eLife Assessment

This work presents a valuable resource combining scRNA-seq and spatial transcriptomics studies to map mouse pre-clinical models of colorectal cancer, identifying distinct cellular programs and microenvironments that could enhance patient stratification and therapeutic approaches in colorectal cancer. While the evidence provided in the manuscript are not fully validated, these solid data were collected and analyzed using a validated methodology that will be of interest to the community in future studies.

eLife Assessment

In this valuable study, Taber et al. used a battery of biophysical and structural approaches to characterize the impact of erythrocytosis-related mutations in prolyl hydroxylase domain protein 2 (PHD2). The authors show that PHD2 mutant proteins are destabilized, thus supporting the tenet that dysregulation of PHD2/hypoxia induced factor (HIF) axis underpins erythrocytosis, while providing solid evidence that N-terminal ODD prolyl hydroxylation of HIF is indispensable for these phenotypes. These findings were found to be of interest for researchers focusing on oxygen sensing in homeostasis and pathological states.

eLife Assessment

This study presents a valuable and interesting finding that a combination of arginine methyltransferase inhibitors synergize with PARP inhibitors to eliminate ovarian and triple negative cancer cell lines in vitro and in vivo using preclinical mouse models. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for the development of novel therapeutics. The work will be of broad interest to scientists working in the field of breast cancer and ovarian cancer.

eLife Assessment

This valuable study provides a comprehensive description of the Nematostella vectensis matrisome - the genes encoding the proteins of the extracellular matrix. The authors combine new mass spectrometry data with bioinformatic analyses of previously published genomic and single-cell RNAseq data. The analysis is thorough, and the discussion and conclusions are convincing. This work will be of interest to biologists working on the evolution of the matrisome, as well as more broadly those working with non-bilaterian animals.

eLife Assessment

This fundamental work demonstrates that compartmentalized cellular metabolism is a dominant input into cell size control in a variety of mammalian cell types and in Drosophila. The authors show that increased pyruvate import into the mitochondria in liver-like cells and in primary hepatocytes drives gluconeogenesis but reduces cellular amino acid production, suppressing protein synthesis. The evidence supporting the conclusions is compelling, with a variety of genetic and pharmacologic assays rigorously testing each step of the proposed mechanism. This work will be of interest to cell biologists, physiologists, and researchers interested in cell metabolism, and is significant because stem cells and many cancers exhibit metabolic rewiring of pyruvate metabolism.

eLife Assessment

This study presents a screen for small-molecule activators of the kinase GCN2 that phosphorylates the eukaryotic translation initiation factor 2 alpha (eIF2α) in response to diverse stress stimuli. Among the compounds identified, one stands out as a potent activator that functions independently of GCN1, which is important for probing mechanisms of Integrated Stress Response regulation and may have translational relevance in the context of pathogenic GCN2 mutations. While some reviewers found the biochemical analyses convincing, others viewed the cellular evidence as limited, particularly with respect to time points, endogenous readouts, and broader cell-type validation, which prevents a clear assessment of the compound's potential potency in a physiological context.

eLife Assessment

This fundamental work substantially advances our understanding of tissue deformation and growth patterns during the earliest stages of mammalian heart development. One of the strengths of the work is the compelling quantitative approach to analyzing time-lapse imaging data using an original computational pipeline, which goes beyond the current state of the art and provides new insights into heart tube formation. Overall, this rigorous study will be of broad interest to computational and developmental biologists studying tissue dynamics.

eLife Assessment

This work presents valuable new data on the role of D-Serine and how it competes with its stereoisomer L-Serine to influence metabolism. The work presents a variety of solid experimental data combined with simulated results to investigate the mechanisms focused on one-carbon metabolism, which is relevant for several research fields. However, some claims are only partially supported by data, and critical areas comparing L- vs D-Serine and further mechanistic studies are incomplete. Furthermore, while the work has potential for various fields, the work has only been studied in a limited cell type and context.

eLife Assessment

Plasmodesmata are channels that allow cell-cell communication in plants; based on the functional similarities between facilitated transport within plasmodesmata and into the nucleus, the authors speculate that nuclear pore complex proteins might be involved in plasmodesmata function. If supported, this would transform our understanding of cell-to-cell communication in plants. The authors localize nuclear pore complex proteins to plasmodesmata using proteomics and heterologous overexpression; however, the data are incomplete since key controls for localization, functionality, and expression level of fluorescent protein fusions are absent.

eLife Assessment

This important study demonstrates the potential of synthetic gene circuits to detect and target aberrant RAS activity in cancer cell lines. The circuit design is novel and the evidence supporting the claims is convincing. As a proof-of-concept, this will be of broad interest to researchers in synthetic biology and therapeutics development, while future work will be required to help translate this technology toward clinical applications in cancer therapeutics and address potential limitations of the strategy.

eLife Assessment

This study constitutes a fundamental advance for the uveal melanoma research field that might be exploited to target this deadly cancer and, more generally, for targeting transcriptional dependency in cancers. This work substantially advances our understanding of pharmacological inhibition of SWI/SNF as a therapeutic approach for cancer. The study is well written and provides compelling evidence, including comprehensive datasets, compound screens, gene expression analysis, epigenetics, as well as animal studies.

eLife Assessment

The is a valuable evaluation of a previously published simulation model on the role of heterozygote advantage in shaping MHC diversity, showing that the conclusions from this model hold only within a narrow parameter range that might be unrealistic. The author presents an alternative model, in which MHC homozygotes with duplicated MHC genes outperform heterozygotes with single genes, thereby challenging the explanation that heterozygote advantage will lead to high allelic variation at a given MHC gene. The topic is highly relevant for eco-immunology and evolutionary genetics, but several major aspects of the author's claim need to be clarified to make the model interpretable. While the work has the potential to improve our understanding of the question of how the extraordinary diversity at the MHC locus evolves, without this addition, the conclusions remain incomplete.

eLife Assessment

This valuable study reveals that the GSK-3 inhibitor AZD2858 inhibits the formation of TOPBP1 condensates and hence DNA damage responses in colorectal cancer cells. The evidence supporting the claims of the authors is convincing, although uncovering how this drug blocks bio-condensate formation would have strengthened the study. The work will be of interest to cancer researchers searching for synergistic drug combination strategies.

