eLife assessment

This study presents important findings on how cells sense and respond to their surroundings, in particular when two environmental signals are presented periodically, in alternation or conjunction. The compelling analyses reveal some unexpected behaviors that could not have been drawn, from simpler experimental designs, related to the dynamic interplay between the starvation and hyper-osmotic stress responses in budding yeast, exemplifying that applying complex signals can unveil new biological insights, even for well-studied systems. The work will be of broad interest to researchers interested in fungal biology, dynamic systems, cell signaling, and cell biology.

eLife assessment

This study of extrachromosomal DNA (ecDNA) identifies genes that distinguish ecDNA+ and ecDNA- tumors. The findings in the manuscript are important and the genomic analyses convincing. However, some of the data remain observational and the inferences would therefore be more robust with experimental validation. This manuscript could well be of relevance to biologists interested in cancer biology and gene regulation.

eLife assessment

This important study extends existing sequentially Markovian coalescent approaches to include the use of hypervariable loci such as epimutations. This is an intriguing addition 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 -- and thus the potential use of this approach -- there would be additional value in more extensive consideration of when and where these methods are best used.

eLife assessment

This useful study provides the first assessment of the potentially interactive effects of seasonality and blood source on mosquito fitness, together in one study. However, the experimental approach is incomplete because it is limited without replication of the experiments and because of the small sample sizes for some groups. The work will be of interest to those studying mosquito biology.

eLife assessment

This work presents important insights regarding the mechanism underlying the assembly, maintenance, and disassembly of a very stable microtubule-based structure, termed quiescent-cell nuclear microtubule (Q-nMT) bundle, which is formed in quiescent yeast cells to ensure cell survival and viability. This insight will help to elucidate how very stable microtubules can exist alongside very dynamic microtubules, which is still poorly understood. While the experimental support is overall solid, additional analyses using state-of-the-art methodology would further strengthen some of the claims.

eLife assessment

This valuable study seeks to disentangle the different selective forces shaping the evolutionary dynamics of transposable elements (TEs) in the wild grass Brachypodium distachyon. Using haplotype-length metrics, and genetic and environmental differentiation tests, the authors present convincing evidence that positive selection on TE polymorphisms is rare and that the distribution of TE ages points to purifying selection being the main force acting on TE evolution in this species. This study will be relevant for anyone interested in the role of TEs in evolution and adaptation.

eLife assessment

This study presents a valuable finding on the impact of metformin-induced shifts in gut microbial community structure and metabolite levels for drug efficacy in a mouse model of liver injury. The current evidence supporting the claims of the authors is solid. This paper will be of broad interest to researchers across multiple disciplines, including the microbiome, liver disease, and pharmacology.

eLife assessment

This important study provides new insights into the development and function of medullary thymus epithelial cells (mTEC). The authors provide compelling evidence to support their claims as to the differentiation and lineage outcomes of CCL21+ mTEC progenitors, which further our understanding of how central tolerance of T cells is enforced within the thymus.

eLife assessment

The fMRI study is important because it investigates fundamental questions about the neural basis of multimodal binding using an innovative multi-day learning approach. The results provide solid evidence for learning-related changes in the anterior temporal lobe, however, the interpretation of these changes is not straightforward, and the study does not (yet) provide direct evidence for an integrative code. This paper is of potential interest to a broad audience of neuroscientists.

eLife assessment

This valuable study advances our understanding of how the viral protease in a D-type retrovirus is activated and in particular how the exposure of the myristoyl group is required for processing of the Gag matrix precursor. The supporting evidence is convincing, but the work would benefit from additional data in support of the claims. This manuscript is of interest to retrovirologists and structural biologists.

eLife assessment

This study presents a useful assessment of the possible role of type I interferons in inhibiting Adam17 protease/sheddase activity and their correlation with decreased Langerhans Cells signature in lesional and nonlesional CLE and murine models as cause of photosensitive lupus. The data were collected and analyzed using a solid methodology. This work will be of interest to scientists interested in photosensitivity in the setting of lupus.

eLife assessment

This important study used a novel method to relate gastric acidity to subjective ratings of emotions induced by video clips. The findings are solid but could be strengthened by additional analyses and/or visualization. The findings have broad implications for the field of emotion research and opens new avenues of research for understanding psychosomatic disorders.

eLife assessment

This manuscript presents the lack of effect of closed-loop SWR disruption in guiding behavior and remembering the recent past in short-term memory tasks in rats. These negative results may have important theoretical and practical implications in the field of memory and learning. However, while SWR detection methods are carefully validated, the strength of evidence is incomplete and some additional controls are required.

eLife assessment

This study presents valuable findings on the role of the Drosophila ubiquitin-conjugating enzyme UBE2D/eff in maintaining proteostasis during aging. Protein levels of UBE2D decrease with age, and knockdown of UBED2 leads to an accumulation of ubiquitinated proteins, and a shortened lifespan that can be rescued by ectopic expression of the human homologous gene. The work supports a role of this ubiquitin conjugating enzyme in proteostasis, although the evidence is still incomplete. The study will be of broad interest to cell biologists working in aging and age-related diseases.

eLife assessment

Pak et al. examined the relationship between the most common spatial patterns of neurodegeneration and transcriptional markers of the density of different cell types in the cerebral cortex. This valuable study uses innovative methods to provide convincing evidence that patterns of grey matter loss in various forms of dementia are correlated with the anatomical distribution of non-neuronal cell types.

eLife assessment

This important work identifies a previously uncharacterized capacity for songbird to recover vocal targets even without sensory experience. The evidence supporting this claim is convincing, with technically difficult and innovative experiments exploring goal-directed vocal plasticity in deafened birds. This work has broad relevance to the fields of vocal and motor learning.

eLife assessment

This important study assesses anatomical, behavioral, physiological, and neurochemical effects of early-life seizures in rats, describing a striking astrogliosis and deficits in cognition and electrophysiological parameters. The solid results come from a wide range of convergent techniques that were used to understand the effects of early-life seizures on behavior as well as hippocampal prefrontal cortical dynamics. This paper will be of interest to neurobiologists, epileptologists, and behavioral scientists.

