eLife assessment

The manuscript by Brunetti et al. represents an important contribution where SARS-CoV-2 infection of T-helper cells is implicated and found to be mediated by CD4. The work progressed through a computationally driven hypothesis, by analyzing the interaction partners of SARS-CoV-2 spike glycoprotein (as initially modelled through similar SARS-CoV-1), followed by experimental validations, and further computational and experimental insights on the mechanism of binding. The study identifies the interaction between spike RBD domain and N Terminal domain of CD4 molecule as the specific viral attachment strategy. The evidence supporting the claims of the authors is solid, the results look significant and the data is clear and enough for understanding the manuscript. It also provides a potential usefulness of their approach in future work in understanding how viruses mediate infection of T cells. The work will be of interest to medical biologists working on SARS-CoV-2.

eLife assessment

This fundamental work advances our understanding of the effects of metformin on bone healing in hyperglycemic conditions. The evidence supporting the conclusion is convincing, using three different types of bone fracture models in type-2 diabetes (T2D) mice. This paper is of potential interest to skeletal biologists, orthopaedic surgeons, and endocrinologists who study the effects of metformin on fracture healing.

eLife assessment

In their current study, Detraux D and colleagues provide some evidence suggesting a role for heme biosynthesis on FGF-ERK and TGF beta signalling and exit from naïve pluripotency, and in controlling the 2-cell-like cell state. The observations provided by the authors are interesting and potentially relevant in the field of pluripotent cell state transitions.

eLife assessment

Dhekne et al report a novel pathway for activation of the multi-domain LRRK2 protein kinase by Rab12 GTPase. LRRK2, which is mutated in Parkinson's Disease phosphorylates a subset of Rab proteins involved in intracellular trafficking, and Parkinson's disease-linked mutations increase this phosphorylation. This work adds an important new layer of understanding of this highly complex pathway by revealing that LRRK2's binding to Rab12 enhances its ability to phosphorylate Rab10. This conclusion is supported by compelling evidence from a wide array of rigorous approaches.

eLife assessment

This valuable study reports on the role of transposable elements in gene expression variation in rice and how TE-associated expression changes could have been selected during domestication. The combination of evidence from linkage studies and selection scans for a subset of insertions is convincing, although it is difficult to know in how many cases linkage of TE insertions to other regulatory variants is responsible for altered gene expression and in how many cases the TE insertions themselves are the bona fide cause of altered gene expression. The work will be of interest to colleagues working on the role of transposable elements in adaptation and to biologists working on domestication.

eLife assessment

This manuscript describes a valuable method to study the mechanism of action of essential genes and novel putative drug targets. Evidence for the effectiveness of the system, which is based on engineering pre-validated targets for RNA-mediated knockdown into genes of interest, is compelling, and the method should find use as an orthogonal method for generating gene specific knockdowns.

eLife assessment

This important study demonstrates that the human FUS protein, which is implicated in ALS and related conditions, interacts with RNAs containing GGGGCC repeats and can regulate their translation by altering three-dimensional structures caused by these repeats. The study is carefully executed and the data provide convincing evidence for its major claims. This work will likely be of interest to researchers studying RNA binding proteins, and to those working on ALS and related diseases.

eLife assessment

This important work provides evidence that artificial recurrent neural networks can be used to investigate neural mechanisms underlying reversible remapping of spatial representations. Authors perform convincing state of the art analyses showing how population activity preserves the encoding of spatial position despite remappings due to the tracking of an internal variable. This paper will be of interest to neuroscientists studying contextual computations, neural representation of space and links between artificial neural networks and the brain.

eLife assessment

In this valuable study, the authors report a structural model of full-length kinesin-1, describing its autoinhibitory mechanism using cryo-EM, AlphaFold structural predictions, cross-linking, and mass spectrometry, which together indicate that the previous model for kinesin-1 auto-inhibition using a small motif in the kinesin tail was not adequate. The data offer a convincing model for how kinesin-1 is autoinhibited, although the evidence is in some places still incomplete and would thus benefit from additional analyses. The work will be of significant interest to the research community working on cytoplasmic transport and microtubule motors.

eLife assessment

This important study makes use of AlphaFold2 to predict the models of tens of cohesin subcomplexes from different species. The models are in most cases consistent with published cohesin mutants with defects in cohesin function in vitro and in vivo. The models provide solid evidence that leads to testable hypotheses of cohesin dynamics and regulation. More broadly, this study serves as an example of how to use AlphaFold2 to build models of protein complexes that involve the docking of flexible regions to globular domains.

eLife assessment

This study offers a model that is used to interrogate how microscopic epistasis and factors like clonal interference affect evolutionary dynamics. The study offers several important insights that can aid in our understanding of the forces that operate in adaptation. The evidence provided is solid, in the form of models and analytical descriptions that describe how these forces manifest themselves.

eLife assessment

The manuscript provides valuable insights into the regulatory role and mechanisms of the spectrin cytoskeleton in mechanotransduction in Drosophila. The data are compelling in establishing that alpha and beta spectrin regulate the Hippo signaling pathway independently via their effect on cytoskeletal tension. The work will be of interest to cell and developmental biologists, particularly those who focus on mechanotransduction and the cytoskeleton.

eLife assessment

This paper presents a valuable advance in the ability to manipulate the integrity of the barrier between endothelial cells. A wide range of data are presented, offering convincing support for the effectiveness of the method. This work is likely to attract a diverse audience of both cell biologists and researchers developing tools to manipulate cell and tissue function.

eLife assessment

This paper presents important computational modeling work that provides a mechanistic account for how memory representations become integrated or differentiated (i.e., having distinct neural representations despite being similar in content). The authors provide convincing evidence that simple unsupervised learning in a neural network model, which critically weakens connections of units that are moderately activated by multiple memories, can account for three empirical findings of differentiation in the literature. The paper also provides insightful discussion on the factors contributing to differentiation as opposed to integration, and makes new predictions for future empirical work.

