eLife Assessment

This study presents a valuable finding on linking the frequency of neural activity to cortical depths of blood flow in a naturalistic setting of participants listening to music. The presentation of evidence in the version of the original submission is incomplete, as further clarifications in methods and results, as well as performing additional analyses, would strengthen the study. The work will be of interest to cognitive neuroscientists working on multimodal recordings, auditory perception and music.

eLife Assessment

This study provides a useful anatomical resource by mapping the expression of four putative chemoreceptors in spinal cerebrospinal fluid-contacting neurons (CSF-cNs) of larval zebrafish. These descriptive findings offer an interesting entry point to explore how the nervous system senses signals within the spinal fluid microenvironment. The evidence supporting the spatial expression patterns of these receptors is convincing, utilizing high-resolution hybridization chain reaction (HCR) to validate previous transcriptomic data. However, the evidence remains incomplete regarding the actual functional roles of these receptors, as the study lacks protein-level validation, evidence of ligand availability in the CSF, or functional assays to demonstrate active chemoreception.

eLife Assessment

This work provides a reassessment of VBIT-4, a compound previously proposed to inhibit oligomerization of the crucial protein known as the mitochondrial voltage-dependent anion channel. Combining complementary experimental approaches with molecular dynamics simulations, the authors provide compelling evidence that VBIT-4 primarily disrupts lipid membranes and induces channel-independent cytotoxicity. The study has important implications for interpreting previous work using VBIT-4 as a probe of channel function and highlights the need to consider membrane-disruptive effects when evaluating drug mechanisms.

eLife Assessment

This valuable study investigates the mechanisms underlying inter-item biases in visual working memory. By experimentally manipulating the relative noise levels of target and non-target items, the authors report bias patterns that are broadly consistent with predictions of their previously proposed normative demixing theory. However, the supporting evidence remains incomplete, as the manuscript lacks a sufficient description of the underlying theory, key assumptions, and a quantitative link between the model and behavioral data. The manuscript would be substantially strengthened by clearer exposition and stronger tests, including analyses of the full error distributions and comparisons with alternative models, which would increase its potential interest to the cognitive neuroscience and computational cognitive science communities.

eLife Assessment

This useful study reports on lifespan extension in C. elegans males that carry a mutation in a gene for an insulin receptor; while the observations are striking, the strength of evidence is currently incomplete. The central claim of male-specificity is undermined by the absence of direct hermaphrodite healthspan comparisons, and the reliance on a single mutant allele leaves open the possibility that background mutations, rather than daf-2 loss-of-function, drive the phenotype. Methodological details critical for reproducibility are also lacking, particularly regarding male housing density, censoring of plate-leaving animals, and the adequacy of replication for the key epistasis experiment. The work could be substantially strengthened by a targeted set of additional experiments and fuller engagement with the existing literature on sex-specific aging in C. elegans.

eLife Assessment

This valuable study provides novel evidence that congenital aphantasia is associated with structural differences in frontotemporal and cingulate systems, with relative sparing of early visual regions and major visual pathways. The multimodal structural imaging approach is carefully implemented and will be of interest to researchers studying mental imagery and aphantasia. However, the strength of evidence is incomplete because the data cannot adjudicate between alternative cognitive interpretations, and the multiple discovery streams make the findings better viewed as key exploratory evidence, rather than as establishing a definitive structural phenotype of aphantasia.

eLife Assessment

This valuable study identifies Gcn5 as a regulator of blood cell development in the Drosophila lymph gland, with links to autophagy and nutrient-sensing mTORC1 signalling. The evidence is solid that altering Gcn5, autophagy genes and mTORC1 activity perturbs blood cell homeostasis, and the revised manuscript adds helpful genetic and quantitative analyses. However, the evidence for a clean linear Gcn5-mTORC1-TFEB/autophagy pathway is insufficient, because several cell-type-specific phenotypes remain difficult to reconcile and the pathway logic relies on different genetic tools, cell populations and pharmacological perturbations.

eLife Assessment

This study uses convincing modeling methods and analyses of rich behavioral datasets to investigate the role of attention in value-based decision making; for instance, as when choosing between two snacks. The results are important, as they challenge existing theories that assume that paying attention to an available option biases the eventual choice toward that option. The results suggest that the correlation between attention and decision-making is formed largely after rather than before the (internal) choice process has terminated, a finding that offers an intuitively appealing rethinking of how attention and decision-making processes interact during value-based choices.

eLife Assessment

This important study measures single-unit activity in area MT of awake-behaving monkeys to test the idea that sensory adaptation contributes to flexible evidence accumulation during decision making. The authors provide compelling evidence that adaptation to different temporal contexts shapes both perceptual judgements and neural responses. Although the precise computational mechanisms underlying these effects remain uncertain, the results support the conclusion that recent sensory history influences the temporal dynamics of decision formation. This work will be of interest to researchers studying visual perception, sensory adaptation, and decision making.

eLife Assessment

By investigating spine nanostructure and dynamics across multiple genetic mouse models for neurodevelopmental disorders, this important study has the potential to uncover convergent or divergent synaptic phenotypes that may be specifically associated with autism versus schizophrenia risk. The imaging and overall breadth of the methods are convincing. The purely in vitro nature of the study slightly limits the generalisability of the findings, though these limitations are acknowledged and discussed in the manuscript.

eLife Assessment

This useful study combines experiments and mathematical modeling to show that antibiotic protection provided by resistant cells can extend across both surface-associated and freely growing bacterial populations. Notably, they show that treatment efficacy depends on population composition and density. The evidence supporting the main conclusions is incomplete, primarily because the biofilm context is not adequately characterized and demonstrated, raising the concern that it might represent only an aggregate of cells on the surface (rather than a biofilm) under the studied experimental conditions.

eLife Assessment

This important study provides the first in vivo evidence that nonsense-mediated mRNA decay (NMD) in mature astrocytes regulates astrocyte function, synaptic plasticity, and anxiety-related behavior. Using a broad range of approaches, the authors show that conditional deletion of Upf2 alters astrocyte morphology and calcium signaling while impairing synaptic transmission and plasticity, providing solid support for the central conclusion that astrocytic NMD influences neural circuit function. Some key mechanistic claims remain incompletely supported, including whether phenotypes reflect astrocyte remodeling versus loss, the interpretation of synaptic engulfment data, the link between NMD targets and calcium signaling, and the extent to which calcium dysregulation explains the observed synaptic and behavioral effects.

eLife Assessment

This is a valuable paper looking at nanoscale organization of the membrane associated periodic cytoskeleton in mouse sciatic nerve axons. Despite previous studies, the precise organisation of the structure remains unclear, especially in vivo, and this manuscript significantly adds to this knowledge with solid data. An unexpected observation is the presence of discrete nanoscale clusters, regularly distributed around sections of axons. However, the paper misses a description of these clusters along the longitudinal axis of the axons.