eLife assessment

This is an important study examining the neural profile of weak and strong fear memories using a variety of imagining and interrogation neural techniques. The data are convincing in detailing the neural profile of neutral, aversive and fear conditioned stimuli in the LC and its input to the dorsal hippocampus and support the conclusion that dopaminergic input from the LC is the key instigator of trace fear conditioning in hippocampus. This paper is of interest to behavioural and neuroscience researchers studying learning, memory and neural networks.

eLife assessment

This useful study addresses the interesting and challenging problem of how neural networks (including possibly the brain) can optimize performance while multi-tasking. The authors address this problem by introducing an information-theoretic framework that balances the costs of control and of automaticity to achieve a desired level of overall performance. They present detailed analyses of this framework, but overall the manuscript is not easily accessible to a broad audience, and the supporting evidence is currently incomplete (but could be greatly improved with substantial revisions). They use information-theoretic terminology in non-standard ways that are not clearly explained, leading to difficulties in interpreting the framework and comparing it to other computational approaches, and the relationship between their findings and empirical data is not always clear.

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 solid, with appropriate experimental methods, data, and analysis, though some additional analysis would strengthen comparisons with past work.

eLife assessment

This fundamental study substantially advances our understanding of the role of different-sized soil invertebrates in shaping the rates of leaf litter decomposition, using an experiment across seasons along an aridity gradient. The authors provide compelling evidence that the summed effects of all invertebrates (with large-sized invertebrates being more active in summer and small-sized invertebrates in winter) on decomposition rates result in similar levels of leaf litter decomposition across seasons. The work will be of broad interest to ecosystem ecologists interested in soil food webs, and researchers interested in modeling carbon cycles to understand global warming.

eLife assessment

This important work substantially advances our understanding of episodic memory in individuals with aphantasia, and sheds light on the neural underpinnings of episodic memory and mental imagery. The evidence supporting the conclusions is convincing, including evidence from a well-established interview paradigm complemented with fMRI to assess neural activation during memory recall. The work will be of broad interest to memory researchers and mental imagery researchers alike.

eLife assessment

Amacrine cells are a heterogeneous and understudied set of retinal interneurons. This study presents valuable new insights into the structure, function, and circuit connectivity of a particular subset of wide field amacrine cells (WACs). The authors use an impressive set of techniques to study structural and functional properties of these cells and to establish their postsynaptic circuit partners. Evidence for the central conclusions is solid, although some of the most interesting results could be pursued more completely.

eLife assessment

This important study describes patterns of anatomical connectivity between the cortex and the thalamus using magnetic resonance imaging data in humans and non-human primates. The measures are related to numerous other modalities to develop a robust understanding of the organisation of the system. The authors provide solid evidence that there is a difference between sensory and association cortices in terms of their connectivity with the thalamus, which may have downstream effects on brain function. This work will be of interest to neuroscientists interested in the organization and dynamics of cortico-thalamic circuits.

eLife assessment

This important study introduces a new cortical circuit model for predictive processing. Simulations effectively illustrate that, with appropriate synaptic plasticity, a canonical layer 2/3 cortical circuit - comprising two classes of interneurons providing subtractive and divisive inhibition - can generate uncertainty-modulated prediction errors by pyramidal neurons. The model's effectiveness is supported by solid numerical analysis. Although the model is convincing and offers testable predictions, it currently lacks direct comparison to experimental data, and the presentation clarity could be improved. Nonetheless, the model is expected to be of great interest to those involved in cortical and predictive processing research.

eLife assessment

This study presents important findings on the differential activity of noradrenergic and dopaminergic input to dorsal hippocampus CA1 in head-fixed mice traversing a runway in a virtual environment that is familiar or novel. While the data appear to be rigorously analysed, and the observed divergence in the dynamics of activity in the dopaminergic and noradrenergic axons is solid, there are some methodological concerns that mean the strength of evidence is currently incomplete.

eLife assessment

Alpha-synuclein is a synaptic vesicle associated protein that is linked to a number of neurodegenerative disorders. In this manuscript, the authors provide compelling evidence of alpha-synuclein's interaction with E-domain synapsins as the main culprit mediating the suppression of neurotransmitter release and synaptic vesicle recycling by alpha-synuclein. This important work provides molecular mechanisms underlying alpha-synuclein functions.

eLife assessment

This important study proposes a new method for tracking neurons recorded with Neuropixel electrodes across days. The methods and the strength of the evidence are convincing, but the authors do not address whether their approach can be generalized to other brain areas, species, behaviors, or tools. Overall, this method will be potentially of interest to many neuroscientists who want to study long-term activity changes of individual neurons in the brain.

eLife assessment

This manuscript details a new method and tool for examining TDP-43 loss of nuclear and gain of cytoplasmic function in neurons. This is a valuable resource that does not rely on artificial knockdown or overexpression. While the authors seek to use this new system to induce disease-associated TDP-43 pathology), their overall evaluation is incomplete and requires further characterization to enhance the applicability and utility of this new tool.

Evaluation statement (17 January 2024; revised 31 January 2024)

Feng and colleagues investigate the molecular basis of lipid scrambling in a fungal member of the TMEM16 family of Ca²⁺-dependent lipid scramblases. These proteins possess a groove in their 3D structure that has been implicated in lipid scrambling, which the authors investigate in the absence and presence of Ca²⁺ using a combination of cryo-EM structure determination, mutagenesis and functional assays. Their closed-groove structure reveals a continuous file of lipid molecules around the catalytic groove region, providing a structural basis for lipid interaction with the protein. Additionally, the authors capture three novel states of TMEM16, completing the picture of conformational transitions that this protein undergoes. Strikingly, the authors show that both structure and distribution of the protein’s conformations depend on lipid composition and nanodisc scaffold protein.

Biophysics Colab considers this to be exceptional work and recommends it to scientists interested in plasma membrane lipid homeostasis and cryoEM.

