eLife assessment

This important study extends existing sequentially Markovian coalescent approaches to include the combined use of SNPs and hypervariable loci such as epimutations. This is an intriguing addition to infer population size history in the recent past, and the authors provide solid validation of their methods via simulation and analysis of empirical data in Arabidopsis thaliana. Given the increasing availability of such data, this work is a timely contribution and represents a foundation for further developments to explore when and where these methods will be best used.

eLife assessment

This study presents a valuable finding on the heterogeneity of tumour metabolism using fluorescence lifetime imaging, measured across 4 cell lines, 4 tumour types of in vivo mouse models, and 29 patient samples. The indication is that the level of heterogeneity of cellular metabolism increases with model complexity and demonstrates high heterogeneity at a clinical level. The evidence supporting the claims of the authors is solid, and at the revision stage, the authors have included additional samples from 8 patients in the data pool, which is helpful for the conclusions that the authors are trying to draw. The work will be of interest to medical biologists developing methods for quantifying metabolic heterogeneity.

eLife assessment

This work presents valuable information on the structure of the spirosome's native extended conformation as the active form of the aldehyde-alcohol dehydrogenase (AdhE) enzyme. The evidence is solid, although the work does not provide a mechanistic understanding of the function and dynamics of AdhE.

eLife assessment

In this important manuscript, the authors used unbiased approaches to identify somatic mutations in publicly available databases that would disrupt clinically approved antibodies targeting HER2. Using a solid combination of both computational and experimental approaches they identify mutations that could restore therapeutic antibody sensitivity in a series of disease-relevant model systems. Additional cell-based and in vivo assays would strengthen the work and increase the translational and potential clinical relevance of the proposed work.

eLife assessment

This important study demonstrates that combining AlphaFold2 with the author's sampling method AF2-RAVE improves protein-ligand docking for three protein kinases and their inhibitors. The evidence is compelling and the results will be of interest to researchers who work on computer-aided drug design.

eLife assessment

This valuable manuscript describes a novel role of Vangl2, a core planar cell polarity protein, in linking the NF-kB pathway to selective autophagic protein degradation in myeloid cells. The mechanistic studies provide convincing evidence that Vangl2 targets p65 for NDP52-mediated autophagic degradation, limiting inflammatory NF-kB response, with functional significance of the proposed mechanism in sepsis. Additional future studies dissecting autophagic Vangl2 functions in various myeloid subsets in the context of inflammation could be informative, and additional Vangl2 targets in the inflammatory pathway, including IKK2, could also be explored. Overall, this exciting study can advance our understanding of NF-kB control, particularly in the context of inflammatory diseases.

eLife assessment

This study provides an important, original framework to study locomotion on the ground with physics-based simulations. Through numerical simulations, the authors propose that intermediate numbers of body modules and high body symmetry enhance speed. The current way discussions and conclusions are written is overly broad: evidence that evolution may favour bilateral symmetry and modularity for efficient directed locomotion is still incomplete as further performance metrics and a more accurate description of the dynamics in water are needed.

eLife assessment

This valuable study presents a new framework (ASBAR) that combines open-source toolboxes for pose estimation and behavior recognition to automate the process of categorizing behaviors in wild apes from video data. The authors present compelling evidence that this pipeline can categorize simple wild ape behaviors from out-of-context video at a similar level of accuracy as previous models, while simultaneously vastly reducing the size of the model. The study's results should be of particular interest to primatologists and other behavioral biologists working with natural populations.

eLife assessment

This important study shows that in teleost fish, the RIG-I-like protein MDA5 can compensate for the absence of RIG-I by detecting 5'-triphosphorylated RNA. A fish virus containing such RNA can nevertheless evade MDA5 detection through a mechanism involving m6A methylation-induced silencing. The conclusions, which are supported by solid data, advance our understanding of antiviral immunity and virus-host conflicts in vertebrates.

eLife assessment

This fundamental study provides a modeling regime that provides new insight into the energy-preservation parameters among schooling fish. The strength of the evidence supporting observations such as distilled dynamics between leading and lagging schooling fish which are derived from emergent properties is compelling. Overall, the study provides exciting insights into energetic coupling with respect to group swimming dynamics.

eLife assessment

This study presents valuable findings describing how the midbrain periaqueductal gray matter and basolateral amygdala communicate when a predator threat is detected. Though the periaqueductal gray is usually viewed as a downstream effector, this work contributes to a growing body of literature from this lab showing that the periaqueductal gray produces effects by acting on the basolateral amygdala, the experimental design, data collection and analysis methods provide solid evidence for the main claims. The anatomical and immediately early gene evidence that the paraventricular nucleus of the thalamus may serve as a mediator of dorsolateral periaqueductal gray to basolateral amygdala neurotransmission provides and impetus for future functional assessment of this possibility. This study will appeal to a broad audience, including basic scientists interested in neural circuits, basic and clinical researchers interested in fear, and behavioral ecologists interested in foraging.

eLife assessment

This study explores the role of calcyphosine-like (CAPSL) in Familial Exudative Vitreoretinopathy (FEVR) via the MYC pathway, offering valuable insights into disease mechanisms that are supported by a solid, multi-pronged approach. The manuscript, which presents the phenotype of an interesting new mouse model, provides convincing evidence that CAPSL variants cause disease.

eLife assessment

This study provides important new insights into the contribution of local DNA features to the molecular mechanisms and dynamics of copy number variation (CNV) formation during adaptive evolution. While limited to a single CNV, the experiments are carefully controlled and present convincing evidence that supports the conclusions. This work will be of general interest to those studying genome architecture and evolution from yeast biologists to cancer researchers.

eLife assessment

This solid and innovative study explores the uptake of fixed nitrogen in maize chloroplasts facilitated by symbiotic Gluconacetobacter diazotrophicus bacteria. The findings provide valuable insights into plant-microbe interactions, particularly highlighting a symbiotic mechanism of nitrogen delivery independent nodule formation. Additional controls would help to substantiate the findings and enhance the overall strength of the evidence.

