eLife Assessment

This important study by Jeong and Choi studied neural activity in the medial prefrontal cortex (mPFC) while rats performed a foraging paradigm in which rats forage for rewards in the absence or presence of a threatening object (Lobsterbot). The authors present interesting observations suggesting that the mPFC population activity switches between distinct functional modes conveying distinct task variables- such as the distance to the reward location and types of threat-avoidance behaviors-depending on the location of the animal. The reviewers thought that the results are overall convincing, appreciated the value of studying neural coding in naturalistic settings, and felt that this work offers significant insights into how the mPFC operates during foraging behavior involving reward-threat conflict.

eLife Assessment

This important study investigates nerve-injury-induced allodynia by studying the role of a subpopulation of excitatory dorsal horn CCK+ neurons that express the estrogen receptor GPR30 and potentially modulate nociceptive sensitivity via direct inputs from primary somatosensory cortex. In this revised version, the authors addressed many of the critiques raised through added analyses that convincingly support the notion that spinal GPR30 neurons are indeed an excitatory subpopulation of CCK+ neurons that contribute to neuropathic pain. While evidence of a direct functional corticospinal projection to CCK+/GPR30+neurons is not fully demonstrated, this work will be of broad interest to researchers interested in the neural circuitry of pain.

eLife Assessment

Cryptovaranoides, a Late Triassic animal (some 230 Ma old), was originally described as a possibly anguimorph squamate, i.e., more closely related to snakes and some extant lizards than to other extant lizards, making Squamata much older than previously thought and providing a new calibration date inside it. Following a rebuttal and a defense, this fourth important contribution to the debate makes a convincing argument that Cryptovaranoides is not a squamate. Further comparisons to potentially closely related animals such as early lepidosauromorphs would greatly benefit this study, and parts of the text require clarification.

eLife Assessment

This manuscript describes the identification and characterization of 12 specific phosphomimetic mutations in the recombinant full-length human tau protein that trigger tau to form fibrils. This fundamental study will allow in vitro mechanistic investigations. The presented evidence is convincing. This manuscript will be of interest to all scientists in the amyloid formation field.

eLife Assessment

The present study employed transcriptomics to investigate the impact of methionine restriction (MR) and cold exposure (CE) on liver and adipose tissues in mice. The authors demonstrate that responses to MR and CE are tissue-specific, while both MR and CE have a similar effect on beige adipose tissue. While these findings are somewhat descriptive, this work is considered important, as it provides a comprehensive resource for enhancing our understanding of these lifestyle interventions. The study is of high scientific quality, and the analyses are convincing.

eLife Assessment

This useful study demonstrates that microsaccade direction primarily indexes shifts rather than the maintenance of covert spatial attention, offering a focused interpretation that may help reconcile inconsistencies in the prior literature. However, the evidence remains incomplete due to limited engagement with the broader body of existing work and the absence of independent measures, single-trial analyses, and neutral-condition controls needed to substantiate the central claims. The work will be of broad interest to researchers investigating attention, eye movements, and visuomotor mechanisms.

eLife Assessment

This important work significantly advances our understanding of the role of human hippocampal theta oscillations in memory encoding and retrieval. The evidence supporting the conclusions is solid, using both scopolamine administration and intracranial EEG recordings. This work will be of broad interest to neuroscientists and has translational implications.

eLife Assessment

This potentially important study examines the consequences of manipulating the expression of thyroxine-binding and amyloidogenic hepatocyte secretory protein transthyretin (TTR). Solid in vivo evidence from two dietary models supports that TTR production exacerbates liver injury, whereas the evidence for a link between TTR production, uptake, and calcium dysregulation is incomplete. If the findings are confirmed, they would provide evidence for a novel cell biological pathway of liver injury.

eLife Assessment

This manuscript presents valuable findings which reveal an intricate pattern of memory expression following retrieval extinction at different intervals from retrieval-extinction to test. The novel advance is in the demonstration that, relative to a standard extinction procedure, the retrieval-extinction procedure more effectively suppresses responses to a conditioned threat stimulus when testing occurs just minutes after extinction. While the data provide solid evidence that the "short-term" suppression of responding involves engagement of the dorsolateral prefrontal cortex, there are inconsistencies in the analyses reported which obscure the interpretation and leave some of the claims with limited evidence.

eLife Assessment

This study offers valuable insights into how humans detect and adapt to regime shifts, highlighting distinct contributions of the frontoparietal network and ventromedial prefrontal cortex to sensitivity to signal diagnosticity and transition probabilities. The combination of an innovative task design, behavioral modeling, and model-based fMRI analyses provides a solid foundation for the conclusions; however, the neuroimaging results have several limitations, particularly a potential confound between the posterior probability of a switch and the passage of time that may not be fully controlled by including trial number as a regressor. The control experiments intended to address this issue also appear conceptually inconsistent and, at the behavioral level, while informing participants of conditional probabilities rather than requiring learning is theoretically elegant, such information is difficult to apply accurately, as shown by well-documented challenges with conditional reasoning and base-rate neglect. Expressing these probabilities as natural frequencies rather than percentages may have improved comprehension. Overall, the study advances understanding of belief updating under uncertainty but would benefit from more intuitive probabilistic framing and stronger control of temporal confounds in future work.

eLife Assessment

This study presents a fundamental discovery of how cerebellar climbing fibers modulate plastic changes in the somatosensory cortex by identifying both the responsible cortical circuit and the anatomical pathways. The evidence supporting the conclusions is convincing and well supported by modern neuroscience methodologies. Overall, this work represents a significant contribution that will be of broad interest to neuroscientists, especially those studying the long-distance cerebellar influence on non-motor brain functions.

eLife Assessment

This study presents important findings on the role of Slit-Robo signaling in cardiac innervation. The evidence supporting the main claims of the authors is convincing. The use of several mouse models including constitutive and cell type specific knockout models make the findings more robust. The scope of the presented studies is fitting, as they primarily focus on evaluating the phenotypic changes in cardiac innervation following the loss of various Slit or Robo genes

eLife Assessment

The study introduces a valuable dataset for investigating the relationship between vision and language in the brain. The authors provide convincing evidence that decoders trained on brain responses to both images and captions outperform those trained on responses to a single modality. The dataset and decoder results will be of interest to communities studying brain and machine decoding.