eLife Assessment

This fundamental manuscript describes a key role for the integrated stress response-regulated transcription factor CHOP in regulating liver biology in response to endoplasmic reticulum stress through both the downregulation of transcription factors involved in regulating hepatic identity and altering the capacity for integrated stress response and unfolded protein response signaling to induce protective signaling. The data supporting this model is convincing, but including some additional discussion on the mechanism and importance of the work in the context of the published literature would be helpful to better define the complex importance of CHOP signaling. This work will be of interest to a wide range of biologists interested in liver biology, stress-responsive signaling, and ER stress.

eLife Assessment

This valuable study shows the impact of the metabolic state of bacteria on phage infection. The experimental results, based on various phages infecting E. coli, are convincing and consistent with a two-step adsorption mathematical model. This study should be of interest to the communities working on cell metabolism and on host-pathogen interactions.

eLife Assessment

This study makes a valuable contribution by broadening the range of eukaryotic model systems and establishing Blastocystis, the most prevalent microeukaryote in the human gut, tractable for reverse-genetics investigations. The presented imaging data are convincing and informative, although confirmation by molecular methods would further strengthen the study. The work should interest readers studying host-microbe interactions in the human gut, as well as those developing new systems for eukaryotic research.

eLife Assessment

This important study explores whether complex structures that are lost during evolution can re-evolve, which is a long-standing debate in evolutionary and developmental biology. The authors demonstrate that re-evolution can occur if the gene regulatory network that underlies the development of complex traits is maintained. The evidence supporting its conclusions is convincing and the work will be of interest to those studying the evolution and development of complex traits.

eLife Assessment

Building on earlier studies, this manuscript reports a role for pol kappa in cisplatin resistance in the very specific scenarios of head and neck squamous cell carcinoma, providing evidence that the PIP box of Pol kappa is critical for cisplatin resistance in these cells. The findings are of a highly focused relevance and will be useful in the field, but the conclusions are limited to very specific cancer cells. Conclusions cannot be generalized to all cisplatin resistance mechanisms and cell types and are based on incomplete evidence that presents uncertainties and discrepancies that need to be resolved.

eLife Assessment

This is a potentially important study comparing LTP mechanisms between primates and rodents. The experimental methods have some possible confounds, and the power (replicates) and design of the statistical methods could be strengthened, hence the support for the central claims of species differences is currently incomplete.

eLife Assessment

This important study assessed the replicability of a selection of lab-based biomedical experiments in papers published by authors based in Brazil. The study adds a unique perspective to the literature on replication, and provides rich data on the approach taken, the outcomes, and the challenges involved in conducting large-scale crowd-sourced research. The evidence supporting the claims is convincing, but there is scope for clarifying the presentation of the results and extending the discussion section.

eLife Assessment

This valuable paper uses a mathematical model applied to a dataset of E coli / ESBL carriage and transmission to infer drivers of drug resistance in France. The strength of support for the study findings is incomplete. While the research question is of importance, and the mathematical model has structural and methodological integrity, numerous issues are noted: insufficient description of the data, lack of included equations and code, definitions of antibiotic use that are not complete, low sensitivity of assays for carriage, technical issues with statistical prior selection and parameter identification, and application of non-regional ECDC surveillance data to France.

eLife Assessment

This study presents an important finding regarding the effect of Yoda molecules on PIEZO2 function, challenging the assumption that they selectively activate PIEZO1. The evidence supporting this claim is solid, but several methodological and conceptual issues need to be addressed. Overall, this work will be of broad interest to researchers working with PIEZO channels across various biological scales.

eLife Assessment

In this manuscript, the authors describe a new member of the KCNE auxiliary subunits of potassium channels from a lamprey. This new subunit represents an early evolutionary member which confers new properties when expressed along with KCNQ channels. The authors present convincing evidence from several experimental approaches. The contents of this manuscript are important and should be relevant to understanding both the mechanism of modulation of KCNQ channels by KCNE subunits and the evolutionary history of these subunits, which this manuscript now extends to the divergence of early vertebrates.

eLife Assessment

In this important study, Boudjema et al. use cell culture models and high quality advanced microscopic imaging to provide detailed analyses of the cellular processes underlying centriole amplification, apical migration, and assembly of hundreds of motile cilia in multi-ciliated cells. The authors present convincing evidence showing that in these cells all the molecular and cellular steps controlling centriole biogenesis that in cycling cells extend over almost two cell cycles, occur within a single cell cycle variant. This work provides a better understanding of the regulation and order of these processes and is of interest to all cell biologists and in particular researchers studying centrioles and cilia.

eLife Assessment

This manuscript provides valuable insight into how genome organization changes as cells progress through the cell cycle after mitotic exit, identifying two sharp genome remodeling events at G1-S and to a lesser extent, at S-G2 transitions. The conclusions are supported by solid, rigorous data, including sequencing and orthogonal imaging data. The use of sorted unsynchronized cells rather than cells treated with drugs is a particular strength.

eLife Assessment

This important study identifies PRRT2 as an auxiliary regulator of Nav channel slow inactivation in vitro and in vivo, proposing that PRRT2 facilitates entry into, and delays recovery from, the slow-inactivated state. The revised manuscript has been substantially strengthened, providing compelling evidence that PRRT2 is relevant to normal brain physiology and disease pathophysiology, providing a mechanistic link between PRRT2 mutations and episodic neurological phenotypes. Overall, this study will be of interest to ion channel biophysicists and neurophysiologists, particularly those studying channelopathies.

eLife Assessment

This important study investigates how surface stickiness shapes whisker mechanics and peripheral neural responses during active touch. The biomechanical evidence that surface stickiness alters whisker mechanics and stick-slip dynamics is compelling, supported by a large and high-quality 3D dataset, while the electrophysiological evidence is solid but limited by a small sample size and insufficient validation of the sticky stimuli. The work will be of broad interest to sensory neuroscientists studying active touch.

eLife Assessment

This study presents a useful compendium of triangulated single-cell eQTLs, Mendelian randomisation and colocalization of genetic signals in prostate cancer datasets. Biological interpretation in the context of the aging prostate gland, the tumour microenvironment and immune cell specificity is incomplete, so this study is a starting point for further study, and would require validation of the resulting putative causal genes.

