eLife Assessment

By using a combination of patch clamp recordings, calcium imaging and computer modeling, the authors analyze the spatial distribution of voltage gated calcium channels at glutamatergic synapses formed between layer 5 pyramidal neurons (L5PNs) and between layer 2/3 and L5PNs in the prefrontal cortex (PFC) and primary somatosensory cortex (S1); they conclude that the calcium channel-vesicle coupling is looser in the PFC compared to S1, although additional experiments are needed to determine how the distinct functional characteristics of these synapses in different brain regions might affect data interpretation. Overall, these findings are important because they have implications for shaping synaptic plasticity and neural circuit function across brain regions. They are solid because they are based on the use of a multi-pronged approach, although the presentation would benefit from stronger integration of the current findings with the existing literature and a more explicit discussion of potential limitations and confounding factors for data interpretation.

eLife Assessment

The findings of this study are important since they cover the repurposing of small molecules as metalloprotease and phospholipase inhibitors for early intervention in the treatment of bothropic envenoming in the Neotropics, and thus provide a strong rationale for the progression of these inhibitors into future preclinical and clinical evaluation for snakebite indications across various ecological zones, albeit the current evidence casts doubts on the viability of repurposing nafamostat. The strength of the evidence is solid; however, there are some weaknesses, such as a lack of translatability of the in vivo model and insufficient venom characterization. Thus, the strength of the evidence can be enhanced by using a mouse model in future studies. The paper remains of interest to ophiologists, biochemists and medicinal chemists.

eLife Assessment

This study introduces an important method to estimate the probability of malaria importation with a new Bayesian approach that integrates epidemiological, travel reports, and genetic data. The authors provide convincing evidence for the value of this model in identifying the main sources of malaria transmission and risk factors. This work will be of interest to the area of genomic epidemiology and public health strategies aiming to eliminate malaria.

eLife Assessment

This is an important study describing 'SPEx', a broadly accessible method that combines cell expansion, laser microdissection, and mass spectrometry to enable subcellular proteomic profiling. The authors provide convincing evidence that this flexible integration of established techniques provides a robust and practical approach for compartment-resolved spatial proteomics. The authors support their main claims with appropriate validation across multiple subcellular compartments and show that the method can recover known markers while also identifying previously uncharacterized components. Overall, the work is likely to be of broad interest to cell and molecular biologists, particularly those seeking scalable and cost-effective strategies for mapping organelle composition.

eLife Assessment

This important study presents a theoretically grounded framework for dimensionality reduction in single-cell RNA sequencing data, utilizing the principles of Riemannian manifolds. The proposed method addresses a critical challenge in bioinformatics-extracting highly informative latent dimensions without relying on the heuristic assumptions common in existing workflows. The evidence supporting the method's utility in estimating intrinsic dimensionality and identifying cell types is convincing, though the work would benefit from more rigorous validation against established ground truths and a clearer strategy for addressing prevalent batch effects.

eLife Assessment

This study reports the relative importance of Tie1 and Tie2 signaling for atrial versus ventricular trabeculation. It is an important study and is one of the few works to date that have carefully and simultaneously analyzed these two processes. In line with a previous study in zebrafish, the authors demonstrate key differences between atrial and ventricular trabeculation. While the imaging and quantitative data were conducted with solid and validated methodology throughout the manuscript, the work would benefit from more rigourous approaches where Tie1/2 signaling is disrupted prior to the onset of atrial/ventricular trabeculation, to allow for a more direct comparison.

eLife Assessment

This Review Article provides a scholarly, clear and well-structured review of intracranial research into the neural correlates of consciousness (NCCs). To our knowledge this is the first such review and is therefore likely to become a must-read for anyone working in the field of consciousness research. The authors discuss the difficulties that researchers must face when studying NCCs and how insights may emerge via intracranial recordings in humans. This no doubt reflects an in-depth, timely, and insightful contribution to the literature.

eLife Assessment

The authors provide a scholarly review of intracranial research into the neural correlates of consciousness (NCCs). To our knowledge, this is the first such review, and it therefore may become a must-read for anyone working in the field of consciousness research. It is not so persuasive that intracranial recordings are better suited to identifying pure NCCs than other methods, which appears a problem instead solved through novel paradigms and better-developed theories - but this no doubt reflects an in-depth, timely, and insightful contribution to the literature.

eLife Assessment

The revised version of the paper demonstrates that a genetic code expansion to tag two ALS proteins associated with stress granules is useful and convincingly evaluates the utility of the genetic code expansion in this context. The data is solid and demonstrates the feasibility of using ANAP-fluorescence for live cell imaging.

eLife Assessment

This important study identifies a physiologically relevant interaction between LRRK2 and drebrin, an actin-binding protein crucial for neuronal structure. A solid body of evidence, including multiple cell models, highlights the complexities of how modifiers like BDNF intersect with LRRK2-kinase dependent function, and that many modifiers between AKT and LRRK2 in different cellular pathways are yet to be identified and understood.

eLife Assessment

This important study provides solid evidence that early childhood malaria exposure affects the development of antibody responses to unrelated pathogens and vaccine-derived antigens in Kenyan children. The findings are of major public health importance and limitations of the observational study design are properly acknowledged.

eLife Assessment

This valuable study identifies a brown adipose tissue-specific heat shock factor 1 (HSF1)-alcohol dehydrogenase 5 (ADH5) axis that regulates oxidative stress and cellular senescence during aging. The authors show that ADH5 deficiency drives BAT dysfunction and contributes to organismal health decline in aged mice. The evidence is convincing, and the work will be of broad interest to the adipose tissue and aging research communities.

eLife Assessment

The study by Reed et al. provides fundamental findings defining the topological changes that occur during tumorigenesis. These compelling findings enhance the understanding of stable long-range connections among genes that reprogram cancer-related functions.

eLife Assessment

This study reports a novel function for syntaxin 11, a specialized SNARE protein critical for the immune system whose mutations cause familial hemophagocytic lymphohistiocytosis type 4. The data convincingly show that depletion of STX11 impairs store-operated calcium entry in Jurkat T cells and that this defect is recapitulated in primary cells from a patient suffering from the disease; the authors further show that the syntaxin interacts with the pore subunit of the ORAI1 channel and propose that it primes the channel by promoting the assembly of multimers before activation by its endogenous ligand, the ER Ca2+ sensing protein STIM1. This is a conceptually important claim that challenges the prevailing view that all structural transitions in ORAI1 are STIM-driven. The data are high-quality and broadly consistent with the interpretation, but alternative mechanisms for the defects are not considered; additional work should rule out vesicular trafficking, discuss other mechanisms, and address methodological issues.