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

eLife Assessment

This study reports the important finding that the dynamin inhibitor Dyngo-4a broadly affects lipid packing and plasma membrane dynamics, independently of its action on dynamin. While solid computational, biophysical, and cell-based evidence supports this conclusion, there is incomplete support for the authors' main claim on the role of lipid packing in caveolae internalization, as the causal relationship remains unclear and direct analyses are lacking. With stronger evidence, this work would be of significant interest to cell biologists, biophysicists, and chemists interested in membrane remodeling and drug-membrane interactions.

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

eLife Assessment

This manuscript describes a novel method for determining the mechanical parameters of the kinesin, KIF1A, that uses fluorescence microscopy and does not require an optical tweezer apparatus. The length of a tethered fluorescent DNA nanospring is measured as the kinesin moves processively along the microtubule and then stalls. The work reports important findings, and (barring a few exceptions) the evidence supporting the claims is generally convincing.

eLife Assessment

This paper presents valuable findings on how autophagosomes are positioned along microtubules for their efficient fusion with lysosomes, providing significant insights into the mechanism. The evidence supporting the conclusions is solid, with high-quality fluorescence microscopy combined with Drosophila genetics. This work will be of broad interest to cell biologists interested in autophagy and related cell biology fields.

eLife Assessment

This is an important study that utilizes proteomic and genetic approaches to identify the glycoprotein quality control factor malectin as a pro-viral host protein involved in the replication of coronavirus. The evidence supporting this conclusion is convincing, although continued elucidation of the mechanistic basis of malectin-mediated viral replication would further strengthen these findings. This work will be of interest to cell biologists studying the molecular mechanisms of glycoprotein quality control and virologists studying the host-pathogen interactions.

eLife Assessment

The paper is a fundamental study examining the role of CDK12 loss in prostate cancer. While previous studies have suggested that CDK12 loss confers HRD phenotypes, clinical trials using PARPi in CDK12 altered patients have not demonstrated significant benefit. This work investigates these mechanisms in depth and provides compelling evidence. A comprehensive genomic analysis serves an excellent resource to the field, showing that biallelic CDK12 alterations do not have genomic features of HRd. Moreover, the study explored both acute and chronic deletion of CDK12, with data suggestive of CDK12-altered cells being uniquely sensitive to CDK13 inhibition. While some minor weaknesses have been previously noted by the reviewers, the authors have adequately addressed these concerns with appropriate rigor.

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 convincingly support to the main conclusions. The study will be of general interest to the fields of neuronal development and neurodegeneration.

eLife Assessment

Shen et al. present a computational account of individual differences in mouse exploration when faced with a novel object in an open field from a previously published study (Akiti et al.) that relates subject-specific intrinsic exploration and caution about potential hazards to the spectrum of behaviors observed in this setting. Overall, this computational study is an important contribution that leverages a very general modeling framework (a Bayes Adaptive Markov Decision Process) to quantify and interrogate distinct drivers of exploratory behavior under potential threat. Given their assumptions, the modeling results are convincing: the authors are able to describe a substantial amount of the behavioral features and idiosyncracies in this dataset, and their model affords a normative interpretation related to inherent risk aversion and predation hazard "flexibility" of individual animals and should be of broad interest to researchers working to understand open-ended exploratory behaviors.

eLife Assessment

The manuscript by Li and coworkers analyzed astrocytic differentiation of midbrain floor plate-patterned neural cells originating from human iPS cells, with a LMX1A reporter. This valuable work identifies transcriptomic differences at the single-cell level, between astrocytes generated from LMX1A reporter positive or negative cells, as well as non-patterned astrocytes and neurons. The evidence is solid, but the paper can be strengthened by further analyses of the transcriptomic data, and astrocytic morphology; also, searching for some of the differentially expressed genes by immunohistochemistry in different regions of the mammalian brain, or in human specimens, would be very informative.

eLife Assessment

This manuscript reports valuable results on the role of MDC1 and Treacle in DSB repair in rDNA repeats. It has been previously established that MDC1 is replaced by Treacle as the main adaptor in the nucleolar DNA damage response. This work provides convincing evidence that MDC1 is required for the recruitment of RAD51 and BRCA1 to DSBs in rDNA. The work involves multiple MDC1 knockout models and establishes that RFN8-RNF168 act downstream of MDC1 in the recruitment of the HR machinery to nucleolar DSBs.

eLife Assessment

In this important work, the authors present a new transformer-based neural network designed to isolate and quantify higher-order epistasis in protein sequences. They provide solid evidence that higher-order epistasis can play key roles in protein function. This work will be of interest to the communities interested in modeling biological sequence data and understanding mutational effects.

eLife Assessment

This manuscript uses simulations to describe the dynamics of the Pseudomonas-derived cephalosporinase PDC-3 β-lactamase and its mutants to better understand antibiotic resistance. The finding that clinically observed mutations alter the flexibility of the Ω- and R2-loops, reshaping the cavity of the active site, is useful to the field. However, the evidence is considered incomplete; there is a lack of description of methods, and there is a need for additional analysis to demonstrate statistical significance, visualisation of the Markov states, analysis to explain changes due to the different mutations, and possible simulations in the presence of substrates to shed direct light on modulation mechanisms.

eLife Assessment

This manuscript employs cryo-EM, mutational analysis, and biochemical assays to explore the molecular basis by which glutamine promotes filamentation and regulates the activity of human glutamine synthetase (hGS) by stabilizing interactions between hGS decamers. The studies supporting this mechanism are solid, but could be improved by providing more clarity and by addressing methodological issues in the cryoEM data processing workflow. This work will be of particular interest and useful to groups interested in understanding the molecular basis of nutrient sensing, cellular metabolism, and structural regulation of enzyme activity.

eLife Assessment

This valuable work explores the timely idea that aperiodic activity in human electrophysiology recordings is dynamically modulated in response to task events in a manner that may be relevant for behavioral performance. Moreover, the authors present solid evidence that, in some circumstances, these aperiodic changes might be misinterpreted as oscillatory changes.