eLife Assessment

This useful study explores how macrophage cell-cycle state may influence endocytosis, Mycobacterium tuberculosis uptake, and the intracellular stress experienced by bacteria. While the question is interesting and the experimental approach has promise, the evidence for the central claim that endocytic capacity is specifically regulated by cell-cycle stage is incomplete. The main concern is that fluorescence-based sorting and total-fluorescence measurements likely covary with cell size, so the reported phenotypes could reflect biomass accumulation or other cell-cycle-associated changes rather than endocytic capacity as the causal determinant. As a result, whilst the study raises a hypothesis that is of importance, additional controls are required before the proposed mechanism can be considered well supported.

eLife Assessment

This important submission from Ambler and colleagues brings new insights into how torpor conditions may confer resilience in cases of cardioprotection. It has novelty, which can be enhanced by additional in vivo support. The study is backed by solid evidence, and represents a unique interoceptive mechanism of interest.

eLife Assessment

This study addresses a recent discovery by others that electroconvulsive therapy (ECT) generates seizure activity and spreading depolarization (SD), reflected in large increases in calcium, which can be followed by imaging calcium fluctuations in neurons. This work is useful. However, the evidence to show that SD, rather than seizures, confers the neuroplastic and other therapeutic effects of ECT is incomplete.

eLife Assessment

This important study establishes a robust live-imaging toolkit to characterize excitatory and inhibitory synaptic dynamics during neuronal development, advancing our mechanistic understanding of synaptic homeostasis and neural circuit maturation. The core findings clarify how stable E/I balance is maintained despite persistent synaptic turnover, with broad implications for developmental neurobiology and neurodevelopmental disorders. The methodology and quantitative data are convincing and well validated, and this work represents a significant advance that will be of significant interest to researchers in synaptic biology, cell imaging and neuroscience.

eLife Assessment

This important study shows that regions of the human auditory cortex that respond strongly to human voices are also sensitive to vocalizations from closely related primate species. The evidence is convincing and methodologically strong. The work offers significant insight into the evolutionary continuity of voice processing and would be of interest to researchers studying auditory processing and evolutionary neuroscience in general.

eLife Assessment

Argunşah et al. investigate the mechanisms underlying the differential response dynamics of barrel vs septa domains in shaping the responses to single vs multiple whiskers. Based on the observation of a higher density of SST+ interneurons in the septa, the authors investigate the hypothesis that Elfn1-dependent short-term plasticity shapes these responses. This important study is, however, supported by incomplete evidence; factors restricting the strength of evidence are the limited spatial resolution of the multi-unit activity, as well as the lack of a mechanistic explanation. This provocative and intellectually stimulating hypothesis provides a contribution to work on how different cell types shape cortical representation.

eLife Assessment

This potentially valuable study aims to investigate neural correlates of spatial attention in whisker somatosensory cortex (S1) in mice, finding increased sensory-evoked spiking when the mice appear to be attending to the contralateral whiskers. Although some of the results appear to be robust despite relatively small effect sizes, overall the findings are incompletely supported, because attentional modulation is insufficiently distinguished from learning of stimulus-response contingencies, and because the analyses do not adequately consider orofacial movements that may contribute key confounds.

eLife Assessment

This valuable study compares hippocampal-cortical functional connectivity to various other brain measures and examines their development across youth. It uses sophisticated analyses replicated in multiple datasets, but provides incomplete evidence to support the primary claim that hippocampal-cortical connectivity relates to cognitive maturation. The manuscript would benefit from a more nuanced consideration of the biological basis of some of the derived imaging measures and the limitations of the cross-sectional design. This work will be of interest to neuroimaging specialists and cognitive neuroscientists.

eLife Assessment

This valuable manuscript investigates how Drosophila larvae make foraging decisions in patchy environments with controlled resource density and valence; using movement tracking in bounded arenas, the authors show that larvae's patch residence time (PRT) differs depending on resource type, environmental context, and prior experience. A drift-diffusion model is used to describe patch-leaving behaviour, suggesting that an integration process may underlie stay-leave decisions during foraging. The strength of the evidence is mostly solid, but the interpretation and use of PRT needs further investigation, as PRT could be a direct effect of resource concentration on locomotion. Explicit reports of PRT statistical tests are needed for rigorous interpretation.

eLife Assessment

This useful study investigates noise-robust and energy-efficient circuit mechanisms for working memory by optimizing connectivity and reports that the resulting networks exhibit rotational dynamics and better match aspects of PFC population recording. However, the supporting evidence remains incomplete, given the restricted linear, task-specific training and analysis, and limited comparisons with other prominent models. The manuscript would be strengthened by extending the analysis to nonlinear dynamics, providing more rigorous comparisons with alternative models, and establishing a stronger link to prior theoretical and experimental work.

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

The authors developed a new Agbl5 KO allele, extending the deletion to the N-terminus of CCP5 to explore its function in mouse ependymal cells and trachea. They show that the KO mice exhibit severe hydrocephalus due to mislocated basal bodies and impaired ciliary beating. The findings are valuable with implications in the subfield of cell biology. The evidence is solid in that the methods, data and analyses largely support the claims with only a few remaining weaknesses.

eLife Assessment

This paper addresses a valuable research question on the modest heritability of the brain's response to movie watching, and how heritability varies under different parameters such as regional spatial hyperalignment and BOLD frequency bands. The topic of this paper is of interest to fMRI methodological experts, and potentially to a broader cognitive neuroscience audience, and those with an interest in understanding the heritable sources of individual differences in brain function. Although some of the conclusions could be strengthened by future cross validation studies in independent and larger family-based samples, and through complementary twin/family and SNP-based models, taken altogether, the analyses and results provide convincing evidence for the overall conclusions.

eLife Assessment

This study presents important findings by identifying small molecules that can stabilize and refold missense-mutated VHL tumor suppressor protein, offering a potential therapeutic approach for clear cell renal cell carcinoma. The computational design approach is well-executed, but the evidence is incomplete due to insufficient demonstration that HIF2 downregulation occurs through on-target VHL rescue rather than off-target effects. Additional experiments with appropriate controls are needed to establish the specificity of the mechanism.

eLife Assessment

This important study advances our understanding of the biomechanics of seed processing in birds by providing a comprehensive 3D kinematic analysis of coordinated bill and tongue movements across two species with contrasting biting forces. The evidence is convincing, combining high-speed XROMM with Bayesian statistical modeling in a rigorous and technically innovative framework that advances the understanding of avian feeding kinematics. Strengthening the statistical validation of qualitative claims, particularly for tongue-seed velocity relationships, and improving the accessibility of the probabilistic modeling framework would further solidify the conclusions.

eLife Assessment

This valuable study investigates the neural basis for recovery of complex wheel running behaviour following a unilateral spinal cord injury in mice. By combining behavioural analyses, whole-brain mapping, and tracing techniques, the authors provide incomplete evidence that new cortico-medullary connections can drive effective motor recovery. The paper could be strengthened with manipulations to establish causality, a more fine-grained analysis of the behaviour, and some reorganisation of how the data are presented and discussed.