eLife assessment

This important study shows that two methods of sleep induction in the fly, optogenetically activation of the dorsal fan-shaped body (which is rapidly reversible and maintains a neuronal activity signature similar to wakefulness), and Gaboxadol-induced sleep (which shuts down neuronal activity), produce distinct forms of sleep and have different effects on brain-wide neural activity. The majority of the conclusions of the paper are supported by compelling data, but the evidence supporting the claim that the two interventions trigger distinct transcriptional responses is incomplete.

eLife assessment

This is a potentially important study that contributes to our understanding of the role of beta-arrestins in endosomal activation of the vasopressin type 2 receptors. While the methodology is innovative, the evidence provided is still incomplete, which precludes drawing strong conclusions from the current data.

eLife assessment

This important study advances our understanding of how historical human activities have driven changes in freshwater biodiversity and ecosystem functioning. The authors highlight the value of including not only spatiotemporal scales in biodiversity assessments but also some of the possible drivers of biodiversity loss. Analyzing their joint contribution as environmental stressors, the authors provide compelling evidence that ecosystem assessment methods currently used by environmental regulators throughout Europe are not fit-for-purpose, and they identify several alternatives, more robust indicators of freshwater ecosystem health. The work will be of broad interest to anyone studying changes in biodiversity and their drivers.

eLife assessment

In this Tools and Resources article, the authors overcome the challenge of low Borrelia burgdorferi numbers during infection for analyses such as RNA-sequencing or mass spectrometry. They do so by physically enriching for spirochetes, which is important, as it provides technical advances for the study of global transcriptomic changes of B. burgdorferi during tick feeding, helping to build on the knowledge already collected by the field. The evidence presented is compelling, and the strategy described here could benefit researchers in the field and possibly also support broader applications.

eLife assessment

The authors provide a fundamental resource, detailing genetic variation of nutrient-responsive islet calcium regulation in mice through the lens of proteomics. The evidence for the mechanisms identified using this resource is compelling and strongly supported by integration with results from genome-wide association studies in humans. The construction of a streamlined and searchable web interface for the data maximizes their accessibility and utilization by the community.

eLife assessment

In this valuable study, the authors investigate the mechanism of amyloid nucleation in a cellular system using their novel ratiometric measurements and uncover interesting insights regarding the role of polyglutamine length and the sequence features of glutamine-rich regions on amyloid formation. Overall, the problem is significant and being able to assess nucleation in cells is of considerable relevance. The data, as presented and analyzed, are currently still incomplete. The specific claims would be stronger if based on in vitro measurements that avoid the intricacies of specific cellular systems and that are more suitable for assessing sequence-intrinsic properties.

eLife assessment

Secondary cell walls support vascular plants and conduct water throughout the plant body, and are important resources for lignocellulosic feedstocks. Here the authors present convincing genetic and biochemical evidence that secondary cell wall synthesis, known already to be under complex transcriptional control, is also controlled post-transcriptionally by MUSASHI-like RNA-binding proteins. These important results point to a new mechanism for control of secondary cell wall synthesis, which will be interesting to cell biologists and biochemists studying and attempting to manipulate plant biomass.

eLife assessment

Overall, this manuscript presents an intriguing potential refinement of models for adult SVZ neurogenesis, and highlights the role of RNA splicing at specific stages in the lineage. As such, the findings are valuable to the field of adult neurogenesis. Yet, the reviewers found the strength of the evidence to be incomplete and in some areas inadequate to support the claims. Thus, the conclusions require additional experimental support.

eLife assessment

This study presents a useful inventory of the joint effects of genetic and environmental factors on psychotic-like experiences, and identifies cognitive ability as a potential underlying mediating pathway. The data were analyzed using solid and validated methodology based on a large, multi-center dataset. However, the claim that these findings are of relevance to psychosis risk and have implications for policy changes are only partially supported by the results.

eLife assessment

This important paper reveals how cells in adjacent tissues use the extracellular matrix to establish mechanical connections. Through a series of crisp genetic manipulations and quantitative image analyses, the authors provide compelling evidence to show how an essential adhesion between the uterus and the seam cells in the nematode C. elegans is formed. The assembly of type IV collagen triggers internalization of a cell surface receptor, which then signals from endocytic vesicles to strengthen the connection.

eLife assessment

This study reports valuable findings on the influence of acute stress on prosocial behavior and its neural correlates. Though the evidence is generally solid, concerns about confounding and sampling bias detract from the potential impact.

eLife assessment

This valuable study examined the mechanisms underlying reduced excitability of ventral tegmental area dopamine neurons in mice that underwent a chronic mild unpredictable stress treatment. The authors identify NALCN and TRPC6 channels as key mechanisms that regulate spontaneous firing of ventral tegmental area dopamine neurons and examined their roles in reduced firing in mice that underwent a chronic mild unpredictable stress treatment. The evidence supporting the authors' conclusions are solid yet the reviewers pointed out some limitations in the study including statistics, specificity in pharmacological and gene knockdown experiments, and the relevance to depressions.

eLife assessment

This study represents a valuable finding on the neuron-glia communication and glial responses to traumatic brain injury (TBI). The data supporting the authors' conclusions on TBI analysis, RNA-seq on FACS sorted astrocytes, genetic analyses on Pvr-JNK/MMP1 are solid. However, astrocyte proliferation upon TBI and some of the quantitative methods are incomplete, which could be further strengthened by more rigorous analyses.

eLife assessment

This important work advances our understanding of TLR7 signaling at epithelial surfaces that drives monocytes expansion and its impact on viral responses. The evidence supporting this conclusion is solid, particularly data demonstrating TLR7 stimulation and the requirement for TLR7 in the monocyte expansion. The work will be of interest to immunologists and virologists.