eLife assessment

This important study offers insights into the function and connectivity patterns of a relatively unknown afferent input from the endopiriform to the CA1 subfield of the ventral hippocampus, suggesting a neural mechanism that suppresses the processing of familiar stimuli in favor of detecting novelty. The strength of evidence is solid, with careful anatomical and electrophysiological circuit characterization, although the functional role of this pathway in behavior is not firmly established. The work will be of broad interest to researchers studying the neural circuitry of behavior.

eLife assessment

The study by Asabuki et al. is a valuable contribution to understanding how cortical neural networks encode internal models into spontaneous activity. It uses a recurrent network of spiking neurons subject to predictive learning principles and provides a novel mechanism to learn the spontaneous replay of probabilistic sensory experiences. While promising in its ability to explain spontaneous network dynamics, the manuscript is incomplete in terms of the strength of support for its main findings. The difference of the proposed sampling dynamics from Markovian types of sampling is unclear and the use of non-negative synaptic strengths is applied in a non-biological manner.

eLife assessment

This study is a valuable observation that deals with the toxic effects of an intermediary in lipid degradation [trans-2-hexadecenal (t-2-hex)] in yeast through modification of mitochondrial protein import via the TOM complex. However, we find that the claim that the TOM complex is a main target of t-2-hex are supported by incomplete evidence, thus allowing multiple various interpretation. Despite the shortcomings, this study is inspiring for researchers from the organellar, protein trafficking and lipid field and serves as a starting point to further precise and mechanistic analyses of the phenomenon.

eLife assessment

This manuscript is an important contribution, assessing the role of intraspecific consumer interference in maintaining diversity using a mathematical model. Consistent with long-standing ecological theory, the authors convincingly show that predator interference allows for the coexistence of multiple species on a single resource, beyond the competitive exclusion principle. Notably, the model matches observed rank-abundance curves in several natural ecosystems.

eLife assessment

This valuable paper presents findings showing that different brain regions were best described by a distinct accumulation model, which all differed from the model that best described the rat's choices. These findings are solid because the authors present a very strong methodological approach. This work will be of interest to a wide neuroscientific audience.

eLife assessment

This study provides valuable new insights into the trade-offs associated with the evolution of drug resistance in the yeast S. cerevisiae, based on a solid approach to evolving and phenotyping hundreds of independent strains. The authors identify distinct phenotypic clusters, defined by their growth across defined conditions, which suggest that tradeoffs are diverse but at the same time could be limited to a few classes according to the underlying resistance mechanisms. The methodologies used align with the current state-of-the-art, and the data and analysis are solid as they broadly support the claims, with only a few minor weaknesses remaining after revision. This work will interest molecular biologists working on the evolution of new phenotypes and microbiologists studying multi-drug therapy.

eLife assessment

This paper describes an important advance in an in vitro neural culture system to generate mature, functional, diverse, and geometrically consistent cultures, in a 384-well format with defined dimensions and the absence of the necrotic core, which persists for up to 300 days. The well-based format and conserved geometry make it a promising tool for arrayed screening studies. Some of the evidence is incomplete and could benefit from a more direct head-to-head comparison with more standard culture methods and standardization of cell seeding density as well as further data on reproducibility in each well and for each cell line.

eLife assessment

This study presents an important set of results illuminating how movement sequences are planned. Using several different behavioural manipulations and analysis methods, the authors present compelling evidence that multiple future movements are planned simultaneously with execution, and that these future movement plans influence each other. The work will be of great interest to those studying motor control.

eLife assessment

This valuable research identifies Smim32 as a new genetic marker for the claustrum and generates transgenic mouse lines aimed at enhancing specificity when studying this brain region. However, the evidence supporting the increased specificity of this marker and its associated transgenic lines is inadequate, as Smim32's specificity to the claustrum is limited. Nevertheless, this work will be of interest to researchers studying the molecular organization of the claustrum.

eLife assessment

This study presents valuable new insights into a HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, and delineates the kidney cell types that express HIV genes and are injured in these HIV-transgenic mice. A series of compelling experiments demonstrated that PKR inhibition can ameliorate HIVAN with reversal of mitochondrial dysfunction (mainly confined to endothelial cells), a prominent feature shared in other kidney diseases. The data support that inhibition of PKR and mitochondrial dysfunction has potential clinical significance for HIVAN.

eLife assessment

Chang et al. have investigated the catalytic mechanism of I-PpoI nuclease, a one-metal-ion dependent nuclease, by time-resolved X-ray crystallography using soaking of crystals with metal ions under different pH conditions. This convincing study revealed that I-PpoI catalyzes the reaction process through a single divalent cation. The study uncovers important details of the roles of the metal ion and the active site histidine in catalysis.

eLife assessment

The study answers the important question of whether the conformational dynamics of proteins are slaved by the motion of solvent water or are intrinsic to the polypeptide. The results from neutron scattering experiments, involving isotopic labelling, carried out on a set of four structurally different proteins are convincing, showing that protein motions are not coupled to the solvent. A strength of this work is the study of a set of proteins using spectroscopy covering a range of resolutions. The work is of broad interest to researchers in the fields of protein biophysics and biochemistry.

eLife assessment

Zhu, et al. present convincing data that details the function of the infertile crescent gene (ifc) in fly development with implications on human neurodegenerative disease. The authors unveil interesting and novel phenotypes of ifc loss-of-function in glia. The experiments are well planned and executed, and the data support the conclusions. These important findings have theoretical and practical implications beyond a single subfield and the methods are in line with current state-of-the-art.

eLife assessment

This study presents a useful modification of a standard model of genetic drift by incorporating variance in offspring numbers, claiming to address several paradoxes in molecular evolution. It is unfortunate that the study fails to engage prior literature that has extensively examined the impact of variance in offspring number, implying that some of the paradoxes presented might be resolved within existing frameworks. In addition, while the modified model yields intriguing theoretical predictions, the simulations and empirical analyses are incomplete to support the authors' claims.