eLife Assessment

To evaluate phenotypic correlations between complex traits, this study aimed to measure the genetic overlap of traits by evaluating GWAS signals assisted by eQTL signals. They suggested an improved version of the previous Sherlock to integrate SNP-level signals into gene-level signals. Then they compared 59 human traits to identify known and novel genetic distance relationships. This work is valuable to the field, but still needs substantial improvement because many parts of the paper are incomplete.

eLife Assessment

In this manuscript, the authors investigate the migration of human cortical interneurons under hypoxic conditions using forebrain assembloids and developing human brain tissue, and probe the underlying mechanisms. The study provides the first direct evidence that hypoxia delays interneuron migration and identifies adrenomedullin (ADM) as a potential therapeutic intervention. The findings are important, and the conclusions are convincingly supported by experimental evidence.

eLife Assessment

This study provides novel and fundamental insights into the long-term use of DREADDs to modulate neuronal activity in nonhuman primates. The exceptional evidence demonstrates the peak dynamics and the subsequent stability of chemogenetic effects for 1.5 years, informing the experimental designs and the interpretation of highly impactful chemogenetic studies in macaques. The protocols, data, and outcomes can serve as guidelines for future experiments. Therefore, the findings will be of significant interest to the field of chemogenetics and may also be of broader interest to researchers and clinicians who seek to utilize viral vectors and/or related genetic technologies.

eLife Assessment

This study presents an important finding on the role of GATA4 in aging- and OA-associated cartilage pathology. The conclusions are well supported by compelling in vitro and in vivo evidence. This work will be of broad interest to both cell biologists and orthopedic/skeletal health clinicians.

eLife Assessment

This is a useful tool for code-less analysis of patterns in cell migratory behaviours in vivo using intravital microscopy data and allows correlation with spatial features of the tumour microenvironment. There is a clear need for these tools to make quantitative analysis, comparison and interpretation of complex cell tracking data more accessible and solid evidence is provided of its applicability to tracks generated by both proprietary and open tracking software.

eLife Assessment

This 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 valuable finding that the ankyrin spring transmits force through torsional rather than compression forces may help understand the entire TRP channel family. The evidence is considered to be solid, although full opening of the channel is not seen, and it has been noted that experimental validation of reduced mechanosensitivity through mutagenesis of proposed ankyrin/TRP domain coupling interactions would help substantiate the findings.

eLife Assessment

This important study examined the complexity of emergent dynamics of large-scale neural network models after perturbation (perturbational complexity index, PCI) and used it as a measurement of consciousness to account for previous recordings of humans at various anesthetized levels. The evidence supporting the conclusion is convincing and constitutes a unified framework for different observations related to consciousness. There are many fields that would be interested in this study, including cognitive neuroscience, psychology, complex systems, neural networks, and neural dynamics.

eLife Assessment

This useful study examines the contribution of synaptotagmin 1 and synaptotagmin 7 to metabolite antigen presentation to mucosal-associated invariant T (MAIT) cells; it begins to address a critical gap in our understanding of the antigen presentation mechanisms to these cells. Strengths of the study include the use of Mtb to study the dynamics of antigen presentation to MAIT cells instead of a synthetic antigen. However, the strength of the evidence to support the conclusion is currently incomplete. The conclusions could be enhanced by additional dissection of some of the cell biological events that lead to antigen presentation by MR1.

eLife Assessment

This important study shows how hunger alters avoidance of harmful heat in C. elegans by reconfiguring the activity of key sensory neurons. The evidence is convincing, with well-designed behavioural, genetic, and imaging experiments that support the main conclusions. The work will be of interest to neuroscientists studying how internal states shape sensory processing and behaviour across species.

eLife Assessment

This study presents a valuable quantitative framework for analyzing transcription dynamics data for enhancers and genes expressed in the early Drosophila embryo. By analyzing existing data across both synthetic reporters and an endogenous gene (eve), this work provides evidence that spatial gene expression patterns within the embryo are largely determined by "activity time" - the time during which a gene is bursting. The methods and evidence are solid and should be of broad interest to researchers in developmental biology and quantitative gene regulation, but the study would be significantly enhanced by clarifying the novelty of the findings relative to prior work and presenting a rigorous benchmarking of their algorithm against previously used algorithms.

eLife Assessment

There is a growing interest in understanding the individuality of animal behaviours. In this important article, the authors build and use an impressive array of high throughput phenotyping paradigms to examine the 'stability' (consistency) of behavioural characteristics in a range of contexts and over time. The results show that certain behaviours are individualistic and persist robustly across external stimuli while others are less robust to these changing parameters. The data supporting their findings is extensive and convincing.

eLife Assessment

This valuable study analyzes aging-related chromatin changes through the lens of intra-chromosomal gene correlation length, which is a novel computational metric that captures spatial correlations in gene expression along the chromosome. The authors propose that this metric reflects chromatin structure and can serve as a proxy for its changes during aging. While currently the strength of evidence is somewhat incomplete, if revised with further supporting data, this work will provide a systems-level understanding of aging and genome regulation, which is predicted to have a substantive impact on the field.

eLife Assessment

This study presents a new toolbox for Representational Similarity Analysis, representing a valuable contribution to the neuroscience community. The authors offer a well-integrated platform that brings together a range of state-of-the-art methodological advances within a convincing framework, with strong potential to enable more rigorous and insightful analyses of neural data across multiple subfields.

eLife Assessment

This important study uses advanced computational methods to elucidate how environmental dielectric properties influence the interaction strengths of tyrosine and phenylalanine in biomolecular condensates. The evidence supporting the claims of the authors is convincing, as the simulations are performed rigorously providing mechanistic insights into the origin of the differences between the two aromatic amino acids considered. This study will be of broad interest to researchers studying biomolecular phase separation.

eLife Assessment

This valuable study reports evidence that items maintained in working memory can bias attention in an oscillatory manner, with the attentional capture effect fluctuating at theta frequency. The study provides incomplete evidence that this dynamic attentional bias is associated with oscillatory neural mechanisms, particularly in the alpha and theta bands, as measured by EEG. The study will be relevant for researchers studying attention, working memory, and neural oscillations, particularly those interested in how memory and perception interact over time.