eLife assessment

In this work, the authors provide important mechanistic insights into how the intracellular effector protein Calcineurin B homologous protein 3 (CHP3) can be regulated in a calcium-independent manner to expose its lipid binding site. Compelling evidence demonstrates a binding partner protein (NHE1) triggers a conformation change and exposure of the myristoyl group in CHP3 resulting in membrane association. This provides mechanistic insight into the signalling mechanisms achieved by CHP3 in a target-dependent manner, which will be of broad scientific interest.

eLife assessment

Although largely descriptive, this meta-analysis of 13,000 published Typhi genomes is hugely important to public health. The dataset and presented analysis represents the first wholesale analysis of all available Typhi genomes from the last 21 years. The findings are of great significance to tracking the emergence and maintenance of AMR in Typhi and include novel insights into XDR strain emergence in Pakistan as well as the relationship between MDR maintenance and chromosomal integration.

eLife assessment

The authors describe a sophisticated method to follow enhancer activity in both live embryos and fixed embryos in Tribolium and present important data about the function of a number of enhancers in early development. They show that some of the enhancers are "dynamic" and others are "static" and use this to provide support for the "enhancer-switching" model of gene regulation suggested by some of these authors in the past. However, the evidence they provide is incomplete and although it is consistent with the model, it does not directly support it.

eLife assessment

This study presents findings that are important for understanding plant-soil feedbacks in agriculture. The authors use a large-scale agricultural field experiment to demonstrate the role of root-emitted secondary metabolites in enhancing the yield of the next crop. By using a benzoxazinoid-deficient maize genotype, the authors provide compelling evidence that biomass production and grain yield of several wheat varieties can be increased when grown in soil conditioned by maize plants able to release benzoxazinoids.

eLife assessment

This valuable work investigates the fundamental concept of how the energy of agonist binding is converted into the energy of the conformational change that opens the pore of a ligand-gated ion channel. The conclusions are based on analysis of solid data in terms of a mechanistic model, but adequate statistical analysis is lacking and the uniqueness of the proposed model is not discussed. The findings will be interesting to biophysicists working on ligand-gated ion channels and, more generally, to enzymologists focused on allosteric enzyme regulation.

eLife assessment

This valuable study examines the distribution of four states of brain activity across a variety of cognitive conditions, linking systems neuroscience with cognition and behavior. The work is convincing, using null models and replication in independent datasets to support their findings.

eLife assessment

This important work shows how a transcription factor, fruitless isoform C, fine-tunes the expression of stemness genes to maintain proper stem-cell identity during neurogenesis in Drosophila. The rationale of the work is well-thought-out, conclusions are supported by compelling evidence, and experiments are performed in a rigorous manner, although additional statistics would improve the conclusions. Overall, this work will be of interest to those working on chromatin regulation, transcription regulation, and stem-cell biology.

eLife assessment

This study presents a fundamental meta-analysis on the causes of glucocorticoid variation in birds and mammals. It provides convincing evidence that an increase in metabolic rates also increases glucocorticoid concentrations. As such, the work will be of broad interest to animal physiologists.

eLife assessment

This valuable study provides insights into the IDA peptide with dual functions in development and immunity. The approach used is solid and helps to define the role of IDA in a two-step process, cell separation followed by activation of innate defenses. The main limitation of the study is the lack of direct evidence linking signaling by IDA and its HAE receptors to immunity. As such the work remains descriptive but it will nevertheless be of interest to a wide range of plant cell biologists.

eLife assessment

The manuscript reports useful findings by resolving the crystal structure of Sedoheptulose-1,7-Bisphosphatase (SBPase) from the green algae Chlamydomonas reinhardtii, which is involved in the Calvin cycle. The data presented are solid based on validated methodologies, which help in understanding the structure and function of this enzyme.

eLife assessment

This important study combines experiments and fluid mechanics modeling to determine the mechanism of the ultrafast ejection of the polar tube of the Microsporidia parasite and of transport through this tube. The methods and the analysis, based on the variation of the viscosity of the external medium, are solid, allowing for the first time to discriminate among proposed ejection mechanisms. More details about the model, regarding both the actual topology of the system and the pressure, would be, however, helpful for the reader. The approach implemented here, where simple physical principles are used for distinguishing between mechanisms when the precise geometry is inaccessible through imaging, is potentially applicable to other systems in microbiology.

eLife assessment

This important study used a battery of cutting-edge technologies including whole exosome sequencing, knockout/knockdown animal models and comparative proteomics to define the physiological roles of ZMYND21 in the regulation of sperm flagellar development and male fertility. The data supporting the conclusion are solid, although inclusion of more patients and ultrastructural studies would have further strengthened the study. This work will be of interest to clinicians and researchers who work on male fertility, but also those working on organs/systems containing motile cilia (e.g., trachea, oviduct, ventricular ependymal cells).

elife assessment:

This small-sized clinical trial comparing nebulized dornase-alfa to best available care in patients hospitalized with COVID-19 pneumonia is valuable, but in its present form the paper is incomplete: the number of randomized participants is small, investigators describe also a contemporary cohort of controls and the study concludes about decrease of inflammation (reflected by CRP levels) after 7 days of treatment but no other statistically significant clinical benefit.

eLife assessment

This manuscript represents a valuable study showing that microplastics indeed accumulate in both bovine and human ovarian follicular fluid. It also presented data that direct exposure of bovine eggs to polystyrene, a microplastic commonly found in follicular fluid, negatively affects oocyte maturation, probably through the downregulation of key proteins involved in oxidative stress, DNA damage, apoptosis, and oocyte maturation. Despite the solid supporting evidence, inclusion of the demographics and reasons for assisted reproduction of the human subjects used, as well as the details on quality control for proteomic analyses would further strengthen the study. The work will be of interest to reproductive toxicologists, regulatory scientists and reproductive health care professionals.