(This evaluation by Biophysics Colab refers to version 2 of this preprint, which has been revised in response to peer review of version 1.)

eLife assessment

This important study explores numerous lines of evidence for the surprisingly diverse diets of a group of toothed birds that lived over 100 million years ago. The large amount of data the authors collected forms a solid dataset. The methods might in principle be extensible to other limbed vertebrates, although there are concerns regarding some of the details. The article will be of interest to colleagues studying ecological evolution in birds or dinosaurs more generally, as well as to anyone studying the impact of the mass extinction event 66 million years ago.

eLife assessment

This study presents an important finding on the splicing regulatory function of RBM7 and its functional impact in breast cancer metastasis. The evidence supporting the claims of the authors is solid, although the inclusion of more delineation of how RBM7 regulates NF-kB and coordinates splicing would have strengthened the study. The work will be of interest to scientists working on breast cancer.

eLife assessment

This useful study utilizes proteomics analysis across a large panel of 51 cancer cell lines to elucidate mechanisms underlying the sensitivity of cancer cells to high-dose vitamin C (Ascorbate). While the associations between specific molecular pathways and sensitivity to ascorbate are interesting, a major limitation is that the study is largely descriptive and incomplete, lacking evidence on the molecular underpinnings of cancer cells' sensitivity to high-dose vitamin C.

eLife assessment

This useful study proposes a role of lysosomal Ca2+ release in inflammasome signaling and metabolic inflammation. While the proposed model would be of considerable interest to the field of immunology if validated, the experimental approaches to study calcium dynamics are problematic, with one of several concerns being the transfection efficiency. The major claims of the paper are thus only incompletely supported.

eLife assessment

This important study uses a multi-pronged empirical and theoretical approach to advance our understanding of animal cognition. It presents convincing data on how differences in learning relate to differences in the ways that male versus female animals cope with urban environments, and more generally how reversal learning may benefit animals in urban habitats.

eLife assessment

This is an important study for understanding the pathogenesis of ulcerative colitis. It convincingly demonstrates reduced levels of the vesicular trafficking protein Rab7 in ulcerative colitis and Crohn's disease, leading to altered levels of calcium-activated chloride channel regulator 1 (CLCA1) and subsequent mucin dysregulation, highlighting Rab7's significance in gut homeostasis maintenance. The manuscript advances the field as it provides insights into a novel regulatory pathway implicated in ulcerative colitis, potentially paving the way for the development of targeted therapeutic interventions.

eLife assessment

Pluripotent stem cells can be obtained from embryos (embryonic stem cells, ESCs) or through induction by transfection (induced pluripotent stem cells, iPSCs). This valuable study uses semi-quantitative proteomics to compare both types of cells, finding interesting differences. The value of the study lies in demonstrating that ESCs and iPSCs cannot be used interchangeably. The conclusions are backed by solid data even if a greater number and diversity in ESC and iPSC clones would help in generalizing the observations.

eLife assessment

This important study contributes to the current knowledge in the field of acute and chronic infarction. It is a significant study because the results provide convincing evidence for the need to incorporate additional risk factors for assessing patients after myocardial infarction.

eLife assessment

This fundamental study evaluates the evolutionary significance of variations in the accuracy of the intron-splicing process across vertebrates and insects. Using a powerful combination of comparative and population genomics approaches, the authors present convincing evidence that higher rates of alternative splicing tend to be observed in species with lower effective population size, a key prediction of the drift-barrier hypothesis. The analysis is carefully conducted and has broad implications beyond the studied species. As such, it will strongly appeal to anyone interested in the evolution of genome architecture and the optimisation of genetic systems.

eLife assessment

The present study provides valuable evidence on the neurochemical mechanisms underlying working memory in obesity. The authors' approach considering specific working memory operations (maintenance, updating) and putative dopaminergic genes is solid, though the inclusion of a more direct measure of dopamine signaling and further theoretical analysis and interpretation of findings would have strengthened the work.

eLife assessment

This study provides the fundamental insight that TGN46, a single-pass membrane protein, acts as a cargo receptor for proteins at the Trans-Golgi Network. The authors demonstrate that the luminal domain of TGN46 is crucial for the incorporation of the soluble secretory protein PAUF into CARTS, a class of vesicles mediating TGN to surface traffic. The data presented are compelling, yielding a clear model for the sorting of cargos destined for secretion.

eLife assessment

The study addresses a central question in systems neuroscience (validation of active inference models of exploration) using a combination of behavior, neuroimaging, and modelling. The data provided are useful but incomplete, missing critical detail. Additionally, some of the conclusions require a comparison model, and proper consideration of alternative explanations.

eLife assessment

This study reports important findings about new locomotory dynamics of crawling Drosophila larva based on imaging the reaction forces during larval crawling. The evidence with the new high-resolution microscopy method is compelling, as it significantly improves the spatial, temporal, and force resolution compared to previous methods for studying Drosophila larva and could be applied to other crawling organisms. The manuscript explains the new technology, WARP microscopy, and provides analysis of the data to characterize small animal behavior and discover new crawling-associated anatomical features and motor patterns. The work will be of interest to the broad neuroscience community interested in the mechanisms of locomotion in a highly tractable model.

eLife assessment

The microRNA lin-4, originally discovered in C. elegans, has a key role in developmental timing across species, but how its expression is developmentally controlled is poorly understood. Here, the authors provide convincing evidence that two MYRF transcription factors are essential positive regulators of lin-4 during early C. elegans larval development. These results provide important insight into the molecular nature of developmental timing that could have significant implications for understanding these processes in more complex systems.

eLife assessment

This important study combines a range of advanced ultrastructural imaging approaches to define the unusual endosomal system of African trypanosomes. Compelling images reveal that, unlike a conventional set of compartments, the endosome in these protists forms a continuous membrane system with functionally distinct subdomains, as defined by canonical markers for early, late, and recycling endosomes. The findings compellingly support that the endocytic system in bloodstream stages has adapted to support remarkably high rates of membrane turnover necessary for immune complex removal and survival in the blood. This research is particularly relevant to those investigating infectious diseases

eLife assessment

This fundamental study addresses the earliest events that enable plant roots to reorient growth in response to gravity. Compelling molecular and cell biological data establish that plasma membrane localization of the LAZY or NEGATIVE GRAVITROPIC RESPONSE OF ROOTS (NGR) protein family is required for rapid and polar redirection of D6 protein kinase, an activator of the PIN3 auxin transporter. This work complements and extends recent publications on the NGR family in gravity sensing (PMID: 37741279 and PMID: 37561884). Collectively these papers advance our understanding of rapid plant gravity sensing and response.