eLife Assessment

Marshall et al describe the effects of altering metabotropic glutamate receptor 5 activity on activity of D1 receptor expressing spiny projection neurons in dorsolateral striatum focusing on two states - locomotion and rest. The authors examine effects of dSPN-specific constitutive mGlu5 deletion in several motor tests to arrive at this finding. Effects of inhibiting the degradation of the endocannabinoid 2-arachidonoyl glycerol are also examined. Overall, this is a valuable study that provides solid new information of relevance to movement disorders and possibly psychosis.

eLife Assessment

The important paper presents a new behavioral assay for Drosophila aggression and demonstrates that social experience influences fighting strategies, with group-housed males favoring high-intensity but low-frequency tussling over aggressive lunging observed in isolated males. The experiments are solid and the conclusions are of interest to researchers studying the impact of social isolation on aggression.

eLife Assessment

This fundamental work provides novel insights into the blood flow-dependent mechanisms of neuronal migration and the role of Gherlin signaling in the adult brain. The authors present convincing evidence that newborn rostral migratory stream (RMS) neurons are closely situated alongside blood vessels, preferentially along arterioles, and that migratory speed is correlated with blood flow. They also provide evidence (in vitro and some in vivo) that Ghrelin from blood is involved in augmenting RMS neuron migration speed.

eLife Assessment

This important work begins to understand how BDNF regulates the phosphorylation and activity of LRRK2. The overall strength of evidence has been assessed as compelling, though some claims are only partially supported. The work will be of interest for those that might pursue specific LRRK2 interactions and mutational effects on these pathways as the work continues to develop.

eLife Assessment

This manuscript presents a valuable and insightful contribution to the understanding of how Legionella pneumophila remodels its vacuolar niche through coordinated ubiquitination mechanisms. The identification of Rab5 as a target of both canonical and phosphoribosyl ubiquitination, and the demonstration of a detergent-resistant ubiquitin "cloud" surrounding the LCV, represent significant advances in the field. The findings are supported by rigorous experimental design, robust quantitative analyses, and clear mechanistic insight, meeting a standard of evidence that is compelling and exceeds current state-of-the-art approaches.

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 important study provides a novel approach for delineating subcortical-cortical white matter bundles. The authors provide convincing evidence by harnessing state-of-the-art methods and cross-species data. Together, this effort will be of interest to scientists across multiple subfields and accelerate progress in a biologically critical but methodologically challenging area.

eLife Assessment

This valuable study presents an analysis of evolutionary conservation in intrinsically disordered regions, identified as key drivers of phase separation, leveraging a protein language model. The strength of evidence is convincing, but a clearer justification of the methods and analyses is needed to fully support the main claims.

eLife Assessment

This Review Article takes an original angle and covers several aspects of the leukocytes extravasation process with a focus on the role of ECM proteins. It is a timely piece with an original viewpoint. The current manuscript would benefit from improvement in writing and organization.

eLife Assessment

This important study explored a number of issues related to citations in the peer review process. An analysis of more than 37000 peer reviews at four journals found that: i) during the first round of review, reviewers were less likely to recommend acceptance if the article under review cited the reviewer's own articles; ii) during the second and subsequent rounds of review, reviewers were more likely to recommend acceptance if the article cited the reviewer's own articles; iii) during all rounds of review, reviewers who asked authors to cite the reviewer's own articles (a practice known as 'coercive citation') were less likely to recommend acceptance. However, when an author agreed to cite work by the reviewer, the reviewer was more likely to recommend acceptance of the revised article. The evidence is convincing, but article would benefit from a clearer presentation of the results and a more nuanced discussion of the motivations of reviewers.

eLife Assessment

This is a useful study, describing transcriptome-based PPGL subtypes and exploring the mutations, immune correlates, and disease progression of cases in each subtype. The cohort is a reasonable size, and a second cohort is included from TCGA. The identification of driver mutations in PPGL is incomplete, and this compromises characterisation for prognostic purposes. This is a reasonable starting point from which to further elucidate PPGL subtypes.

eLife Assessment

This valuable study presents an analysis of evolutionary conservation in intrinsically disordered regions, identified as key drivers of phase separation, leveraging a protein language model. The strength of evidence presented is convincing overall, though the theoretical grounding could benefit from further development.

eLife Assessment

This investigation presents a valuable contribution by elucidating the genetic determinants of growth and fitness across multiple clinical strains of Mycobacterium intracellulare, an understudied non-tuberculous mycobacterium. Employing transposon sequencing (Tn-seq), the authors identify a core set of 131 genes essential for bacterial viability, offering a solid foundation for anti-mycobacterial drug discovery. However, there are minor but nonetheless significant concerns about data organization, which need to be addressed for greater scientific impact.

eLife Assessment

This important study provides evidence supporting the idea that postnatal experience plays an instructive role in shaping the patterns of functional connectivity between extrastriate visual cortex and frontal regions during development, by comparing neonates, blind and sighted adults. The evidence supporting the authors' claim is solid. Nevertheless, substantial weaknesses remain in mechanistic interpretation and alignment with relevant developmental frameworks. This study will be of significant interest to neuroscientists and neuroimaging researchers focused on vision, plasticity and development.

eLife Assessment

This important study highlights the novel role of RSPO mimetic SZN-043 in the activation of hepatic WNT signaling and promoting hepatocyte regeneration. The authors provide convincing evidence of SZN-043 increasing hepatocytes proliferation in various mouse models, including a humanized mouse liver model, ALD model and CCL4 fibrosis model. This study will be of interest to researchers in liver regeneration and repair mechanisms.

eLife Assessment

This study presents a valuable finding that the blood-brain barrier (BBB) may be modulated through specific modes of electroacupuncture stimulation. The data were collected and analyzed using a solid and validated methodology, and can be used as a starting point for functional studies of the BBB for drug delivery across healthy and diseased states. The work will be of broad interest to scientists working in the field of drug delivery and drug development.

eLife Assessment

This valuable study explores the role of the chromatin regulator ATAD2 in mouse spermatogenesis. It convincingly demonstrates that ATAD2 is essential for proper chromatin remodeling in haploid spermatids, influencing gene accessibility, H3.3-mediated transcription, and histone eviction. Using Atad2 knockout (KO) mice, the authors link ATAD2 to the DNA-replication-independent incorporation of sperm-specific proteins like protamines and histone H3.3. Although the findings highlight chromatin abnormalities and impaired in vitro fertilization in KO mice, natural fertility remains unaffected, suggesting possible in vivo compensatory mechanisms. However, in its current form, the study lacks mechanistic insight and provides only partial evidence for ATAD2's molecular role, limiting its functional conclusions.