eLife Assessment

This study presents a large, systematically curated catalog of non-canonical open reading frames (ncORFs) in human and mouse by reanalyzing nearly 400 Ribo-seq datasets using a standardized pipeline; the resulting atlas consolidates ncORF annotations across tissues and provides a valuable reference for understanding non-canonical translation and ORF emergence. The main conclusions are supported by consistent data processing and multiple computational measures of translation and conservation. While the pipeline is transparent and robust, several downstream analyses are descriptive, and some evolutionary interpretations remain correlative; dataset heterogeneity, uneven tissue representation, and limited experimental validation also constrain the strength of a subset of the findings. Overall, the evidence is solid, and the resource will be broadly used by the community.

eLife Assessment

Recent studies have shown that mRNA can be acetylated (ac4c), altering mRNA stability and translation efficiency; however, the role of mRNA acetylation in the brain remains unexplored. In this valuable study, the authors demonstrate that ac4c occurs in synaptically localised mRNAs, mediated by NAT10. Conditional reduction of NAT10 protein levels led to decreases in ac4c of mRNAs and deficits in synaptic plasticity and memory. These solid results suggest that mRNA acetylation may play a role in memory consolidation.

eLife Assessment

This is a valuable study that investigates peptidoglycan (PG) recycling in Caulobacter crescentus, demonstrating its importance for β-lactam resistance, cell morphology, and cell division. The findings are compelling, although limited complementation somewhat constrains the interpretation of specific gene functions.

eLife Assessment

This is a valuable study of the physiological mechanisms promoting network activity during fever in the mouse neocortex. The supporting evidence is solid, and has improved with revision, along with increased clarity of presentation.

eLife Assessment

This study provides a useful investigation of human-AI interaction and decision-making, using both behavioral and electrophysiological measures. However, the theoretical framework and experimental design are incomplete, with an unclear task structure and feedback implementation limiting interpretability. With these issues addressed, the work could make a significant contribution to understanding human-AI collaboration.

eLife Assessment

This important study provides convincing evidence that envelope-carrying Ty3/gypsy retrotransposons (errantiviruses) are ancient, widespread, and actively expanding across nearly all major animal phyla. Using comprehensive phylogenetic and AlphaFold2-based structural analyses, the authors show that these elements independently acquired membrane fusion proteins early in metazoan evolution, likely predating the bilaterian-non-bilaterian split. While some aspects could be more clearly contextualized and explained better, the work offers insights into the deep evolutionary roots of retroelement-envelope associations and the origins of retroviruses.

eLife Assessment

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

eLife Assessment

This paper reports a valuable finding that gastric fluid DNA content can be used as a potential biomarker for human gastric cancer. The evidence supporting the claims of the authors is solid, although an inclusion of explanations for the methodological limitations, moderate diagnostic performance, and the unexpected survival correlation would have strengthened the study. The work will be of interest to medical biologists working in the field of gastric cancer.

eLife Assessment

This study concerns how macaque visual cortical area MT represents stimuli composed of more than one speed of motion. The study is valuable because little is known about how the visual pathway segments and preserves information about multiple stimuli, and the study involves perceptual reports from both humans and one monkey regarding whether there are one or two speeds in the stimulus. The study presents compelling evidence that (on average) MT neurons shift from faster-speed-takes-all at low speeds to representing the average of the two speeds at higher speeds. Ultimately, this study raises intriguing questions about how exactly the response patterns in visual cortical area MT might preserve information about each speed, since such information could potentially be lost in an average response as described here, depending on assumptions about how MT activity is evaluated by other visual areas.

eLife Assessment

This paper presents the fundamental discovery that lipid metabolic imbalance induced by Snail, an EMT-related transcription factor, contributes to the acquisition of chemoresistance in cancer cells. The evidence, supported by a wide range of methods and adequate quantification, provides a convincing mechanistic explanation of how Snail drives ectopic expression of the cholesterol- and drug-efflux transporter ABCA1. This work, which introduces a novel therapeutic concept targeting invasive cancer, will be of broad interest to researchers in cancer biology, lipid metabolism, and cell biology.

eLife Assessment

This study reports the important development and characterization of next-generation analogs of the molecule AA263, which was previously identified for its ability to promote adaptive ER proteostasis remodeling. The evidence supporting the conclusions is convincing, with rigorous assays used to benchmark the changes in potency and efficacy of the AA263 analogs as well as AA263 targets. The ability of AA263 analogs to restore the loss of function associated with disease-associated proteins prone to misfolding will be of interest to pharmacologists, chemical biologists, and cell biologists, as well as those working on protein misfolding disorders.

eLife Assessment

This useful study develops an individual-based model to investigate the evolution of division of labor in vertebrates, comparing the contributions of group augmentation and kin selection. The model incorporates several biologically relevant features, including age-dependent task switching and separate manipulation of relatedness and group-size benefits. However, the evidence remains incomplete to support the authors' central claim that group augmentation is the primary driver of vertebrate division of labor. Key modelling assumptions, such as limited opportunities for task synergy, the structure of helper and floater dynamics, and the relatively narrow parameter space explored, continue to restrict the potential for kin selection to produce division of labor, thereby limiting the generality of the conclusions.

eLife Assessment

The authors identify the Bearded-type small protein E(spl)m4 as a physical and genetic interactor of TRAF4 in the Drosophila wing disc. These valuable findings with potential biomedical relevance are, however, supported by incomplete evidence based largely on overexpression studies that lack quantification, limited molecular support for their model, and issues with Bearded family protein specificity. The work could be of interest to researchers in the fields of cell signaling and developmental biology.

eLife Assessment

This important study applies an innovative multi-model strategy to implicate the ribosomal protein (RP) encoding genes as candidates causing Hypoplastic Left Heart Syndrome. The evidence from the screen in stem cell-derived cardiomyocytes and whole genome sequencing of human patients, followed by functional analyses of RP genes in fly and fish models, is convincing and supports the authors' claims. This work and methodology applied would be of broad interest to medical biologists working on congenital heart diseases.

eLife Assessment

This valuable work substantially advances our understanding of prognostic value of total gfDNA in gastric cancer. The evidence supporting the conclusions is solid, supported by a large, well-classified patient cohort and controlled clinical variables. The work will be of broad interest to scientists and clinical pathologist working in the field of gastric cancer.