eLife Assessment

The worldwide decline in the health of coral reefs is well documented, and overgrowth by microbial consortia can be a contributing factor. Kelman and colleagues used metagenomic analysis to interrogate potential changes in phage-associated genes predicted to be involved in central carbon metabolism. The study addresses the hypothesis that metabolic genes associated with carbon metabolism that are encoded by viruses reflect the health of the corals. The study contributes a valuable perspective on the potential role of phages in coral health, although limitations of the data and analyses offer an exploratory examination rather than a definitive result. Overall, the evidence supporting the major findings is incomplete, in part because the conceptual model relies on qualitative assumptions rather than empirical data.

eLife Assessment

This Review Article puts forth a normative theory for the grid cell representations found in the entorhinal cortex. It discusses a range of theoretical models and experimental findings, organizing them around a proposed framework in which grid cells are interpreted as biologically constrained, high-fidelity codes for path integration. This framing can be potentially interesting both for readers seeking a conceptual entry point into the grid cell literature and for those more generally interested in the promises and limitations of normative theories in neuroscience. Some logical gaps and points requiring conceptual or technical clarification were nonetheless identified. Moreover, the empirical support for the path-integration account is not yet as definitive as the manuscript's framing sometimes suggests. The review would thus be strengthened by clearer justification of key arguments and fuller discussion of biological complexities, model limitations, and competing interpretations. Some stylistic choices in how arguments and literature are sometimes rhetorically framed may lessen the review's appeal for key segments of its intended audience.

eLife Assessment

This study presents a valuable and well-documented computational pipeline for the scalable analysis and spike sorting of large extracellular electrophysiology datasets, with particular relevance for high-density recordings such as Neuropixels. The authors demonstrate the pipeline's utility for benchmarking spike sorter performance and evaluating the effects of data compression, supported by thorough testing, clear figures, and openly available code. The workflow is reproducible, portable, and practical, providing concrete guidance on computational cost and runtime. Overall, the evidence supporting the pipeline's performance and output quality is compelling, and this work will be of broad interest to the systems neuroscience community.

eLife Assessment

The authors describe a valuable finding that the Streptococcus pyogenes secreted protease SpeB is expressed in response to protease activity that degrades the Vfr repressor. Proteases can be released from host neutrophils (possibly by NETosis), as well as a positive feedback mechanism by SpeB itself. The authors utilize a dual fluorescent reporter system to simultaneously read speB and capsule gene expression, providing solid evidence that demonstrates that proteases can regulate Vfr; however, the data indicating that this is physiologically relevant and that extracellular traps themselves have a functional role are incomplete. This work will be of interest to microbiologists studying the regulation of virulence factors at the host-pathogen interface.

eLife Assessment

The study presents valuable findings of a new E. coli cell-free protein synthesis (eCFPS) system that has been simplified by reducing the number of core components from 35 to 7; furthermore, the findings communicate a simplified 'fast lysate' preparation that eliminates the need for traditional runoff and dialysis steps. It is interesting that the system's robustness is exhibited by its applicability to nanoluc, a protein that expresses readily in many systems, to more challenging proteins like the functional self-assembling vimentin and the active restriction endonuclease Bsal. Despite the study representing an advancement towards simplifying protein expression workflows, the evidence is solid and supports the main claims however minor weakness exists i.e. the efficiency claims about the new system needs to be supported by accurate comparisons with typical cell free expression systems, in addition, investigations into the mechanistic basis of the observations would provide more evidence. Despite this shortcoming, the paper remains of interest to scientists in cell and molecular biology, microbiology, biotechnology and protein synthesis.

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 convincing, 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

The authors present important evidence for a WIPI2-Retriever complex (termed CROP2) that couples cargo selection to carrier fission at endosomes. CROP2 appears to function analogously to the previously described CROP1 complex, formed by WIPI1 and Retromer, with which it shares structural similarities. They provide compelling evidence that CROP1 and CROP2 regulate the trafficking of distinct subsets of cargoes; however, the cellular evidence for the existence of these distinct complexes is mostly inferred from immunoprecipitation analysis and would benefit from further validation.

eLife Assessment

This paper reports the findings of a neuroimaging experiment that tested the hypothesis that the cortex, specifically early visual areas, reinstates certain content from past episodic events. This is a useful study that highlights the role of early sensory cortices in supporting rapid, one-shot learning of location information for long-term memory. The strength of the evidence is solid, with the methods, data, and analyses broadly supporting the claims.

eLife Assessment

This fundamental study provides convincing evidence that distinct molecular mechanisms underlie AAV-associated retinal toxicity in retinal pigment epithelial cells and photoreceptors, advancing our understanding of gene therapy-related retinal injury. The authors employ a rigorous and comprehensive experimental approach, including multiple knockout mouse models, transcriptomic analyses, and genetic loss-of-function studies, which substantially strengthen the mechanistic conclusions. Some concerns remain regarding vector characterization, the absence of procedural injection controls, and the limited interpretation of adult versus neonatal studies; nevertheless, the study makes a substantial contribution to the field and provides a strong foundation for future translational investigations.

eLife Assessment

This study presents a useful methodological advance that better enables the simultaneous measurement of gene expression and chromatin accessibility in individual cells. The evidence supporting the improved detection of gene expression is solid. The method has the potential to be more broadly impactful if it were expanded to include orthogonal validation strategies. This method will be of interest to those studying transcription and gene regulation.

eLife Assessment

This important study shows that NPAS4, a gene that is switched on by neural activity, enhances the spatial and temporal precision of hippocampal neurons during navigation. These findings, based on selective and sparse gene deletion, are supported by convincing evidence. However, the experiments were performed entirely in animals exposed to long-term environmental enrichment, which leaves open the question of whether the same effects would emerge under standard housing conditions. This study will be of interest to neuroscientists studying neuronal circuits and spatial coding.

eLife Assessment

This revised study presents valuable findings implicating nuclear export in the regulation of protein condensate behaviour and TDP-43 phase behaviour, suggesting a link to pathogenic aggregation in ALS/FTD. The work contains several observations that will be of interest to the field; however, the underlying mechanistic links proposed by the authors remain insufficiently supported by the current data. The research relies extensively on synthetic, non-physiological protein variants and a homozygous disease model, with limited mechanistic validation, leaving many of the conclusions largely correlative. Thus, despite its technical strengths, the findings presented are currently incomplete, and while the results are invaluable to the field, these do not provide sufficient evidence to substantiate claims about the direct role of nuclear export in pathological protein aggregation and disease.