eLife assessment

The manuscript describes human intracranial neural recordings in the auditory cortex during speech production, showing that the effects of delayed auditory feedback correlate with the degree of underlying speech-induced suppression. This is an important finding, as previous work has suggested that speech suppression and feedback sensitivity often do not co-localize and may be distinct processes, in contrast with findings in non-human primates where there is a strong correlation. The strength of the evidence is convincing, with appropriate experimental methods, data, and analysis.

eLife assessment

This important study demonstrates that the Pseudomonas aeruginosa-derived quorum sensing signal, 2-aminoacetophenone, induces immune tolerization in macrophages by perturbing metabolism, particularly in the context of mitochondrial respiration and bioenergetics. The authors present convincing evidence for 2-aminoacetophenone-mediated reduction of pyruvate transport into mitochondria, with downstream effects that result in reduced ATP production in tolerized macrophages. The work will be of interest to those studying host-pathogen interactions.

eLife assessment

This manuscript is a valuable study of the responses of GPi neurons to deep brain stimulation (DBS) in human Parkinson disease and dystonia patients and it finds convincing evidence for altered short-term and long-term plasticity in response to DBS between the two patient populations. This dataset is of interest to both basic and clinical researchers working in the field of DBS and movement disorders.

eLife assessment

This study provides useful findings on how phonetic properties of words, i.e., their difficulty and prior knowledge, influence the outcome of targeted memory reactivation (TMR) during sleep. While these findings are supported by solid evidence, they are based on a small sample size warranting future work to shed further light on the impact of TMR in language learning.

eLife assessment

This important study explores the potential influence of physiologically relevant mechanical forces on the extrusion of vesicles from C. elegans neurons. The authors provide compelling evidence to support the idea that uterine distension per se can induce vesicular extrusion from adjacent neurons. Overall, this work will be of interest to neuroscientists and investigators in the extracellular vesicle and proteostasis fields.

eLife assessment

How neural circuits represent sensory signals during and after stimulus presentation is a central question in neuroscience. Here, a model of the insect mushroom body, constructed from simple, known synaptic connectivity rules, is shown to convincingly explain stimulus discrimination and associative memory, even in the presence of variability in the input signals as experimentally measured from the antennal lobe of the honeybee. This important study makes testable predictions for the role of specific neurons in a neural circuit for associative memory, of relevance to any study of neural network design and operation.

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 tool will be broadly applicable to single-particle tracking studies. While some reviewers feel that the methodology has been convincingly tested by computational comparisons and experimental data, others feel that the mathematical foundation needs to be strengthened and clearly defined.

eLife assessment

The study describes a link between beta-amyloid monomers, regulation of microglial activity and assembly of neocortex during development. It brings valuable findings that have theoretical and practical implications in the field of neuronal migration, neuronal ectopia and type II lissencephaly. Unfortunately, the evidence is incomplete and the manuscript would benefit from additional experiments to clarify the relationship between Ric8a and APP and bolster the findings.

eLife assessment

This useful study presents a resource for researchers using Drosophila to study neural circuits, in the form of a collection of split-Gal4 lines with an online search engine, which will facilitate the mapping of neuronal circuits. The evidence is convincing to demonstrate the utility of these new tools, and of the search engine, for understanding expression patterns in adults and larvae, and differences between the sexes. These resources will be of broad interest to Drosophila researchers in the field of neurobiology.

eLife assessment

This useful study uses high-field fMRI to test the hypothesized involvement of subcortical structure, particularly the striatum, in WM updating. It overcomes limitations in prior work by applying high-field imaging with a more precise definition of ROIs. Thus, the empirical observations are of use to specialists interested in working memory gating or the reference back task specifically. However, evidence to support the broader implications, including working memory gating as a construct, is incomplete and limited by the ambiguities in this task and its connection to theory.

eLife assessment

The study by Takagi and colleagues is an important contribution to the question of how homologous neuronal circuits might be wired differently to elicit different behaviours. The authors combine genetic, neuroanatomical, and behavioral data to provide convincing evidence that Dfz2/DWnt4 signaling controls the innervation pattern of wave command neurons in the fly larva, and thereby behavioral locomotion program selection.

eLife assessment

The authors design and implement an elegant strategy to delete genomic sequences encoding the dopamine receptor dop1R2 from specific subsets of mushroom body neurons (ab, a'b' and gamma) and show that while none of these manipulations affect short term appetitive or aversive memory, loss of dop1R2 from ab or a'b' block the ability of flies to display measurable forms of longer forms of appetitive memory. These findings are valuable in confirming and/or moderating prior observations, with better genetic perturbation techniques and convincing data to support the authors' main conclusions.

eLife assessment

This study provides important information on pre-existing epigenetic modification in T cell plasticity. The evidence supporting the conclusions is compelling, supported by comprehensive transcriptional and epigenetic analyses. The work will be of interest to immunologists and colleagues studying transcriptional regulation.

eLife assessment

This study employed a comprehensive approach to examining how the MT+ region integrates into a complex cognition system in mediating human visuo-spatial intelligence. While the findings are useful, the experimental evidence is incomplete and the study designs, hypotheses, and data analyses need to be improved. The work will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife assessment

A combination of molecular dynamics simulation and state-of-the-art statistical post-processing techniques provided valuable insight into GPCR-ligand dynamics. This manuscript provides solid evidence for differences in the binding/unbinding of classical cannabinoid drugs from new psychoactive substances. The results could aid in mitigating the public health threat these drugs pose.

eLife assessment

This useful study reports on the discovery of an antimicrobial agent that kills Neisseria gonorrhoeae. Sensitivity is attributed to a combination of DedA assisted uptake of oxydifficidin into the cytoplasm and the presence of a oxydifficidin-sensitive RpIl ribosomal protein. Due to the narrow scope, the broader antibacterial spectrum remains unclear and therefore the evidence supporting the conclusions is incomplete with key methods and data lacking. This work will be of interest to microbiologists and synthetic biologists.

eLife assessment

This study convincingly shows that aquaporins play a key role in blood vessel formation during zebrafish development. In particular, the paper implicates hydrostatic pressure and water flow as mechanisms controlling endothelial cell migration during angiogenic sprouting. This important study significantly advances our understanding of cell migration during morphogenesis. As such, this work will be of great interest to developmental and cell biologists working on organogenesis, angiogenesis, and cell migration.