Editors Assessment:

Coded and written up as part of the African Society for Bioinformatics and Computational Biology (ASBCB) Omicscodeathons, EMImR is a novel Shiny application for transcriptomic and epigenomic change identification and correlation wrapped up using a combination of Bioconductor and CRAN packages. Case studies are on publicly available GEO data corresponding to sequencing data of human blood cell samples of multiple sclerosis patients to demonstrate how the tool works. And a documentation and videos are provided. Peer review and the study highlighting the usefulness of the developed tool for analyzing transcriptomic and epigenomic data.

This evaluation refers to version 1 of the preprint

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 evidence is solid in the investigation of prediction in reading, with one caveat that the text materials used could be biased against the aging population. The work will be of interest to cognitive neuroscientists working on reading, language comprehension, and executive control.

eLife Assessment

M proteins are essential group A streptococci virulence factors that bind to numerous human proteins; a small subset of M proteins, such as M3, have been reported to bind collagen, which is thought to promote tissue adherence. In this important paper, the authors provide a solid characterization of M3 interactions with collagen. The work raises significant questions regarding the specificity of the structure and its interactions with different collagens, with implications for the variable actions of M protein collagen interactions on biofilm formation.

eLife Assessment

This important study introduces the Life Identification Number (LIN) coding system as a powerful and versatile approach for classifying Neisseria gonorrhoeae lineages. The authors show that LIN codes capture both previously defined lineages and their relationships in a way that aligns with the species' phylogenetic structure. The compelling evidence presented, together with its integration into the PubMLST platform, underscores its strong potential to enhance epidemiological surveillance and advance our understanding of gonococcal population biology.

eLife Assessment

This valuable study uses zebrafish as a model to reveal a role for the cell cycle protein kinase CDK2 as a negative regulator of type I interferon signaling. The evidence supporting the authors' claims is convincing, including both in vivo and in vitro investigative approaches that corroborate a role for CDK2 in regulating TBK1 degradation. In this latest version, the authors included data addressing a concern raised by the reviewer in the previous peer review round. This work will interest cell biologists, immunologists, and virologists.

eLife Assessment

The authors investigated the potential role of IgG N-glycosylation in Haemorrhagic Fever with Renal Syndrome (HFRS), which may offer significant insights for understanding molecular mechanisms and for the development of therapeutic strategies for this infectious disease. The findings are valuable to the field and the strength of evidence to support the findings is solid.

eLife Assessment

This study presents a useful overview of the taxonomic composition of the microbiome associated with Dactylorhiza traunsteineri, a widely distributed orchid species in Central Europe. The evidence supporting the claims of the authors is incomplete, especially when it comes to the (secondary) metabolic pathways found in the metagenome assembled genomes, and requires more substantial analysis to be able to claim that these pathways play a key role in microbiome-orchid symbiosis.

eLife Assessment

This manuscript makes a valuable contribution to the concept of fragility of meta-analyses via the so-called 'ellipse of insignificance for meta-analyses' (EOIMETA). The strength of evidence is solid, supported primarily by an example of the fragility of meta-analyses in the association between Vitamin D supplementation and cancer mortality, but the approach could be applied in other meta-analytic contexts. The significance of the work could be enhanced with a more thorough assessment of the impact of between-study heterogeneity, additional case studies, and improved contextualization of the proposed approach in relation to other methods.

eLife Assessment

In the gram-positive model organism Bacillus subtilis, the membrane associated ParA family member MinD, concentrates the division inhibitor MinC at cell poles where it prevents aberrant division events. This important study presents compelling data suggesting that polar localization of MinCD is largely due to differences in diffusion rates between monomeric and dimeric MinD. This finding is exciting as it negates the necessity for a third, localization determinant, in this system as has been proposed by previous investigations.

eLife Assessment

This study, from the group that pioneered migrasome, describes a novel vaccine platform of engineered migrasomes that behave like natural migrasomes. Importantly, this platform has the potential to overcome obstacles associated with cold chain issues for vaccines such as mRNA. In the revised version, the authors have addressed previous concerns and the results from additional experiments provide compelling evidence that features methods, data, and analyses more rigorous than the current state-of-the-art. Although the findings are important with practical implications for the vaccine technology, results from additional experiments would make this an outstanding study.

eLife Assessment

This paper reports the fundamental finding of how Raman spectral patterns correlate with proteome profiles using Raman spectra of E. coli cells from different physiological conditions and found global stoichiometric regulation on proteomes. The authors' findings provide compelling evidence that stoichiometric regulation of proteomes is general through analysis of both bacterial and human cells. In the future, similar methodology can be applied on various tissue types and microbial species for studying proteome composition with Raman spectral patterns.

eLife Assessment

The authors analyzed spectral properties of neural activity recorded using laminar probes while mice engaged in a global/local visual oddball paradigm. They found solid evidence for an increase in gamma (and theta in some cases) for unpredictable versus predictable stimuli, and a reduction in alpha/beta, which they consider evidence towards a "predictive routing" scheme. The study is overall important because it addresses the basis of predictive processing in the cortex, but some of the analytical choices could be better motivated, and overall, the manuscript can be improved by performing additional analyses.

eLife Assessment

Mark and colleagues developed and validated a valuable method for examining subspace generalization in fMRI data and applied it to understand whether the entorhinal cortex uses abstract representations that generalize across different environments with the same structure. The manuscript presents convincing evidence for the conclusion that abstract entorhinal representations of hexagonal associative structures generalize across different stimulus sets.

eLife Assessment

This important study advances our understanding of population-level immune responses to influenza in both children and adults. The strength of the evidence supporting the conclusions is compelling, with high-throughput profiling assays and mathematical modeling. The work will be of interest to immunologists, virologists, vaccine developers, and those working on mathematical modeling of infectious diseases.