eLife assessment

This valuable study identifies an uncharacterized yeast gene regulating chronological lifespan in a mitochondrial-dependent pathway. The approach to identify and characterise this new gene is appealing, but the evidence in support of some of the major conclusions is incomplete. The paper focuses on chronological lifespan and mitochondrial function, and it will be of interest to yeast biologists working in metabolism and aging.

eLife assessment

This important study combines experimental and computational data to address crucial aspects of RNA methylation by a vital RNA methyltransferase (MTase). The authors have provided compelling, strong evidence, utilizing well-established techniques, to elucidate aspects of the methyl transfer mechanism of methyltransferase-like protein 3 (METTL3), which is a part of the METTL3-14 complex. This work will be of broad interest to biochemists, biophysicists, and cell biologists alike.

eLife assessment

This important study presents findings regarding the role of Juvenile Hormone in development and cell differentiation in the ametabolous insect Thermobia domestica, providing an in-depth analysis of JH's roles in a member of this basally branching group. The evidence supporting the claims of the authors is convincing, drawing on a broad range of approaches and variety of experimental techniques. While the interpretation of this work in the wider context - its relevance for the evolution of metamorphosis - is in some places somewhat speculative, the work will be of interest to evolutionary developmental biologists studying the evolution of metamorphosis, and the evolution of insects in general.

eLife assessment

This study reports important findings on identifying sequence motifs that predict substrate specificity in a class of lipid synthesis enzymes. It sheds light on a mechanism used by bacteria to modify the lipids in their membrane to develop antibiotic resistance. The evidence is convincing, with a careful application of machine learning methods, validated by mass spectrometry-based lipid anlaysis experiments. This interdisciplinary study will be of interest to computational biologists and to the community working on lipids and on enzymes involved in lipid synthesis or modification.

eLife assessment

This important study addresses the problem of detecting weak similarity between protein sequences, a procedure commonly used to infer homology or assign putative functions to uncharacterized proteins. The authors present a convincing approach that combines recently developed protein language models with well-established methods. The benchmarks provided show that the proposed tool is fast and accurate for remote homology detection, making this paper of general interest to all researchers working in the fields of protein evolution and genome annotation.

eLife assessment

The findings in the manuscript are important and the strength of evidences from the genomic analyses is convincing. However, the evidence for the existence of functional MER21B/C remnants in mice, as well as for the imprinting status of Zdbf2 in rabbits and non-human primates was viewed as mainly correlative and incomplete. This manuscript will be of interest to developmental biologists and those working on possible novel mechanisms of gene regulation.

eLife assessment

This valuable study examines the relationship between positional anchoring of grid cell activity and performance in spatial navigation tasks that requires path integration. The authors demonstrate that grid cells can either fire in relation to the position relative to task-relevant virtual stimuli or independently based on the distance covered. Their findings convincingly reveal that mice exhibited better performance in the path integration task when grid cell activity was anchored to their position on the virtual track rather than the distance traversed, highlighting the contribution of grid firing to spatial navigation behavior. The work will be of interest to experimental and computational neuroscientists interested in spatial navigation.

eLife assessment

This work describes a novel and powerful affinity interactomics approach that allows investigators to identify networks of protein-protein interactions in cells. The important findings presented here describe the application of this technique to the SH3 domain of the membrane remodeling Bridging Integrator 1 (BIN1), the truncation of which leads to centronuclear myopathy. The authors present solid evidence that BIN1 SH3 engages with an unexpectedly high number of cellular proteins, many of which are linked to skeletal muscle disease, and evidence is presented to suggest that BIN1 may play a role in mitosis creating the potential for new avenues in drug development efforts. Some of the findings, however, are rather preliminary, and questions about differences in affinities between whole intact protein and fragment binding partners are not adequately discussed.

eLife assessment

This article reports an important fluorescence-based reporter system to evaluate kinase conformations. This assay is applied to four different kinases that have very unique regulatory features, thereby indicating that the assay can be used to provide solid evidence on the conformational state of a large number of kinases. This paper will be of interest to researchers working on kinases and their conformational states.

eLife assessment

The authors identify new mechanisms that link a PIK3R1 mutant to cellular signaling and division in Activated PI3 Kinase Delta Syndrom 1 and 2 (APDS1/2). The conclusion that this mutant serves as a dominant negative form of the protein, impacting PI3K complex assembly and IRS/AKT signaling, is important, and the evidence from constitutive and inducible systems in cultured cells is convincing. Nevertheless, there are several limitations relating to differences between cell lines and expression systems, as well as more global characterization of the protein interaction landscape, which would further enhance the work.

eLife assessment

This valuable study sheds light on the pivotal role of alterations in chondrocyte glycan metabolism in two contexts: The onset of cartilage degeneration and early onset of osteoarthritis (OA). The action is through hypertrophic differentiation of chondrocytes, a finding that provides insights into the identification of nascent markers for early-stage OA. The evidence supporting the claims is solid, with the authors clearly demonstrating the role of articular cartilage corefucosylation in the development of OA. The authors' inferences would be further enhanced through future experiments aimed at analyzing the mechanisms underlying the changes in glycometabolism in cartilage.

eLife assessment

This manuscript describes fundamental single-molecule correlative force and fluorescence microscopy experiments to visualize the 1D diffusion dynamics and long-range nucleosome sliding activity of the yeast chromatin remodelers, RSC and ISW2. Compelling evidence shows that both remodelers exhibit 1D diffusion on bare DNA but utilize different mechanisms, with RSC primarily hopping and ISW2 mainly sliding on DNA. These results will be of interest to researchers working on chromatin remodeling.

