eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

eLife assessment

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

eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

eLife Assessment

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

Challenging to address high error rate for minority groups

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

ML emphasizes societal stereotypes.

disparities -> discrimination

Important example of using experience and intuition over data

flaws in only relying on examples.

The need for "learning" over "branching"

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

eLife Assessment

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

eLife Assessment

This important study fills a gap in our knowledge of the evolution of GPCRs in holozoans, as well as the phylogeny of associated signaling pathway components such as G proteins, GRKs, and RIC8 proteins. The evidence supporting the conclusions is compelling, with the analysis of extensive new genomic data from choanoflagellates and other non-animal holozoans. Overall, the study is thorough and well-executed. It will be a resource for researchers interested in both the comparative genomics of multicellularity and GPCR biology more broadly, especially given the importance of GPCRs as highly druggable targets

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, as well as in their natural habitat. While the data strongly suggest that starvation may induce predation, further work is needed to fully establish this link. Similarly, the evidence for a social component in the predation process remains incomplete. This study will be very impactful to those interested in the diversity of microbial predator-prey interactions and controlling toxic algal bloom, but the paper could be strengthened by more clearly showing the degree of replication, by better defining the terms used to describe the observed behaviour, and by providing better support for starvation and collective behaviour.

eLife Assessment

How secretion is regulated during cell division and how membrane trafficking factors cooperate with the cytoskeleton during cell division remain poorly understood. In this work the authors find protein-protein interactions and localization dependencies between the polymeric septin cytoskeleton and the exocyst complex, using fission yeast as a model organism and using alphafold 3 based structural predictions. The work provides a valuable body of new information that will be of great interest to the cell biology community. The evidence is solid and provides the authors and the community a framework to test if the identified interfaces reflect bona fide interaction sites in vivo and in vitro in future.

eLife Assessment

This work presents important findings suggesting that a combination of transcranial stimulation approaches applied for a short period could improve memory performance. Solid methods and evidence, in line with current standards for non-invasive stimulation and recording, are included to broadly support the main findings. The results potentially have implications for non-invasive enhancement of cognitive functions.

eLife Assessment

This study presents a valuable finding that KDM5 inhibitors may enable a wide therapeutic window as compared to STING agonists or Type I Interferons. The evidence supporting the claims of the authors is convincing. The work will be of broad interest to scientists working in the field of breast cancer research.

eLife Assessment

The study showcases a significant and important enhancement of the MAGIC transgenesis method, by extending it genome-wide to all chromosomes. The authors convincingly demonstrate that the MAGIC mosaic clones can be generated for genes from all, including the 4th chromosome. With this toolkit extension, the method is now most likely set to strongly rival the classical FRT/Flp recombination system for gene manipulation in flies.

eLife Assessment

This study provides valuable insights into human valve development by integrating snRNA-seq and spatial transcriptomics to characterize cell populations and regulatory programs in the embryonic and fetal outflow tract. The methods, data, and analyses are solid overall, but with some weaknesses that can be strengthened. The findings will be of interest to those who work in the field of heart development and congenital heart disease.

eLife Assessment

This manuscript reports important findings that have theoretical or practical implications beyond a single subfield. However, despite the combination of numerous analytical tools established and applied in the study, the work has substantial experimental limitations leading to incomplete evidence, indicating that the conclusions may be an over-interpretation of the findings.

eLife Assessment

This fundamental study provides new insights into the plasticity mechanisms underlying the formation of spatial maps in the hippocampus. Supported by a large and comprehensive dataset, the evidence is convincing. This study will be of interest to neuroscientists focusing on spatial navigation, learning, and memory.

eLife Assessment

This manuscript describes a useful study describing an interesting infection phenotype that differs between adult male and female zebrafish. The authors argue that male-biased expression of Cyp17a2 is implicated in mediating infection levels through STING and USP8 activity regulation. Thus, this study highlights an unexpected factor involved in antiviral immunity that could open new avenues of investigation for infection, metabolism, and other contexts. Although the manuscript presents some evidence supporting its main claims, the evidence for the main argument made in the study on sex dimorphism remains incomplete at this stage.

eLife Assessment

The study by Reed et al. provides fundamental findings and convincing evidence defining the topological changes that occur during tumorigenesis. The findings enhance the understanding of stable long-range connections among genes that reprogram cancer-related functions. Nevertheless, performing additional experiments is recommended.

eLife Assessment

This study demonstrates that conditional knockout of afadin disrupts retinal laminar organization and reduces the number of photoreceptors, while preserving certain aspects of retinal ganglion cell structure and light responsiveness. The work is valuable and well-supported by revised figures and comprehensive data on retinal cell types, lamination patterns, and visual functio. The findings are solid and intriguing, and the study provides insights into the relationship between retinal lamination and neural circuit function.

eLife Assessment

This valuable study employs a formalized computational model of learning to assess memory deficits in Alzheimer's Disease with the goal of developing an early diagnosis tool. Using an established mouse model of the disease, the authors studied multiple behavioral tasks and ages with the goal of showing similarities in behavioral deficits across tasks. Using the model, the authors indicate specific deficits in memory (overgeneralization and over differentiation) in mice with the transgene for the disease. The evidence presented is solid, yet certain concerns remain regarding the interpretation of the results of the modeling.