eLife Assessment

This is a useful study that examines the relationship between neuropeptide signaling and the precision of vocal motor output using the songbird as a model system. The study presents evidence based on differential expression patterns and genetic or pharmacological inhibition of various neuropeptide genes for a causal role in song performance; however, this evidence is incomplete.

eLife Assessment

The authors aim to understand why Kupffer cells (KCs) die in metabolic-associated steatotic liver disease (MASLD). This is a useful study using in vitro studies and an in vivo genetic mouse model, suggesting that increased glycolysis contributes to KC death in MASLD. However, the data presented are incomplete as some inconsistencies in the results presented are identified in the characterisation of KCs. This work will be of interest to researchers in the immunology and metabolism fields.

eLife Assessment

This study examines the role of the fungal pathogen Candida albicans in the progression of colorectal cancer, a relevant and urgent topic given the global incidence of colon cancer. While the findings are useful and provide solid experimental work and insight into how Candida may contribute to tumor progression, the small patient sample size, reliance on in vitro models, and absence of in vivo validation may limit its impact. This work will interest scientists studying cancer progression and the role played by pathogens.

eLife Assessment

This is a valuable study describing transcriptome-based pheochromocytoma and paraganglioma (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 the Cancer Genome Atlas (TCGA). One of the key premises of the study is that identification of driver mutations in PPGL is not complete and that compromises characterisation for prognostic purposes. This is a solid starting point on which to base characterisation using different methods.

eLife Assessment

This important series of studies provides converging results from complementary neuroimaging and behavioral experiments to identify human brain regions involved in representing regular geometric shapes and their core features. Geometric shape concepts are present across diverse human cultures and possibly involved in human capabilities such as numerical cognition and mathematical reasoning. Identifying the brain networks involved in geometric shape representation is of broad interest to researchers studying human visual perception, reasoning, and cognition. The evidence supporting the presence of representation of geometric shape regularity in dorsal parietal and prefrontal cortex is solid, but does not directly demonstrate that these circuits overlap with those involved in mathematical reasoning. Furthermore, the links to defining features of geometric objects and with mathematical and symbolic reasoning would benefit from stronger evidence from more fine-tuned experimental tasks varying the stimuli and experience.

eLife Assessment

The authors present valuable empirical and modelling evidence that statistical learning in speech perception may contain sub-processes. While the evidence for statistical learning effects is solid, the link between the pattern of effects (both empirical and simulated) and the theoretical concepts of the sub-processes (e.g., segmentation, anticipation) could be further developed. This work is of broad interest to researchers working on, or with, statistical learning, and to any researcher interested in the challenges of how data and models adjudicate between competing theoretical constructs.

eLife Assessment

This study presents an important finding that ant nest structure and digging behavior depend on ant age demographics for a ground-dwelling ant species (Camponotus fellah). By asking whether ants employ age-polyethism in excavation, the authors address a long-standing question about how individuals in collectives determine the overall state of the task they must perform. The experimental evidence that the age of the ants and the group composition affect the digging of tunnels is convincing, and their model is able to replicate the colony's excavation dynamics qualitatively, results that may prove to be a key consideration for interpreting results from other studies in the field of social insect behavior.

eLife Assessment

The present manuscript by Cordeiro et al., shows convincing evidence that α-mangostin, a xanthone obtained from the fruit of the Garcinia mangostana tree, behaves as a strong activator of the large-conductance (BK) potassium channels; macroscopic currents and single-channel experiments show that α-mangostin produces an increase in the probability of opening, without affecting the single-channel conductance. The authors put forward that α-mangostin activation of the BK channel is state-independent, and molecular docking and mutagenesis suggest that α-mangostin binds to a site in the internal cavity. Additionally, the authors show that α-mangostin can relax arteries, further suggesting the plausibility of the proposed effects of this compound. These are valuable findings that should be of interest to channel biophysicists and physiologists alike.

eLife Assessment

The one-carbon tetrahydrofolate metabolism plays a crucial role in producing essential metabolic intermediates. In this study, the authors employ a genetics-based approach to demonstrate that three different metabolic pathways are essential for synthesizing 1C-tetrahydrofolates (1C-THF). Disrupting any of these pathways impairs both growth and virulence. Although the work presented is valuable, the experimental evidence remains incomplete without direct quantification of folate intermediates.

eLife Assessment

The study highlights development of a multiplex coregulator TR-FRET (CRT) assay that detects ligands with theoretical full agonist, partial agonist, antagonist, and inverse agonist signatures within the same chemical series. The findings are valuable and will have theoretical and practical implications in the subfield, with respect to guiding the design of non-lipogenic liver X receptor (LXR) agonists. The strength of the evidence is solid, whereby the methods, data, and analyses broadly support the claims with only minor weaknesses that can be dealt with through improvements in the data analysis and the discussion. This study will be of interest to experts working in the areas of pharmacology, medicinal chemistry, and drug discovery in Alzheimer's diseases and dementias.

eLife Assessment

This manuscript describes a valuable screening approach to identifying nanobodies with the potential to modulate gene expression via epigenetic regulators. While the concept is of interest and the screening strategy is well designed, the current evidence supporting mechanistic specificity remains incomplete.

eLife Assessment

This important study presents convincing evidence that uncovers a novel signaling axis impacting the post-mating response in females of the brown planthopper. The findings open several avenues for testing the molecular and neurobiological mechanisms of mating behavior in insects, although broad concerns remain about the relevance of some claims.

eLife Assessment

This valuable study addresses a critical and timely question regarding the role of a subpopulation of cortical interneurons (Chrna2-expressing Martinotti cells) in motor learning and cortical dynamics. However, while some of the behavior and imaging data are impressive, the small sample sizes and incomplete behavioral and activity analyses make interpretation difficult; therefore, they are insufficient to support the central conclusions. The study may be of interest to neuroscientists studying cortical neural circuits, motor learning, and motor control.

eLife Assessment

This valuable study shows that regions of the human auditory cortex that respond strongly to voices are also sensitive to vocalizations from closely related primate species. The study is methodologically solid, though additional analyses - particularly those isolating the acoustic features that differentiate chimpanzee from bonobo calls - would further strengthen the conclusions. With additional analyses and discussions, the work has the potential to offer key insights into the evolutionary continuity of voice processing and would be of interest to researchers studying auditory processing and evolutionary neuroscience in general.