eLife Assessment

This study presents useful findings on the molecular mechanisms driving female-to-male sex reversal in the ricefield eel (Monopterus albus) during aging, which would be of interest to biologists studying sex determination. The manuscript describes an interesting mechanism potentially underlying sex differentiation in M. albus. However, the current data are incomplete and would benefit from more rigorous experimental approaches for Western blotting.

eLife Assessment

This study provides a valuable advance in understanding how disordered proteins interact with cell membranes by identifying the sequence rules that enable aromatic residues to penetrate deeply into the membrane interior. The integration of complementary computational approaches, including molecular simulations, large-scale sequence analysis, and the development of an online prediction server, makes the work potentially impactful for the membrane protein and intrinsically disordered protein communities. The evidence supporting the main conclusions is generally convincing, although its transferability across diverse membrane compositions and its validity as a prediction tool for real protein-membrane systems remain to be further established.

eLife Assessment

This important study combines chromatin accessibility and genomic DNA sequence conservation data from low-coverage genome sequencing of related species (without assembly), for the in silico identification of cis-regulatory elements in large genomes. The approach and results are compelling and well supported by the experimental validations. The work will be of interest to researchers working in the field of gene regulation and evolution, particularly because the methodology proposed can be applied to a large variety of experimental organisms.

eLife Assessment

This is an important study showing the interaction of the endoplasmic reticulum (ER)-resident tyrosine phosphatase PTP1B with the developing phagocytic cup in macrophages, and its role in inhibiting microbicidal superoxide production. The authors show convincing evidence that PTP1B interacts with Syk, a plasma membrane tyrosine kinase that plays an essential role in phagocytosis, and that ablation of PTP1B increases superoxide production and Syk phosphorylation without affecting phagocytosis. Further evidence suggests that PTP1B may inhibit a Syk/Shc1/NOX2 axis; however, robust demonstration of the proposed chain of events and of the actual role of ER-plasma membrane contact sites in the PTP1B-dependent downregulation of NOX2 activity will require additional experimental evidence. The integration of advanced imaging methods to study contact site formation with functional assays related to phagocytosis and signaling is inspiring.

eLife Assessment

This important study combined careful computational modeling, a large patient sample, and replication in an independent general population sample to provide convincing evidence in support of a computational account of a difference in risk-taking between people who have attempted suicide and those who have not. It is proposed that this difference reflects a general change in the approach to risky (high-reward) options and a lower emotional response to certain rewards. While the findings advance our understanding of cognitive mechanisms at the group level, the observation that computational phenotype is predictive of suicidal behavior only in the clinical sample and not in the online sample limits its applicability for individual prediction, early detection and prevention of suicidality.

eLife Assessment

In this important study, the authors present an interesting platform for digital twin construction of iPSC-CMs using an AI-based approach. The concept is timely and could have meaningful impact as the field continues to explore integration of computational and experimental models. The evidence is convincing overall, although additional attention to framing and calibration of claims would enhance clarity and better reflect the current level of validation.

eLife Assessment

This important study shows that long-range somatostatin-expressing neurons in the ventrolateral periaqueductal grey that project to the rostral ventromedial medulla selectively suppress pain responses during conditioned fear. The evidence supporting these conclusions is exceptional, with methods spanning a novel cued fear-conditioned analgesia paradigm, cell-type-specific optogenetic activation and inhibition, anatomical circuit tracing, and in vivo spinal cord electrophysiology. These results will be of broad interest to systems and behavioral neuroscientists studying fear, pain, and descending pain-control circuitry.

eLife Assessment

This important work challenges current models of merozoite surface protein function by showing that MSP2 is dispensable for parasite growth while modulating immune responses to AMA1, with implications for malaria vaccine design. The conclusions are supported by compelling experimental evidence, including state-of-the-art technologies and well-characterized monoclonal antibodies. These findings provide new insights into immune evasion and antigen targeting that will be of broad interest to parasitology, immunology, and vaccine researchers.

eLife Assessment

This important work addresses a very relevant biological question: what is the cellular basis of wound healing? Using the Drosophila pupal notum as a model, the paper provides an elegant, thorough, descriptive characterization of syncytia-driven wound closure using state-of-the-art confocal live imaging of the pupal notum. The authors meticulously characterize the cell-cell fusion events during wound healing and inhibit cell fusion to show to that it is necessary to speed wound closure. In addition, the study provides convincing evidence that cell fusion allows actin resources at be partitioned to the leading edge.

eLife Assessment

This study provides fundamental insights into the mechanisms of visual object categorization in primates through a scalable behavioral framework for assessing category learning and generalization in macaque monkeys. The evidence is compelling, based on extensive behavioral characterization, rigorous control experiments, and comprehensive comparisons with humans and computational models, although extending the model analyses to the secondary monkey experiments would further strengthen the conclusions.

eLife Assessment

This useful study presents the first application of engineered NK-92 cell-derived extracellular vesicles displaying CD19 scFv for the treatment of systemic lupus erythematosus (SLE). The concept of using targeted extracellular vesicles as a "cell-free" alternative to CAR-T/CAR-NK therapies is good. However, the current results are incomplete and do not provide strong support for the experimental hypothesis, particularly with respect to EV purification, characterization, mechanistic validation, and adherence to current EV field standards. Several major concerns should be addressed to strengthen the translational relevance, reproducibility, and biological interpretation of the study.

eLife Assessment

This study provides important findings regarding the efficacy of a chronotherapeutic protocol (termed LiFE), combining timed light, food, and exercise exposure in improving several physiological and health metrics in a rodent model. The evidence advanced in wild-type mice is solid but inconclusive and underpowered when applied to two transgenic mouse models of Alzheimer's Disease. Additionally, the potential of such protocols in clinical human studies is an open question. Overall, the study suggests that LiFE intervention may have positive effects on metabolic and brain health.

eLife Assessment

This valuable study establishes an improved long-term in vitro culture system for Schistosoma mansoni that enables progression of juvenile parasites to advanced developmental stages exhibiting sexual dimorphism. The work has significant implications for experimental studies of schistosome development and for reducing dependence on animal infection models. The evidence is compelling, supported by robust phenotypic characterization, and integrated molecular and metabolic analyses. The results show that host-derived culture conditions promote essential developmental programs associated with parasite maturation, although the system does not fully recapitulate reproductive development, as evidenced by low pairing frequencies and the lack of egg production.

eLife Assessment

This important study presents a computational framework inspired by cycleGAN that enables denoising and realistic simulation of cryo-electron tomography data, addressing central challenges in tomogram cleaning, simulation, and downstream annotation. The approach coherently links several key problems in the field and demonstrates strong performance across benchmark datasets, with additional benefits for particle detection and missing-wedge completion, indicating broad relevance across electron tomography. The evidence is solid, with appropriate quantitative benchmarks and applications to diverse datasets supporting the main claims, although validation on additional, more recent tomograms would further strengthen the conclusions.