eLife Assessment

This manuscript describes an AI-automated microscopy-based approach to characterize both bacterial and host cell responses associated with Shigella infection of epithelial cells. The methodology is compelling and should be helpful for investigators studying a variety of intracellular pathogens. The authors have acquired important findings regarding host and bacterial responses in the context of infection, which should be followed up with further mechanistic-based studies.

eLife Assessment

This study presents a computational-experimental workflow for optimizing RNA aptamers targeting SARS-CoV-2 RBD. While the integrated approach combining docking, molecular dynamics, and experimental validation shows some promise, the useful findings are limited by the extremely weak binding affinities (>100 µM KD) and restriction to a single target system. The evidence is incomplete, with experimental design issues in the antibody competition assays and a lack of specificity testing undermining confidence in the conclusions.

eLife Assessment

This study is a valuable contribution to the evidence base. However, the evidence provided is incomplete as the study results only partially support the study conclusions. Addressing the methodological and reporting issues raised by the peer reviewers and properly aligning the claim made for providing a tool for early warning with the study analysis/results would improve the study quality and usefulness of its findings.

eLife Assessment

This landmark manuscript comprehensively examines the roles of nine structural proteins in herpes simplex virus 1 (HSV-1) assembly and nuclear egress. By integrating cryo-light microscopy and soft X-ray tomography, the study presents an innovative approach to investigating viral assembly within cells. The research is thoroughly executed, yielding exceptional data that explain previously unknown functions expected to bear widespread influence. This work is of broad interest to virologists, cellular biologists, and structural biologists, offering a robust, contextually rich methodology for studying large protein complex assembly within the cellular environment, serving as an excellent starting point for high-resolution techniques.

eLife Assessment

The ratio of nuclei to cell volume is a well-controlled parameter in eukaryotic cells. This study now reports important findings that expand our understanding of the regulatory relationship between cell size and number of nuclei. The evidence supporting the conclusions is convincing obtained by applying appropriate and validated methodology in line with current state-of-the-art. The paper will be of broad interest for cell biologists and fungal biotechnologists seeking to understand mechanisms determining cell size and number of nuclei and why this knowledge might also be of importance for the production of enzymes and thus production strains not only of Aspergillus oryzae but also other industrially used fungi.

eLife Assessment

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

eLife Assessment

This computational modeling study builds on multiple previous lines of experimental and theoretical research to investigate how a single neuron can solve a nonlinear pattern classification task. The revised manuscript presents convincing evidence that the location of synapses on dendritic branches, as well as synaptic plasticity of excitatory and inhibitory synapses, influences the ability of a neuron to discriminate combinations of sensory stimuli. The ideas in this work are very interesting, presenting an important direction in the computational neuroscience field about how to harness the computational power of "active dendrites" for solving learning tasks.

eLife Assessment

This important computational study investigates homeostatic plasticity mechanisms that neurons may employ to achieve and maintain stable target activity patterns. The work extends previous analyses of calcium-dependent homeostatic mechanisms based on ion channel density by considering activity-dependent shifts in channel activation and inactivation properties that operate on faster and potentially variable timescales. The model simulations convincingly demonstrate the potential functional importance of these mechanisms.

eLife Assessment

This study presents a valuable investigation into cell-specific microstructural development in the neonatal rat brain using diffusion-weighted magnetic resonance spectroscopy. The evidence supporting the core claims is solid, with innovative in vivo data acquisition and modeling, noting residual caveats with regard to the limitations of diffusion-weighted magnetic resonance spectroscopy for strict validation of cell-type-specific metabolite compartmentation. In addition, the study provides community resources that will benefit researchers in this field. The work will be of interest to researchers studying brain development and biophysical imaging methods.

eLife Assessment

This valuable work explores how synaptic activity encodes information during memory tasks. All reviewers agree that the work is of very high quality and that the methodological approach is praiseworthy. Although the experimental data support the possibility that phospholipase diacylglycerol signaling and synaptotagmin 7 (Syt7) dynamically regulate the vesicle pool required for presynaptic release, a concern remains that the central finding of paired-pulse depression at very short intervals could be due to a mechanism that does not depend on exocytosis, such as Ca²⁺ channel inactivation, rather than vesicle pool depletion. Overall, this is a solid study although the results still warrant consideration of alternative interpretations.

eLife Assessment

This valuable study introduces a non-perturbative pulse-labeling strategy for yeast nuclear pore complexes (NPCs), employing a nanobody-based approach in order to selectively capture Nup84-containing complexes for imaging and biochemical analysis. The data convincingly demonstrate that a short induction period (20 minutes to 1 hour) yields a strong and sustained signal, enabling affinity purification that faithfully recapitulates the endogenous Nup84 interactome. This tool offers a powerful framework for investigating NPC dynamics and associated interactomes through both imaging and biochemical assays.

eLife Assessment

The authors examined the frequency of alternative splicing across prokaryotes and eukaryotes and found that the rate of alternative splicing varies with taxonomic groups and genome coding content. This solid work, based on nearly 1,500 high-quality genome assemblies, relies on a novel genome-scale metric that enables cross-species comparisons and that quantifies the extent to which coding sequences generate multiple mRNA transcripts via alternative splicing. This timely study provides an important basis for improving our general understanding of genome architecture and the evolution of life forms.

eLife Assessment

This important study examines the evolution of virulence and antibiotic resistance in Staphylococcus aureus under multiple selection pressures. The evidence presented is convincing, with rigorous data that characterizes the outcomes of the evolution experiments. However, the manuscript's primary weakness is in its presentation, as claims about the causal relationship between genotypes and phenotypes are based on correlational evidence. The manuscript needs to be revised to address these limitations, clarify the implications of the experimental design, and adjust the overall narrative to better reflect the nature of the findings.