eLife assessment

This important study, characterizing the epigenetic and transcriptomic response of a variety of cell types representative of somatic, germline, and pluripotent cells to BPS, reveals the cell type-specific changes in DNA methylation and the relationship with the genome sequence. The findings are convincing and provide a basis for future analyses in vivo. This work should be of interest to biomedical researchers who work on epigenetic reprogramming and epigenetic inheritance.

eLife assessment

This manuscript provides important results that assessed the contribution of two catecholaminergic projections to the hippocampus during environment-guided reward behavior. The authors use 2-photon imaging in the hippocampus of behaving mice to provide solid evidence that there are dissociable roles of dopamine and norepinephrine in this structure. Although of great interest to the field of learning and memory, the results would be strengthened by additional data collected from dopaminergic projections to the hippocampus.

eLife assessment

In this study the authors revisited the question of the embryonic origin of telencephalic oligodendrocytes using some new and powerful genetic tools. There is convincing evidence to support previous suggestions of a predominantly cortical origin of oligodendrocytes in the cerebral cortex, however the new studies suggest that LGE/CGE-derived oligodendrocytes make a modest contribution in some areas, while MGE/POA-derived oligodendrocytes make a small but enduring contribution. The findings are valuable and should be of interest to developmental and myelin biologists.

eLife assessment

This study presents valuable data on sensory integration in a model pre-motor neuron, the Mauthner cell. The authors use both stimulation of the optic tectum (a proxy for vision) and auditory stimulation to study the integration of these modalities in the Mauthner cell using convincing, technically demanding, and well done experiments. There are, however, concerns about the degree to which the two modalities interact; multisensory integration of subthreshold unisensory stimuli appears uncommon, and not significantly above events observed from single modalities. This work will be of interest to both synaptic physiologists and neurophysiologists working on sensory-motor integration.

eLife assessment

Here, the authors developed a cell-based screening assay for the identification of small molecule inhibitors of nonsense-mediated decay (NMD), and used it to validate KVS0001, a new small molecule SMG1 kinase inhibitor derived from the existing inhibitor SMG1i-11, showing it inhibits NMD in cultured cells leading to expression of neoantigens from NMD-targeted genes and slows tumor growth of cancer cell lines possessing a significant number of out-of-frame indel mutations. The conclusions are supported by convincing evidence, and the significance of this work consists in the development of a new and very promising NMD inhibitor drug that acts as an inhibitor of the SMG1 NMD kinase and is effective in animal tumor studies. This is an important advance for the field, as previous NMD inhibitors were not specific, lacked efficacy, or were very toxic and hence not suitable for animal applications.

eLife assessment

This important study analyzes in an original way how tension pattern dynamics can reveal the contribution of active versus passive intercalation during tissue elongation. The authors develop a compelling, elegant analytical framework (isogonal tension decomposition) to disentangle the passive (adjacent tissues pulling) and active (local tension anisotropy) contributions to intercalation events. This allows the generation of global maps of tissue mechanics that will be extremely helpful in the field of biomechanics.

eLife assessment

This useful study describes a single set of label-chase mass spectrometry experiments to confirm the molecular function of YafK as a peptidoglycan hydrolase, and to describe the timing of its attachment to the peptidoglycan. Confirmation of the molecular function of YafK will be helpful in further studies to examine the function and regulation of the outer membrane-peptidoglycan link in bacteria. The evidence supporting the molecular function of YafK and that lpp molecules are shuffled on and off the peptidoglycan is solid, however, data supporting conclusions relating to the locations of lpp-peptidoglycan attachment are incomplete. The work will be of interest to researchers studying lipoproteins in gram negative bacteria.

eLife assessment

This study offers a useful treatment of how the population of excitatory and inhibitory neurons integrates principles of energy efficiency in their coding strategies. The analysis provides a comprehensive characterisation of the model, highlighting the structured connectivity between excitatory and inhibitory neurons. However, the manuscript provides an incomplete motivation for parameter choices. Furthermore, the work is insufficiently contextualized within the literature, and some of the findings appear overlapping and incremental given previous work.

eLife assessment

This important work addresses the relationship between the transdiagnostic compulsivity dimension and confidence as well as confidence-related behaviours like reminder setting. The relationship between confidence and compulsive disorders has recently received a lot of attention and has been considered to be a key cognitive change. The authors paired an elegant experimental design and pre-registration to give convincing evidence of the relationship between compulsivity, reminder setting, and confidence. Future work should clarify the link of their findings with prediction error-related processes to test whether they could be causally related to their results, and further clarify some of the implications for their findings and refine hypotheses about confidence-related cognitive changes with compulsivity and OCD.

eLife assessment

This study presents useful, yet preliminary findings on the transcriptomic changes in cardiac lymphatic cells after myocardial infarction in mice. The conclusions of the authors remain uncertain as sample sizes for lymphatic endothelial cells are very low. The single-cell transcriptomic data were analyzed using solid advanced methodology and may be used as a starting point for future studies of the impact of lymphatic cells on heart disease.

eLife assessment

This study provides a valuable contribution to the development of small molecules that inhibit the aggregation of tau, a protein involved in several neurodegenerative diseases. The authors present convincing evidence that analogs of the plant alkaloid tryptanthrin can prevent the formation of larger aggregates by targeting the early stages of tau oligomerization. Nevertheless, further studies are needed to elucidate the precise mechanisms of action and to provide a detailed kinetic analysis. This work will be of interest to biochemists and biophysicists focused on designing small molecules to inhibit fibril formation.

eLife assessment

This paper presents a valuable pipeline based on state-of-the-art analytical software that was used to study genetic pleiotropy between neuropsychiatric disorders. The presented evidence supporting the claims is convincing and now includes an appropriate comparison to previously published methods as well as a detailed exploration of the findings. The created pipeline can thus be used by researchers from diverse fields to study different combinations of diseases and traits.