eLife Assessment

This study presents a platform to implement closed-loop experiments in mice based on auditory feedback. The authors provide convincing evidence that their platform enables a variety of closed-loop experiments using neural or movement signals, indicating that it will be a valuable resource to the neuroscience community. The authors make this platform more accessible by complementing the paper with a detailed tutorial explaining how to implement the software and hardware.

eLife Assessment

The article presents important findings of a dissociation between phasic and tonic pain functions in adaptive behavior, combining immersive VR, computational modeling, skin conductance, and EEG data. The methodology used is convincing. Its ecological design and sophisticated computational modeling are major strengths.

eLife Assessment

This important study clearly demonstrates that Sox17 is key for the formation and function of the Sertoli valve, a transition region between the rete testis and seminiferous tubules, which remains an understudied domain of testicular biology. The supporting data are generally convincing but remain incomplete. This work will be of interest to reproductive biologists and andrologists who work on male fertility and men's health.

eLife Assessment

The authors show that innate defensive behavior in mice is shaped by threat intensity, reward value, and social hierarchy, highlighting how value and social context influence instinctive decisions. The authors provide a valuable characterization of escape behavior which approximates naturalistic conditions. Despite minor methodological limitations, the work provides a solid foundation for future investigation of how reward and social context interact to influence behavior.

eLife Assessment

This valuable study draws on large-scale multimodal MRI measurements of human brain structure across the lifespan to offer a new perspective on visual cortex architecture. The data provide compelling evidence for two cortical architectural gradients that show distinct functional, cytoarchitectural, behavioural, and lifespan profiles. One gradient captures a broad early-to-higher-level visual cortical hierarchy in which cortical thickness tissue density covary; the other reflects more localised divergence from this relationship, notably predicting putative anterior temporal visual field representations that have not previously been described.

eLife Assessment

In this valuable manuscript, the authors tackle a highly relevant question in biology: how cells integrate attractive and repulsive cues to achieve directed migration. They present solid data demonstrating that two wunen genes act as negative regulators of Hedgehog signalling, thereby enabling efficient primordial germ cell (PGC) migration in Drosophila embryos. Beyond its immediate scope, this work has broader implications, particularly for understanding key mechanisms underlying complex processes such as cancer metastasis, where the coordinated interpretation of guidance cues is critical.

eLife Assessment

The focus of this manuscript is a computational procedure to reveal signatures of selection on transcription factor binding sites through assessing changes in predicted binding affinity, setting out to avoid biases inherent in previous tests. The general approach could become a valuable resource for the community that can also be used for a broader range of questions. However, in its current implementation, the methods are inadequate to sufficiently support the primary claims.

eLife Assessment

This paper presents important findings on how the shapes of leaves might be biased towards simpler shapes due to biases in how variation is generated by developmental processes rather than selection. The authors present solid evidence that combines image analysis of a herbarium dataset and computational analysis of a model of leaf development. The paper should be of interest to diverse researchers, ranging from plant development to the evolution of complexity more broadly.

eLife Assessment

This useful study introduces a statistical model and accompanying software for jointly analysing how an organism's own genotype, and those of its neighbors, shape its traits (assessing both direct and indirect genetic effects), based on simulations and three datasets from plants. The implementation and its behavior on simulated data are solid, but the evidence that the approach is more powerful, more interpretable, or more novel than established alternatives is incomplete, because the authors do not benchmark against existing methods, nor validate the candidate genes they identify, nor test realistic scenarios in which neighbor effects are weaker than direct effects. The work will be of interest to quantitative geneticists and plant breeders studying competition among neighboring genotypes.

eLife Assessment

This valuable study advances our understanding of genes contributing to Drosophila resistance to octanoic acid, a primary toxin present in Morinda fruit, which is the natural host plant for Drosophila sechellia, a species that has become a model for understanding evolutionary specialization. The authors provide solid results from an original combination of experimental evolution and cell-based CRISPR screens. This work will be of interest to the Drosophila community and researchers interested in the genetic basis of polygenic traits.

eLife Assessment

The framework of the study - with the integration of multiple levels of analysis, glymphatic MRI, transcriptomics, functional MRI, and public amyloid maps, in one framework - is clever. The assertion that regional amyloid vulnerability may depend not just on neural activity alone, but on whether clearance is appropriately matched to activity is an interesting and novel concept. However, the chosen approach to imaging glymphatic clearance relies on indirect inferences from a small subgroup. In its current form, the main conclusions of this study are therefore incompletely supported.

eLife Assessment

This important study systematically investigates parent-of-origin (POE) effects on gene expression using large trio-based data from the Framingham Heart Study, identifying thousands of potentially novel associations. However, the statistical support for classifying POE eQTLs is incomplete, and as a result, downstream analyses of the identified POE eQTLs are not fully supported.

eLife Assessment

The study presents a valuable conceptual framework by classifying pattern-forming gene subnetworks into three established categories. However, the supporting evidence remains incomplete, as the mathematical generalizations rely on simplified assumptions that may not hold in more complex or realistic scenarios.

eLife Assessment

This study presents an important finding that loss or blockade of key integrins unexpectedly enhances central nervous system accumulation of T-cell acute lymphoblastic leukemia cells and may increase their sensitivity to chemotherapy. The evidence is convincing, supported by well-designed in vivo models, CRISPR-based perturbations, competitive assays, imaging, and complementary therapeutic experiments. However, the mechanistic basis linking integrin loss, altered spatial distribution, and increased proliferation remains incompletely defined, and the translational implications would be strengthened by additional survival studies and validation in more clinically relevant models.

eLife Assessment

This study of BDNF signaling in heterogeneous spinal cord cultures provides a fundamental conceptual advance by demonstrating that cell identity and maturation state, rather than receptor stoichiometry alone, ultimately determine how a trophic message is interpreted, in a framework the authors call "prepared competence." The evidence is compelling, with the discrete subpopulation behavior, the maturation-dependent acquisition of signaling competence, and the dissociation between receptor abundance and signaling output emerging clearly from the high-dimensional dataset. This study will be of interest to neurobiologists as well as cell biologists who study the molecular basis of cell signaling.