eLife assessment

This paper presents an important effort to develop an open source software framework for monitoring trends and variations in healthcare over time in England. They demonstrate a compelling example of how this system can track key health care indicators over the course of the COVID-19 pandemic. The paper will likely be mainly of interest to stakeholders in England, but could inspire the creation of similar systems in other countries.

eLife assessment

This is an important theoretical study providing insight into how fluctuations in excitability can contribute to gradual changes in the mapping between population activity and stimulus, commonly referred to as representational drift. The authors provide convincing evidence that fluctuations can contribute to drift, though certain modeling choices could benefit from justification or further exploration of alternatives. Overall, this is a well-presented study that explores the question of how changes in intrinsic excitability can influence memory representations.

eLife assessment

This useful study investigates the role of mechanotransduction channels in controlling food ingestion in Drosophila and localizes the role of some of these genes to sensory neurons in the fly pharynx. The evidence supporting several of the authors claims is incomplete and would benefit from additional investigation. With additional evidence, this paper would be of interest to biologists interested in mechanosensation and feeding behavior.

eLife assessment

This important study combines genetically barcoded rabies viruses with spatial transcriptomics in vivo in the mouse brain to decode connectivity of neural circuits. The data generated by the combination of these approaches in this new way is mostly convincing as the authors provide validation and proof-of-concept that the approach can be successful. While this new combination of established techniques has promise for elucidating brain connectivity, there are still some nuances and caveats to the interpretations of the results that are lacking especially with regards to noting unexpected barcodes either due to unexpected/novel connections or unexpected rabies spread.

eLife assessment

This valuable work proposes a new model of basal ganglia function termed the "Triple Control Model" consisting of one direct pathway and two indirect pathways. The study provides evidence that the firing dynamics of substantia nigra reflect action selection but not interval time or reward and makes a case for the need for the Triple Control Model to explain the results of their manipulations of D1 and D2 receptor-expressing cells in the striatum. Although this work may be of interest to neuroscientists who study basal ganglia, without additional analyses of the relationship of neural activity to movements, and direct experimental evidence of two indirect pathways, the evidence for this model is somewhat incomplete.

eLife assessment

The formation of the place cell map in the hippocampus is foundational to many models and is thought to form a substrate onto which memories can be structured. This paper presents an important new observation to our understanding of place cell formation - namely that task learning changes or interferes with the process of place cell map stabilization. Reviewers found that there was incomplete evidence for this result, however, in this version of the manuscript because of a confound between the duration of experience in an environment and task-specific learning.

eLife assessment

This study presents a valuable and comprehensive mutagenesis map of the AAV2 rep gene, which will undoubtedly capture the interest of scientists working with adeno-associated viruses and those engaged in the field of gene therapy. The thorough characterization of massive rep variants across multiple AAV production systems bolsters the claims made in the study, highlighting its utility in enhancing our understanding of Rep protein function and advancing gene therapy applications. Despite some limitations, such as the lack of measurements on AAV transduction efficiency, the evidence presented is solid and establishes a strong foundation that will stimulate and inform future research in the field.

eLife assessment

This study presents valuable findings on the organization of respiratory chain complexes in mitochondria, but the evidence supporting the main claims is currently incomplete, as the structural reasons for and significance of supercomplex formation are unclear. The work will be of interest to the community working on mitochondrial bioenergetics.

eLife assessment

This study presents a useful set of experiments to test how a salivary protein might facilitate planthopper-transmitted rice stripe virus infection by interfering with callose deposition. If the conclusions can be confirmed, the study will enhance our understanding of the mechanisms mediating tripartite virus-insect vector-plant interactions and would be of general interest in plant science research. Whereas most experimental data is compelling, the conclusions rely on inadequate evidence for the salivary protein carbonic anhydrase being present two weeks post injection in the plant, which seems unlikely.

eLife assessment

The full role of small RNAs, often key global regulators of gene expression in connection with environmental adaptation, in flagella regulation has not been determined. This study presents important findings regarding the function of small RNAs in bacterial motility and regulation of flagella biosynthesis regulation and number. The authors combine multiple methods, including RIL-seq, structural probing, RNA blots and reporter assays, to provide convincing biochemical evidence for direct effects of specific small RNAs, whose expression is dependent on flagella sigma 28 (FliA), on transcriptional attenuation of flagella operons via regulation of ribosomal proteins.

eLife assessment

This study presents a valuable finding on the immunophenotypes of cancer treatment-related pneumonitis. The evidence supporting the claims of the authors is solid, although the inclusion of controls, as suggested by one of the reviewers, strengthened the study. The work will be of interest to cancer immunologists

eLife assessment:

This important study represents a comprehensive computational analysis of Plasmodium falciparum gene expression, with a focus on var gene expression, in parasites isolated from patients; it assesses changes that occur as the parasites adapt to short-term in vitro culture conditions. The work provides technical advances to update a previously developed computational pipeline. Although the findings of the shifts in the expression of particular var genes have theoretical or practical implications beyond a single subfield, the results are incomplete and the main claims are only partially supported.

eLife assessment

This study presents important findings regarding the quantification of dynamics in fish communities in changing ecosystems by combining a large-scale environmental DNA metabarcoding time series with novel statistical approaches. The methods are convincing, with controlled experiments, thorough statistical analyses, and a substantial dataset covering two years of detailed observation, which can provide sufficient power to detect fine-scale ecological interactions. This work is relevant for informing future research on assessing community stability under climate change.

eLife assessment

This study makes valuable observations about the representation of "value" in the mouse brain, by using a nice task design and recording from an impressive number of brain regions. The combination of state-of-the-art imaging and electrophysiology data offer solid support for the authors' conclusions. The paper will be of interest to a broad audience of neuroscientists interested in reward processing in the brain.

eLife assessment

This manuscript provides a description of an approach for efficiently integrating diverse libraries into the C. elegans genome and tools that enable researchers to use the method. It is a valuable contribution for researchers carrying out experiments that would benefit from easy generation of such libraries, and the data for the effectiveness of the method is solid. The advantages of this approach in terms of ease and effectiveness relative to others with similar aims will emerge as they are put to more general use in addressing biological problems.