eLife assessment

This fundamental work quantifies the stochastic dynamics of neural population activity in the lateral intraparietal area (LIP) of the macaque monkey brain during single perceptual decisions. These single-trial dynamics have been subject to intense debate in neuroscience, and they have significant implications for modelling decision-making in various fields including neuroscience and psychology. Through a combination of state-of-the-art recordings from many LIP neurons and theory-driven data analyses, the authors provide convincing evidence for the notion that single-trial neural population dynamics in LIP encode the decision variable postulated by the drift-diffusion model of decision-making.

eLife assessment

This study presents high-quality experiments and data analysis of C. elegans locomotion for spontaneous exploration as well as in the presence of an aversive stimulus. This important work shows that the activation of distinct turn types enhances escape performance as well as exploration. The strength of the evidence is still incomplete, particularly regarding optimal exploration and the identification of the range of the aversive stimulus at the boundary of the arena. The work will be of interest to a broad audience extending from movement ecology, to the biology of Caenorhabditis elegans.

eLife assessment

This study presents a valuable finding on a new role of Foxp3+ regulatory T cells in sensory perception, which may have an impact on our understanding of somatosensory perception. The authors identified a previously unappreciated action of enkephalins released by immune cells in the resolution of pain and several upstream signals that can regulate the expression of the proenkephalin gene PENK in Foxp3+ Tregs. The generation of transgenic mice with conditional deletion of PENK in Foxp3+ cells and PENK fate-mapping is novel and generates compelling data; they also show a comprehensive analysis of Tregs in control and transgenic mice, longitudinal data on heat sensitivity and co-localization of PENK+ Tregs with thermal sensory neurons in the skin further supporting their hypothesis. The study would be of interest to the biologists working in the field of neuroimmunology and inflammation.

eLife assessment

The work provides valuable genomic resources to address the endocrine control of a life cycle transition in the Malabar grouper fish. The revised manuscript is more solid and the resources and experimental data help to build up a meaningful biological understanding of thyroid signaling in grouper fish.

eLife assessment

This meta-analysis presents valuable findings that reexamine the function of butterfly eyespots in predator avoidance and report for conspicuousness over mimicry. The analysis is robust, but the evidence supporting the importance of conspicuousness is incomplete due to the limitations of the literature, and this debate would benefit from additional experiments that would strengthen these claims. This paper is of interest to evolutionary biologists and ecologists working on the evolution of morphology and predator-prey interactions.

eLife assessment

This important study utilizes humanized mice, in which human immune cells are introduced into immune-deficient mice, to provide solid evidence that two helper CD4 T-cell subsets, T-follicular helper (Tfh) and T-peripheral helper (Tph) cells, are able to drive both autoantibody production and induction of autoimmunity. The work will be of broad interest to medical scientists engaged in deciphering how human immune cells mediate immune responses and contribute to the development of autoimmune diseases.

eLife assessment

This valuable and well-executed study describes how deletion of the autism spectrum disorder risk gene CNTNAP2 in mice increases dorsolateral striatal projection neuron excitability and promotes repetitive behaviors and cognitive inflexibility. The evidence supporting this claim is solid, although additional experimental evidence would strengthen claims of how corticostriatal activity is altered and linked to behavioral changes. The study provides a potential cellular explanation for the repetitive and inflexible behavior in Cntnap2 knockout mice and CNTNAP2 disorder in humans, which would interest both basic and translational neuroscientists.

eLife assessment

This study represents an important contribution to the study of decision-making under risk, bringing an interdisciplinary approach spanning economic theory, behavioral neuroscience, and computational modeling to test how choice preference is influenced by rare and extreme events. The authors present evidence that rats are indeed sensitive to these rare and extreme events despite their infrequent occurrence, driven primarily by an almost complete avoidance of "Black Swans" - rare and extreme losses. The evidence for specific sensitivity to rare and extreme events however remains incomplete, owing in part to the difficulty of isolating the effect of these events beyond that arising from risk preferences more generally in both task design and in the computational modeling of the choice behavior. Given the approach here brings a relatively novel perspective, with a more detailed treatment of these confounds this paper will be of broad interest to those seeking to understand animal behavior through the lens of economic choice.

eLife assessment

Lloyd et al. used an evolutionary comparative approach to study DNA damage repair in response to sleep deprivation in Astyanax mexicanus, highlighting how the cavefish population has evolved a reduced DNA damage response compared to the surface-dwelling population. The cavefish have elevated expression of signals commonly associated with aging but do not show evidence of reduced life span nor increased aged-linked pathology, a potentially valuable finding for the field of aging research. A link to alterations in sleep behaviour is outlined, but the evidence for such a link is incomplete.

eLife assessment

This valuable study provides insights into how the brain learns to better detect a target by predicting when the target may appear. Overall, solid evidence is provided that the power fluctuations of alpha- and beta-band oscillations can reflect the predicted occurrence time of the target, but some conclusions, especially ones related to the neural-network model and temporal gain control account, need further consideration. The study highlights an advanced EEG analysis approach as well as a close combination of human EEG analysis and computational modeling using recurrent neural networks.

eLife assessment

This is an important characterization of mouse auditory cortex receptive field organization, using two-photon imaging of specific subpopulations. They demonstrate a degradation of tonotopic organization from the input to output neurons. The strength of the evidence is solid, but some controls are needed to further strengthen the conclusion.

eLife assessment

This study resolves a cryo-EM structure of the GPCR, human GPR30, which responds to bicarbonate and regulates cellular responses to pH and ion homeostasis. Understanding the ligand and the mechanism of activation is important to the field of receptor signaling and potentially facilitates drug development targeting this receptor. While the overall structures are solid, the identification of the bicarbonate binding site is only partly supported by the structural data and cell-based functional assays, leaving a major aim of the study incomplete.

eLife assessment

This convincing study advances our understanding of the physiological consequences of the strong overexpression of non-toxic proteins in baker's yeast. The findings suggest that a massive protein burden results in nitrogen starvation and a shift in metabolism likely regulated via the TORC1 pathway, as well as defects in ribosome biogenesis in the nucleolus. The study presents findings and tools that are important for the cell biology and protein homeostasis fields.