eLife Assessment

This valuable simulation study proposes a new coarse-grained model to explain the effects of CpG methylation on nucleosome wrapping energy. The model accurately reproduces the all-atom molecular dynamics simulation data, and the evidence to support the claims in the paper is solid. This work will be of interest to researchers working on gene regulation, mechanisms of DNA methylation and effects of DNA methylation on nucleosome positioning.

eLife Assessment

This useful study identifies knowledge of letter shape as a distinct component of letter knowledge and shows that children acquire it even before formal reading instruction and without knowing the corresponding letter sounds. However, the evidence supporting the main conclusions is incomplete at the current stage. With additional analyses examining the relationships among the underlying variables and/or revising interpretations, the work would be of broad interest to researchers studying language and vision.

eLife Assessment

This important work develops a new protocol to experimentally perturb target genes across a quantitative range of expression levels in cell lines. The evidence supporting their new perturbation approach is convincing, and we propose that focusing on single modality (activation or inhibition) would be sufficient to draw their conclusions. The study will be of broad interest to scientists in the fields of functional genomics and biotechnology.

eLife Assessment

This study presents a valuable tool named TSvelo, a computational framework for RNA velocity inference that models transcriptional regulation and gene-specific splicing. The evidence supporting the claims of the authors is solid, although elaboration of the computational benchmark and datasets would have strengthened the study. The work will be of interest to computational scientists working in the field of RNA biology.

eLife Assessment

This valuable study investigates the role of P-bodies in yeast proliferation and mRNA regulation within the phyllosphere, proposing that P-body assembly contributes to methanol metabolism and stress adaptation. The findings are of interest to researchers studying post-transcriptional gene regulation and microbial ecology in plants. However, the evidence is incomplete, as most experiments were performed under artificial conditions, relied on limited genetic validation, and were supported primarily by qualitative or low-resolution imaging.

eLife Assessment

This fundamental study presents experimental evidence on how geomagnetic and visual cues are integrated in a nocturnally migrating insect. The evidence supporting the conclusions is compelling. The work will be of broad interest to researchers studying animal migration and navigation.

eLife Assessment

This important work introduces a family of interpretable Gaussian process models that allows us to learn and model sequence-function relationships in biomolecules. These models are applied to three recent empirical fitness landscapes, providing convincing evidence of their predictive power. The findings should be of interest to the community working on the sequence-function relationship, on epistasis, and on fitness landscapes.

eLife Assessment

This important study describes a novel Bayesian psychophysical approach that efficiently measures how well humans can discriminate between colors across the entire isoluminant plane. The evidence was considered compelling, as it included successful model validation against hold-out data and published datasets. This approach could prove to be of use to color vision scientists, as well as to those who use computational psychophysics and attempt to model perceptual stimulus fields with smooth variations over coordinate spaces.

eLife Assessment

This valuable study demonstrates that self-motion strongly affects neural responses to visual stimuli, comparing humans moving through a virtual environment to passive viewing. However, evidence that the modulation is due to prediction is incomplete as it stands, since participants may come to expect visual freezes over the course of the experiment. This study bridges human and rodent studies on the role of prediction in sensory processing, and is therefore expected to be of interest to a large community of neuroscientists.

eLife assessment

This meta-analysis provides a fundamental synthesis of evidence demonstrating that transcranial magnetic stimulation targeting the hippocampal-cortical network reliably enhances episodic memory performance across diverse study designs. The evidence is convincing, with rigorous methodology and consistent effects observed despite modest sample sizes and some heterogeneity in stimulation approaches. The work highlights the specificity of memory improvements to hippocampal-dependent memories and identifies key methodological factors-such as individualized targeting-that influence efficacy. Overall, this study offers a timely and integrative framework that will inform both basic memory research and the design of future clinical trials for cognitive enhancement.

eLife Assessment

This useful study provides a well-constructed computational investigation of how intermittent theta-burst stimulation (iTBS) influences synaptic plasticity within the corticothalamic circuit, improving our mechanistic understanding of how stimulation parameters interact with intrinsic brain oscillations. The authors build a corticothalamic population model that generates individual alpha rhythms with a calcium-dependent metaplasticity rule, and provide solid evidence that aligning stimulation frequencies to brain-intrinsic oscillatory subharmonics enhances plasticity effects. This insight could open a route toward personalized, more effective stimulation protocols.

eLife Assessment

This study is an important contribution to the field of viral sequencing, providing methods for more accurate characterization of viral genetic diversity using long-read sequencing and unique molecular identifiers (UMIs). Although it is a small pilot study, it shows promise as a convincing, validated methodology with broad applicability.

eLife Assessment

This study presents a useful method based on flow cytometry to study partitioning noise during cell division. The methods, data and analysis support the claims of the authors is convincing. This work will be of interest to cell biologists and biophysicists working on asymmetric partitioning during cell division.

To Taylor the VHS tapes are like a secret world. She ties the horror movies to a connection with her father and they foreshadow themes of this work.

eLife Assessment

This important study combines brain stimulation with fMRI and behavioural modelling to probe the role of the left superior frontal sulcus in perceptual and value-based decision making. The evidence that the left SFS plays a key role in perceptual decision making is convincing; the results also suggest that the value-based decision process was largely unaffected by the stimulation, despite a change in response times.

eLife Assessment

This important study presents a cross-species and cross-disciplinary analysis of cortical folding. The authors use a combination of physical gel models, computational simulations, and morphometric analysis, extending prior work in human brain development to macaques and ferrets. The findings support the hypothesis that mechanical forces driven by differential growth can account for major aspects of gyrification. The evidence presented is overall strong and convincingly supports the central claims; the findings will be of broad interest in developmental neuroscience.

eLife Assessment

This important study provides insights into the neurodevelopmental trajectories of structural and functional connectivity gradients in the human brain and their potential associations with behaviour and psychopathology. The evidence supporting the findings is solid. This study will be of interest to neuroscientists interested in understanding functional connectivity across development.