eLife Assessment

This valuable study demonstrates that a multi-step differentiation programme in bacteria combining a bistable switch with two quorum-sensing systems is capable of generating autonomous and self-organized spatial patterns. The evidence for the core engineering system supporting patterning across several conditions is convincing, albeit incomplete for the stronger differentiation/maturation claims because the irreversibility of the proposed states is not consistently established, and some modelling and conceptual interpretation details require further clarification.

eLife Assessment

This important study provides detailed insights into the metabolic states of hemocyte populations across developmental stages and in both physiological and pathological contexts, including during immune challenge. The study provides convincing evidence by comparing the relative utilization of glycolysis and oxidative phosphorylation in Drosophila larval immune cells, and can have implications for metabolic programs that shape immune function in health and disease.

eLife Assessment

This important study combines single-molecule imaging and CUT&TAG to address the molecular mechanism underlying the differentiation process that initiates the formation of red blood cells in the bone marrow. The authors provide evidence that the transcription factor GATA2 transiently associates with a new set of genomic loci early in the differentiation process before it is replaced by GATA1. Together, the experiments across three biological systems are solid, but they could benefit from additional details and controls to strengthen the conclusions.

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 convincing, 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

This is a valuable study presenting convincing data indicating that the bacterial GTPases EngA and ObgE enable single-step reconstitution of functional 50S ribosomal subunits under near-physiological conditions. The study elegantly bridges the gap between the non-physiological aspects of the previous two-step reconstitution method and the extract-dependent iSAT system to enable assembly of highly functional ribosomes under translation-compatible conditions. The reported findings represent substantial progress towards achieving a bottom-up reconstruction of the translation machinery from synthetic parts.

eLife Assessment

This study investigates how the HIV inhibitor lenacapavir influences capsid mechanics and interactions with the nuclear pore complex. It provides important insights into how drug-induced hyperstabilization of the viral shell can compromise its structural integrity during nuclear entry. The modeling is technically sophisticated, and the analyses provide convincing support for the mechanistic conclusions.

eLife Assessment

This valuable study examines the cleavage of motor neuron nucleoporins by proteases of enterovirus D68, a pathogen associated with acute flaccid myelitis. The evidence supporting the effects of EV-D68 proteases on nuclear import and export is generally solid, as is the independent examination of EV-D68 protease on spinal cord neuron toxicity. The specific conclusions related to RNA export were considered overstated relative to the data presented.

eLife Assessment

This study offers an important advance by extending an intuitive visualization tool that enables assessment of how dendritic and synaptic currents potentially shape neuronal output. The evidence supporting the tool's capabilities is convincing, with well-documented code, algorithmic innovation, and application to hippocampal pyramidal neurons. The work will be of interest to computational and systems neuroscientists seeking accessible methods to examine dendritic computations.

eLife Assessment

This important study reports characterisation of hepatocyte molecular pathways affected by a glycyrrhizin derivative in both in vivo and in vitro mouse models of alcohol-associated liver disease. The authors show convincing evidence indicating that IPP delta isomerase 1 (Idi1) is an intermediate in these pharmacological effects, via the binding of the glycyrrhizin derivative to an upstream regulator of Idi1, HSD11B1, although significant questions remain about some of the experiments and analyses provided. The findings would be of interest to immunologists and pharmacologists interested in liver inflammation and its amelioration.

eLife Assessment

This valuable study advances our understanding of how organisms respond to chronic oxidative stress. Using the nematode C. elegans, the authors identified key neuronal signaling molecules and their receptors that are required for stress signaling and survival. The evidence supporting the conclusions is solid, including rigorous genetics, stress response analysis, and transcriptional profiling. This research will be of broad interest to neuroscientists and researchers working in the field of oxidative stress regulation.

eLife Assessment

In this valuable study, the authors conducted an impressive amount of atomistic simulations with a glycosylated HIV-1 envelope glycoprotein (Env) trimer in a realistic asymmetric lipid bilayer. The aim was to probe how Env transmembrane domain, cytoplasmic tail, and membrane environment influence ectodomain orientation and antibody epitope exposure. The simulations convincingly show that ectodomain motion is dominated by tilting relative to the membrane and explicitly demonstrate the role of membrane asymmetry in modulating the protein conformation and orientation. Additional analyses of the authors' deposited MD trajectories could serve as invaluable extensions of this work to probe, for example, for exposure of cryptic epitopes and potential allosteric coupling.

eLife Assessment

This study provides fundamental insights by demonstrating that the Nanog mRNA coding sequence (CDS) and 3′UTR domains are spatially segregated and functionally distinct in pluripotent stem cells and blastocysts, with 3′UTR-enriched border cells primarily influencing morphogenesis and CDS-enriched inner cells largely regulating transcription and epigenetic programs. The work opens a novel conceptual avenue for understanding how separable mRNA domains can differentially control cell behavior and differentiation. However, the evidence is incomplete, as key aspects of the molecular nature, biogenesis, and precise characterization of the separated 3′UTR and CDS RNA species, as well as causal links between their perturbation and the observed phenotypes (e.g., via rescue and deeper characterization of 3′UTR elements), remain to be fully established.

eLife Assessment

There is a need for better and safer dengue virus live attenuated vaccines. This manuscript describes important findings that could lead to the design of a strongly immunogenic, tetravalent live attenuated vaccine for dengue, without the risk of causing antibody-dependent enhancement. However, the experimental evidence presented is incomplete since only constructions of one serotype were tested to prove the principle.

eLife Assessment

The authors propose a "simplified" model for intrinsically bursting neurons with explicitly controllable parameterization of oscillatory dynamics. The evidence that the modeling approach is generally appropriate and practical for modeling rhythmic bursting neurons and neural circuits is currently incomplete. Based on what the authors present, this model appears to have limited neurobiological relevance and utility but may be useful as a controller for an artificial system, such as in neuro-robotics applications.