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

This useful study examines excitation/inhibition (E/I) balance in the CA3-CA1 circuit of the hippocampus. Experimental and computational modeling results are presented. The computational modeling results were viewed as a novel advance supported by solid evidence, but incomplete evidence was provided to support the paper's main experimental claims due to deficiencies in the experimental methodology and concerns about the neurobiological relevance of the experimental observations.

eLife Assessment

This study makes a valuable contribution to understanding how negative affect shapes food-choice decision making in bulimia nervosa by using a mechanistic drift diffusion model to quantify the weighting and temporal integration of tastiness and healthiness attributes. The approach is solid and has clear potential to advance understanding of the decision processes underlying pathological food choices. The evidence is strengthened by the randomised crossover design and appropriate statistical analyses. The results are consistent across different analytic approaches, increasing confidence in the robustness of the findings.

eLife Assessment

This important study investigates frequency-dependent effects of transcutaneous tibial nerve stimulation (TTNS) on bladder function in healthy humans and, through a computational model, shows that low-frequency stimulation accelerates, and high-frequency delays, the urge to void. The integration of experimental and modeling approaches provides a solid proof-of concept foundation for clinical trials targeting urinary retention. However, concerns were raised about over-interpretation of modest effects and the limited physiological validity of the computational model, and the need for replication in clinical populations. Some conclusions, particularly in the abstract, could be further tempered to better align with the strength of the available evidence.

eLife Assessment

This study reports important findings by showing that two classes of kinase inhibitors, which stabilise the LRRK2 enzyme in either an active (Type I) or inactive state (Type II), have distinct effects on the formation of LRRK2 filaments and their association with cellular structures. Using correlative light microscopy, cryo-electron tomography and sub-tomogram averaging, the authors provide convincing evidence that a Type I inhibitor leads to the extensive decoration of microtubules with LRRK2 in a closed-kinase conformation, and that such decoration is not seen for a type-II inhibitor. The conclusions are consistent with previous work, although the physiological relevance of the work remains somewhat limited due to reliance on overexpression and the use of a rare mutation in a single cell type.

eLife Assessment

This important study identifies inhibitory cerebellar nuclei neurons as drivers of dystonic crisis and shows that their modulation can both induce and alleviate severe motor symptoms, proposing a cerebello-thalamic circuit mechanism with clear therapeutic relevance. The evidence is convincing, supported by rigorous bidirectional optogenetic manipulations, iCNN-to-CL thalamic monosynaptic tracing, and deep brain stimulation experiments, although the specificity of the genetic strategy remains to be fully resolved. The study will be of broad interest to neuroscientists and clinicians working on movement disorders and circuit-based therapies.

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 convincing evidence that ripples and locus coeruleus activity are inversely correlated to levels of arousal and noradrenaline tone is modulated by hippocampo-cortical coupling. Overall, the work will be of interest to neuroscientists studying large-scale brain coordination and memory processes.

eLife Assessment

This valuable study shows that macaque monkeys preferentially fixate regions in natural scenes that are classified as "meaningful" by a computational model - an earlier model that was developed to identify locations that are semantically informative to humans - suggesting that overt attention to structured visual content is shared across primates. However, support is incomplete for the stronger claim that macaques are guided by semantic meaning, which is confounded by lower-level visual features that co-vary with it and by methodological limitations that complicate interpretation. If the semantic interpretation were more reliably established, the significance of the findings would increase, as they would connect the human cognitive process of scene understanding to neural circuit mechanisms accessible in non-human primates.

eLife Assessment

This valuable study rigorously examines how motor learning is influenced by the feedback response to a previous movement error. Using a series of well-conducted experiments, the authors provide solid evidence that the learning response following a cursor jump does not depend on the timing of the perturbation and is influenced by the tonic component of the feedback responses. Further work is needed to determine whether this generalizes to other perturbation paradigms and to more fully understand the relationship between learning and the tonic and phasic components of the feedback response.

eLife Assessment

This valuable study analyses correlations between traits of Chinese frog species and their Red List status and finds differences between adults and larvae. Of broad relevance, this solid study makes the statement to consider different life-cycle stages when assessing species extinction risks, although many conclusions are based on limited data and thus offer hypotheses rather than direct conservation advice.

eLife Assessment

This study leverages publicly available datasets to confirm, validate and extend the knowledge of the transcriptional profile of beta cells that resist destruction in Type 1 diabetes. The significance of the findings is considered valuable as they could be used for engineering stem cell-derived islets and for identifying therapeutic targets to preserve beta cell survival. The strength of the evidence is solid, in that the findings are supported by a sophisticated bioinformatic analysis pipeline and are largely consistent with and extend the existing literature.

eLife Assessment

This study provides an important assessment of how body size influences the occurrence of macro-organisms in urban areas across the globe. Size in most plants, but only some animal families, was positively associated with urban affinity. The data set is impressive and the strength of evidence solid.

eLife Assessment

This important study investigates how the brain categorizes written words from different writing systems (e.g., alphabetic vs. non-alphabetic). The evidence supporting the authors' claims is solid and sheds light on the neural basis of language's social‑categorization function.

eLife Assessment

This valuable study compares auditory cortex responses to sounds and cochlear implant stimulation measured with surface electrode grids in rats. Beyond the reduced frequency resolution of cochlear implants observed previously, this study suggests key discrepancies between neuronal representations of cochlear stimulations and natural sounds. The evidence for this result is solid but could be strengthened with a clarification of the methodology and an adaptation of the claim to the actual precision of the measurements. This study is of interest to researchers in the auditory neuroscience field and clinicians implementing treatments with cochlear implants.

eLife Assessment

This valuable study explores the role of Pink1 in regulating mitochondria-organelle contacts and glial function, advancing our understanding of the mechanisms underlying neurodegenerative diseases. The findings highlight key genes and cellular processes that are critical in maintaining neuronal health, with implications for glial biology and Parkinson's disease research. The methodology and data are solid. This work will be of significant interest to researchers in neuroscience, cell biology, and neurodegenerative diseases.

eLife Assessment

This important study reveals intriguing connections between chromosome breakage and DNA elimination during programmed genome rearrangement in the ciliate Tetrahymena thermophila. By developing a novel FISH approach that distinguishes germline and somatic telomeres, the authors provide compelling evidence that chromosome breakage removes germline telomeres along with hundreds of kilobases of germline-limited sequences. By disrupting a single chromosome breakage site, they further showed that DNA elimination was globally affected, which opens up a new direction for mechanistic studies. Thus, this work reveals additional similarity between the programmed DNA elimination in ciliates and nematodes that underlies the transition from germline to somatic telomeres.

eLife Assessment

This valuable study presents convincing data demonstrating that alpha herpesvirus triggers nuclear export of HDACs, which are then degraded in an MDM2-dependent manner. This virus-driven process leads to histone hyperacetylation and activation of the DNA damage response, which promotes viral replication.