eLife Assessment

In this valuable technical report, Verma et al. provide convincing evidence that endogenously tagged dynein and dynactin form processive motor complexes that move along microtubules in living cells. Using quantitative fluorescence microscopy, they directly compare the stoichiometry and motility of these complexes to kinesin-1, revealing distinct transport behaviors and regulatory properties. This study offers key methodological and conceptual advance for understanding the dynamics of native motor proteins within the cellular environment and will be of interest to the cell biology community.

eLife Assessment

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

eLife Assessment

This important study combines a comprehensive range of biophysical, kinetic, and thermodynamic techniques, together with high-quality experimental and computational analysis, to carry out a series of well-designed experiments to explore whether glutamine-binding protein binds glutamine via an induced fit or a conformational selection process. The evidence supporting the major conclusion of the work is compelling. The work will be of broad interest to biochemists and biophysicists.

eLife Assessment

This study presents an important finding linking the bacterial metabolite trimethylamine and its receptor to circadian rhythms and olfaction. The current evidence supporting the claims of the authors is compelling. This work will be of broad interest to researchers interested in nutrition, microbial metabolism, circadian rhythms, and host-microbiome interactions.

eLife Assessment

This important study uses innovative microfluidics-based single-cell imaging to monitor replicative lifespan, protein localization, and intracellular iron levels in aging yeast cells. The evidence for the proposed role of Ssd1 and reduced nutrients for lifespan through limiting iron uptake is convincing, even though some mechanistic details remain unclear. This work will be of interest to cell biologists working on aging and iron metabolism.

eLife Assessment

This valuable study investigates how perceptual and semantic features of maternal behavior adapt to infants' attention during naturalistic play, providing new insights into the bidirectional and hierarchical organization of early social interaction. The methodology is innovative and overall solid, supported by comprehensive multimodal analyses and advanced information-theoretic methods, though some developmental claims warrant further tests of directionality and age effects. The work will be of interest to psychologists, cognitive scientists, and developmental researchers studying early communication, social learning, and methodological innovation in quantifying naturalistic behavior.

eLife Assessment

This valuable study focuses on a unique morphogenetic module, the junction-based lamellipodia (JBL). It provides a biomechanical understanding of how JBLs control endothelial cell-cell junctional remodelling to generate lumenised, multicellular blood vessels. The manuscript represents a robust, thoughtfully executed, and convincing study that uses high-resolution time-lapse imaging combined with pharmacological treatments to advance our understanding of lumen formation in vascular development.

eLife Assessment

The authors of this manuscript study the transcriptional regulators that allow macrophages to assume different functional phenotypes in response to immune stimuli. They generate a computational map of the gene regulatory networks involved in determining macrophage phenotypes and experimentally validate the role of putative regulatory factors in a myeloid cell line. This study represents a valuable approach to understanding how gene regulation impacts macrophage polarization and their conclusions are supported by solid computational and experimental evidence. The revision has clarified that the focus is the identification of the regulatory barcodes in a myeloid cell line. Future studies in primary cells and in vivo will be required to assess the roles of these regulators in a broader context.

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 to support these claims is convincing.

eLife Assessment

This important study substantially advances our understanding of pediatric Crohn's disease, mapping the cellular make-up of this disease and how patients respond to treatment. The evidence supporting the conclusions is compelling, with thorough bioinformatic analyses, underpinned by rigorous methodology and data integration. The work will be of broad interest to pediatric clinicians, immunologists and bioinformaticians.

eLife Assessment

This important study provides solid evidence to support the anti-tumor potential of citalopram, originally an anti-depression drug, in hepatocellular carcinoma (HCC). In addition to their previous report on directly targeting tumor cells via glucose transporter 1 (GLUT1), the authors tried to uncover additional working mechanisms of citalopram in HCC treatment in the current study. The data here suggests that citalopram may regulate the phagocytotic function of TAM via C5aR1 or CD8+T cell function to suppress HCC growth in vivo.

eLife Assessment

This functional MRI study critically tests the hypothesis that poor face recognition in developmental prosopagnosia in humans is driven by reduced spatial integration and smaller receptive fields in face-selective brain regions. The evidence provided is compelling as it is well-powered, uses state-of-the-art functional brain imaging, eye tracking, and computational analyses. The observed lack of difference in population receptive field sizes between face-selective brain regions of individuals with and without prosopagnosia, though a null result, has important implications for the field, and specifically, for theories of face recognition.

eLife Assessment

This manuscript makes a valuable contribution to understanding learning in multidimensional environments with spurious associations, which is critical for understanding learning in the real world. The evidence is based on model simulations and a preregistered human behavioral study, but remains incomplete because of inconclusive empirical results and insufficiencies in the modeling. Moreover, there are open questions about the nature and extent to which the behavioral task induced semantic congruency.

eLife Assessment

AGC kinases, such as PKN1, are regulated by activation loop phosphorylation. This paper reports that exposing cells to high concentrations of monovalent cations induces rapid activation loop dephosphorylation, with rapid re-phosphorylation when physiological salt is restored. Re-phosphorylation is apparently independent of ATP or candidate kinases, and the paper presents an extraordinary and unconventional mechanism involving phosphate exchange between the activation loop and an unknown acceptor molecule. The findings are intriguing and the approach is logical, but the evidence is incomplete and the significance unclear until the biochemical mechanism is identified.

eLife Assessment

This important study uncovers a previously unrecognized light-responsive pathway in C. elegans, centred on ZIP-2/CEBP-2 and the cytochrome P450 enzyme CYP-14A5. The pathway operates independently of known photoreceptors, modulates long-term memory, and can be harnessed as a low-cost light-inducible expression system, opening new directions for sensory biology and genetic engineering in worms. The strength of evidence is compelling if a bacterially derived stimulus is ruled out. Multiple genetic, transcriptional, and behavioural assays support the pathway's role, but a decisive test showing that the initiating light cue is worm-intrinsic rather than mediated by changes in the bacterial food source is still needed.

eLife Assessment

This important study describes a deep learning framework that analyzes single-cell RNA data to identify a tumor-agnostic gene signature associated with brain metastases. The identified signature uncovers key molecular mechanisms, highlights potential therapeutic targets, and demonstrates a metastasis-specific transcriptional signal in circulating platelets, suggesting its promise for non-invasive diagnostics through liquid biopsy. The evidence supporting the findings is solid, utilizing interpretable deep learning methodologies and large-scale datasets across multiple cancer types, though some aspects may benefit from additional analysis and validation.