eLife Assessment

This study presents potentially important findings linking peripheral inflammation to the remodeling of perinodal adipose tissue and draining lymph nodes, suggesting a mechanism by which local tissue inflammation can reshape LN structure and metabolism. The idea is solid and supported by observations. However, the evidence remains incomplete in parts, as several conclusions rely on correlative weight and cellularity measurements, and macrophage involvement requires further validation.

eLife Assessment

This important study provides a comprehensive map of how touch-sensitive neurons in the fly head connect to downstream circuits, revealing parallel pathways that preserve spatial organization and identifying a developmentally defined circuit linking sensory input to grooming behavior. The evidence is convincing, with detailed anatomical reconstruction and quantitative analysis supporting the main claims, while the link to behaviour remains based on prior functional work. The study will be of interest to neuroscientists studying sensory processing and motor control, and provides an invaluable resource for future functional investigations.

eLife Assessment

This important study combines optogenetic manipulations with wide-field cortical imaging to investigate the neural basis of context-dependent sensory processing. It provides compelling evidence that the retrosplenial cortex modulates behavioral responses to whisker deflection depending on the behavioral context. The paper will be of strong interest to neuroscientists studying cortical mechanisms of sensorimotor processing.

eLife Assessment

This is an important contribution that confirms prior evidence that word recognition - a cornerstone of development - improves across early childhood and is related to vocabulary growth. This study is distinguished by its use of a large, multi-study dataset that is uncommon in prior research on cognitive development. It provides compelling evidence that speed, accuracy, and consistency of word learning improve with age, and will therefore prove of interest to those studying language, and more broadly, perception and development.

eLife Assessment

This important study is the first characterization of the phenotype caused by a lack of Eml3 expression in mice. Mutant animals present a disrupted pial basement membrane, leading to focal extrusions from the cerebral cortex, called ectopias. The methodology is convincing and the conclusions are solid, although further investigations on the molecular and cellular mechanisms are required to improve the manuscript. This work would be of interest to neural development biologists and human geneticists working on brain disorders.

eLife Assessment

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

eLife Assessment

This manuscript applies a theoretical analysis to two published datasets on yeast and bacterial evolution to compare different ways of quantifying fitness. It makes an important advance by clarifying how discrepancies can arise by using different approaches and provides recommendations for best practices. Overall, this is an impressive and highly beneficial study that is based on convincing evidence and has the potential of setting standards in this rapidly growing field.

eLife Assessment

This is a valuable study presenting solid data indicating that the bacterial GTPases EngA and ObgE enable single-step reconstitution of functional 50S ribosomal subunits under near-physiological conditions. The study elegantly bridges the gap between the non-physiological aspects of the previous two-step reconstitution method and the extract-dependent iSAT system to enable assembly of highly functional ribosomes under translation-compatible conditions. The reported findings represent progress towards achieving a bottom-up reconstruction of the translation machinery from synthetic parts.

eLife Assessment

This is an important study that develops multiple human iPSC-based models to study the consequences of DNMT3A mutations in Tatton-Brown-Rahman Syndrome. Convincing evidence shows dysregulation of GABAergic interneuron development and function, and the authors identify some of the key signaling mechanisms underlying these changes. This study will be of interest for understanding the functions of DNMT3A in brain development and the causes of neurological dysfunction in Tatton-Brown-Rahman Syndrome.

eLife Assessment

This is a useful study investigating the role of peristalsis in the elongation of the gut, using the chick ceca as a model. The work employs optogenetics together with embryological approaches to establish links between peristaltic muscle contractions and downstream cell behaviors that lead to tube elongation. However, the work is somewhat incomplete, limited in mechanistic insights that would extend beyond prior work in the literature, which has already suggested a role for smooth muscle contractility in avian gut elongation.

eLife Assessment

This valuable study builds a novel auditory-motor paradigm to investigate how the brain learns associations between movements and their auditory consequences. Solid evidence is provided for early ERPs (50-100 ms latency) reflecting violations of established key-pitch mappings. The writing, however, could be streamlined to better emphasize the paper's key contribution, and some statistical analyses might be improved.

eLife Assessment

This useful study asked whether the behaviour of motor units from a hand muscle changed across the two mechanical actions it performs. The authors used high-density intramuscular electrodes to record the activity of several motor units and reported changes in motor unit recruitment order across tasks that were not dependent on motor unit properties, suggesting differential spinal contributions to the two actions. However, the evidence supporting their main claims is incomplete, and some of the conclusions are based on unsubstantiated assumptions: the authors should correct several key analyses and temper claims that are not directly backed up by their data.

eLife Assessment

The authors make the valuable observation that directional memory during epithelial cell migration is enhanced compared to single-cell migration. They attribute this effect to adherens junctions and vinculin dimerization. In the work, central measures should be defined more precisely, and the support for their claims about the roles of adherens junctions and vinculin dimerization in memory enhancement remains incomplete.

[Editors' note: this paper was previously reviewed by another journal.]

eLife Assessment

This important study fills a major geographic and temporal gap in understanding Paleocene mammal evolution in Asia and proposes an intriguing "brawn before bite" hypothesis grounded in diverse analytical approaches. The work rests on a solid methodological base. Some limitations remain, including uncertainty introduced by pooling different tooth positions, limited dietary interpretation, and the predominantly herbivorous taxonomic focus, which narrows the ecological scope of the conclusions. However, the manuscript provides a substantially strengthened and well-supported contribution, while appropriately inviting further work to clarify dietary trends, broader ecological context, and links between dental trait evolution and environmental change.

eLife Assessment

This valuable paper describes the regulation of the association of meiotic chromosome axis proteins on chromosome ends with sub-telomeric elements in budding yeast. The genome-wide analyses of binding of chromosome components as well as chromatin regulators, complemented with the mapping of meiotic DNA double-strand breaks on chromosome ends, provided solid evidence to support the authors' conclusion. The results in the paper are of interest to researchers in meiotic recombination and the structure of genomes and chromosomes.