eLife assessment

This paper reports important findings on giant organelle complexes containing endosomes and lysosomes (termed endosomal-lysosomal organelles form assembly structures [ELYSAs]) present in mouse oocytes and 1- to 2-cell embryos. The data showing the localization and dynamics of ELYSAs during oocyte/embryo maturation are convincing. This work will be of interest to general cell biologists and developmental biologists.

eLife assessment

The study describes a valuable new technology in the field of targeted protein degradation that allows identification of E3-ubiquitin ligases that target a protein of interest. The presented data are convincing, however, it is unclear whether the proposed system can be successfully used in high throughput applications. This technology will serve the community in the initial stages of developing targeted protein degraders.

eLife assessment

This study combines extensive published and new datasets to provide a useful single-cell multi-omics analysis of early cardiac lineage segregation, highlighting the mutual regulation of key regulators for cardiac specification. While the data presentation is robust, the computational methods for delineating cardiac lineage trajectories and the functional analyses are incomplete and require further clarification and additional experiments. If validated, these findings will be of significant interest to researchers in the fields of cardiac development and congenital heart disease.

eLife assessment

This study represents a valuable addition to the catalog of mitochondrial proteins. With the use of methodology based on the bi-genomic split-GFP technology, the authors generate convincing data, including dually localized proteins and topological information, under various growth conditions in yeast. The study represents a starting point for further functional and/or mechanistic studies on mitochondrial protein biogenesis.

eLife assessment

This study provides valuable insights into the complex genetics of dominant optic atrophy. Leveraging a fly model, the investigators provide solid evidence, albeit with small effect sizes, for a dominant negative mechanism of certain pathogenic variants that tend to cause more severe phenotypes, a long held hypothesis in the field. The work is of high interest to those in the optic atrophy and degeneration fields.

eLife assessment

This important study examines the extent to which distinct developmental pathways that result in alternative morphs correlate with transcriptome differences in a marine annelid, Streblospio benedicti. The strengths of the study include the experimental design and dense temporal sampling, which together provide convincing evidence that the two morphs can be clearly distinguished at the transcriptome level, despite relatively modest overall differences. The work will be of particular interest to students of the evolution of development.

eLife assessment

This study presents valuable findings on how the endocannabinoid system is involved in endometriosis progression using CNR1 and CNR2 knockout (KO) mouse models. The evidence supporting the authors' claims is incomplete; including bulk RNA-seq, flow cytometry, and imaging mass cytometry would have strengthened the study. This work might be of interest to medical scientists working on endometriosis.

eLife assessment

This valuable study details an aspect of plant immunity where ATG6 was not previously known to have a role. The results suggest a direct relationship between ATG6 and NPR1, a well-studied salicylic acid receptor protein, which could be of interest to researchers studying the regulation of plant immunity. While the data presented are compelling, there are concerns about the interpretation of results, particularly regarding discrepancies in fluorescence and protein blot data. Addressing these issues would improve the overall impact of the work and consistency with prior studies.

eLife assessment

This valuable manuscript systematically addresses the role of intracellular lipid transfer proteins on cellular lipid levels. It provides convincing evidence on the role of ORP9 and ORP11 in sphingolipid metabolism at the Golgi complex. This article will be of broad interest to cell biologists interested in lipid metabolism and membrane biology.

eLife assessment

This work presents fundamental new insights into the conductivity of freshwater cable bacteria. The evidence supporting the conclusions, which was collected using appropriate techniques, is compelling. The work will be of interest to environmental microbiologists and the microbial electrochemistry community.

eLife assessment

Through cellular, developmental, and physiological analysis, this valuable study identifies a gene that functions to regulate the relative growth of roots and shoots under salt stress. The holistic approach taken provides solid evidence that this gene, a member of a larger tandemly duplicated gene family initially highlighted by association mapping, as well as an upstream regulator contribute to salt tolerance. More robust statistical or biological support for some conclusions could further strengthen this manuscript. The manuscript will be of interest to plant biologists studying mechanisms of abiotic stress tolerance and gene family evolution.

eLife assessment

This useful study presents a real-time transcriptomics analysis, with the aim of providing rapid access to sequenced data to reduce the costs associated with Oxford Nanopore long-read technology. Although the authors illustrate the compelling utility of this approach with three diverse experimental setups, issues with study design and analysis result in incomplete supporting evidence.

eLife assessment

This study develops a useful metric for quantifying codon usage adaptation - the Codon Adaptation Index of Species (CAIS). This metric permits direct comparisons of the strength of selection at the molecular level across species. The study is based on solid evidence, and the authors identify relationships between CAIS and the presence of disordered protein domains. Other correlations, such as the one between CAIS and body size, are weak and non-significant. In summary, the study introduces an interesting new approach to quantifying codon usage across species, which may be helpful in attempts to measure selection at the molecular level.

eLife assessment

This is a valuable study in which the authors provide an expression profile of the human blood fluke, Schistosoma mansoni. A strength of this solid study is in its inclusion of in situ hybridisation to validate the predictions of the transcript analysis.

eLife assessment

This important work provides evidence that glutamate and GABA are released from different synaptic vesicles at supramammillary axon terminals onto granule cells of the dentate gyrus. The study uses complementary electrophysiological and anatomical experimental approaches. Together, these provide solid evidence that the co-release of glutamate and GABA from different vesicles within the same terminal could modulate granule cell firing in a frequency-dependent manner, although thorough elimination of alternative mechanisms would have strengthened the study. The work will be of interest to neuroscientists investigating co-release of neurotransmitters in various synapses in the brain and those interested in subcortical control of hippocampal function.

eLife assessment

This study provides a novel and valuable alternative explanation for volatility-induced changes in choice behavior, commonly attributed to learning-rate adaptations. Through rigorous and comprehensive computational modeling of previously published data, the authors provide convincing support for the claim that apparent learning-rate adaptations may instead reflect a mixture of decision strategies. Furthermore, they demonstrate that differential weighting of the optimal decision strategy is predicted by psychopathology common to depression and anxiety. This work should be of interest to a wide range of scientists, including psychologists, neuroscientists, computer scientists, and clinicians.