eLife assessment

This important study employs multiscale simulations to show that PIP2 lipids bind to DIV S4-S5 linkers within the inactivated state of a voltage-gated sodium channel, affecting the coupling of voltage sensors to the ion-conducting pore. The authors demonstrate that PIP2 prolongs inactivation by binding to the same site that binds the C-terminal during recovery from inactivation, and they suggest that binding to gating charges in the resting state may impede activation, both findings that contribute to our understanding of sodium channel modulation. The coarse-grained and atomistic molecular dynamics simulations are convincing, including state dependence and linker mutants to back up the claims.

eLife assessment

This landmark study sheds light on a long-standing puzzle in Protein kinase A activation in Trypanosoma. Extensive experimental work provides exceptional evidence for the conclusions of the work, which represents a significant advancement in our understanding of the molecular mechanism of cyclic nucleotide binding domains. The work is relevant for researchers with interests in kinases and their mechanistic study.

eLife assessment

This important study reports on key characteristics of MYC-driven cancers: dysregulated pre-mRNA splicing and altered metabolism, with the data being overall solid. The manuscript should be of broad interest to cancer biologists due to its therapeutic implications.

eLife assessment

This potentially useful study aims to advance our understanding of the structure of the native form of a viral toxin secreted from infected cells. While some of the findings confirm previous reports, the new claims in this study are unfortunately only inadequately supported by the methods and analyses used. More rigorous approaches are needed to justify the main conclusion that the structure of the viral toxin derived from infected cells in this study is distinct from previously reported structures of recombinantly expressed versions of the toxin.

eLife assessment

This important study elucidates the molecular divergence of caspase 3 and 7 in the vertebrate lineage. Convincing biochemical and mutational data provide evidence that in humans, caspase 7 has lost the ability to cleave gasdermin E due to changes in a key residue, S234. The diversification and specialization of gasdermins such as gasdermin E in humans compared to early vertebrates such as teleosts may enable each human gasdermin molecule to have more restricted and tightly regulated physiological functions in different cell death pathways.

eLife assessment

This important work suggests that the observed cosine-like activity in the head direction circuit of insects not only subserves vector addition but also minimizes noise in the representation. The authors provide solid evidence using the locust and fruit fly connectomes. The work raises important theoretical questions about the organization of the navigation system and will be of interest to theoretical and experimental researchers studying navigation.

eLife assessment

This study provides important new insights into the structural diversity of effectors – proteins secreted by pathogens and symbionts into host cells – from the plant-associated fungus Fusarium oxysporum f. sp. lycopersici. The study provides a convincing approach to elucidate how effectors navigate their host environment by exploiting both computational and experimental approaches to understand how their structure influences binding partners. The work will be of interest to those studying molecular host-microbe interactions and disease protection.

eLife assessment

This study provides a fundamental advance in palaeontology by reporting the fossils of a new invertrebrate, Beretella spinosa, and inferring its relationship with already described species. The analysis placed the newly described species in the earliest branch of moulting invertebrates. The study, supported by convincing fossil observation, hypothesizes that early moulting invertebrate animals were not vermiform.

eLife assessment

The work by Lewis and co-workers presents important findings on the role of myosin structure/energetics on the molecular mechanisms of hibernation by comparing muscle samples from small and large hibernating mammals. The solid methodological approaches have revealed insights into the mechanisms of non-shivering thermogenesis and energy expenditure.

eLife assessment

This paper presents valuable findings that shed light on the mental organisation of knowledge about real-world objects. It provides diverse, if incomplete and tentative, evidence from behaviour, brain, and large language models that this knowledge is divided categorically between relatively small objects (closer to the relevant scale for direct manipulation) and larger objects (further from the typical scope of human affordances for action).

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 can induce vesicular extrusion from adjacent neurons. The work would be strengthened by using an additional construct (preferably single-copy) to demonstrate that the observed phenotypes are not unique to a single transgenic reporter. Overall, this work will be of interest to neuroscientists and investigators in the extracellular vesicle and proteostasis fields.

eLife assessment

This is a saturation mutagenesis screening of the CDKN2A gene, successfully assessing the functionality of the missense variants. The results seem robust, but currently, the manuscript is incomplete with a number of weaknesses. The work has the potential to serve as a valuable resource for diagnostic labs as well as cancer geneticists.

eLife assessment

This study presents a useful comparison of the dynamic properties of two RNA-binding domains. The data collection and analysis are solid, making excellent use of a suite of NMR methods. However, evidence to support the proposed model linking dynamic behavior to RNA recognition and binding by the tandem domains remains incomplete. The work will be of interest to biophysicists working on RNA-binding proteins.

eLife assessment

This valuable study combines multidisciplinary approaches to examine the role of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a potential novel host dependency factor for Zika virus. The main claims are partially supported by the data, but remain incomplete. The evidence would be strengthened by improving the immunofluorescence analyses, addressing the role of IGF2BP2 in "milder" infections, and elucidating the role of IGF2BP2 in the biogenesis of the viral replication organelle. With the experimental evidence strengthened, this work will be of interest to virologists working on flaviviruses.

eLife assessment

The manuscript explores the ways in which the genetic code evolves, specifically how stop codons are reassigned to become sense codons. The authors present phylogenetic data showing that mutations at position 67 of the termination factor are present in organisms that nevertheless use the UGA codon as a stop codon, thereby questioning the importance of this position in the reassignment of stop codons. Alternative models on the role of eRF1 would reflect a more balanced view of the data. Overall, the data are solid and these findings will be valuable to the genomic/evolution fields.

eLife assessment

This study presents a valuable finding on the process of brown to white adipogenic transdifferentiation within the perirenal adipose depot. The evidence supporting the claims is convincing, although limited sequencing depth of single nuclei and lack of regulatory insights somewhat lessens the impact of these findings. The work will be of interested to adipose tissue biologists.

eLife assessment

This study presents valuable insights into the evolution of the gasdermin family, making a strong case that a GSDMA-like gasdermin activated by caspase-1 cleavage was already present in early land vertebrates. Convincing biochemical evidence is provided that extant avian, reptilian, and amphibian GSDMA proteins can still be activated by caspase-1 and upon cleavage induce pyroptosis-like cell death -- at least that they do so in the context of human cell lines. The caspase-1 cleavage site has only been lost in mammals, which use the more recently evolved GSDMD as a caspase-1 cleavable pyroptosis inducer. The presented work will be of considerable interest to scientists working on the evolution of cell death pathways, or on cell death regulation in non-mammalian vertebrates.