eLife Assessment

This valuable study presents the first detailed and comprehensive description of brain sulcus anatomy of a range of carnivoran species based on a robust manual labeling model allowing species comparisons. The database and method for reconstructing cortical surfaces are compelling, and the evidence supporting the conclusions is solid. Despite the additional specimen, the evaluation of intra-species variations remains limited, but an insight into the inter-individual variability is now available for certain species. Exploring the associations between sulcal length and behavioral characteristics further suggests the potential of sulci as a proxy of functional organization. Setting an instructive foundation for comparative anatomy, this study will be of interest to neuroscientists and neuroimaging researchers interested in that field, as well as in brain morphology and sulcal patterns, their phylogeny and ontogeny in relation to functional development and behaviour.

eLife Assessment

This valuable study examines the role of IL17-producing Ly6G PMNs as a reservoir for Mycobacterium tuberculosis to evade host killing activated by BCG immunisation. The authors provide solid data reporting that IL17-producing polymorphonuclear neutrophils harbour a significant bacterial load in both wild-type and IFNg-/- mice and that targeting IL17 and Cox2 improved disease outcomes whilst enhancing BCG efficacy. The specific contribution of neutrophil-derived IL-17 to disease pathogenesis remains to be definitively established through direct demonstration of IL-17 production by neutrophils and targeted depletion studies.

eLife Assessment

This important study provides new insights into the neuronal dynamics of the locus coeruleus in relation to hippocampal sharp-wave ripples. Using high-temporal-resolution, multi-site electrophysiological recordings in rats, the authors present solid evidence supporting their main claims. Nonetheless, some aspects of the evidence remain incomplete, and several points in the data presentation would benefit from clarification. Overall, the work will be of interest to neuroscientists studying large-scale brain coordination and memory processes.

eLife Assessment

Using a combination of connectomics, optogenetics, behavioral analysis and modeling, this study provides important findings on the role of inhibitory neurons in the generation of leg grooming movements in Drosophila. The data as presented provide convincing evidence that the identified neuronal populations are key in the generation of rhythmic leg movements. Based on reconstructions from ventral nerve cord electron microscopy data, the authors uncover distinct pathways to the motor neurons, which they propose inhibit and disinhibit antagonistic sets of motor neurons. This results in an alternation of flexion and extension. By analyzing limb kinematics upon silencing of specific populations of premotor inhibitory neurons and using computational modelling, they show the potential role of these neurons in rhythmic leg movement. The work will interest neuroscientists and particularly those working on motor control.

eLife Assessment

This manuscript provides important information on the neurodynamics of emotional processing while participants were watching movie clips. This work provides convincing results in deciphering the temporal-spatial dynamics of emotional processing. This work will be of interest to affective neuroscientists and fMRI researchers in general.

eLife Assessment

The conclusions of this work are based on valuable simulations of a detailed model of striatal dopamine dynamics. Establishing that lower dopamine uptake rate can lead to a "tonic" level of dopamine in the ventral but not dorsal striatum, and that dopamine concentration changes at short delays can be tracked by D1 but not D2 receptor activation, is invaluable and will be of interest to the community, particularly those studying dopamine. The model simulations provide convincing evidence for differences between dorsal and ventral striatum dopamine concentrations, while evidence for differential tracking of dopamine changes by D1 vs D2 receptors is solid.

eLife Assessment

In this useful study, the authors utilize published scRNA-seq data to highlight the potential importance of mast cells (MCs) in TB granulomas, presenting a solid comparative assessment of chymase- and tryptase-expressing MCs in the lungs of Mycobacterium tuberculosis-infected individuals and non-human primates. While the authors appropriately discussed the inconsistencies across models, adoptive transfer experiments in MC-deficient mice would substantially strengthen the causal link between MCs and TB outcomes, providing more direct functional validation of the proposed role of MCs in TB pathogenesis.

eLife Assessment

This important study demonstrates a reduction in airway hyperresponsiveness (one of the mechanisms of allergic asthma) in the absence of IgM in a house dust mite-induced mouse model of allergic asthma. While this result suggests a new mechanistic role for IgM, the proposed new function is not as yet robustly supported by the current experiments and thus the evidence remains incomplete. A connection between the findings and human disease is not established so far, but the study will be interest to clinical immunologists.

eLife Assessment

This study used deep neural networks (DNN) to reconstruct voice information (viz., speaker identity), from fMRI responses in the auditory cortex and temporal voice areas, and assessed the representational content in these areas with decoding. A DNN-derived feature space approximated the neural representation of speaker identity-related information. The findings are valuable and the approach solid, yielding insight into how a specific model architecture can be used to relate the latent spaces of neural data and auditory stimuli to each other.

eLife Assessment

This study makes a valuable contribution by elucidating the genetic determinants of growth and fitness across multiple clinical strains of Mycobacterium intracellulare, an understudied non-tuberculous mycobacterium. Using transposon sequencing (Tn-seq), the authors identify a core set of 131 genes essential for bacterial adaptation to hypoxia, providing a convincing foundation for anti-mycobacterial drug discovery. Minor concerns remain regarding the presentation of Fig. 8C and the interpretation of data related to hypoxia.

eLife Assessment

This work offers important insights into the protein CHD4's function in chromatin remodeling and gene regulation in embryonic stem cells, supported by extensive biochemical, genomic, and imaging data. The use of an inducible degron system allows precise functional analysis, and the datasets generated represent a key resource for the field. While some interpretations of complex data could be more strongly substantiated, the study overall provides compelling evidence and makes a significant contribution to understanding CHD4's role in epigenetic regulation. This work will be of interest to the epigenetics and stem biology fields.

eLife Assessment

Dong et al. present a valuable analysis of mutant phenotypes of the Rab GTPases Rab5, Rab7, and Rab11 in Drosophila second-order olfactory neuron development. This is a solid characterization and comparison of the different Rab mutants on projection neuron development, with clear differences for the three Rabs, and by inference for the early, late, and recycling endosomal functions executed by each.