eLife assessment

This is an important study, as PIM1/2 control of protein synthesis in differentiated cells has implications beyond T cells. The evidence is convincing in that it makes extensive use of the mouse knockout model and validation in mouse T cells with inhibitors. A rescue experiment in mouse KO T cells would be even stronger than the inhibitor studies to validate the KO phenotype and the evidence would be truly impressive if the results from the rescue experiment support the working model. Extending the observations to human T cells would also be a step towards translation and would further increase the potential impact of the work.

eLife assessment

This paper explores the relationships among evolutionary and epidemiological quantities in influenza, and presents fundamental findings that substantially advance our understanding of the drivers of influenza epidemics. The authors use a rich set of data sources to gather and analyze compelling evidence on the roles of genetic distance, other influenza dynamics and epidemiological indicators in predicting influenza epidemics. The central findings highlight the significant influence of genetic distance on A(H3N2) virus epidemiology and emphasize the role of A(H1N1) virus incidence in shaping A(H3N2) epidemics, suggesting subtype interference as a key factor. This paper also makes relevant data available to the research community.

eLife assessment

Maestri et al report the absence of phylogenetic evidence supporting codiversification of mammalian coronaviruses and their hosts, leading to the important conclusion that the evolutionary history of the virus and its hosts are decoupled through frequent host switches. The evidence for frequent host switching, derived from state-of-the-art probabilistic modeling of co-evolution, is convincing. The study adds a new perspective to the ongoing debate over the timescale of coronavirus evolution.

eLife assessment

This work by Shin et al. demonstrated that a different form of PTH (R25C PTH) generated a comparable anabolic signal to rhPTH 1-34 using a large animal model. This valuable finding may have therapeutic potential in promoting bone formation or the healing process, and the methods seem solid, although there remains a concern regarding the small sample size and surgical procedure.

eLife assessment

This important paper on measuring molecular connectivity using combined serotonin PET and resting-state fMRI provides both novel methods for studying the brain as well as insights into the effects of ecstasy administration. The methods are solid, with a few doubts that need to be dispelled surrounding the high anaesthetic dose used.

eLife assessment

In this manuscript, the authors present valuable findings on the apparent role of a salience-network anterior insula node in directing fronto-parietal and default-mode network activity within a tripartite network during control of memory, drawn from an impressive invasive human neurophysiological dataset. While we commend the use of a large intracranial EEG dataset to approach this question, the study at present is incomplete in its methodologies, analysis, and interpretation to support the authors' central claims. The manuscript could be improved by addressing the concerns described.

eLife assessment

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

eLife assessment

This study describes the development and validation of an Automated Reproducible Mechano-stimulator (ARM), a valuable tool for standardizing and automating somatosensory behavior experiments. The data supporting the use of the ARM system are compelling, though the determination of whether that device emits any sounds, including in the ultrasonic range when in operation or when at rest, would add value to the study. Nevertheless, the ARM system is anticipated to be popular amongst somatosensory and pain researchers.

eLife assessment

This manuscript focuses on understanding if and how the glycosylation of SARS-CoV2 spike protein affects a putative allosteric network of interactions controlled by the binding of a fatty acid. The main conclusion is that glycans do not significantly affect the network of allosteric interactions. This useful information - albeit mainly consisting of negative results - is based on solid evidence. It will be of interest to scientists focusing on SARS CoV2 protein structure and dynamics.

eLife assessment

This study makes a valuable contribution to understanding antiviral responses in fish by revealing a role for the cell cycle protein kinase CDK2 in type I interferon signaling. The evidence supporting the authors' claims is solid, including both in vivo and in vitro investigative approaches. However, the mechanisms underlying CDK2 activity are not completely established. This work will be of interest to cell biologists, immunologists, and virologists.

eLife assessment

This study provides a useful advance in generating mouse oligodendrocytes by direct lineage conversion from cortical astrocytes. The authors demonstrate that Sox10 converts astrocytes to MBP+ oligodendrocytes, whereas Olig2 expression converts astrocytes to PDFRalpha+ oligodendrocyte progenitor cells. The data supporting the conclusions are solid, but there are concerns regarding select figures and the experiments being limited to in vitro studies.

eLife assessment

The manuscript presented by Moyse and colleagues provides valuable insight into the origin, morphology, dynamics, and behavior of several populations of mononuclear phagocytes in the zebrafish heart. The study presents solid evidence through the use of transgenic lines and live imaging, although some limitations related to lineage tracing and molecular profiles should be considered. This work exemplifies the use of zebrafish as a model to study the role of leukocytes in cardiac development and regeneration and potentially draw broader interest to biologists working in immunology fields.

eLife assessment

This useful study describes an antibody-free method to map G-quadruplexes (G4s) in vertebrate cells. While the method might have potential, the current analysis is primarily descriptive and does not add substantial new insights beyond existing data (e.g., PMID:34792172). While the datasets provided might constitute a good starting point for future functional studies, additional data and analyses would be needed to fully support the major conclusions and, at the same time, clarify the advantage of this method over other methods. Specifically, the strength of the evidence for DHX9 interfering with the ability of mESCs to differentiate by regulating directly the stability of either G4s or R-loops is still incomplete.

eLife assessment

This valuable paper compares blood gene signature responses between small cohorts of individuals with mild and severe COVID-19. The authors provide solid evidence for distinct transcriptional profiles during early COVID-19 infections that may be predictive of severity, within the limitations of studying human patients displaying heterogeneity in infection timelines and limited cohort size.

eLife assessment

This study provides valuable insights into the specificity and promiscuity of toxic effector and immunity protein pairs. While the work is improved over a previous version, there are still some questions regarding the methodology used to draw certain conclusions, rendering the study somewhat incomplete. Nevertheless, this work will likely be of interest to microbiologists and biochemists working with toxin-antitoxin systems and effector-immunity proteins.