eLife assessment

Bladder dysfunction following spinal cord injury (SCI) represents a severe and disabling complication without effective therapies. Following evidence that AMPA receptors play a key role in bladder function the authors show convincingly that AMPA allosteric activators can ameliorate many of the subacute defects in bladder and sphincter function following SCI, including prolonged voiding intervals and high bladder pressure thresholds for voiding. These valuable results in rodents may help in the development of these agents as therapeutics for humans with SCI-induced bladder dysfunction.

eLife assessment

This important study identifies the TNXB-AKT pathway as a potential mechanism underlying hemophilia-associated cartilage degeneration. The evidence supporting the conclusions is convincing, with murine and human patient evidence as well as genome-wide DNA methylation analysis. This paper would be of interest to cell biologists and biochemists working on musculoskeletal disorders.

eLife assessment

This important study identifies the role of Caveolin1 and Cavin1 as regulators of TransEndothelial Macroaperture (TEM). The methodology used is rigorous and compelling, and further research can point to more mechanistic understanding of the process.

eLife assessment

This valuable study introduces an innovative method for measuring interocular suppression depth, which implicates mechanisms underlying subconscious visual processing. The evidence is solid in suggesting a limitation of measuring conventional bCFS threshold alone that could be remediated by the new method. It will be of interest not only to cognitive psychologists and neuroscientists who study sensation and perception but also to philosophers who work on theories of consciousness.

eLife assessment

The manuscript from Richter et al. is a very thorough anatomical description of the external sensory organs in Drosophila larvae. It represents a fundamental step forward for sensory physiology, and provides a tool for investigating the relationship between the structure and function of sensory organs. Using improved electron microscopy analysis and digital modelling, the authors provide compelling evidence that form the basis for further molecular and functional studies to decipher the sensory strategies used by larvae to navigate through their environment.

eLife assessment

This important paper uses a multifaceted approach to implicate the locus coeruleus-noradrenaline system in the stress-induced transcriptional changes of dorsal and ventral hippocampus. It provides an inventory of dorsal and ventral hippocampal gene expression upregulated by activation of LC-NA system, which can be used as starting point for more functional studies related to the effects of stress-induced physiological and pathological changes. The results convincingly support the conclusions. This paper will be of interest to those interested in stress neurobiology, hippocampal, and/or noradrenaline function.

eLife assessment

This valuable manuscript by Lane introduces an exciting way to measure SARS-CoV-2 aerosolized shedding using a disposable exhaled breath condensate collection device (EBCD). The paper draws the conclusion that the contagious shedding of the virus via the aerosol route persists at a high level until 8 days after symptoms. While the methodology is potentially of high importance and the paper is clearly written, the conclusions are incomplete and only partially supported by the data.

Editors Assessment:

The snake pipefish, Entelurus aequoreus, is a species of fish that dwells in open seagrass habitats in the northern Atlantic. As a pipefish, it is a member of the Syngnathidae family of fish which also includes seahorses and seadragons. In recent years it has expanded its population size and range into arctic waters. To better understand these demographic changes genomic data is useful, and to address this a high-quality reference genome has been produced. Building on a previous short-read reference, a near chromosome-scale genome assembly for the snake pipefish was assembled using PacBio CLR and Hi-C reads. After revisions the authors provided more details on the assembly metrics, the final assembly has a length of 1.6 Gbp, with scaffold and contig N50s of 62.3 Mbp and 45.0 Mbp respectively. Demographic inference analysis of the snake pipefish genome using this data enables tracing of population changes over the past 1 million years, and this reference will allow further analyses and studies relating these to changes in climate.

**This evaluation refers to version 1 of the preprint *

eLife assessment

This valuable study uses multiple large neuroimaging data sets acquired at different points through the lifespan to provide solid evidence that birthweight (BW) is associated with robust and persistent variations in cortical anatomy, but less-substantial influences on cortical change over time. These findings, supported by robust statistical methods, illustrate the long temporal reach of early developmental influences and carry relevance for how we conceptualize, study, and potentially modify such influences more generally. The paper will be of interest to people interested in brain development and aging.

eLife assessment

In this valuable study, the authors explore regulatory cascades governing mammalian cochlear hair cell development and survival. They confirm previous studies that the transcription factors Pou4f3 and Gfi1 are necessary for hair cell survival, and use compelling evidence to demonstrate that the RNA binding protein gene RBM24 is regulated by Pou4f3, but not Gfi1. These findings will be of interest to those working on hearing loss, and hold significance for viral gene delivery methods aiming to manipulate gene expression.

Editors Assessment: Understanding the distribution of Anopheles mosquito species is essential for planning and implementing malaria control programmes, a task undertaken in this study that assesses the composition and distribution of the Anopheles in different districts of Kinshasa in the Democratic Republic of Congo. Mosquitoes were collected using CDC light traps, and then identified by morphological and molecular means. In total 3,839 Anopheles were collected, and data was digitised, validated and shared via the GBIF database under a CC0 waiver. The project monitoring the monthly dynamics of four species of Anopheles, showing a fluctuation in their respective frequencies during the study period. Review improved the metadata by adding more accurate date information, and this data can provide important information for further basic and advanced studies on the ecology and phenology of these vectors in West Africa.