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. The evidence for visuomotor mismatch responses is solid, although the interpretation in terms of prediction remains somewhat preliminary. 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 important study convincingly shows that Vibrio bacteria act as predators of ecologically significant algae that contribute to harmful blooms in the lab and in their natural habitat, and that predation is induced by starvation. The authors suggest a working model that can be the basis for future work on this system. The study will be very impactful to those interested in the diversity of microbial predator-prey interactions and controlling toxic algal bloom.

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 employ computational psychophysics and attempt to model perceptual stimulus fields with smooth variations over coordinate spaces.

eLife Assessment

This study addresses the mechanism of action of benzoylurea insecticides and explores the metabolic consequences of inhibiting glycogen breakdown in insects. Both reviewers identify major flaws with the premise of the work. The strength of the provided evidence is inadequate as the data do not, or poorly, support several central claims. The significance of the findings is considered marginal.

eLife Assessment

The study provides valuable findings suggesting that modifying the donor's diet improves the effectiveness of fecal transplant therapies for liver disease. Although the reported results are of value, the evidence supporting the overall conclusions is incomplete. In particular, causal inferences regarding the effects of microbiota composition, as well as caproic acid signaling on the phenotypes studied, need further confirmation.

eLife Assessment

This Review Article provides a compendium of advice for MD-PhD students to consider when deciding which, if any, clinical field they will select for residency training. It is grounded in published data and effectively considers factors including the potential for clinical disciplines to sustain research integration, provide mentorship, meet lifestyle expectations, and foster a long-term career as a research-focused physician-scientist.

eLife Assessment

This valuable study presents a tool that uses brain anatomy to predict the layout and size of early visual maps, and it is strengthened by the use of a large and diverse collection of scans to examine differences across people and groups. The evidence is solid for the general usefulness of the approach, but incomplete for some of the broader claims about prediction accuracy and use across data sets, particularly for estimates of map size and for showing that the model improves on repeated functional measurements. This paper is likely to be of significant interest to visual perception researchers, especially those who use fMRI.

eLife Assessment

This is an important and rigorous study that addresses the question of what determines the spatial organization of endocytic zones at synapses. The authors use compelling approaches, in both Drosophila and rodent model systems, to define the role of activity and active zone structure on the organization of the peri-active zone. While the findings are primarily negative, they are carefully executed and contribute to the field by refining existing models of presynaptic organization.

eLife Assessment

This potentially useful manuscript addresses the 3D chromatin architecture in monocytes from a few patients with alcohol-associated hepatitis and its relationship to enhanced transcription of innate immune genes. While the concept and methodological approach are interesting in principle, the evidence is incomplete as a result of insufficient sample sizes as well as other substantive analytical concerns.

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 transcriptomic analysis and biodistribution studies, and demonstration of antibody-dependent cellular phagocytosis as the primary clearance mechanism mediated by the decoy. The work will be of interest to researchers working in vaccine development and associated immune responses.

eLife Assessment

This study integrates large-scale behavioral, genetic, and molecular analyses in animal models to investigate morphine response. Utilizing high-quality, time-series Quantitative Trait Loci (QTL) mapping, the work provides compelling evidential support for novel, time-dependent genetic interactions (epistasis). A fundamental result of this rigorous analysis is the discovery of a novel Oprm1-Fgf12-MAPK signaling pathway, which offers new insights into the mechanisms of opioid sensitivity.

eLife Assessment

This important study investigates how the nervous system adapts to changes in the mechanics of the body, which are altered through a tendon transfer surgery affecting finger extensor and flexor muscles. By measuring task performance, joint kinematics, and muscle activity for several weeks post surgery, the authors provide convincing evidence that monkeys undergo a two-phase adaptation process. First, they adopt a maladaptive strategy to overcome the functional challenges imposed by the surgery, and then revert to a strategy that uses the same patterns of muscle coactivation observed pre-tendon transfer.

eLife Assessment

This useful study uses a chemoinformatics pipeline to identify a list of candidate mosquito repellants that may be pleasant to smell and safe for humans. The strength of evidence and in particular the computational methodology are incomplete because it is insufficiently benchmarked against other leading models. At the high concentrations tested, there may also be off-target effects of the repellents on the mosquitoes that are not considered.

eLife Assessment

This manuscript proposes a valuable idea on how cortical networks may learn a helpful representation of sensory stimuli. The model implementing this idea is tested in multiple experimental paradigms. However, the evidence remains incomplete as to whether the method supports both invariance and equivariance and whether it can estimate the dynamics of the moving object.

eLife Assessment

This valuable study examines how the prelimbic cortex represents learned and generalized threat over time and identifies potentially distinct stable and dynamic subnetworks that may support these functions. The work is conceptually interesting and is strengthened by the longitudinal calcium imaging approach and the inclusion of key control groups. However, the evidence supporting the claims is incomplete, particularly because the interpretations regarding inference, time-dependent representational change, and the dissociation of neural activity from freezing behavior extend beyond what is currently established by the data.

eLife Assessment

This short report is an important study that visual acuity declines nonlinearly with cone dropout, while eye motion partially compensates by improving sampling from remaining cones. The method for experimentally simulating cone dropout is compelling, leveraging state-of-the-art imaging and testing in human subjects. Inclusion of additional analysis on absolute cone density and eye motion would further strengthen the study.

eLife Assessment

Fujita et al. examine the effects of AM-2099, a Nav1.7 inhibitor, on the excitability of human dorsal root ganglion neurons and compare these results to their prior study of Nav1.8 inhibition by suzetrigine. They show that the Nav1.7 inhibitor primarily alters action potential threshold and initiation, but not repetitive firing, whereas Nav1.8 inhibition elicits much stronger inhibition on repetitive firing. These complementary roles of Nav1.7 and Nav1.8 provide a plausible cellular explanation for the limited clinical success of Nav1.7 inhibitors compared to Nav1.8 inhibitors for chronic pain. While the conclusions are important and solid, there are some key shortcomings that should be addressed to strengthen the study.

eLife Assessment

This valuable study analyses correlations between traits of Chinese frog species and their Red List status, finding differences between adults and larvae and thus pointing to the importance of considering different life-cycle stages in this and possibly other animal groups when assessing species extinction risks. The current study is, however, incomplete because of unclear threat categories for tadpoles, the omission of other key species traits, and insufficient statistical analysis.