eLife Assessment

This study reports on the development and characterization of chickens with genetic deficiencies in type I or type III interferon receptors, which is an important contribution to the field of avian immunology. The data reflecting the development of the new interferon-receptor-deficient chickens is compelling. However, the characterization of IFN biology and infection responses in these knockout chickens is somewhat incomplete and could be improved by addressing the noted weaknesses.

eLife Assessment

Non-essential amino acids such as glutamine have been known to be required for T cell general activation through sustaining basic biosynthetic processes, including nucleotide biosynthesis, ATP generation, and protein synthesis. In this important study, the authors found that extracellular asparagine (Asn) is required not only for T cells to generally refuel metabolic reprogramming, but to produce helper T cell lineage-specific cytokine, for instance, IL17. In particular, the importance of Asn in IL17 production was convincingly demonstrated in the mouse experimental autoimmune encephalomyelitei (EAE) model, mimicking human multiple sclerosis disease.

eLife Assessment

This study illustrates a valuable application of BID-seq to bacterial RNA, allowing transcriptome-wide mapping of pseudouridine modifications across various bacterial species. The evidence presented includes a mix of solid and incomplete data and analyses, and would benefit from more rigorous approaches. The work will interest a specialized audience involved in RNA biology.

eLife Assessment

This study presents valuable data suggesting that ATP-induced modulation of alveolar macrophage (AM) functions is associated with NLRP3 inflammasome activation and enhanced phagocytic capacity. While the in vivo and in vitro data reveal an interesting phenotype, the evidence provided is incomplete and does not fully support the paper's conclusions. Additional investigations would be of value in complementing the data and strengthening the interpretation of the results. This study should be of interest to immunologists and the mucosal immunity community.

eLife Assessment

This convincing study, which is based on a survey of researchers, finds that women are less likely than men to submit articles to elite journals. It also finds that there is no relation between gender and reported desk rejection. The study is an important contribution to work on gender bias in the scientific literature.

eLife Assessment

This valuable study introduces a modern and accessible PyTorch reimplementation of the widely used SpliceAI model for splice site prediction. The authors provide convincing evidence that their OpenSpliceAI implementation matches the performance of the original while improving usability and enabling flexible retraining across species. These advances are likely to be of broad interest to the computational genomics community.

eLife Assessment

This fundamental work advances our understanding of how SP5 and SP8 promote neuromesodermal competent progenitors in murine embryos. Generally the evidence is compelling, with strong developmental genetics, transcriptomic, and genomic transcription binding surveys contributing to the strength of the data. Some of the language could be softened to avoid overinterpretation of the data, and figures and diagrams could be improved.

eLife Assessment

This work presents important information on rhythmicity of overlapping target and distractor processing and how this affects behaviour. The methods are, in general, clearly laid out and defensible, with several supplementary analyses leading to a solid base of evidence for their claims.

eLife Assessment

This fundamental work significantly advances our understanding of gravity sensing and orientation behavior in the ctenophore, an animal of major importance in understanding the evolution of nervous systems. Through comprehensive reconstruction with volumetric electron microscopy, and time-lapse imaging of cilia motion, the authors provide compelling evidence that the aboral nerve net coordinates the activity of balancer cilia. The resemblance to the ciliomotor circuit in marine annelids provides a fascinating example of how neural circuits may convergently evolve to solve common sensorimotor challenges.

eLife Assessment

This valuable work presents a novel computational framework for modeling macroscopic traveling waves in the mouse cortex by integrating open-source connectomic and transcriptomic data into a spiking network model. This approach allows the computational model to assign excitatory/inhibitory connections based on neurotransmitter profiles and extends simulations to the 3D domain. The authors present results that demonstrate how spatiotemporal dynamics such as slow oscillations (0.5-4 Hz) emerge and self-organize at the whole-brain scale. This study provides convincing initial insights into the structural basis of traveling waves at the whole-brain scale in the mouse.

eLife Assessment

This important study utilizes behavioral data and computational modeling to show that spatial properties of visual attention affect human planning. The methodology and statistical analyses are solid, though the way attention is conceptualized and modeled could be refined. The findings of this study will interest cognitive scientists studying attention, perception, and decision-making.

eLife Assessment

This study presents a valuable and rigorous molecular resource, offering subtype-specific insight into the composition of ribosome-associated protein complexes in the developing cerebral cortex. The evidence is compelling in terms of data quality and is strongly supported by the results, given the rigorous technical execution. However, the findings remain primarily descriptive, as the study lacks functional validation to support mechanistic conclusions.

eLife Assessment

This valuable model-based study seeks to mimic bat echolocation behavior and flight under conditions of high interference, such as when large numbers of bats leave their roost together. Although some of the assumptions made in the model may be questioned, the simulations convincingly suggest that the problem of acoustic jamming in these situations may be less severe than previously thought. This finding will be of broad interest to scientists working in the fields of bat biology and collective behaviour.

eLife Assessment

In this fundamental manuscript, Richter et al. present a thorough anatomical characterization of the Drosophila melanogaster larval pharyngeal sensory system, which is involved in taste-guided behaviors. This study fills a major gap in the larval sensory map, providing a compelling neuroanatomical foundation for future investigations into sensory circuits and behavior. The data presented here are of exceptional quality and will be of interest to the Drosophila neurobiology community.