*This evaluation refers to version 1 of the preprint

eLife assessment

This study presents a valuable set of calcium imaging data to analyze the dynamics of excitatory and inhibitory responses in the projection neurons of the honeybees during and after odor presentations. The neural circuit model fed with the imaging data recapitulated odor-specific activity in the Kenyon cells in the post-odor period and the timing shift of behavioral response in associative learning. This solid work will be of interest to researchers working on associative learning.

eLife assessment

This important study develops a machine learning method to reveal hidden unknown functions and behavior in gene regulatory networks by searching parameter space in an efficient way. The evidence for some parts of the paper is still incomplete and needs systematic comparison to other methods and to the ground truth, but the work will be of broad interest to anyone working in biology of all stripes since the ideas reach beyond gene regulatory networks to revealing hidden functions in any complex system with many interacting parts.

eLife assessment

This study provides important insights into the role of neurexins as regulators of synaptic strength and timing at the glycinergic synapse between neurons of the medial nucleus of the trapezoid body and the lateral superior olive, key components of the auditory brainstem circuit involved in computing sound source location from differences in the intensity of sounds arriving at the two ears. Through an elegant combination of genetic manipulation, fluorescence in-situ hybridization, ex vivo slice electrophysiology, pharmacology, and optogenetics, the authors provide convincing evidence to support their claims. While further work is needed to reveal the mechanistic basis by which neurexins influence glycinergic neurotransmission, this work will be of interest to both auditory and synaptic neuroscientists.

eLife assessment

This study provides important evidence supporting the ability of a new type of neuroimaging, OPM-MEG system, to measure beta-band oscillation in sensorimotor tasks on 2-14 years old children and to demonstrate the corresponding development changes, since neuroimaging methods with high spatiotemporal resolution that could be used on small children are quite limited. The evidence supporting the conclusion is solid but lacks clarifications about the much-discussed advantages of OPM-MEG system (e.g., motion tolerance), control analyses (e.g., trial number), and rationale for using sensorimotor tasks. This work will be of interest to the neuroimaging and developmental science communities.

eLife assessment

This useful study seeks to address the importance of physical interaction between proteins in higher-order complexes for covariation of evolutionary rates at different sites in these interacting proteins. Following up on a previous analysis with a smaller dataset, the authors provide compelling evidence that the exact contribution of physical interactions, if any, remains difficult to quantify. The work will be of relevance to anyone interested in protein evolution.

eLife assessment

This paper investigates the impact of intranasal instillation of SARS CoV2 spike protein in mouse models of lung inflammation. The authors conclude that the spike protein can interact with macrophages through carbohydrate recognition and can induce recruitment and NETosis of neutrophils, contributing to lung inflammation. They also use the cremaster muscle model to investigate effect of the spike proteins on neutrophil dynamics and death using intravital microscopy. Given that mucosal vaccines using SARS CoV2 spike variants could be envisioned as desirable, the observation that spike can induce lung/mucosal inflammation even without an adjuvant is important. Despite limitations of some loose terminology and some weak controls, the key observations are solid and demand further attention given the importance of the antigen.

eLife assessment

This fundamental study provides insight into the fascinating process of self- and non-self-recognition in the protist Tetrahymena thermophila, a species with seven distinct mating types. Using an elegant combination of phenotypic assays, protein studies, and imaging, the authors present convincing evidence that a large multifunctional protein complex at the cell surface mediates both self- and non-self mating-type recognition. This study extends our understanding of how more than two mating types/sexes may be specified in a species, and it will be relevant for anyone interested in sexual systems and cell-cell communication.

eLife assessment

This valuable study advances our understanding of the potential therapeutic strategies for the treatment of pheochromocytomas using single-cell transcriptomics. The authors propose a new molecular classification criterion based on the characterization of tumor microenvironmental features, based on solid evidence. The work, which could be improved further through delineating the choice of the PASS scoring system, will be of broad interest to clinicians, medical researchers, and scientists working in the field of pheochromocytoma.

eLife assessment

This important paper provides solid evidence that the angular gyrus plays a role in insight-based memory updating. The study is well conducted, timely, and presents clear-cut behavioral results. While the study provides robust evidence that transcranial magnetic stimulation to the angular gyrus impacts memory, evidence for the strong claim of a causal contribution of the angular gyrus in particular – apart from other connected regions, including the hippocampus – is not conclusive.

eLife assessment

This important study identifies novel small molecule antagonists of CXCR4 that disrupt nanocluster formation and chemotactic function without blocking CXCL12 binding and downstream signals. The conclusions are based on solid evidence, but the work could be improved by including kinetic and dose information on the most active inhibitors. We also note that modeling and mutagenesis implicate helix V and VI in an allosteric mechanism, but that the description of the modeling is not sufficiently detailed such that others could replicate it.

eLife assessment

The authors report the cryo-EM structure of human vesicular monoamine transporter 2 (VMAT2) bound to the noncompetitive inhibitor tetrabenazine (in an occluded state). This important achievement captures the structure of a major facilitator superfamily (MFS) transporter critical for human neurotransmission. The evidence for the structure is solid, but the molecular dynamics aspect of the study is incomplete.

eLife assessment

The authors have made important contributions to our understanding of the pathogenesis of erectile dysfunction (ED) in diabetic patients. They have identified the gene Lbh, expressed in pericytes of the penis and decreased in diabetic animals. Overexpression of Lbh appears to counteract ED in these animals. The authors also confirm Lbh as a potential marker in cavernous tissues in both humans and mice. While solid evidence supports Lbh's functional role as a marker gene, further research is needed to elucidate the specific mechanisms by which it exerts its effects. This work is of interest to those working in the fields of ED and angiogenesis.

eLife assessment

This useful study examines how deletion of a major DNA repair gene in bacteria may facilitate the rise of mutations that confer resistance against a range of different antibiotics. Although the phenotypic evidence is intriguing, the interpretation of the phenotypic data presented and the proposed mechanism by which these mutations are generated are incomplete, relying on untested assumptions and suboptimal methodology. If substantially improved, this work could be of interest to microbiologists studying antibiotic resistance, genome integrity, and evolution, but as yet is of unclear significance.

eLife assessment

This important study advances our understanding of early Cambrian cnidarian paleoecology and suggests that the reconstructed ancestral feeding and respiration mechanisms predate jet-propelled swimming utilized by modern jellyfish. The work combines solid evidence of fluid and structural mechanics modeling, simulating for the first time the feeding and respiratory capacities in a microfossil (Quadrapyrgites), which in turn opens new possibilities using this approach for paleontological research. Assuming that the prior interpretations and assumptions concerning the modeled organism's soft part and skeletal anatomy are correct, the hypotheses that (1) the organism could alternately contract and expand the oral region and (2) such movement increased feeding efficiency seem plausible.

