, alongside phenotypic and geographic information. The paper providing insight into how the database was put together, presenting the code for the SMARTER—frontend, backend and API, alongside instructions for users. Peer review tested the platform and provided suggestions on improving the metadata. Demonstrating the project provides valuable information on sheep and goat populations around the world, that can be an essential tool for ruminant researchers. Enabling them to generate new insights and offer the possibility to store new genotypes and drive progress in the field.

This evaluation refers to version 1 of the preprint

Editors Assessment:

This paper presents NucBalancer, a R-pipeline and Shiny app designed for the optimal selection of barcode sequences for sample multiplexing in sequencing. Providing a user-friendly interface aiming to make this process accessible to both bioinformaticians and experimental researchers, enhancing its utility in adapting libraries prepared for one sequencing platform to be compatible with others. Important now with the introduction of additional sequencing platforms by Element Biosciences (AVITI System) and Ultima Genomics (UG100) increasing the diversity and capability of genomic research tools available. NucBalancer’s incorporation of dynamic parameters, including customizable red flag thresholds, allows for precise and practical barcode sequencing strategies. This adaptability is key in ensuring uniform nucleotide distribution, particularly in MGI sequencing and single-cell genomic studies, leading to more reliable and cost-effective sequencing outcomes across various experimental conditions. All the code is available under an open source license, and upon review the authors have also shared the code for the Shiny app.

This evaluation refers to version 1 of the preprint

论文提出了一种名为RepoUnderstander的新颖方法，该方法指导代理通过以下几个步骤来全面理解整个代码仓库：

• 构建代码仓库知识图谱：通过自上而下的方式将整个仓库的关键信息压缩成知识图谱，以降低仓库的复杂性。
• 基于蒙特卡洛树搜索的仓库探索策略：赋予代理理解整个仓库的能力，通过模拟多种路径并评估它们的奖励分数，逐步缩小搜索空间，引导代理关注最相关的区域。
• 信息利用与补丁生成：指导代理总结、分析和规划，然后操作工具动态获取信息并生成解决现实世界GitHub问题的补丁。

eLife Assessment

This manuscript offers a modeling platform in which horizontal gene transfer (HGT) is incorporated into the ecological dynamics of microbial communities. The investigation is valuable as it brings to the forefront a potentially significant process and highlights its implications. However, the investigation in its current form is incomplete because it is based on a narrow range of parameters and assumptions. As a result, the scope and relevance of the findings are not fully clear. A more in-depth description of model assumptions and the formulation structure and a more thorough analysis of the impact of different parameters would strengthen the manuscript. This work will be of interest to microbiologists as well as researchers in ecological and evolutionary biology.

eLife Assessment

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

eLife Assessment

This manuscript provides important structural insights into the recognition and degradation of the host tRNA methyltransferase TRMT1 by SARS-CoV-2 protease nsp5 (Mpro). The data provide compelling support for the main conclusions of the authors. These results will be of interest to researchers studying structures, substrate recognition and specificity of viral proteases and their action on cellular targets.

eLife Assessment

This study provides valuable insights into the cellular responses to complex aneuploidy in human preimplantation embryos. The evidence supporting the claims of the authors is now convincing after addressing previous concerns. This work will be of interest to embryologists, geneticists and scholars working on reproductive medicine by increasing our understanding of how human embryos respond to chromosomal abnormalities.

eLife Assessment

This work introduces an important new method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, demonstrating its applicability for studying heterogeneity in microbial biofilms. The findings provide convincing evidence for a distinct subpopulation of cells at the biofilm base that upregulates PdeI expression. Future studies exploring the functional relationship between PdeI and c-di-GMP levels, along with the roles of co-expressed genes within the same cluster, could further enhance the depth and impact of these conclusions.