eLife Assessment

This important work provides convincing evidence of the cognitive and neural mechanisms that give rise to feelings of shame and guilt, as well as their transformation into compensatory behavior. The authors combine well-designed manipulations of responsibility and harm with computational cognitive modeling and neuroimaging to provide a comprehensive account of how emotions are experienced and acted upon.

eLife Assessment

This is a useful analysis of STORM data that characterizes the clustering of active zones in retinogeniculate terminals across ages and in the absence of retinal waves. The design makes it possible to relate fixed time point structural data to a known outcome of activity-dependent remodeling. However, the evidence is incomplete, weakening the claims the authors make regarding how activity influences the clustering of these synapses. This basic criticism has not improved with revisions.

eLife Assessment

This manuscript uses modeling approaches to provide mechanistic insight into the structural and dynamic properties of enhancer-promoter interactions in Drosophila. Given the interest in this field, this is a timely approach, and the results give useful insights by providing predictions about the processivity of cohesin loop extrusion in Drosophila and concluding that the compartmental interaction strength is poised near criticality in the coil-globule phase space. The evidence provided to support some of the conclusions is, however, incomplete and would be strengthened by better considering some of the caveats in the data used to constrain the models, such as the use of "homie" genetic elements in the dynamic data. There is insufficient evidence provided for the dynamics being criticality-driven, and in addition, consideration of alternative models would further strengthen the conclusions of the manuscript.

eLife Assessment

This paper explores the role of extracellular vesicles in providing extracellular matrix signals for migration of vascular smooth muscle cells. The evidence, based on cell culture experiments and supporting imaging of human samples, is mostly convincing. The paper will be valuable for researchers investigating cell migration during vessel repair and atherogenesis.

eLife Assessment

Decron and colleagues combine common psychiatric treatments with a probabilistic reward learning task and trial-by-trial ratings of affect, confidence, and engagement. Using computational cognitive modeling, they show that, while both treatments serve to counter negative biases in affect and confidence, cognitive distancing and antidepressant medication have dissociable effects on subjective evaluations and reward-based choice behavior. This work provides convincing evidence regarding an important line of investigation into the dynamic integration of affect, cognition, and learning.

eLife Assessment

This important study describes the development and validation of an Automated Reproducible Mechano-stimulator (ARM), a tool for standardizing and automating tactile behavior experiments. The data supporting the use of the ARM system are compelling, and demonstrate that by removing experimenter effects on animals, it reduces variability in various parameters of stimulus application. Moreover, the authors demonstrate that any noise emitted from the ARM does not induce an increased stress state. Once commercially available, the ARM system has the potential to increase experimental reproducibility between laboratories in the somatosentation and pain fields.

eLife Assessment

This paper discusses the cognitive implications of potential intentional burial, wall engraving creation, and fire as light source use behaviors by relatively small-brained Homo naledi hominins. The discussion presented in the paper is valuable theoretically in its healthy questioning of prior assumptions concerning the socio-biological constraints of hominin meaning-making behavior. The discussion also contributes practically given that these behaviors have been ascribed to Homo naledi in two associated papers. Still, the strength of evidence in this contribution relies on the validity of the conclusions from the two associated papers, which remain actively questioned. The ultimate assessment of this work will vary among individual readers depending on how they view this debate, but if the conclusions from the associated papers hold up, the conclusions in the current paper can be considered solid.

eLife Assessment

This manuscript introduces a useful protein-stability-based fitness model for simulating protein evolution and unifying non-neutral models of molecular evolution with phylogenetic models. The model is applied to five viral proteins that are of structural and functional importance. While the general modelling approach is solid, and effectively preserves folding stability, the evidence for the model's predictive power remains limited, since it shows little improvement over neutral models in predicting protein evolution. The work should be of interest to researchers developing theoretical models of molecular evolution.

eLife Assessment

This work characterizes the function and localization of SLC4A1 variants associated with distal renal tubular acidosis in human patients. Cell culture and limited animal studies provide partial but incomplete support to the authors' claim that the variants disrupt normal protein degradative flux by alkalinizing the intracellular pH. The study is valuable in providing preliminary evidence for future exploration of the link between intracellular pH regulation by SLC4A1 and kidney cell function in vivo.

eLife Assessment

This study presents the important finding that lysosomal damage triggers inflammatory signaling through ubiquitination and the TAB-TAK1-IKK-NF-kB axis. The data obtained from the unbiased transcriptomic and proteomic analyses are convincing and provide invaluable information to the field. Although further experiments will be required to clarify how TAB2/3 are recruited after various types of lysosome damage, this work will be of interest to researchers in the fields of organelle biology and inflammation.

eLife Assessment

This important work describes the adaptation and evaluation of two red-shifted anion channelrhodopsins (RubyACRs) for optogenetic inhibition in Drosophila. The study provides convincing evidence for the effectiveness of RubyACRs in fly neurons, including electrophysiology, calcium imaging, and behavioral analysis. With minor revisions to address potential toxicity and compatibility with 2-photon imaging, this paper and the publicly available fly lines it describes will be resources that are of value to the neuroscience community.