eLife Assessment

This important study establishes an environmental sampling workflow for the discovery of bacteriophages capable of infecting antibiotic-resistant pathogens. The authors convincingly demonstrate the effectiveness of the approach, even with the limited sampling scheme and the current challenges in viral taxonomy. This study will interest researchers working on bacterial infections, environmental microbiology, and phage-based alternatives for addressing antimicrobial resistance.

eLife Assessment

This important study uses a feedback-driven recurrent neural network framework to explore the dynamics underlying learning of BCI decoder perturbations. With convincing evidence, the authors demonstrate that behavioral learning trajectories that match those of primates learning within-manifold and outside-manifold perturbations are likely tied to the dynamical controllability of the network and input-driven learning. This work is likely to motivate a new generation of BCI and learning experiments combining large-scale neural recordings with latent dynamical systems analyses.

eLife Assessment

This important study employed a multi-stage behavioural paradigm of increasing cognitive complexity to investigate the role of inhibitory interneurons in the medial prefrontal cortex (mPFC) in avoidance behaviour in mice. The authors used imaging and optogenetic techniques combined with this behavioural task to show that mPFC interneurons are necessary for encoding but not executing avoidance under threat. The evidence supporting these claims is compelling, and findings will be of interest to researchers in behavioural and systems neurosciences.

eLife Assessment

This important study demonstrates that paternal diet influences not only testicular morphology but also placental and fetal development, supporting a role for paternal contributions to offspring health. The study also considers potential links between the microbiome and male reproductive health. By combining transcriptomic and histological analyses across multiple tissues, the evidence supporting the central conclusions of the study is convincing.

eLife Assessment

This study presents a valuable finding on the direct cytotoxic effects of DuoHexaBody-CD37 in diffuse large B-cell lymphoma through antibody clustering, independent of complement. The central findings are supported by solid evidence, although some mechanistic details, including the specific Fc receptor requirements for crosslinking-mediated cytotoxicity, remain unresolved. As the findings are based primarily on in vitro models, further validation would be required to support broader translational conclusions. The previous review comments were addressed by the authors and have improved the work.

eLife Assessment

This valuable study re-evaluates a published simulation model on the role of heterozygote advantage in shaping MHC diversity. By modifying key modeling assumptions, the author argues that the original conclusions depend on a narrow and potentially unrealistic parameter range. While the work is in principle solid, the robustness of this claim is viewed differently by the reviewers. The manuscript further proposes an alternative modeling framework in which expansion of the MHC gene family allows homozygotes to outperform heterozygotes, thereby challenging the idea that heterozygote advantage alone can account for high allelic diversity at MHC loci. The topic is highly relevant for eco-immunology and evolutionary genetics, although it is not clear yet how well the model generalizes to other genes with different patterns of haplotype diversity in the population and different degrees of heterozygous advantage.

eLife Assessment

This study reports important findings by showing that two classes of kinase inhibitors, which stabilise the LRRK2 enzyme in either an active (Type I) or inactive state (Type II), have distinct effects on the formation of LRRK2 filaments and their association with cellular structures. Using correlative light microscopy, cryo-electron tomography and sub-tomogram averaging, the authors provide convincing evidence that a Type I inhibitor leads to the extensive decoration of microtubules with LRRK2 in a closed-kinase conformation, and that such decoration is not seen for a type-II inhibitor. The conclusions are consistent with previous work, although the physiological relevance of the work remains somewhat limited due to reliance on overexpression and the use of a rare mutation in a single cell type.

eLife Assessment

This solid paper reports on the use of artificial intelligence to assess bone marrow adipose tissue in the skull. The method employing MRI is novel and that approach allows for the identification of genetic loci that regulate this trait as well as others using data from the UK biobank. Overall this is an important contribution although the authors should consider several points: 1-validation of the T1-weighted MRI signal intensity; 2-further discussion of the sex differences; and 3-cross-trait linkage disequilibrium score regression (LDSC) for osteoporosis, Parkinson's disease, and cognitive function.

eLife Assessment

This study provides conditionally useful evidence that amino acid starvation and other stresses induce RNF25-dependent ubiquitination of RPS27A/eS31, extending this pathway beyond A-site-trapping conditions and implicating GCN1. However, incomplete and largely indirect evidence was provided to support key mechanistic claims-notably competition between RNF25 and GCN2 for GCN1 and a role in resolving ribosome collisions. Additional direct and orthogonal evidence is required to substantiate these conclusions.

eLife Assessment

Using a genetic screen in C. elegans, Benbow et al., identify mutations in alpha-tubulin genes that suppress Tau-induced neurodegenerative phenotypes. The results provide solid support the authors' claim that the tubulin mutants protect against neurodegeneration without altering tau aggregation and hyperphosphorylation. While precise mechanisms of protection by tubulin mutants remain to be established, the results are valuable for understanding the underlying cellular mechanisms of Tauopathies and for the development of therapeutic interventions.

eLife Assessment

This potentially valuable study describes the development of protein binders targeting DELE1, a protein involved in activating the integrated stress response when mitochondria are perturbed (the mitoISR pathway. The strategy appears to be successful, as several designed proteins were shown to bind DELE1, disrupt DELE1 oligomerization, and attenuate ISR activation. However, the demonstration of the utility of these inhibitory binders is incomplete, particularly given the limited biological outcomes examined in the current study, thus limiting the significance of the paper in its current form.

eLife Assessment

This study presents a valuable finding that coordinated changes in epigenetic modifications and three-dimensional chromatin architecture may drive primary trastuzumab resistance in HER2+ breast cancer. Moreover, this manuscript identifies SGK1 as a potential therapeutic target. The evidence supporting the claims of the authors is solid, although the inclusion of a more direct validation of the key findings using tumor samples from patients with clinical trastuzumab resistance would have strengthened the study. The work will be of interest to scientists or clinicians working in the field of BCs.

eLife Assessment

This manuscript provides a timely and important statistical re-evaluation of a paper by Epp et al., on the discordance of BOLD and CMRO2 measures. The authors present a convincing case based on rigorous re-analysis of the data that these previous results arise predominantly from uncertainty in measurement, rather than physiological features. These findings have implications that are of importance to all studies of brain function using BOLD FMRI.

eLife Assessment

This useful study employs longitudinal widefield cortical imaging to investigate how bilateral vision loss reshapes spontaneous activity across the mouse cortex over time, revealing a state-dependent alteration in the locomotion-related modulation of visual cortical activity. The work provides solid support for its main findings and offers a thorough characterization of the large-scale reorganization of cortical dynamics following adult vision loss. However, the mechanistic interpretation remains limited, as the conclusions are based on a single abrupt and irreversible manipulation without sham controls and on a recording approach that cannot resolve the cell-type-specific mechanisms invoked in the discussion.