eLife Assessment

This work provides a fundamental advance through a detailed and integrative analysis of how the tsetse fly feeds on blood, demonstrating that successful penetration depends on subtle structural adaptations rather than extreme forces or unusual anatomy. By combining high-resolution imaging, innovative biomechanical measurements, and experiments on artificial skin, the study offers complementary and compelling evidence, with clear data supporting a robust mechanistic interpretation. These findings have broad significance as they clarify the biomechanics of vector feeding with implications for the transmission of diseases such as African trypanosomiasis across diverse hosts.

eLife Assessment

This useful work addresses a longstanding question of how the extant genetic code came to be selected and conserved almost universally across life. Using a mutational approach and a small set of reporters, the authors demonstrate that the mutational impact was similar for non-standard genetic codes. Considering the limitations of the approach, the data are incomplete in supporting the claim of having provided 'experimental verification of the error minimization theory'.

eLife Assessment

This important study fills a major geographic and temporal gap in understanding Paleocene mammal evolution in Asia and proposes an intriguing "brawn before bite" hypothesis grounded in diverse analytical approaches. The work rests on a solid methodological base. Some limitations remain, including uncertainty introduced by pooling different tooth positions, limited dietary interpretation, and the predominantly herbivorous taxonomic focus, which narrows the ecological scope of the conclusions. However, the manuscript provides a substantially strengthened and well-supported contribution, while appropriately inviting further work to clarify dietary trends, broader ecological context, and links between dental trait evolution and environmental change.

eLife Assessment

This important study links allelic expression imbalance with replication timing, suggesting a stochastic model for haploinsufficiency in dosage-sensitive disease. The integration of allele-specific RNA-seq and replication timing in clonal systems provides solid evidence for an association between asynchronous replication and allelic imbalance, although the scope and generality should be addressed in future work. This study will interest epigeneticists and genome regulation researchers studying replication timing and monoallelic expression, as well as developmental biologists and human geneticists concerned with clonal heterogeneity, haploinsufficiency, and variable disease penetrance.

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

eLife Assessment

This important study highlights how cell size influences various cellular responses, with a particular focus on ferroptosis. The evidence presented is convincing, employing multiple model systems and experimental approaches to support the conclusions. This work will be of significant interest to the fields of cell size, ferroptosis, and cancer biology.

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

eLife Assessment

This study thoroughly assesses tactile acuity on women's breasts, for which no dependable data currently exists. The study provides two important contributions, by convincingly showing that tactile acuity on the breast is poor in comparison to other body parts, and that acuity is worst in larger breasts, indicating that the number of tactile sensors is fixed. This study will be of interest to the broader community of touch, as well as those interested in breast reconstruction and sexual function.

eLife Assessment

This important work demonstrates the role of physically linking the core and CTD kinase modules of TFIIH via separate domains of subunit Tfb3 in confining RNA Polymerase II Serine 5 CTD phosphorylation to promoter regions of transcribed genes in budding yeast. The main findings, resulting from analyses of viable Tfb3 mutants in which the linkage between TFIIH core and kinase modules has been severed, are supported by solid evidence from in vitro and in vivo experiments. The new findings raise the intriguing possibility that the Tfb3-mediated connection between core and kinase modules of TFIIH is an evolutionary addition to an ancestral state of physically unconnected enzymes.

eLife Assessment

This manuscript reports a high-quality genome assembly of the European cuttlefish, Sepia officinalis, a representative species of the Cephalopod lineage. This solid work relies on current best practices in genome sequencing and assembly, combining PacBio HiFi long reads and Hi-C chromatin conformation capture, and on state-of-the-art comparative genomic analyses, including chromosome number evolution and analyses of expanded gene families. The resulting genome will be a valuable resource for researchers interested in cuttlefish biology and comparative genomics in general.

eLife Assessment

This study presents valuable evidence of sex differences in oxycodone relapse-related behavior alongside novel characterization of synaptic adaptations in the paraventricular thalamus - nucleus accumbens shell circuit. The authors show that females exhibit heightened cue-induced seeking after 14 days, but not 1 day, of abstinence, while both sexes display similar time-dependent strengthening of paraventricular thalamus - nucleus accumbens shell glutamatergic transmission. The revised manuscript strengthens the work through improved statistical analyses, clearer interpretation, and expanded integration with prior literature. The strength of evidence is solid. However, association among experiments is incomplete, as the sex-specific behavioral effect is not reflected in circuit-level plasticity, and no causal manipulations test pathway involvement in relapse. Future work could link these circuit adaptations to sex-specific relapse vulnerability.

eLife Assessment

This study investigates the role of the Z-disc protein Zasp52 in Drosophila flight muscles and provides evidence that an intrinsically disordered region (IDR) helps to stabilize and promote the localization of the protein to the Z-disc. Overall, this represents an important study that provides insights into Z-disc function and maintenance. The data are convincing, supported by strong genetic evidence and behavioral tests, well-controlled experiments, and detailed statistical analyses. Additional functional analyses designed to tease out specialized regions within the newly described isoform of Zasp52 would further strengthen models regarding the function of the protein.

eLife Assessment

This important study identified Mex3a protein with dual RNA-binding protein/ubiquitin ligase function as a pivotal regulator of olfactory sensory neurons (OSN) differentiation and lineage fidelity. The authors employed a combination of systems biology approaches (e.g., single-cell RNA sequencing, proteomics) and newly developed animal models (e.g., HyperTRIBE) to provide solid evidence that abrogation of Mex3a disrupts cilia structure and polarity of OSNs. Notwithstanding that this article is of a broad potential interest across different biomedical disciplines ranging from RNA to developmental biology, additional mechanistic data connecting identified Mex3a mRNA targets and ensuing OSN phenotypes would further strengthen this study.

eLife Assessment

This important study probes the long-standing failure to resolve evolutionary relationships between the classical "spiralian" taxa-i.e., annelids, molluscs, brachiopods, platyhelminths and nemerteans-and provides convincing evidence that the branches leading to them are so short as to be unreliable guides to their relationships. This, in turn, has wide-ranging implications for our understanding of animal body plan evolution and the interpretation of early animal fossils.

eLife Assessment

This study presents a useful database resource containing protein conformations generated through molecular dynamics simulations, with extensive quality evaluation and benchmarking. While the database is well-constructed and professionally organized, the evidence supporting its claimed representation of protein conformational landscapes is incomplete, as the short simulation times and starting structure bias prevent true Boltzmann sampling of the conformational space.