eLife Assessment

This manuscript is useful as it demonstrates that Rv2577, a Fe³⁺/Zn²⁺-dependent metallophosphatase, is secreted by Mycobacterium bovis BCG and localizes to the nucleus of mammalian cells, altering transcriptional and inflammatory responses. However, the study is incomplete as it lacks activity validation in macrophage cells and with virulent Mycobacterium tuberculosis strains. It is necessary to confirm Rv2577 secretion from a virulent strain and to clarify the direct or indirect role of MmpE in modulating host pathways, together with mechanistic insight into how MmpE influences lysosomal biogenesis and trafficking.

eLife Assessment

This important study applies a novel signal decomposition method to disentangle distinct signals contributing to the decision-making process, and provides convincing evidence for the operation of separate sensory encoding, attentional orienting, and ramping evidence accumulation signals. These findings are consistent with previous work, except for the absence of a motor component, which may relate to limitations of the analysis approach.

eLife Assessment

This important report describes the changing antiviral activity of IFIT1 across mammals and in response to distinct viruses, likely as a result of past arms races. One of the main strengths of the manuscript is the breadth of mammalian IFIT1 orthologs and viruses that were tested, as well as the thoroughness of the positive selection analysis. Overall the evidence is convincing, and the discussion conveys well the limitations due to physical interactions with other IFITs that are not accounted for.

eLife Assessment

In this valuable contribution, the authors present a novel and versatile probabilistic tool for classifying tracking behaviors and understanding parameters for different types of single-particle motion. The software package will be broadly applicable to single-particle tracking studies. The methodology has been convincingly tested by computational comparisons and experimental data, although the mathematical foundation for the hypothesis testing method can be further strengthened.

eLife Assessment

The paper reports valuable findings about the mechanism of regulation of the heat shock response in plants that acts as a brake to prevent hyperactivation of the stress response, which have theoretical or practical implications for a subfield. The study presented by the authors provides solid methods, data, and analysis that broadly support the claims. This report presents helpful information regarding new spliced HSFs forms in Arabidopsis that highlights key information in the understanding of heat stress and plant growth.

eLife Assessment

This manuscript reports the development and characterization of iGABASnFR2, a genetically encoded GABA sensor that demonstrates substantially improved performance compared to its predecessor, iGABASnFR1. The work is comprehensive and methodologically rigorous, combining high-throughput mutagenesis, functional screening, structural analysis, biophysical characterization, and in vivo validation. The significance of the findings is fundamental, and the supporting evidence is compelling. iGABASnFR2 represents a notable advance in GABA sensor engineering, enabling enhanced imaging of GABA transmission both in brain slices and in vivo, and constitutes a timely, technically robust addition to the molecular toolkit for neuroscience research.

eLife Assessment

This paper performs a valuable critical reassessment of anatomical and functional data, proposing a reclassification of the mouse visual cortex in which almost all the higher visual areas are consolidated into a single area V2. However, the evidence supporting this unification is incomplete, as the key experimental observations that the model attempts to reproduce do not accurately reflect the literature. This study will likely be of interest to neuroscientists focused on the mouse visual cortex and the evolution of cortical organization.

eLife Assessment:

This study addresses valuable questions about the neural mechanisms underlying statistical learning of room acoustics, combining robust behavioral measures with non-invasive brain stimulation. The behavioral findings are strong and extend previous work in psychoacoustics, but the TMS results are modest, with methodological limitations and over-interpretation that weaken the mechanistic conclusions. The strength of evidence is therefore incomplete, and a more cautious interpretation of the stimulation findings, alongside strengthened analyses, would improve the manuscript.

eLife Assessment

This important study evaluates a model for multisensory correlation detection, focusing on the detection of correlated transients in visual and auditory stimuli. Overall, the experimental design is sound and the evidence is compelling. The synergy between the experimental and theoretical aspects of the article is strong, and the work will be of interest to both neuroscientists and psychologists working in the domain of sensory processing and perception

eLife Assessment

This study is a fundamental advance in the field of developmental biology and transcriptional regulation that demonstrates the use of hPSC-derived organoids to generate reproducible organoids to study the mechanisms that drive neural tube closure. The work is exceptional in its development of tools to use CRISPR interference to screen for genes that regulate morphogenesis in human PSC organoids. The additional characterization of the role of specific transcription factors in neural tube formation is solid. The work provides both technical advances and new knowledge on human development through embryo models.

eLife Assessment

This useful manuscript reports mechanisms behind the increase in fecundity in response to sub-lethal doses of pesticides in the crop pest, the brown plant hopper. The authors hypothesize that the pesticide works by inducing the JH titer, which through the JH signaling pathway induces egg development, for which the evidence was judged to be solid.

eLife assessment

This is a useful study that applies deep transfer learning to assign patient-level disease attributes to single cells of T2D and non-diabetic patients, including obese patients. This analysis identified a single cluster of T2D-associated β-cells; and two subpopulations of obese- β-cells derived from either non-diabetic or T2D donors. The findings were validated at the protein level using immunohistochemistry on islets derived from non-diabetic and T2D organ donors, contributing solid experimental evidence for the computational analyses.

eLife Assessment

This is an important study that takes a key step towards understanding developmental disorders linked to mutations in the O-GlcNAc transferase enzyme by generating a mouse model harboring the C921Y mutation. The study thoroughly examines behavioral and anatomical differences in these mice and finds behavioral hyperactivity and learning/memory deficits, as well as phenotypic differences in skull and brain formation. However, the experimental evidence is incomplete owing to discrepancy in OGT protein/RNA levels in the C921Y mutant mice in this paper and the previous paper ("Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability "). This line of research will benefit from investigation of the differences in associated glycoproteins and mechanistic insights. This study will be of interest to those studying neurodevelopment, learning and behavior, or associated brain mechanisms.