eLife Assessment

This valuable study uses mathematical modeling and analysis to address the question of how neural circuits generate distinct low-dimensional, sequential neural dynamics that can change on fast, behaviorally relevant timescales. The authors propose a circuit model in which spatially heterogeneous inhibition constrains network dynamics to sequential activity on distinct neural subspaces and allows top-down sequence selection on fast timescales. The study convincingly demonstrates how this mechanism could operate and makes predictions about connectivity patterns and dynamics.

eLife Assessment

This manuscript presents a valuable antiviral approach using an engineered ACE2-Fc fusion protein that demonstrates broad-spectrum neutralization capacity against SARS-CoV-2 variants and achieves significant prophylactic protection in animal models through a novel Fc-mediated phagocytosis mechanism. The study provides convincing evidence for protective efficacy through rigorous in vivo validation in mice, mechanistic characterization via biodistribution studies and macrophage depletion assays, and demonstration of antibody-dependent cellular phagocytosis as the primary clearance mechanism. However, there are some gaps that require attention, including the need for comparison with a previously reported ACE2 decamer, inclusion of control molecules, insufficient discussion of potential limitations such as off-target binding and immunogenicity risks, and lack of clarity regarding certain methodological aspects.

eLife Assessment

This report provides useful evidence that EABR mRNA is at least as effective as standard S mRNA vaccines for the SARS-CoV-2 booster vaccine. Although the methodology and the experimental approaches are solid, the inconsistent statistical significance throughout the study presents limitations in interpreting the results. Also, the absence of results showing possible mechanisms underlying the lack of benefit with EABR in the pre-immune makes the findings mostly observational.

eLife Assessment

This is an important study on how dissociable emotions of shame and guilt emerge from cognitive processes and guide behavioral responses. The task is well designed and yields compelling behavioral, computational, and neural evidence elucidating the cognitive link between emotions and compensatory decisions. The work has broad theoretical and practical implications across a range of disciplines concerned with human behavior, including psychology, neuroscience, economics, public policy, and psychiatry.

eLife Assessment

This Review Article provides a timely review of how the extracellular matrix (ECM), particularly the vascular basement membrane, regulates leukocyte extravasation, migration, and downstream immune function, with a focus on monocytes/macrophages. It integrates molecular, mechanical, and spatial aspects of ECM biology in the context of inflammation, drawing from recent advances.

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, and while the revisions made by the author have addressed most of the concerns the reviewers had about the original version, a small number of concerns remain.

eLife Assessment

This study presents a valuable finding regarding the role of Arp2/3 and the actin nucleators N-WASP and WAVE complexes in myoblast fusion. The data presented is convincing, and the work will be of interest to biologists studying skeletal muscle stem cell biology in the context of skeletal muscle regeneration.

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 authors acknowledge the lack of mechanistic insight which represents the main limitation of the study.

eLife Assessment

This important study addresses a topic that is frequently discussed in the literature but is under-assessed, namely correlations among genome size, repeat content, and pathogenicity in fungi. Contrary to previous assertions, the authors found that repeat content is not associated with pathogenicity. Rather, pathogenic lifestyle was found to be better explained by the number of protein-coding genes, with other genomic features associated with insect association status. The results are considered solid, although there remain concerns about potential biases stemming from the underlying data quality of the analyzed genomes.

eLife Assessment

This potentially valuable work aimed at a better understanding of the mechanisms of response and resistance to androgen deprivation therapy in prostate cancer using genetically engineered mouse models. A key observation relates to the timing of TNF blockage therapy and the concept of a "TNF switch." The solid data were collected using conventional approaches and the conclusions are mostly justified, particularly with the inclusion of more detailed statistics in the revision. The work will be of interest to the prostate cancer research community.

eLife Assessment

This useful study uses a combination of experimental and modeling approaches to investigate the role of actomyosin in epithelial invagination during Ciona siphon tube morphogenesis. Several types of solid quantitative analyses are presented, yet the evidence supporting the central claim of bidirectional translocation of actomyosin remains incomplete. Since epithelial invagination contributes to the morphogenesis of many developing organs, this work has the potential to appeal to both cell biologists and developmental biologists.

eLife Assessment

This important study presents a technically rigorous and carefully controlled analysis of the signalling potential of cancer-associated gain-of-function Notch alleles. The work is clearly presented, and the experiments are robust, comprehensive, and well-controlled. While some data primarily establish the system or report negative findings, the comparative approach in a well-characterized model provides convincing mechanistic evidence for how these Notch variants function. This study will be of interest to researchers in both developmental and cancer biology.

eLife Assessment

This study investigates the influence of genomic information and timing of vaccine strain selection on the accuracy of influenza A/H3N2 forecasting. The authors utilised appropriate statistical methods and have provided convincing evidence, which amounts to an important contribution to the evidence base. Substantial revisions have been made to the manuscript and issues of concern have been clarified, with the necessary study limitations appropriately discussed.

eLife Assessment

This manuscript reports on an FLIM-based calcium biosensor, G-CaFLITS. It represents an important contribution to the field of genetically-encoded fluorescent biosensors, and will serve as a practical tool for the FLIM imaging community. The paper provides convincing evidence of G-CaFLITS's photophysical properties and its advantages over previous biosensors such as Tq-Ca-FLITS. Although the benefits of G-Ca-FLITS over Tq-Ca-FLITS are limited by the relatively small wavelength shift, it presents some advantages in terms of compatibility with available instrumentation and brightness consistency.

eLife Assessment

The manuscript by Mancl et al. provides important mechanistic insights into the conformational dynamics of Insulin Degrading Enzyme (IDE), a zinc metalloprotease involved in the clearance of amyloid peptides. In the revised version, the authors have substantially expanded their analysis by incorporating time-resolved cryo-EM and coarse-grained molecular dynamics simulations, which reveal an insulin-induced allosteric transition and transient β-sheet interactions underlying IDE's unfoldase activity. Supported by a convincing combination of cryo-EM, SEC-SAXS, enzymatic assays, and both all-atom and coarse-grained simulations, this work refines our understanding of IDE's functional cycle and offers a structural framework for developing substrate-selective modulators of M16 metalloproteases.