eLife Assessment

This useful work identifies new monoclonal antibodies produced by cystic fibrosis patients against Pseudomonas aeruginosa type three secretion system. The evidence supporting authors' claim is solid. Nonetheless, the manuscript may benefit from a more in depth description of what the authors learned from their structure-based analyses of antibodies targeting PcrV.

eLife Assessment

This study makes the valuable claim that people track, specifically, the elasticity of control (that is, the degree to which outcome depends on how many resources - such as money - are invested), and that control elasticity is impaired in certain types of psychopathologies. A novel task is introduced that provides solid evidence that this learning process occurs and that human behavior is sensitive to changes in the elasticity of control. Evidence that elasticity inference is distinct from more general learning mechanisms and is related to psychopathology remains incomplete.

eLife Assessment

This study provides valuable insights with solid evidence into altered tactile perception in a mouse model of ASD (Fmr1 mice), paralleling sensory abnormalities in Fragile X and autism. Its main strength lies in the use of a novel tactile categorization task and the careful dissection of behavioral performance across training and difficulty levels, suggesting that deficits may stem from an interaction between sensory and cognitive processes. However, while the experiments are well executed, the reported effects are subtle and sometimes non-significant. The interpretation of results may be over-extended given the nature of the data (solely behavioral) and the absence of mechanistic, causal, or computational approaches limits the strength of the broader conclusions. The work will be relevant to those interested in autism, cognition, and/or sensory processing.

eLife Assessment

This important study reports an endometrial organoid culture system mimicking the window of implantation. The evidence supporting the conclusion drawn is convincing. The data will be of interest to embryologists and investigators working on reproductive biology and medicine.

eLife Assessment

This study presents a valuable finding on whether executive resources mediate the impact of language predictability in reading in the context of aging. The presentation of evidence is incomplete; further conceptual clarifications, methodological details, and addressing potential confounds would strengthen the study. The work will be of interest to cognitive neuroscientists working on reading, language comprehension, and executive control.

eLife Assessment

This study used a conditional knockout mouse line to remove Ptbp1 in retinal progenitors and showed that its deletion has no effect on retinal neurogenesis or cell fate specification, thereby challenging the prevailing view of Ptbp1 as a master regulator of neuronal fate. The findings are convincing, supported by transcriptome analysis, histology, and proliferation assays. This study is important, though the genetic tools employed may not fully capture Ptbp1's potential role during the earliest stages of retinal development.

eLife Assessment

This valuable study presents a mechanistic model of predictive coding by medial entorhinal cortex grid cells, implemented with biologically detailed conductance-based neurons. The evidence supporting the emergence of this coding scheme from specific membrane currents and the anatomical connectivity among inhibitory neurons is solid. However, the justification for the choice of connectivity patterns and other network parameters remains somewhat incomplete. This work will be of interest to neuroscientists working on spatial navigation, circuit dynamics, and neuronal coding.

eLife Assessment

This fundamental study shows how past experiences shape perception across short, medium, and long time scales, using a single behavioural paradigm and reanalysed EEG data. It provides convincing evidence for two processes across all scales: an attention-dependent mechanism that speeds responses to expected events, and an attention-independent mechanism where expected events are encoded less precisely, consistent with feedforward dampening. The work offers a unifying account of temporal context effects, though stronger brain-behaviour links, integration with serial dependence attraction and repulsion models, and extension to other timescale definitions would further strengthen the contribution.

eLife Assessment

Complementing previous work (Namiki et al, 2018), this study provides an important resource for the Drosophila community as it reports 500 lines targeting descending neurons (DN), in addition to compiling 306 existing DN lines from the literature. The compelling work characterizes 146 DNs and makes a critical link with the DNs identified in Electron microscopy (EM). The lines in this paper will be of interest to Drosophila neuroscientists who will be able to use the reported genetic drivers for further functional characterization of DNs and circuit mapping in conjunction with existing EM datasets.

eLife Assessment

This important study presents the development of a novel inhibitor for SARS-CoV-2 Mac1 that has potential utility both as an antiviral therapeutic and as a tool for probing the molecular mechanisms by which infection-induced ADP-ribosylation triggers robust host antiviral responses. Though minor gaps in understanding the compound's precise molecular mechanism of action and its ability to target Mac1 from other coronaviruses remain, the evidence for its effects on SARS-CoV-2 in relevant biological models is compelling.

eLife Assessment

This study reanalyzed previously published scRNA-seq and TCR-seq data to examine the proportion and characteristics of dual-TCR-expressing Treg cells in mice, presenting some useful insights into TCR diversity and immune regulation. However, the evidence is incomplete, particularly with respect to data interpretation, statistical rigor, and the functionality of dual -TCR Treg cells. The study is potentially of interest to immunologists studying T-cell biology.

eLife Assessment

This study proposes an important new approach to analyzing cell-count data, which are often undersampled and cannot be accurately assessed using traditional statistical methods. The case studies presented in the article provide compelling evidence of the superiority of the proposed methodology over existing approaches, which could promote the use of Bayesian statistics among neuroscientists. The authors have taken steps to make the methodology accessible, although some implementation difficulties are likely to remain.

eLife Assessment

Using single-cell transcriptomic data from adult mouse inner ear hair cells, the authors identify the differences and similarities of the four hair cell types. They make an important finding: that vestibular hair cells can express many ciliary motility-related genes. Some hair cell kinocilia display motility, suggesting that the kinocilium of vestibular hair cells may function as an active force generator to increase sensitivity. The evidence is incomplete as to whether all kinocilia beat and what the function of kinocilia movement is.

Editors Assessment:

In the Democratic Republic of Congo (DRC) Aedes mosquitoes are principal vectors of the arboviruses that cause yellow fever, chikungunya and dengue in the human population. However systematic surveillance data on these species remains limited, hindering for entomological and modelling research and control strategies. This paper is one of a series of Data Release papers in GigaByte supported by TDR and the WHO describing datasets hosted in GBIF to tackle these data gaps in vectors of human disease data. To address this data deficiency this paper presents a geo-referenced dataset of 6,577 entomological occurrence records collected in 2024 throughout urban and peri-urban areas of Kinshasa in the Democratic Republic of Congo. The data collected using Larval dipping, Human landing catches, Prokopack aspirator, and BG-Sentinel traps. Data auditing and peer review found the data well validated, but requested some additional fields and methodological details. This work and the extremely useful data provided representing an important step towards building a pan-African resource for Aedes mosquito data collection.