eLife Assessment

This useful study uses fiber photometry, implantable lenses, and optogenetics to show that a subset of subthalamic nucleus neurons is active during movement, and that active but not passive avoidance depends in part on STN projections to substantia nigra. The strength of the evidence for these claims is solid, whereas evidence supporting the claims that STN is involved in cautious responding or the speed of avoidance is incomplete. This paper will be of interest to basic and applied behavioural neuroscientists working on avoidance if suitably streamlined to support the strongest claims.

eLife Assessment

This study demonstrates the potential role of 17α-estradiol in modulating neuronal gene expression in the aged hypothalamus of male rats, identifying key pathways and neuron subtypes affected by the drug. While the findings are useful and provide a foundation for future research, the strength of supporting evidence is incomplete due to the lack of female comparison, a young male control group, unclear link to 17α-estradiol lifespan extension in rats, and insufficient analysis of glial cells and cellular stress in CRH neurons.

eLife Assessment

This is a well-done study that provides compelling data from a diverse set of approaches from single cell transcriptome data and network analysis from genetically diverse mouse cells to identify novel driver genes underlying human GWAS associations. The authors present solid evidence that network analysis of scRNA-seq data from genetically diverse mouse bone-marrow derived stromal cells can be informative for identifying human BMD GWAS driver genes. Their approach should be broadly useful and applicable to other GWAS studies.

eLife Assessment

This manuscript introduces a potentially valuable large-scale fMRI dataset pairing vision and language, and employs rigorous decoding analyses to investigate how the brain represents visual, linguistic, and imagined content. The current manuscript blurs the line between a resource paper and a theoretical contribution, and the evidence for truly modality-agnostic representations remains incomplete at this stage. Clarifying the conceptual aims and strengthening both the dataset technicality and the quantitative analyses would improve the manuscript's significance for the fields of cognitive neuroscience and multimodal AI.

eLife Assessment

This study provides new important insights concerning pathogen variant-specific reproduction parameters from molecular sequencing and case finding. The methods for inferring which variants will likely emerge in subsequent epidemic cycles are solid. This article is of broad interest to infectious disease epidemiology researchers and mathematical modellers of the COVID-19 pandemic.

eLife Assessment

This study provides an important extension of credibility-based learning research with a well-controlled paradigm by showing how feedback reliability can distort reward-learning biases in a disinformation-like bandit task. The strength of evidence is convincing for the core effects reported (greater learning from credible feedback; robust computational accounts, parameter recovery) but incomplete for the specific claims about heightened positivity bias at low credibility, which depend on a single dataset, metric choices (absolute vs relative), and potential perseveration or cueing confounds. Limitations concerning external validity and task-induced cognitive load, and the use of relatively simple Bayesian comparators, suggest that incorporating richer active-inference/HGF benchmarks and designs that dissociate positivity bias from choice history would further strengthen this paper.

eLife Assessment

This valuable study combined careful computational modeling, a large patient sample, and replication in an independent general population sample to provide 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. Evidence for the specificity of the effect to suicide, however, is incomplete, which would require additional analyses.

eLife Assessment

This study presents a valuable finding on the molecular mechanisms that govern GABAergic inhibitory synapse function. The authors propose that Endophilin A1 serves as a novel regulator of GABAergic synapses by acting as a component of the inhibitory postsynaptic density. The findings are convincing and likely to interest a broad audience of scientists focusing on inhibitory synaptic transmission, the excitation-inhibition balance, and its disruption in disorders such as epilepsy.

Editors Assessment:

This paper presents present the genome sequencing of the house sparrow (Passer domesticus) carrying out genome assembly and annotation using in silico approaches with tools that could be a valuable resource for understanding passerine evolution, biology, ethnology, geography, and demography. The final genome assembly was generated using short read sequencing and a computational workflow that included Shovill, SPAdes, MaSuRCA, and BUSCO benchmarking. Producing a 922 MB reference genome with 24,152 genes. The first draft was significantly smaller than this but peer review provided suggestions on how to improve the assembly quality. And after a few attempts and assembly with a reasonable size and BUSCO score was achieved. This openly available data potentially serving as a valuable resource for checking adaptation, divergence, and speciation of birds.

This evaluation refers to version 2 of the preprint

eLife Assessment

This paper presents an important theoretical exploration of how a flexible protein domain with multiple DNA binding sites may simultaneously provide stability to the DNA-bound state and enables exploration of the DNA strand. The authors propose a mechanism ("octopusing") for protein doing a random walk while bound to DNA which simultaneously enables exploration of the DNA strand and enhances the stability of the bound state. This study presents compelling evidence that their findings has implications for the way intrinsically disordered regions (IDR) of transcription factors proteins (TF) can enhance their ability to efficiently find their binding site on the DNA from which they exert control over the transcription of their target gene. The paper concludes with a comparison of model predictions with experimental data which gives further support to the proposed model.

eLife Assessment

This is an important study that examines the impact of Streptococcus pneumoniae genetics on its in vitro growth kinetics, aiming to identify potential targets for vaccines and therapeutics. The study identified significant variations in growth characteristics among capsular serotypes and lineages, linked to phylogeny and high heritability, but genome-wide association studies did not reveal specific genomic loci associated with growth features independent of the genetic background. The evidence supporting these findings is convincing.