eLife Assessment

This is an important study uncovering a new role of the SETD6-PPARγ axis in the regulation of hepatic lipid metabolism. The data convincingly demonstrate that methylation of PPARγ by SETD6 plays a key role in this process, linking lysine methylation to transcriptional control of lipid storage genes.

eLife Assessment

In this useful manuscript, Yang et al attempt to show that platelet recruitment to the liver via macrophages contributes to APAP-induced liver injury, but there were many areas where the data supporting the conclusions were incomplete. For example, the idea that platelets only affected KC glycolysis, but not the metabolism of other cells, to mediate the phenotype after injury is not adequately supported by the evidence. It is recommended to perform additional experiments to strengthen the conclusions.

eLife Assessment

This Review Article nicely synthesizes the development, applications, and recent technical advances of the nitroreductase/prodrug system, highlighting how it enables precise spatiotemporal cell ablation and experimental platforms for studying regenerative mechanisms and screening for pro-regenerative or protective compounds. Together, the article provides a conceptual and practical overview that will help researchers adopt and further develop this versatile approach in regenerative biology. It will be of interest to researchers studying regeneration, disease modelling, and targeted cell ablation, particularly those working with zebrafish and other genetic model systems.

eLife Assessment

This study provides valuable contributions to establish canonical Dhh signaling as a primary mediator in the differentiation of Leydig cells and their steroidogenic capacity. Together, the experimental design using their established stem Leydig cell line alongside relevant genetically mutated models, both derived using the relevant Nile tilapia animal system, provided largely convincing evidence to support their conclusions. The work will be of broad interest to developmental biologists interested in differentiation of steroidogenic or hormone producing cells.

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

eLife Assessment

This important study provides a comprehensive multi-omics characterization of Leishmania donovani stage differentiation, offering insights into the molecular basis of parasite adaptation across host environments. The authors present convincing evidence that stage transitions are not driven by genomic variation but instead rely on coordinated post-transcriptional regulation, including mRNA turnover, translation, and protein degradation. Although experimental validation of these findings and conclusions remains to be completed, the integration of diverse, high-quality datasets establishes a robust resource that will be of broad utility to researchers investigating Leishmania biology and life-cycle progression.

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

eLife Assessment

This study provides valuable insights into mitochondrial cristae organization in Plasmodium falciparum, particularly in the context of its divergent MICOS composition. The authors present convincing evidence, supported by phenotypic and morphological analyses, that cristae junction maintenance can be uncoupled from de novo cristae formation, reinforcing an emerging model of mitochondrial inner membrane organization. Notably, the absence of Mic10 alongside an enlarged and divergent MICOS complex highlights an intriguing evolutionary adaptation, although further characterization of the complex would strengthen the study's overall significance.

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

eLife Assessment

This valuable study used genetic and pharmacological manipulations of insulin/IGF signaling to address the role of insulin/IGF axis in the function of renal glomerular podocyte. Solid data are presented to demonstrate that co-inhibition of insulin/IGF signaling in podocytes led to aberrant splicing of mRNAs, which could contribute to the loss of podocytes in vitro and in vivo in mice. In light of the fact that IR/IGF-1R signaling are critically required for normal development and growth in multiple cells and organs, the lack of the assessment of developmental phenotype of podocytes in the mouse model limits the interpretation of the data.

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

eLife Assessment

This study presents a valuable finding relating to how the state of arousal is represented within the superior colliculus (SC), a principal visuo-oculomotor structure. The main conclusion that the SC's neural representation of arousal is segregated from motor related output appears to have solid support by the data. The work will be of interest to sensory, motor and cognitive neuroscientists.

eLife Assessment

This study explores how exogenous attention operates at the finest spatial scale of vision, within the foveola - a topic that has not been previously explored but is of interest to visual neuroscientists. The question is important for understanding how attention shapes perception, and how it differs between the periphery and the central regions of highest visual acuity. The evidence indicating that attention near the fovea preferentially enhances low spatial frequencies is compelling, as shown by carefully designed experiments with state-of-the-art eye tracking to monitor attended locations just a few tens of minutes of arc away from the fixation target.

eLife Assessment

This is a valuable report describing tracheal terminal cells (TTCs) in Drosophila as an immune privileged organ. The authors demonstrated that TTCs lack expression of the membrane-associated peptidoglycan recognition receptor PGRP-LC, which protects these cells from immune pathway activation and JNK-mediated cell death to maintain TTC homeostasis. While the genetic experiments using RNAi and overexpression are convincing and solid, the broader biological significance of this phenomenon requires further investigation. This work will be of interest to researchers in innate immunity across various model systems.

eLife Assessment

By screening an FDA-approved small-molecule library against a leucine-dependent M. tuberculosis strain, this study identifies semapimod as an inhibitor of Mtb growth that functions by impairing leucine import. The work is useful in linking leucine uptake to cell wall lipid biology in Mtb. However, the mechanistic understanding remains incomplete. Additional experimental evidence is required to clarify how PDIM contributes to or regulates leucine uptake.

eLife Assessment

This study presents valuable findings on the differential effects of RNA on the phase separation, aggregation dynamics, and bioactivity of PSMα3 and LL-37. The authors provide solid evidence from complementary biophysical and cell-based experiments that RNA influences peptide assembly and associated in vitro activities. The study is of interest for understanding interactions between amyloidogenic peptides and nucleic acids, although the physiological significance and some aspects of the mechanistic interpretation would benefit from further clarification.

eLife Assessment

This important work advances our understanding of the development of the visual system. The data presented is compelling and provides a detailed single-cell atlas of post-natal anterior chamber development in mice, highlighting the trabecular meshwork and Schlemm's canal.

eLife Assessment

This study provides a useful demonstration that, at least for the systems examined, aspects of the entropic contribution to protein-ligand binding can be inferred directly from crystallographic data. In doing so, it strengthens a view of crystal structures as heterogeneous ensembles that are amenable to statistical-mechanical analysis rather than purely static models. The analytical approaches are carefully developed and transparently discussed, with thoughtful consideration of both successful and less effective methods, lending solid support to the central conclusions. However, because the analysis is based on a relatively small and narrowly sampled set of protein-ligand complexes, the generality of these findings remains speculative and will require broader validation.