This evaluation refers to version 1 of the preprint

eLife Assessment

This important study provides new insights into the lesser-known effects of the sodium-potassium pump on how nerve cells process signals, particularly in highly active cells like those of weakly electric fish. The computational methods used to establish the claims in this work are compelling and can be used as a starting point for further studies.

eLife Assessment

This important study presents a sequence-based method for predicting drug-interacting residues in intrinsically disordered proteins (IDPs), addressing a significant challenge in understanding small-molecule:IDP interactions. The findings have solid support through examples underscoring the role of aromatic interactions. While predicted binding sites remain coarse, validation was done on a total of 10 IDPs at varying depths. The method builds on the authors' previous work and, with ad hoc modifications, is poised to benefit this emerging field.

eLife Assessment

This fundamental study reveals that aging in yeast leads to chromosome mis-segregation due to asymmetric partitioning of chromosomes, driven by disruption of the nuclear pore complex and pre-mRNA leakage. The findings are convincingly supported by carefully-designed experimental data with a combination of genetic, molecular biology and cell biology approaches.

eLife Assessment

This important study of artificial selection in microbial communities shows that the possibility of selecting a desired fraction of slow and fast-growing types is impacted by their initial fractions. The evidence, which relies on mathematical analysis and simulations of a stochastic model, is compelling. It highlights the tension between selection at the strain and the community level. This study should be of interest to researchers interested in ecology, both theoretical and experimental.

eLife Assessment

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

eLife Assessment

This valuable study characterizes the emergence of the membrane-associated periodic cytoskeleton (MPS) in the axons of human motor neurons derived from induced pluripotent stem cells. Super-resolution imaging of beta-II spectrin provides convincing evidence for the patterned assembly of spectrin-poor gaps and spectrin-rich MPS in the medial region of the axons and its enhancement by the kinase inhibitor staurosporine. The data advocates against gap formation by cytoskeleton disassembly in a continuous MPS. Instead, a continuous MPS may result from nascent MPS patches and their maturation, a model that would benefit from live imaging for validation.

eLife Assessment

The effort is timely and the paper carries valuable insights into the function of UTR mutations. There are still significant concerns about both the quality of the screen data, and its ability to detect significant changes in translation and their direction. Therefore, the ability of the screen to support the extensive downstream statistical analysis is limited and leaves the paper incomplete.

eLife Assessment

In their study, Cummings et al. provide a valuable advance in understanding the hierarchical regulation of tubulin polyglycylation, demonstrating that TTLL8 initiates monoglycylation which is a prerequisite for TTLL10-mediated polyglycylation. The evidence supporting these mechanistic insights is solid, relying on a compelling combination of purified biochemical assays, mass spectrometry, and microscopy. The work is further valued for revealing an unexpected crosstalk between polyglycylation and polyglutamylation that ensures a balanced post-translational modification landscape for proper cilia function.

eLife Assessment

This study provides convincing evidence of coordinated spiking activity of neurons in the anterior cingulate cortex (ACC), and correlated activity in the CA1 subregion of the hippocampus, during observational learning. The authors also show coordinated ACC-CA1 neural activity during rest periods prior to the performance of the observationally learned task. The important findings significantly advance the field's understanding of neural mechanisms underlying social learning.

eLife Assessment

This valuable study introduces a data augmentation approach based on generative unsupervised models to address data imbalance in immune receptor modeling. Support for the findings is solid, showing that the use of generated data increases the performance of downstream supervised prediction tasks, e.g., TCR-peptide interaction prediction. However, the validation, mainly relying on synthetic data, could be completed, especially regarding unseen epitopes, and given the exclusive focus on CDR3β. The results should be of interest to the communities working on immunology and biological sequence data analysis.

eLife Assessment

This valuable study combines microscopy and CRISPR screening in two different cell lines to identify factors involved in global chromatin organization, using centromere clustering as a proxy. Follow-up cell cycle synchronisation studies confirm roles in centromere clustering in mitosis. However, incomplete characterisation of the cell lines used limits the interpretation of the findings. The study will interest researchers studying genome organisation in mitosis.

eLife Assessment

This important study reports that two distinct waves of ovarian follicles contribute to oocyte production in mice. The paper provides large amounts of data that will benefit future studies, although the methods and analysis are considered incomplete at present. Justification for the criteria of wave 1 follicles would benefit from further explanation and discussion. This work will be of interest to ovarian biologists and physicians working on female infertility.

eLife Assessment

This important study reports that higher genetically predicted BMI is associated with a modestly increased risk of head and neck cancer. The convincing evidence is supported by rigorous Mendelian Randomization approaches, using multiple genetic instruments and models that reduce sensitivity to pleiotropy. However, results from pleiotropy-robust analyses were less consistent, which limits the strength of causal inference. The work will be of interest to researchers studying cancer risk factors and genetic epidemiology.

eLife Assessment

This important work examines how microexons contribute to brain activity, structure, and behavior. The authors find that loss of microexon sequences generally has subtle impacts on these metrics in larval zebrafish, with few exceptions. The evidence is solid, using modern high-throughput phenotyping methodology in zebrafish. Overall, this work will be of interest to neuroscientists and generate further studies of interest to the field.

eLife Assessment

This fundamental study explores a novel cellular mechanism underlying the degeneration of locus coeruleus neurons during chronic restraint stress. The evidence supporting the overexcitation of LC neurons after chronic stress is compelling. The topic is timely, the proposed mechanistic pathway is innovative, and the findings have translational relevance, particularly regarding therapeutic strategies targeting α2A-AR internalization in neurodegenerative diseases.