eLife Assessment

This important study describes newly identified light-gated ion channel homologs (channelrhodopsins, ChRs) in several protist species, with a primary focus on the biophysical characterization of ChRs of ancyromonads. The authors employed a powerful combination of bioinformatics, manual and automated patch-clamp electrophysiology, absorption spectroscopy, and flash photolysis. Additionally, they evaluated the applicability of the newly discovered anion-conducting ChRs in cortical neurons of mouse brain slices and in living C. elegans worms. The evidence supporting most of the claims is compelling, and this work will be of interest to the microbial rhodopsin community and neuro- and cardioscientists utilizing optogenetics in their research.

eLife Assessment:

In this revised version, the authors provide a thorough investigation of the interaction of megakaryocytes (MK) with their associated extracellular matrix (ECM) during maturation; they provide compelling evidence that the existence of a dense cage-like pericellular structure containing laminin γ1 and α4 and collagen IV is key to fixing the perisinusoidal localization of MK and preventing their premature intravasation. Adhesion of MK to this ECM cage is dependent on integrin beta1 and beta3 expressed by MK. This strong conclusion is based on the use of state-of-the art techniques such f primary murine bone marrow MK cultures, mice lacking ECM receptors, namely integrin beta1 and beta3 null mice, as well as high-resolution 2D and 3D imaging. The study provides valuable insight into the role of cell-matrix interactions in MK maturation and provides an interesting model with practical implications for the fields of hemostasis and thrombosis.

eLife Assessment

This paper is important in demonstrating a requirement for sulfation in organizing apical extracellular matrix (aECM) during tubulogenesis in Drosophila melanogaster. The authors identify and characterize the organization of some of the first known components of the non-chitinous aECM in the Drosophila salivary gland tube, and these findings are supported by convincing data. This study would be of interest to developmental and cell biologists.

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

eLife Assessment

This valuable study concerns a highly interesting and biologically relevant topic, the regulation of the PIN auxin transporter, which is of broad interest to the plant biology community. The authors propose NPY1 to act downstream of PID in auxin-mediated development by modulating PIN phosphorylation, which, if experimentally solidified, would expand our understanding of PIN regulation. While the genetic evidence is solid, the mechanistic role of NPY1 and the functional relevance of phosphorylated PIN residues are still uncertain. There are also concerns regarding experimental rigor and methodological transparency.

eLife Assessment

This important study investigates how signals from the nervous system can influence the response to different food sources. To demonstrate the role of specific neuronal and intestinal regulators in sensing food quality and modulating digestion, the authors present evidence through a combination of genetic screening, RNA-seq analysis, and functional studies. These findings shed light on an adaptive strategy to integrate food perception with physiological responses, with a mix of solid and convincing evidence supporting the work.

eLife Assessment

In this valuable manuscript, Rao and colleagues investigate the UFD-1/NPL-4 complex, which is involved in extracting misfolded proteins in the plasma membrane and the accumulation of pathogenic bacteria in the intestine. Using convincing methods, the authors find that knockdown of the ufd-1 and npl-4 genes leads to shortened lifespan of the nematode C. elegans and reduced accumulation of the bacterial pathogen P. aeruginosa in the intestine.

eLife Assessment

The identification of RBMX2 as a novel regulator linking mycobacterial infection to Epithelial-Mesenchymal Transition and cancer progression are fundamental findings that advance our understanding of a major research question about the link between infectious and non-infectious diseases, microbiology and oncology. It does so by introducing RBMX2 as a novel host factor, a potential therapeutic target and biomarker for both TB and lung cancer. The evidence provided is convincing because it is appropriate and the validated multi-omics methodologies used are in line with the current state of the art. This study will be of interest to scientists working in the fields of drug discovery, microbiology and oncology.

eLife Assessment

The article presents important findings describing the role of IL27 in maintaining HSCs at steady state, and in emergency haematopoiesis in response to T. goodii by limiting the inflammatory monocyte outcomes. The evidence provided are solid and support that IL27 acts at the level of HSCs and not downstream. This study will be of interest to immunologists and hematologists, as well as infectious disease researchers.

eLife Assessment

This important study describes the effect of beta-glucan innate training of macrophages and its effect on uptake of tumour cells and on the production of inflammatory cytokines. The data are convincing and show decreased phagocytic activity of apoptotic tumour cells accompanied by lower levels of secreted IL-1β, and in vivo findings are also provided in the revision. This finding has potential impact on designing potential macrophage-targeted cancer immuno-therapeutic approaches.

eLife Assessment

The manuscript provides important findings on how striatal projection neurons regulate spontaneous locomotion speed in the context of implicit motivation and distinct contextual valence. The manuscript presented convincing supporting evidence for the findings. This work will be of broad interest to neuroscientists in the fields of basal ganglia, movement control, and cognition.

eLife Assessment

In this manuscript, Park et al. developed a multiplexed CRISPR construct to genetically ablate the GABA transporter GAT3 in the mouse visual cortex, with effects on population-level neuronal activity. This work is important, as it sheds light on how GAT3 controls the processing of visual information. The findings are compelling, leveraging state-of-the-art gene CRISPR/Cas9, in vivo two-photon laser scanning microscopy, and advanced statistical modeling.