eLife Assessment

This study provides valuable insights into how cells maintain sphingolipid homeostasis through transcriptional control and regulated protein degradation in response to changes in sphingolipid levels. The evidence supporting the conclusions is convincing overall, with solid genetic and biochemical approaches, while some mechanistic aspects remain to be clarified. This work will be of interest to researchers studying lipid metabolism and membrane biology.

eLife Assessment

This study presents important findings on the molecular mechanisms governing how the natural killer cell receptor KIR2DL4 interacts with HLA-G and undergoes internalization. The authors provide solid evidence for an allosteric disulfide-bond switch that regulates receptor activity, using a multifaceted approach that includes mutagenesis, mass spectrometry, and imaging. The work would be further strengthened by validating these mechanisms in primary immune cells and providing direct structural evidence for the proposed ligand-binding interface.

eLife Assessment

This study shows that Znhit1, a regulator of chromatin and of the histone variant H2A.Z, is required for progression through meiotic prophase. It is an important observation that describes the role of epigenetics and gene expression during meiosis. The analysis is based on complementary approaches at the cytological, single-cell, and genomic levels that provide solid evidence for the role of Znhit1 in the control of gene expression and in the loading of H2A.Z in mouse spermatocytes.

eLife Assessment

This valuable study provides quantitative data and analysis to reveal that variations in Dorsal (Dl ) nuclear dynamics along the Dorso-ventral axis in the early Drosophila embryo are governed by Dl-Cactus nuclear interactions. The solid evidence partially supports a mechanism where nuclear localized Cactus contributes to the fraction of Dl that binds to DNA, but additional work will be necessary to confirm the claims and the biological significance of these findings.

eLife Assessment

This study provides important insights regarding the temporal dynamics of dopamine across sleep/wake transitions in several brain areas. Using multi-site fiber photometry combined with EEG/EMG recordings, the study revealed heterogenous dynamics across both cortical and several subcortical areas. Although the evidence for these observations is solid, evidence for the proposed mechanisms driving DA dynamics is incomplete. Overall, the study may have a substantial impact on several fields working on the neurobiology of DA signaling.

eLife Assessment

The study presents important findings revealing previously unresolved conformational dynamics of the heterodimeric type IV ABC transporter TmrAB using single-molecule FRET. The evidence presented is solid, integrating careful experimental design with computational approaches to uncover states that are typically masked and difficult to detect. The work will be of interest to scientists studying the molecular mechanisms of primary active transport processes.

eLife Assessment

This study provides direct and compelling evidence that lamellipodial protrusions dynamically adjust Arp2/3 complex incorporation in response to mechanical counterforces, while also modulating cellular responsiveness to upstream signals like Rac GTPase. By combining endogenous labeling, live-cell imaging, and optogenetic signaling activation, the work demonstrates how adhesion state and physicochemical perturbations reproducibly alter branched actin organization, offering a fundamental advance over previous works. The findings deliver significant insights that will resonate broadly with cell biologists and biochemists studying actin dynamics and mechanotransduction.

eLife Assessment

In this study, Yuan and colleagues perform transcriptomic and epigenomic experiments to study open chromatin regions and transcripts that change upon larval settlement in the sponge Amphimedon. The authors present compelling evidence to show that sponge larvae prepare for receiving an environmental cue (sunset) by extensively modifying their chromatin accessibility in the vicinity of genes that are going to be regulated during metamorphosis. The study represents a fundamental advance in understanding the fine genetic control of larval settlement and has significance beyond the immediate field of sponge larval biology.

eLife Assessment

This large-scale comparative study of odorant receptor (OR) genes across more than 100 insect species, combining sequence- and structure-based approaches, aims to explore the evolution of this large gene family involved in the detection of odorant signals by olfactory neurons. This useful work uncovers a structural feature unique to the odorant receptor co-receptor Orco that reduces ligand binding affinity. However, the strength of evidence is incomplete: the pipeline for in silico identification of odorant receptor genes lacks validation through comparison with known odorant receptor repertoires from previously studied species, and claims regarding odor response spectra, evolutionary, and ecological interpretations are not fully supported by the analyses.

eLife Assessment

The study presents useful findings on the behavioral effects of nicotine exposure, suggesting the Drosophila larva as a potential model organism for studying underlying neural circuits. However, the evidence supporting the claims of the authors is incomplete and would benefit from more rigorous analysis and explanations. The study falls short of identifying the neural mechanisms and is therefore of interest to those with an interest in pharmacology and behavior.

eLife Assessment

This work provides an important modeling-based framework for understanding the processes of temporal integration in the claustrum. These mechanisms could support a broader range of integrative brain function. The manuscript presents solid evidence for how claustrum may integrate temporal disparate signals via a novel computational phenomenon with neural dynamics evolving along neural trajectories as opposed to settling into fixed-point attractor states.

eLife Assessment

This important advancement in the field of neurotransmission delivers a novel toolkit for in vivo visualization of vesicular transporters for ACh, GABA, glutamate and monoamines in C. elegans. With the application of newly developed neuron-specific knockout methods for these vesicular transporters, the results convincingly demonstrate that over 10% of the neurons studied show transporter co-expression that may be correlated with co-transmission. These findings and toolkit will be of interest towards the study of neural circuit function.

eLife Assessment

In this important study, the authors used a zebrafish model and scRNAseq analysis to show that a subset of keratinocytes within melanoma microenvironment highly up-regulate Twist and undergo Epithelial-Mesenchymal Transition (EMT). Surprisingly, when overexpressing Twist in keratinocytes, the resulting alteration in keratinocytes is inhibitory for melanoma invasion in both zebrafish and human cell culture models. The results are supported by convincing experimental data that provide new insights into the interactions between melanoma cells and their environment.

eLife Assessment

This important work advances our understanding of the single neuron coding types in the mouse gustatory cortex and the functional roles of these neurons for perceptual decision-making. The conclusions are based on compelling evidence from rigorous behavioral experiments, high-density electrophysiology, sophisticated data analysis, and neural network modeling with in silico perturbations of functionally-identified units. This work will be of broad interest to systems neuroscientists.