eLife assessment

This study makes a fundamental observation about the role of activity in the mouse thalamus on scalp recorded voltage fluctuations. The novel approach and sophisticated analysis of neural signals provides compelling support for the authors' observations. This work will likely be of broad interest to neuroscientists.

eLife assessment

This study presents a valuable examination into the role Notch-RBP-J signaling in regulating monocyte subset homeostasis. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for exploring the mechanisms involved in RBP-J signaling in non-classical monocytes.

eLife assessment

This paper provides a useful set of data examining the role of PTPMT1, a mitochondria-based phosphatase, in mitochondrial fuel selection. The data were collected and analyzed using solid methodology and can be used as a starting point for further studies that build on the findings here.

eLife assessment

The manuscript provides valuable findings that will have practical implications for high throughput cultivation of cardiac tissues. The results demonstrate convincing evidence regarding the ability to create functional cardiac tissues and maintain them over periods of days to weeks. Improving the success rate of tissue integrity over longer periods of time, reproducing the physiological isoproterenol response and studying the impulse propagation in the tissues would garner a further broad interest for the platform.

eLife assessment

This important and compelling study investigates the problem of intracellular acidification induced by commonly-used optogenetic stimulating opsins. The low proton permeability of two high-performance opsins is shown to reduce photostimulated acidification. The findings may be of broad interest in the fields of neuroscience research and optogenetic therapies.

eLife assessment

This fundamental work provides preclinical evidence to support that natural tannins derived from grapeseed can inhibit or prevent infection by the SARS-CoV-2 viruses. The evidence provided is mostly solid to convincing and supports the conclusions. This work will be of broad interest to cell biologists and physicians.

eLife assessment

This is an important study that uncovers a new molecular pathway that links traditional monoaminergic antidepressants with regulation of glutamate neurotransmission. The data provided for the model are convincing and demonstrate the pathway in human plasma and brain, mouse brain, and cultured cells, using the relative strengths of each system. The work will be of interest to psychiatrists studying depression as well as basic neurobiologists interested in monoamine signaling in the brain.

eLife assessment

Mizukami et al. propose a scenario for the evolutionary origin of the coronary artery in amniotes by comparing the morphologies of the vasculatures across several species and developmental timepoints. They show that the coronary arteries of non-amniotes most closely resemble embryonic amniote aortic subepicardial vessels (ASVs), which are replaced by the true coronary arteries during amniote development. While the identification of common vascular structures in diverse taxa is a valuable contribution, additional developmental evidence is needed to confirm that such vessels are truly homologous.

eLife assessment

This important study uses computational simulations to explore how spatial structure can affect the coexistence between different microbial species, ultimately helping to explain diversity in microbial communities. The evidence supporting the conclusions is solid, although the parameter values used in the simulations were deemed to be unrealistic. Further investigation on whether the conclusions would hold under more realistic assumptions would be very interesting to microbial ecologists quite broadly.

eLife assessment

Understanding the heterogeneity of the B cell response induced in autoimmune individuals is important for the development of therapies designed to target the cells underlying disease progression. Here the authors use a new mouse model of autoimmunity to assess the heterogeneity of the B cell response using single-cell RNA-sequencing and BCR-sequencing and found that these B cell responses are similar to those by exogenous protein immunization.

eLife assessment

This manuscript reports important findings that help to understand the function of glutamate transporters and their effects on synaptic function at D1- and D2-MSNs within the dorsolateral striatum. These findings were evaluated to be of interest and well-executed. Overall, the majority of claims are supported by high quality data, but the evidence for some underlying mechanisms and region specificity were incomplete in the manuscript's current form.

eLife assessment

This valuable study assesses how change in reward contingency in the environment affects the dynamics of a realistic large-scale neural circuit model, human choice behavior, and fMRI responses measured in the same individuals. It is not entirely clear which predictions of the neural circuit model go beyond previous work, the current results seem incomplete and could likely be substantially strengthened. This study could be of interest to scientists studying the neural and computational bases of adaptive behaviour.

eLife assessment

Traditional approaches for the analysis of brain rhythms typically rely on measuring spectro-temporal properties of individual oscillations or the interactions between two different oscillations. This manuscript presents a novel multivariate approach that uses a state space model to simultaneously analyze the dynamics and interactions of multiple hippocampal oscillations. Such an approach represents a step forward in the field that highlights the need of taking into account the complexity of network interactions rather than trying to understand each component of the system in isolation.

eLife assessment

This work reports important findings regarding the regulation of ion channels by polyunsaturated fatty acids (PUFAs) through the identification of novel aromatic PUFA analogs with potent effects on the IKs channels, which allow for mechanistic insights into their mode of action. The experiments are solid, combining site-directed mutagenesis, electrophysiological and pharmacological approaches to dissect the different molecular mechanisms and sites involved in the functional interactions. This work will be of broad interest to ion channel biophysicists, physiologists, and medical chemists interested in drug development for LQT syndrome. The study presents some limitations that may need to be addressed or further discussed, in order to strengthen the conclusions reached in the study.

eLife assessment

This study is an important contribution to our understanding of somatic mutation mechanisms in plants, uncovering a surprising constancy in the yearly accumulation of somatic mutations regardless of the species' growth rates. The authors provide compelling evidence, leveraging rigorous sequencing analysis and innovative bioinformatic techniques, to demonstrate that many plant somatic mutations are accumulated in a replication-independent manner. This research is poised to captivate not only scholars focused on plant evolution and development, but also scientists broadly interested in mutation mechanisms in multicellular organisms.