eLife assessment

This fundamental paper reports a new biosensor to study G protein-coupled receptor activation by the pituitary adenylyl cyclase-activating polypeptide (PACAP) in cell culture, ex vivo (mouse brain slices), and in vivo (zebrafish, mouse). Convincing data are presented that show the new sensor works with high affinity in vitro, while requiring very high (non-physiological) concentrations of exogenous PACAP when applied to intact tissues. The sensor has not yet been used to detect endogenously released PACAP, raising questions about whether the sensor can be used for its intended purpose. While further work must be pursued to achieve broad in vivo applications under physiological conditions, the new tool will be of interest to cell biologists, especially those studying the large and significant GPCR family.

eLife assessment

In this fundamental study, the authors use innovative fine-scale motion capture technologies to study visual vigilance with high-acuity vision, to estimate the visual fixation of free-feeding pigeons. The authors present compelling evidence for use of the fovea to inspect predator cues, the behavioral state influencing the latency for fovea use, and the use of the fovea decreasing the latency to escape of both the focal individual and other flock members. The work will be of broad interest to behavioral ecologists.

eLife assessment

The authors performed extensive coarse-grained molecular dynamics simulations of 140 different prion-like domain variants to interrogate how specific amino acid substitutions determine the driving forces for phase separation. The analyses are solid, and the predictive scaling laws can aid in identifying potential phase-separating regions in uncharacterized proteins. Overall, this is a valuable contribution to the field of biomolecular condensates. It exemplifies how data-driven methodologies can uncover new insights into complex biological phenomena.

eLife assessment

This valuable study tests the functional role of food-washing behavior in removing tooth-damaging sand and grit in long-tailed macaques and whether dominance rank predicts the level of investment in the behavior. The evidence that food-washing is deliberate is compelling, but the evidence for variable and adaptive investment depending on rank is incomplete given confounding between sex and rank and limited sample size. A more careful and perhaps restrained interpretation of the findings, as well as a connection to the existing literature on optimal foraging theory, would increase the value of the study to its intended audience, i.e. researchers interested in foraging behavior, cognition, and primate evolution.

eLife assessment

This manuscript is a valuable contribution to our understanding of foraging behaviors in marine bacteria. The authors present a conceptual model for how a marine bacterial species consumes an abundant polysaccharide. Using experiments in microfluidic devices and through measurements of motility and gene expression, the authors offer convincing evidence that the degradation products of polysaccharide digestion can stimulate motility.

eLife assessment

The present paper describes an important methodological development that combines light (confocal) microscopy with scanning and transmission EM and EM tomography. The method expands the level of structural detail accessible to large-volume EM studies and thus represents an approach to integrate analyses of cellular and sub-cellular structures in biological samples. The study, which provides a compelling proof-of-principle, will be of particular value to cell biologists interested in the in-depth interpretation of high-resolution ultrastructural information from sparsely distributed targets - at multiple scales and in diverse biological structures.

eLife assessment

The study presents valuable findings on compensatory mechanisms in response to glycosuria. The evidence supporting the claims is solid, although a causal relationship is somewhat uncertain and the addition of a more clinically relevant model would have strengthened the findings. The work will be of interest to diabetes investigators.

eLife assessment

This valuable study provides new insight into potential subtle dynamics in effector biology. The data presented generally support the claims, but in some cases, significant controls are missing and so the overall work is currently incomplete. If the limitations can be addressed, this work should be of broad relevance for biologists interested in molecular plant-microbe interactions.

eLife assessment

This valuable study provides new insights into the neural circuits involved in post-mating responses in Drosophila females. It presents convincing evidence that the circuits for mating receptivity and egg-laying are distinct. A more thorough discussion regarding the integration of the new findings into the current understanding of post-mating behavior as well as clarification of some experimental details would further improve the manuscript.

eLife assessment

This study highlights an important discovery: a bacterial pathogen's effector influences plant responses that in turn affect how the leafhopper insect vector for the bacteria is attracted to the plants in a sex-dependent manner. The research is backed by convincing physiological and transcriptome analyses. This study unveils a complex interdependence between the pathogen effector, male leafhoppers, and a plant transcription factor in modulating female attraction to the plant, shedding light on previously unexplored aspects of plant-bacteria-insect interactions.

eLife assessment

This important body of work uses state-of-the-art quantitative methods to characterize and compare behaviors across five different fish species to understand which features are conserved and which ones are differentiated. The results from this study will potentially be of interest to ethologists and also have potential utility in understanding the neural mechanisms leading to these behaviors. While some claims are supported with compelling evidence, there are a few results that need further justification or qualification.

eLife assessment

This is a valuable paper that identifies a potential challenge for embryos during fertilization: holding sperm contents in the fertilized embryos away from the oocyte meiotic spindle so that they don't get ejected into the polar body during meiotic chromosome segregation. The authors identify proteins involved in cytoplasmic streaming and maintaining the grouping of paternal organelles as being critical for this process. There remain minor weaknesses in the data presented but the paper provides solid evidence for the majority of its claims, and while the findings may pertain to a narrow audience the tools used and basic characterization shown will likely be relied upon by many in the community and therefore is of high value.

eLife assessment

This fundamental study provides a near-comprehensive anatomical description and annotation of neurons in a male Drosophila ventral nerve cord, based on large-scale circuit reconstruction from electron microscopy. This connectome resource will be of substantial interest to neuroscientists interested in sensorimotor control, neural development, and analysis of brain connectivity. However, although the evidence is extensive and compelling, the presentation of results in this very large manuscript lacks clarity and concision.

eLife assessment

This study presents a valuable development of endometrial organoid culture methodology that mimics the window of implantation. Functional validation to demonstrate its robustness is lacking; therefore, the study is considered incomplete. The data may be interesting to embryologists and investigators working on reproductive biology and medicine.

eLife assessment

Therapeutic treatments for congenital and acquired craniofacial (CF) bone abnormalities are not well developed. This study provides convincing evidence for an innovative regenerative treatment for pediatric craniofacial bone loss using Jagged1-PEG-MAL hydrogel with pediatric human bone cells. The report is a valuable advance in this field.