eLife Assessment

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

eLife Assessment

This valuable study introduces a novel experimental and modeling framework to quantify passive joint torques in Drosophila, revealing that passive forces are insufficient to support body weight, contrary to prior assumptions based on larger insects. The approach is technically impressive, combining genetic silencing, kinematic tracking, and biomechanical modeling. However, the strength of evidence is incomplete, limited by concerns about the specificity of the genetic tools, simplifications in the mechanical model, and limited functional interpretation.

eLife Assessment

This important study characterises the morphogenesis of cortical folding in the ferret and human cerebral cortex using complementary physical and computational modelling. Notably, these approaches are applied to charting, in the ferret model, known abnormalities of cortical folding in humans. The study finds that variation in cortical thickness and expansion account for deviations in morphology, and supports these findings using cutting-edge approaches from both physical gel models and numerical simulations. The strength of evidence is convincing, and although it could benefit from more quantitative assessment, the study will be of broad interest to the field of developmental neuroscience.

eLife Assessment

This is an important study reporting a new phenotype for a gene cluster that has previously been associated with the responses of the Gram-negative opportunistic pathogen Pseudomonas aeruginosa to flow fluid. Expression of the froABCD gene cluster is induced by HOCl in vitro and by activated immune cells, which produce these types of reactive chlorine species. Overall, the evidence presented by the authors is solid; however, the mechanism of fro-induction by HOCl remains unclear, and the evidence in support of the authors' claims is descriptive, which needs to be improved. This study is of interest to infection biologists interested in mechanisms of bacterial pathogenicity.

eLife Assessment

This study provides valuable insights into the host's variable susceptibility to Mycobacterium tuberculosis, using a novel collection of wild-derived inbred mouse lines from diverse geographic locations, along with immunological and single-cell transcriptomic analyses. While the data are convincing, a deeper mechanistic investigation into neutrophil subset functions would have further enhanced the study. This work will interest microbiologists and immunologists in the tuberculosis field.

eLife Assessment

In this important study, the authors develop a microfluidic "Vessel-on-Chip" model to study Neisseria meningitidis interactions in an in vitro vascular system. Compelling evidence demonstrates that endothelial cell-lined channels can be colonized by N. meningitidis, triggering neutrophil recruitment with advantages over complex surgical xenograft models. This system offers potential for follow-on studies of N. meningitidis pathogenesis, though it lacks the cellular complexity of true vasculature including smooth muscle cells and pericytes.

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

eLife Assessment

Yabaji et al. reports a fundamental study highlighting the mechanistic connection for susceptibility to TB infection via the sst1 locus, this was shown to involve increased IFN and Myc production causing the down-regulation of anti-oxidant defence genes and chronic lipidation. Ultimately, lipid peroxidation may underlie infectivity and macrophage dysfunction. Overall, the data presented are compelling, supported by a well designed multi-omics approach and the findings will be of broad interest to researchers investigating the molecular mechanisms of TB infection.

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

eLife Assessment

This useful study shows that stimuli of a certain size elicit theta oscillations in V1 neurons both in spikes and local field potentials, and monkeys performing a dot detection task on these stimuli show theta rhythmicity in their response times. This replicates previous findings showing rhythmic theta activity in V4 and behaviour when stimuli are presented in the receptive field along with a surrounding flanker stimulus. However, there is incomplete evidence that rhythmicity in neural activity is related to the rhythmicity in behavior, and the mechanisms underlying these oscillations remain unclear.

eLife Assessment

In this useful study, ectopic expression and knockdown strategies were used to assess the effects of increasing and decreasing Cyclic di-AMP on the developmental cycle in Chlamydia. The authors convincingly demonstrate that overexpression of the dacA-ybbR operon results in increased production of c-di-AMP and early expression of the transitionary gene hctA and late gene omcB. Whilst the authors have attempted to revise the submission, the model proposed in the revised manuscript is still not fully supported by the data presented.

eLife Assessment

This valuable study revisits the effects of substitution model selection on phylogenetics by comparing reversible and non-reversible DNA substitution models. The authors provide solid evidence that 1) it can be beneficial to include non-time-reversible models in addition to general time-reversible models when inferring phylogenetic trees out of simulated viral genome sequence data sets, and that 2) non time-reversible models may fit the real data better than the reversible substitution models commonly used in phylogenetics, a finding consistent with previous work.

eLife Assessment

This useful paper presents evidence from several experimental approaches that suggest that changes in membrane potential directly affect ERK signaling to regulate cell division. This result is relevant because it supports an ion channel-independent pathway by which changes in membrane voltage can affect cell growth. The reviewers point out that while some experimental results and interpretations are compelling, the strength of evidence is still incomplete and changes to the manuscript are needed to rule out other possible interpretations of the data.

eLife Assessment

This is a fundamental study providing molecular insight into how cross-talk between histone modifications regulates the histone H3K36 methyltransferase SETD2. The manuscript contains excellent quality data, and the conclusions are convincing and justified. This work will be of interest to many biochemists working in the field of chromatin biology and epigenetics.

eLife Assessment

This study identifies novel approaches to improving transgene expression in the injured mammalian myocardium through a combination of a tissue regeneration enhancer element and engineered AAVs - specifically, a liver-detargeting capsid, AAV.cc84, and an in vivo library screen-selected AAV-IR41. The evidence is convincing, and the AAV vectors are of fundamental value to the field of cardiac gene therapy. Future research exploring how to combine the features of AAV.cc84 and AAV-IR41 could yield an even more promising vector for therapeutic use.