eLife Assessment

The analysis of neural morphology across Heliconiini butterfly species revealed brain area-specific changes associated with new foraging behaviours. While the volume of the centre for learning and memory, the mushroom bodies, was known to vary widely across species, new, valuable results show conservation of the volume of a center for navigation, the central complex. The presented evidence is convincing for both volumetric conservation in the central complex and fine neuroanatomical differences associated with pollen feeding, delivered by experimental approaches that are applicable to other insect species. This work will be of interest to evolutionary biologists, entomologists, and neuroscientists.

eLife Assessment

This study offers a valuable theoretical framework for quantifying molecular transport across interfaces between coexisting liquid phases, emphasizing interfacial resistance as a central factor governing transport kinetics. The mathematical derivations are solid. To enhance the paper's relevance and broaden its appeal, it would be helpful to clarify how the key equations connect to existing literature and to elucidate the physical mechanisms underlying scenarios that give rise to substantial interfacial resistance.

eLife Assessment

This work uses enhanced sampling molecular dynamics methods to generate potentially useful information about a conformational change (the DFG flip) that plays a key role in regulating kinase function and inhibitor binding. The focus of the work is on the mechanism of conformational change and how mutations affect the transition. The evidence supporting the conclusions is incomplete.

eLife Assessment

This valuable work advances our understanding of the relation between multimodal MRI, cognition, and mental health. Convincing use of statistical learning techniques in UK Biobank data shows that 48% of the variance between an 11-task derived g-factor and imaging data can be explained. Overall, this paper contributes to the study of brain-behaviour relations and will be of interest for both its methods and its findings on how much variance in g can be explained.

[Editorial note: a previous version was reviewed by Biological Psychiatry]

eLife Assessment

This valuable paper investigates how fish avoid thermal disturbances that occur on fast timescales. The authors use a creative experimental approach that quickly creates a vertical thermal interface, which they combine with careful behavioral analyses. The evidence supporting their results is solid, but there is a potential confounding factor between temperature and vertical positioning, and characterization of the thermal interface would greatly assist in interpreting the results.

eLife Assessment

This important study uses the delay line axon model in the chick brainstem auditory circuit to examine the interactions between oligodendrocytes and axons in the formation of internodal distances. This is a significant and actively studied topic, and the authors have used this preparation to support the hypothesis that regional heterogeneity in oligodendrocytes underlies the observed variation in internodal length. In a solid series of experiments, the authors have used enhanced tetanus neurotoxin light chains, a genetically encoded silencing tool, to inhibit vesicular release from axons and support the hypothesis that regional heterogeneity among oligodendrocytes may underlie the biased nodal spacing pattern in the sound localization circuit.

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

eLife Assessment

This important study combines electrocardiographic (ECG) and heart/torso anatomy data from subjects included in the UK Biobank to analyze sex-specific differences in relationships between those two characteristics. The study has several compelling strengths, including the development of an open-source pipeline for reconstruction and analysis of heart/torso geometry from a large cohort. Nevertheless, technical analysis of the data as presented is incomplete, specifically as it pertains to assessment of co-linearity between regressed parameters, interpretation of regression coefficients for sex and/or presence of myocardial infarction, and discussion of potential roles played by underlying electrophysiological derangements. With improvements to these aspects of the analysis, the paper would be of interest to the cardiovascular research community, especially those studying highly relevant health and treatment disparities arising from sex differences.

eLife Assessment

This valuable study investigates the self-assembly activity of death-fold domains. The data collected using advanced microscopy and distributed amphifluoric FRET-based flow cytometry methods provide solid evidence for the conclusions, although the interpretations based on these conclusions remain speculative in some cases. This paper is broad interest to those studying a variety of biological pathways involved in inflammatory responses and various forms of cell death.

eLife Assessment

During the development of the unicellular eukaryote Dictyostelium discoideum, cells aggregate into mounds, which then form protrusions called tips, and the tips then become the front of migrating slugs and the top of fruiting bodies. This valuable study identifies a protein called adenosine deaminase-related growth factor (ADGF) as a key regulator of tip formation, and the authors convincingly show that ADGF catalyses the formation of ammonia from adenosine, allowing ammonia to initiate tip formation, and they then elucidate pathways upstream and downstream from ADGF. The authors discuss the intriguing possibility that mammalian ADGF may also regulate development in a similar manner.

eLife Assessment

This study provides a valuable examination of the social discrimination abilities of a jumping spider, Phippidus regius, based on visual cues. Behavioral essays yielded solid evidence that these spiders discriminate between familiar and unfamiliar individuals on the basis of visual cues, however the experimental support for individual recognition and long-term memory is incomplete. While the results supply evidence of discrimination, additional experiments would be needed to verify the evidence of individual recognition.

eLife Assessment

This important study uses data on over 56 million articles to examine the dynamics of interdisciplinarity and international collaborations in research journals. The data analytics used to quantify disciplinary and national diversity are convincing, and support the claims that journals have become more diverse in both aspects.

eLife Assessment

This important study combines imaginative and innovative experiments with a finite element modelling to demonstrate the relevance of poroelasticity in the mechanical properties of cells across physiologically relevant time and length scales. The authors present convincing evidence that cytosolic flows and pressure gradients can persist in cells with permeable membranes, generating spatially segregated influx and outflux zones. These findings are of interest to the cell biology and biophysics communities.

eLife Assessment

In flies defective for axonal transport of mitochondria, the authors report the upregulation of one subunit, the beta subunit, of the heterotrimeric eIF2 complex via mass spectroscopy proteomics. Neuronal overexpression of eIF2β phenocopied aspects of neuronal dysfunction observed when axonal transport of mitochondria was compromised. Conversely, lowering eIF2β expression suppressed aspects of neuronal dysfunction. While these are intriguing and useful observations, technical weaknesses limit the interpretation. On balance, the evidence supporting the current claims is suggestive but incomplete, especially concerning the characterization of the eIF2 heterotrimer and the data regarding translational regulation.

eLife Assessment

This study provides valuable results on how entorhinal and hippocampal activity may support human thinking in perceptual spaces. It replicates the hexagonal symmetry of fMRI activity in the entorhinal cortex, reports novel findings on 3-fold symmetry in both behavioral performance and hippocampal fMRI activity, and links these results within a computational model. However, the methods – while potentially creative and interesting – are not fully justified or explained, and the conclusions remain incomplete. With further explanation, justification, and interpretation, this work could represent a significant step forward in understanding how cognitive maps are utilized.