eLife assessment

This study highlights a valuable finding that chromosomal instability can change immunes responses, in particular macrophages behaviours. The convincing results showing that the use of CD47 targeting and anti-Tyrp1 IgG can overcome changes in immune landscape in tumors and prolong survival of tumor-bearing mice. These findings reveal a new exciting dimension on how chromosomal instability can influence immune responses against tumor.

eLife assessment

This article examines the effect of indole-3-acetate dietary supplementation on a fatty liver phenotype upon exposure to a western diet. The strength of evidence is solid and the significance is useful. The results while not necessarily unique, further support the possible therapeutic value of supplementation in treating fatty liver disease.

eLife assessment

This study presents a valuable conceptual advance of how Vitamin A and its derivatives contribute to atherosclerosis. There is solid evidence invoking the contributions of specialized populations of T cells in atherosclerosis resolution, including use of multiple in vivo models to validate the functional effect. The significance of the study would be strengthened with more detailed interrogation of lesions composition and consolidation with previous work on the topic from human studies.

eLife assessment

Kim et al. investigated the molecular mechanism by which uremic toxin indoxyl sulfate induces trained immunity, resulting in augmented pro-inflammatory cytokine production. They also provided convincing evidence demonstrating that uremic sera from end-stage renal disease patients can generate trained immunity in healthy control-derived monocytes. This work is important as it introduces the new concept of trained immunity and its clinical implication.

eLife assessment

This paper covers a large range of effects of delivering SAR-CoV2 spike protein to the airway of mice with some in vitro analysis of effect on human cells. The observations will be valuable to the field in raising the possibility that the SAR-CoV2 spike protein has pro-inflammatory effects following uptake by macrophages and may lead to neutrophil recruitment and netosis, a pro-inflammatory mode of cell death. Two of the three reviewers felt the evidence was incomplete, based on what were felt to be some weak controls, but another expert felt the evidence was solid.

eLife assessment

This important study increases our understanding of the role of heterochromatin domain dynamics during early embryonic development by annotating the change in chromatin-associated proteins as a function of cell state. The authors provide solid evidence to demonstrate that DNA Topoisomerase II Binding protein (TOPBP1) is an ESC-specific chromatin-bound factor that potentially regulates chromocenter reorganization during the 2CLC-ESC transition through interaction with the SWI/SNF complex component SMARCAD1. However, a lack of mechanistic studies to interrogate how TOPBP1 and SMARCAD1 contribute to the reorganization of H3K9me3-heterochromatin or chromocenter concomitant with alterations in stem cell state leaves the current work incomplete.

eLife assessment

This study reports a new approach to determine the architecture of peptidoglycan (PG), the primary component of the bacterial cell wall, validating the pipeline through an architectural analysis of several members of the human gut microbiota. The technique is potentially valuable for this sub-field as it would enable researchers interested in peptidoglycan in a range of organisms to easily assess muropeptide composition in an easy, automated manner. However, there is some uncertainty about whether the pipeline was fully automated. Additionally, the use of the technique to support that PG cross-bridge length is a determinant of cell wall stiffness resulted in incomplete evidence that would need substantiating, more direct support.

eLife assessment

This manuscript describes mechanisms underlying the activation of the receptor tyrosine kinase FGFR1 and stimulation of intracellular signaling pathways in response to FGF4, FGF8, or FGF9 binding to the extracellular domain of FGFR1. Useful data on quantitative binding experiments are presented to demonstrate that FGF4, FGF8, and FGF9 exhibit distinct binding affinities towards FGFRs. The analysis of the data, however, is inadequate.

eLife assessment

This study presents a potentially valuable discovery which indicates that activation of the P2RX7 pathway can reduce the degree of lung fibrosis caused by other inflammatory pathways. If confirmed, the study could clarify the role of specific immune networks in the establishment and progression of lung fibrosis. However, the presented data and analyses are incomplete as they rely on limited pharmacological treatments and because there is an absence of key control studies, validation experiments and statistical analyses.

eLife assessment

This study describes a useful method to monitor the behavior of Drosophila larvae in a uniform environment over much longer time scales than was possible with previous methods. The authors provide a solid characterization of aspects of the method and show that the behavior of single larvae can be quantified over several hours. The experiments offer a proof-of-concept for a robotic device that will enable the investigation of behavior in long-term experiments in ways that were previously unimaginable.

eLife assessment

This manuscript provides a structural analysis of bushy cells in the mouse cochlear nucleus. These neurons receive a large synaptic contact from the auditory nerve termed an endbulb that preserves the temporal information present in the auditory nerve and are key elements of binaural sound localization circuits. The analysis combines volume electron microscopy techniques with computational models to predict heterogeneous bushy cell responses. The analysis takes morphological analysis of bushy cells to a new level, and the modeling is well done.

eLife assessment

This potentially important paper investigates the mechanisms that contribute to building inhibitory synapses through differential protein release from microtubules. The experiments are generally designed well, but the evidence supporting the conclusions is incomplete. This manuscript will be of interest to neuroscientists and cell biologists interested in intracellular trafficking and synapse maturation.

eLife assessment

These valuable findings presented by Wu et al. advance our understanding in novel cell signaling regulators of hepatic metabolism. The evidence supporting these conclusions are solid, utilizing in vivo and in vitro gain and loss of function studies. These work will be of interest to biologists working in the field of hepatic steatosis.

eLife assessment

The paper provides important insight into the function of FAM76B protein as a regulator of inflammation. The knockout/overexpression data are solid, however, the mechanism of regulation and the role of FAM76B in neurodegeneration is incomplete and requires additional experimentation. The work will be of interest to researchers studying inflammation, particularly neuroinflammation.

eLife assessment

This important study shows that exercise improves cerebrovascular function during aging using convincing methods, the authors show that aerobic exercise reverses aging-induced deficits in microvascular perfusion and oxygenation and potentially improves short-term memory. This work will be of broad interest to researchers and clinicians studying vascular function, age-related cognitive decline, and the effects of aerobic exercise on reversing age-related dysfunction.