eLife Assessment

This study presents valuable findings on the physiological and computational underpinnings of the accumulation of intermittent glimpses of sensory evidence. The evidence supporting the claims of the authors is solid, although a more exhaustive characterisation of how the different signals interact would have strengthened the study. The work will be of interest to cognitive and systems neuroscientists working on decision-making.

eLife Assessment

This valuable cross-sectional longitudinal study leverages high-definition transcranial direct current stimulation to the left dorsolateral prefrontal cortex to examine its effect on procrastination behavior over an extended time span. The cross-sectional longitudinal study provided evidence for how stimulating DLPFC impacts reveal-world procrastination behavior. Support for the conclusions is incomplete owing to missing information about the analyses, and results, as well as some potential alternative interpretations.

eLife Assessment

This study provides valuable insights with convincing evidence detailing 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 and quantitative 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. The behavioral experiments are well executed and set the stage for subsequent mechanistic, causal, and computational approaches. The work is relevant to those interested in autism, cognition, and/or sensory processing.

eLife Assessment

Du et al. present a valuable study examining neural activation in medial prefrontal cortex (mPFC) subpopulations projecting to the basolateral amygdala (BLA) and nucleus accumbens (NAc) during behavioral tasks assessing anxiety, social preference, and social dominance. The strength of the evidence linking in vivo neural physiology to behavioral outcomes was considered solid; however, the slice electrophysiology data and their interpretation were less well received. Overall, the reviewers felt that the revised work provides insight into how distinct mPFC→BLA and mPFC→NAc pathways influence anxiety, exploration, and social behaviors.

eLife Assessment

This manuscript examines the evolution of molluscan shells using single-cell analyses of the adult mantle of Crassostrea gigas and compares these data with previous datasets from embryonic and larval stages of this species and other spiralians. The authors provide important support for a scenario in which secretory cells are broadly conserved across spiralians, and the incorporation of lineage-restricted genes contributes to the evolution of molluscan shells. While some of the conclusions of the authors are convincing, many aspects of the manuscript remain incomplete and could be improved, especially aspects of cell-type classification and validation.

eLife Assessment

This study presents a valuable perspective on platelet-mediated fibrin compaction, proposing that fibrin fibers undergo "winding" or coiling, an intriguing framework with potential implications for thrombosis and clot mechanics. However, the evidence supporting an active platelet-driven winding mechanism remains incomplete, relying largely on correlative observations without direct or quantitative validation of the proposed dynamics. Overall, the work is thought-provoking and of clear interest to the field, but stronger mechanistic evidence will be required to substantiate the central claims.

eLife Assessment

This study introduces the "Training Village," a valuable system for which solid evidence shows that it enables group-housed rodents to autonomously learn complex tasks while preserving natural social interactions. The platform is flexible, allowing animals to learn multiple tasks sequentially and supporting applications in continual learning. This approach is likely to be of broad interest to behavioral researchers using rodent models in systems and cognitive neuroscience.

eLife Assessment

This study provides a valuable contribution to our understanding of the neural basis of perceptual decision-making by jointly modeling behavioral outcomes and EEG signals in a contrast comparison task. The methods and analyses are solid, systematically comparing standard models assuming continuous evidence accumulation with models that track evidence without temporal integration (extrema detection). The authors show that behavior and neural signals are equally consistent with both alternatives, highlighting limitations in current modeling approaches and questioning the generality of evidence accumulation mechanisms.

eLife Assessment

This fundamental work significantly advances our understanding of the circuit-level implementation of predictive processing by elucidating the functional influence between putative prediction error neurons in layer 2/3 and putative internal representation neurons in layer 5. The evidence demonstrating that neither the hierarchical nor the non-hierarchical variant of predictive processing fully accounts for the presented data is convincing. Moving forward, this line of work would benefit from explicitly comparing different theories, thereby clearly articulating the points raised in this paper.

eLife Assessment

This study presents a valuable finding on the mutational landscape and expression profile of ZNF molecules in 23 Kenyan women with breast cancer. The evidence supporting the claims of the authors is solid, although inclusion of a larger number of patient samples, more statistical details and sufficient comparison with existing large-scale datasets would have strengthened the study. The work will be of interest to medical biologists working in the field of breast cancer.

eLife Assessment

This valuable study characterises the activity of motor units from two of the three anatomical subdivisions ("heads") of the triceps muscle while mice walked on a treadmill at various speeds. Altogether, this is the most thorough characterisation of motor unit activity in walking mice to date, providing convincing evidence for probabilistic recruitment of motor units that differed between the two heads.

eLife Assessment

The authors use single molecule imaging and in vivo loop-capture genomic approaches to investigate estrogen mediated enhancer-target gene activation in human cancer cells. These potentially important results suggest that ER-alpha can, in a temporal delay, activate a non-target gene TFF3, which is in proximity to the main target gene TFF1, even though the estrogen responsive enhancer does not loop with the TFF3 promoter. To explain these results, the authors invoke a transcriptional condensate model. The claim of a temporal delay and effects of the target gene transcription on the non-target gene expression are supported by solid evidence but there is no direct evidence of the role of a condensate in mediating this effect. The reviewers appreciate that the authors have done a lot of work to strengthen the study. This work will be of interest to those studying transcriptional gene regulation and hormone-aggravated cancers.

eLife Assessment

This important study provides a detailed characterization of individual sarcomeres' contractility and of their synchrony in spontaneously beating cardiomyocytes derived from human induced pluripotent stem cells. The combination of high-resolution tracking, statistical analysis and mesoscopic modeling leads to compelling evidence that sarcomeres operate as dynamically unstable units, leading to stochastic heterogeneities in their contraction-elongation cycles depending on substrate stiffness. The work will be relevant to scientists interested in muscle biophysics, nonlinear dynamics and synchronization phenomena in biological systems.

eLife Assessment

This is a theoretical analysis that gives compelling evidence that length control of bundles of actin filaments undergoing assembly and disassembly emerges even in the absence of a length control mechanism at the individual filament level. Furthermore, the length distribution should exhibit a variance that grows quadratically with the average bundle length. The experimental data are compatible with these fundamental theoretical findings, but further investigations are necessary to make the work conclusive concerning the validity of the inferences for filamentous actin structures in cells.