eLife Assessment

By combining the 'pinging' technique with fMRI-based multivariate pattern analysis, this important study provides compelling evidence for a dual-format representation of attention during the preparatory period. The findings help reconcile the debate between sensory-like and non-sensory accounts of attentional templates and shed light on how the brain flexibly deploys different forms of templates to guide attention. This work will be of broad interest to researchers in psychology, vision science, and cognitive neuroscience.

eLife Assessment

The article presents important findings on the impact of climate change on odonates, integrating phenological and range shifts to broaden our understanding of biodiversity change. The study leverages extensive natural history data, offering a convincing analysis of temporal trends in phenology and range limit and their potential drivers.

eLife assessment

This paper provides valuable insights into the consequences of hydrogen sulfide (H2S) exposure on the behavior and physiology of the nematode C. elegans. While solid evidence supports most of the paper's findings, the evidence that H2S is detected by the nervous system to mediate behavioral avoidance is incomplete. The paper provides a wide range of intriguing observations that could serve as a foundation for future work to synthesize these disparate results or provide insight into the mechanisms of H2S detection in C. elegans.

eLife Assessment

This study presents significant and novel insights into the roles of zinc in mammalian meiosis/fertilization events. These findings are useful to our understanding of these processes. The evidence presented is solid, with experiments being well-designed, carefully described, and interpreted with appropriate rigor. The main limitation of lack of mechanistic insight needs to be acknowledged.

eLife Assessment

This study in the Drosophila antennal lobe, which contains multiple non-equivalent sensory channels, provides valuable new insight into how early-life sensory experience can produce lasting, cell-type-specific changes in neural circuit function. The work convincingly demonstrates that glial-mediated pruning during a defined developmental window leads to persistent suppression of odor responses in one olfactory neuron type, while sparing another. The evidence is solid and supported by multiple complementary approaches, although some mechanistic interpretations remain speculative and would benefit from additional functional testing.

eLife Assessment

The authors used three genetically diverse mouse models to investigate the impact of genome diversity on metabolic disease outcomes, such as obesity and glucose tolerance. This study is important because it integrates comprehensive metabolic analyses and multi-tissue phenotyping across sexes to reveal pathways relevant to obesity and its complications; the data are convincing and uncover several pathways that advance understanding of disease etiology while suggesting potential therapeutic avenues to prevent obesity-related health risks. There are limitations, such as a limited number of mouse strains used in the work, the 9-week feeding regime may be too short to capture full metabolic remodeling, and the mechanisms by which the immune-adipose axis impacts the broader phenotype are not fully described. Overall, the study is compelling, but the manuscript could be improved by justifying the strain selection, addressing the concern about the feeding duration, and providing stronger mechanistic support or discussion.

eLife Assessment

This work provides an important resource identifying 72 proteins as novel candidates for plasma membrane and/or cell wall damage repair in budding yeast, and describes the temporal coordination of exocytosis and endocytosis during the repair process. The data are convincing; however, additional experimental validation will better support the claim that repair proteins shuttle between the bud tip and the damage site.

eLife Assessment

This important manuscript presents a novel application of the SANDI (Soma and Neurite Density Imaging) model to study microstructural alterations in the basal ganglia of individuals with Huntington's disease (HD). The compelling methods, to our understanding, the first application of SANDI to neurodegenerative diseases, provide strong evidence for HD-related neurodegeneration in the striatum, account significantly for striatal atrophy, and correlate with motor impairments. The integration of novel diffusion acquisition and modelling methods with multimodal behavioural data are both of high value in their own right, and create a framework for future studies.

eLife Assessment

In this important manuscript, Cassell and colleagues set out on a mechanistic and pharmacological exploration of an engineered chimeric small conductance calcium-activated potassium channel 2 (SK2). They show compelling evidence that the SK2 channel possesses a unique extracellular structure that modulates the conductivity of the selectivity filter, and that this structure is the target for the SK2 inhibitor apamin. The interpretations are sound and the writing is clear, and the manuscript was strengthened during review by providing more detailed information for the electrophysiological experiments and the structural analyses attempted, in addition to relating dilation of the filter to mechanisms of inactivation in other potassium channels. This high-quality study will be of interest to membrane protein structural biologists, ion channel biophysicists, and chemical biologists, and will help to inform future drug development targeting SK channels.

eLife Assessment

This manuscript presents useful insights into the molecular basis underlying the positive cooperativity between the co-transported substrates (galactoside sugar and sodium ion) in the melibiose transporter MelB. Building on years of previous studies, this work improves on the resolution of previously published structures and reports the presence of a water molecule in the sugar binding site that would appear to be key for its recognition, introduces further structures bound to different substrates, and utilizes HDX-MS to further understand the positive cooperativity between sugar and the co-transported sodium cation. Although the experimental work is solid, the presentation of the data lacks clarity, and in particular, the HDX-MS data interpretation requires further explanation in both methodology and discussion, as well as a clearer description of the new insight that is obtained in relation to previous studies. The work will be of interest to biologists and biochemists working on cation-coupled symporters, which mediate the transport of a wide range of solutes across cell membranes.

eLife Assessment

This important study significantly advances our understanding of the skeleton of cartilaginous fishes by using a range of state of the art and complementary approaches to compare the skeleton amongst three cartilagenous fishes (catshark, little skate and ratfish). The evidence presented is compelling and likely to impact several fields of study.

Challenging to address high error rate for minority groups

minorities under-represented in data used for training leads to performance issues

ML emphasizes societal stereotypes.

disparities -> discrimination

Important example of using experience and intuition over data

flaws in only relying on examples.

The need for "learning" over "branching"

Data-driven decisions triumph over intuition or experience. However, intuition and experience plays an important role in addressing or resolving unusual (outlier) situations.

eLife Assessment

This study presents valuable findings on the ability of a state-of-the-art method – temporally delayed linear modelling (TDLM) – to detect the replay of sequences in human memory. The investigation provides convincing evidence that TDLM has limitations in its sensitivity to detect replay when being applied to extended (minutes-long) rest periods, though a more thorough treatment of the relationship to prior positive findings would make the demonstration even stronger. The work will be of particular interest to researchers investigating memory reactivation in humans, especially using iEEG, MEG, and EEG.