eLife assessment

By assessing what it means to replicate a null finding, and by proposing two methods that can be used to evaluate whether null findings have been replicated (frequentist equivalence testing, and Bayes factors), this article represents an important contribution to work on reproducibility. Through a compelling re-analysis of results from the Reproducibility Project: Cancer Biology, the authors demonstrate that even when 'replication success' is reduced to a single criterion, different methods to assess replication of a null finding can lead to different conclusions.

eLife assessment

In this important study by Theriot et al., the authors utilize an impressive set of innovative approaches to conduct a CRISPRi pooled screen in human cells using large-scale microscopy screen data. They leverage an improved barcoding approach to identify genes targeted in specific cells and examine the effects on cell morphology using high-dimensional phenotypic analysis. The method and data presented are compelling.

eLife assessment

The findings of this study are valuable as they challenge the dogma regarding the link between lowered bacterial metabolism and tolerance to aminoglycosides. The authors propose that the well-known tolerance to AG of mutants such as those of complexes I and II is not due to a decrease in the proton motive force and thus antibiotic uptake. The results presented here are solid but incomplete and the conclusions require additional experimental support.

eLife assessment

This study presents a valuable finding on the possible use of vilazodone in the management of thrombocytopenia through regulating 5-HT1A receptor signaling. The evidence supporting the claims of the authors is solid, with the combined use of computational methods and biochemical assays. The work will be of broad interest to scientists working in the field of thrombocytopenia.

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 solid evidence that the degradation products of polysaccharide digestion can stimulate motility.

eLife assessment

The authors of this study implemented an important toolset for 3D reconstruction and segmentation of dissection photographs, which could serve as an alternative for cadaveric and ex vivo MRIs. The tools were tested on synthetic and real data with compelling performance. This toolset could further contribute to the study of neuroimaging-neuropathological correlations.

eLife assessment

This study presents a valuable investigation of how people approach and avoid uncertainty, with a particular focus on the effects of overall uncertainty. They find that individuals approach uncertainty to a point, but when uncertainty is particularly high, they avoid it. The results are interpreted under a cognitive cost-resource rational framework. The methods are convincing, using appropriate and current methodologies, but more details on analyses and placing the work more fully in the context of the existing literature would make the contribution more significant.

eLife assessment

The work by Hornberger and team presents a novel workflow for the visualisation of myofibrils with high resolution and contrast that will be highly valued by the scientific community. The novel methods include solid validation of both sample preparation and analysis, and have been used to make the fundamental discovery of myofibrillogenesis as the mechanism of mechanical loading-induced growth. However, whether this mechanism is present in other settings of muscle growth (i.e non-loading), other striated tissue (e.g myocardium), or is sex-dependent requires future experiments.

eLife assessment

The work by Hornberger and team presents a novel workflow for the visualisation of myofibrils with high resolution and contrast that will be highly valued by the scientific community. The methods include solid validation of both sample preparation and analysis, and have been used to make the fundamental discovery of myofibrillogenesis as the mechanism of mechanical loading-induced growth. Whether this mechanism is present in other settings of muscle growth (i.e., non-loading), other striated tissue (e.g myocardium), or is sex-dependent, will require future experiments.

eLife assessment

This valuable work performed fMRI experiments in a rodent model of absence seizures. The results provide new information regarding the brain's responsiveness to environmental stimuli during absence seizures. The authors suggest reduced responsiveness occurs during this type of seizure, and the evidence leading to the conclusion is solid, although reviewers had divergent opinions.

eLife assessment

This important study demonstrates that the cells in the behavior of the presomitic mesoderm in zebrafish embryos depends on both an intrinsic program and external information, which provides new insight into the biology underlying embryo axis segmentation. The findings are supported convincingly by a thorough and quantitative single-cell real-time imaging approach, both in vitro and in vivo, which the authors developed.

eLife assessment

This valuable prospective study develops a new tool to accelerate pharmacological studies by using neural networks to emulate the human ventricular cardiomyocyte action potential. The evidence supporting the conclusions is convincing, based on using a large and high-quality dataset to train the neural network emulator. There are nevertheless a few areas in which the article may be improved through validating the neural network emulators against extensive experimental data. In addition, the article may be improved through delineating the exact speed-up achieved and the scope for acceleration. The work will be of broad interest to scientists working in cardiac simulation and quantitative system pharmacology.

eLife assessment

This important study combines experimental infections with laboratory and field Plasmodium falciparum isolates to quantify the force of human malaria parasite transmission. By using compelling methodological approaches, the authors establish clear positive correlations between mosquito infection levels (as determined by oocyst numbers), sporozoite loads in salivary glands, and sporozoites expelled during feeding. The link between heterogenous infection levels in the mosquitoes and malaria transmission would be of interest to vector biologists, parasitologists, immunologists, and mathematical modellers.

eLife assessment

This important study advances our understanding of the biological significance of the DNA sequence adjacent to telomeres. The data presented convincingly demonstrates that subtelomeric repeats are non-essential and have a minimal, if any, role in maintaining telomere integrity of budding yeast. The work will be of interest to telomere community specifically and the genome integrity community more broadly.

eLife assessment

This important work presents an example of how genomic data can be used to improve understanding of an ongoing, long-term bacterial outbreak in a hospital with an application to multi-drug resistant Pseudomonas aeruginosa, and will be of interest to researchers concerned with the spread of drug-resistant bacteria in hospital settings. The convincing genomic analyses highlight the value of routine surveillance of patients and environmental sampling and show how such data can help in dating the origin of the outbreak and in characterising the epidemic lineages. These findings highlight the importance of understanding environmental factors contributing to the transmission of P. aeruginosa for guiding and tailoring infection control efforts; however, epidemiological information was limited and the sampling methodology was inconsistent, complicating interpretation of inferences about exact transmission routes.

eLife assessment

This study presents valuable findings on the role of the sirtuins SIRT1 and SIRT3 during Salmonella Typhimurium infection. Although the work increases our understanding of the mechanisms used by this pathogen to interact with its host and may have implications for other intracellular pathogens, the reviewers found that the evidence to support the claims is incomplete. In particular, the discrepancy between results obtained using cultured cell lines and the animal model of infection stands out.