eLife assessment

This valuable study identifies three independent patient mutations in MAD2L1BP (p31 comet) that cause infertility. Consistent with the known functions of p31 comet, solid experiments in mouse oocytes imply that infertility could be caused by a failure to silence the spindle assembly checkpoint, though the mechanism was not determined. Although the sample size is small, a rescue experiment in human oocytes promises the potential for therapy.

eLife assessment

This report is a useful demonstration of how to predict the mutational pathways to antimicrobial resistance (AMR) emergence, particularly in the enzyme DHFR (dihydrofolate reductase). The methodology is overall solid but some of the claims are only partially supported. The work will be of interest to microbiologists and evolutionary biologists interested in antimicrobial resistance and its population genetics dynamic.

eLife assessment

In this interesting manuscript, Pietsch et al. develop innovative machine learning approaches for automated analysis of budding yeast live-cell imaging data obtained with a dedicated microfluidic device that retains mother cells. Developing such tools is crucial to enable high-throughput image analysis. These methods will be useful for researchers studying these cells, and may also inspire similar approaches for other types of cells.

eLife assessment

Extracellular vesicles (EVs) are emerging as important mediators of cell-to-cell signaling. Lee et al show convincingly that Stranded at second (Sas), a Drosophila cell surface protein, is trafficked by and localized to Drosophila EVs. However, the data supporting interaction with dArc and whether Sas facilitates the intercellular transfer of dArc protein or mRNA is incomplete. Moreover, almost all experiments rely on gain-of-function and over-expression of Sas, thus the relevance to normal physiological signaling is unclear.

eLife assessment

This is an elegant study combining virally-delivered lineage-tracing with single cell RNA-sequencing of the developing chicken enteric nervous system, showing potentially differential contribution of cell identities from the sacral and vagal neural crest. Addressing this important issue is pivotal to understanding basic enteric nervous system development as well as to devise therapeutic approaches to enteric neuropathies. The study is therefore generally interesting and in particular to researchers in the fields of enteric neuroscience and peripheral nervous system development. Lack of a basic classification scheme of neuronal cell types in the chicken, limited computational and functional analysis on a relatively immature stage and makes the conclusions of this work preliminary in its current state.

eLife assessment

The creation of a single-cell atlas of normal and degenerative human anterior cruciate ligament (ACL) tissues using a single-cell RNA sequencing method is an important approach to understanding the pathological mechanisms of ACL degeneration. The data of this study showed the existence of fibroblasts, endothelial cells, pericytes, and immune cells in healthy ACL, and their ratios altered in the degenerative ACL, mainly exhibited as an increase in fibroblasts and immune cells. The data analysis suggests that alterations of spatial transcriptome and changes in gene expression and signaling pathways may contribute to ACL degeneration.

eLife assessment

This important study pinpoints nitrite oxide synthase 2 activity and decreased microtubule acetylation as distinct regulators of altered autophagic flux that may contribute to pathogenesis in a mouse model of Duchenne muscular dystrophy. While most of the evidence to support these claims is convincing, the claim that autophagy is improved with increased microtubule acetylation is incompletely supported. This work may be of broad interest to muscle biologists and has translational potential for the treatment of Duchenne muscular dystrophy.

eLife assessment

The authors used the Multiethnic Cohort (MEC) study to study how COVID-19 impacted access to cancer screenings and treatment. This study's important findings served to identify key factors associated with cancer-related screening and healthcare-seeking during the pandemic. This investigation provides solid evidence to inform future policies, particularly in older and vulnerable populations.

eLife assessment

This is an important study that examined multiple biological age measures in children, which has been lacking in literature. The findings of this study provided convincing evidence to interpret and understand the aging and developmental processes in children.

eLife assessment

The authors analyze changes in the gene expression of different immune cells during heart regeneration using single-cell RNA-sequencing and assess changes upon drug treatment that depletes macrophages. They find that drug treatment affects the gene expression profiles of different and abundance of immune cells. The work provides a wealth of gene expression data and a nice analysis supporting immune cell interactions during heart regeneration, so will be a useful resource.

eLife assessment

Roe et al. provide a large-sample analysis of hemispheric lateralisation in brain structure, synthesising local cortical thickness and surface area data from 7 different datasets. The study provides a rich descriptive catalogue of phenomena related to hemispheric anatomical asymmetries. These results are convincing and will prove an important point of reference to neuroscientists who might want to compare their own future results to the ones from this large and varied data set.

eLife assessment

This valuable manuscript delineates the role of YAP/TAZ-dependent transcriptional suppression in a mechanodransductive feedback loop. The evidence presented in the manuscript is generally solid. Additional validation using an in vivo system would significantly strengthen the model proposed by the authors.

eLife assessment

The study is important as the authors successfully developed a human telencephalon-eye organoid model that exhibited remarkable pathfinding and growth of retinal ganglion cell (RGC) axons. The identification of cell-surface markers for RGCs could have significant implications for understanding the molecular mechanisms involved in RGC axon development and regeneration. While the authors' data on the developmental patterning organoid model are compelling, the reviewers had significant concerns, implying that the study could still be substantially improved.

eLife assessment

This paper provides valuable new information on the mechanisms by which Vibrio cholerae integrates and responds to environmental signals. The strength of the evidence provided in support of the conclusions made and the model proposed is solid. The revision resolved many of the issues raised by the reviewers and improved the manuscript. The work is relevant for a broad audience of microbiologists interested in the mechanisms by which bacteria sense their environment.

eLife assessment

This is an important study that describes the coordinated regulation of cellular size and protein translation in response to chronic stress as an adaptive mechanism regulated by the heat shock response. The evidence supporting this conclusion is solid, utilizing diverse methods to monitor and manipulate cell size and evaluate stress resistance; however, it is currently unclear in the manuscript to what extent the effects observed are confounded by cell overcrowding. Additionally, the study could be strengthened by the inclusion of more experiments focused on defining the mechanistic basis of this coordination. This work will be of broad interest to researchers interested in diverse fields including cellular proteostasis, stress-responsive signaling, and aging and senescence.

eLife assessment

This study provides an important connection between cellular metabolism and proteostasis through MAGIC, a previously proposed protein quality control pathway for clearing cytosolic misfolded and aggregated proteins by import into mitochondria. Using a split-GFP reporter system, the authors reveal the role of Snf1, a yeast AMPK, in preventing the import of misfolded proteins to mitochondria for MAGIC, controlled by transcription factor Hap4 as a function of cellular metabolic status. The experimental evidence provided by the authors is still inadequate for explaining the regulatory mechanism of MAGIC by Snf1 or HAP4 and incomplete for explaining the cellular mechanism of substrate selection for MAGIC.

eLife assessment

This manuscript provides a useful reconstruction of the structure of the sirtuin-class histone deacetylase Sirt6 bound to a nucleosome based on cryo-EM observations, and additional characterization of the flexibility of Sirt6 based on molecular dynamics simulations. The analysis of the cryo-EM data is incomplete for some of the conclusions, and certain elements of the presentation were inadequate to allow sufficient evaluation. Biochemical validation of the conclusions is not provided, but some of this evidence has been published recently by two other groups in their analyses of the same complex. While much in this manuscript is confirmatory, the work also includes new insights into the potential dynamics of Sirt6 bound to a nucleosome.

eLife assessment

This valuable study contributes to understanding how retinal activity shapes the response properties of excitatory and inhibitory neurons in a major visual target, the superior colliculus. The evidence supporting the claim is solid: the work is technically excellent but the interpretation was limited without more detailed knowledge of cell types involved and the lack of loss or gain of function manipulations. This work will be of interest to visual neuroscientists.

eLife assessment

This study presents a novel, and potentially valuable transhumeral prosthesis control method based on artificial intelligence and virtual reality. The data were collected and analyzed using solid and validated methodology with several participants, including people with limb difference. Results are compelling and can be used as a starting point for further clinical work. Care should be taken when generalizing the results to issues not directly tested in the experiment, for example as treating phantom-limb-pain, which were not investigated in the experiments.

eLife assessment

This important study demonstrates a link between an acute high fat diet, microglial metabolism and improved higher cognitive function. The evidence supporting the proposed model is incomplete at this stage and would benefit from additional experiments probing the link between microglial metabolism and higher cognitive function. Following more mechanistic dissection, this work will be of interest to a broad audience in the field of neuroscience, metabolism, and immunology.

eLife assessment

This study presents a valuable finding that TNFAIP2 interacts with IQGAP1 and Integrin β4. Moreover, Integrin β4 activates Rac1 through TNFAIP2 and IQGAP1 and confers drug resistance in triple-negative breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer or drug resistance.

eLife assessment

The findings of this article provide valuable information on the changes of cell clusters induced by chronic periodontitis. The observation of a new fibroblast subpopulation, which was named as AG fibroblasts, was quite interesting, but needs further evidence. The strength of evidence presented is incomplete.

eLife assessment

This study by Koh et al reports an important role of key fatty-acid synthesis enzyme, acetyl-coA-carboxylase 1 (ACC1) in development and homeostasis of invariant natural killer T iNKT cells, as well as its significance in asthma etiology. The findings reveal that ACC1 induces de novo fatty acid synthesis via fatty acid- binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR)γ axis in iNKT cells, which is critical for iNKT cells survival and their pathogenic roles in allergic asthma. The data reported in the manuscript are convincing, and the work adds to our understanding of the metabolic regulation of iNKT cells.

eLife assessment

This important study uses an innovative GWAS approach and targeted testing to highlight S. aureus genes that modify susceptibility to serum, serum-derived antimicrobial products, and commonly used antibiotics. These findings are significant in that they highlight evidence of evolution of virulence determinants in the setting of exposure to host stressors expected to be present during bacteremia and antibiotic therapy. Compelling results build on a foundation of work attributing loss-of-function mutations in tcaA to glycopeptide non-susceptibility.

eLife assessment

This study is of fundamental importance, addressing the regulation of the carbon concentrating mechanism in cyanobacteria. It is a well-controlled investigation of low affinity regulatory binding of small molecules, processes that are typically difficult to examine. The work provides compelling evidence that the adenylate pool, rather than any single metabolite, regulates a key bicarbonate transporter (SbtA) to provide efficient bicarbonate supply while preventing futile cycling that can result from escape of unfixed CO2.

eLife assessment

This is a fundamental work identifying the components of the N6-methyladenosine methyltransferase complexes in yeasts and showing its major differences with the same complexes in mammals and flies. The evidence supporting the conclusions is convincing, with rigorous high-throughput sequencing approaches and detailed functional analysis. This work will be of broad interest to those in the RNA modification and meiosis fields.

eLife assessment

This is an important study that addresses the interesting question of whether stimulation of Ventral midbrain input to prefrontal cortex (PFC) during adolescence can be used to rescue genetic defects in PFC function. The conclusions are solidly supported by the data and will of interest to a broad group of neuroscientists.

eLife assessment

The authors provide an important demonstration that pharmacologically enhanced catecholamine levels and increased voluntary spatial attention have largely dissociable effects on perceptual decision making. Their findings provide solid evidence that neuromodulatory arousal and selective spatial attention shape perception in qualitatively different ways.

eLife assessment

This important study expands on current knowledge of allosteric diversity in the human kinome by C-terminal splicing variants using as a paradigm DCLK1. The authors provide solid evolutionary and some mechanistic evidence how C-terminal isoform specific variants generated by alternative splicing can regulate catalytic activity by means of coupling specific phosphorylation sites to dynamical and conformational changes controlling active site and substrate pocket occupancy, as well as protein-protein interactions. The data will be of interest to researchers in the kinase and signal transduction field.