eLife assessment

This is an important and methodologically compelling paper that reports the first application of optogenetics to inner hair cell ribbon exocytosis mechanisms in the inner ear and rapid flash-and-freeze techniques to a ribbon synapse. The conclusions of the paper are mostly well supported by the data and it will capture the interests of a broad audience of neurobiologists and sensory physiologists. Paired recordings of inner hair cells and afferents validate the optogenetic protocols of stimulation. A surprising finding is the nearly complete absence of docked vesicles at rest and after stimulation, but upon stimulation vesicles rapidly associate with the ribbon. The reviewers agreed that this is a high-quality study, but that some additional work is needed to address certain pitfalls of the methods used and to rule out alternative explanations of the data.

eLife assessment

This manuscript provides a successful model to study the ultrafast brain oscillation-mediated brain circuitry and cellular mechanisms in sensory processing. Utilizing this model, the authors studied potential cellular mechanisms that generate ultrafast oscillations (250-600Hz) in the cortex. These oscillations correlate with sensory stimulation and might be relevant for perceiving relevant sensory inputs. The data reasonably support most of the claims by the authors in this manuscript.

eLife assessment

This important paper provides a convincing mechanism for relative binding specificity of Type II inhibitors to kinases. The combination of a sequence-derived Potts-model with experimental dissociation constants and calculated free energies of binding to the DFG-out state is highly compelling and goes beyond the current state of the art. Given the importance of kinases in pathophysiological processes, the results will be of interest to a broad audience and, in addition, the combination of computational methods can be applicable to a wide variety of other biophysical processes that involve conformational rearrangements.

eLife assessment

This paper reports a useful set of results that uses a reduced network model based on a previously published large-scale network model to explain the generation of theta-gamma rhythms in the hippocampus. Combining the detailed and reduced models and comparing their results is a powerful approach. However, the evidence for the main claim that CCK+ basket cells play a key role in theta-gamma coupling in the hippocampus is currently incomplete.

eLife assessment

Powers and colleagues reveal that commonly used "genetic markers" (selectable cassettes that allow for genome modification) may lead to unintended consequences and unanticipated phenotypes. These consequences arise from cryptic expression directed from within the cassettes into adjacent genomic regions. In this work, they identify a particularly strong example of marker interference with a neighboring gene's expression and develop and test next-generation tools that circumvent the problem. The work will be primarily of interest to yeast biologists using these types of tools and interpreting these types of data.

eLife assessment

This manuscript provides compelling evidence that in response to calcium, the C-lobe of calmodulin changes its interaction with the C-terminal domain of an SK2 small-conductance calcium-activated potassium channel. These findings will be of interest to those in the field of ion channels and calcium signaling as they are valuable to understanding the molecular mechanics by which calcium activates SK2 channels, which are important for a wide variety of physiological signaling processes.

eLife assessment

This is an extremely thorough investigation of the role of cadherins in generating a functional motor circuit. The presented data support a model whereby combinations of redundant adhesion molecules create a code to wire the breathing circuit. This study advances understanding of the molecular basis of circuit wiring in the brain.

eLife assessment

This study models the predictions a listener makes in music in two ways: how different model algorithms compare in their performance at predicting the upcoming notes in a melody, and how well they predict listeners' brain responses to these notes. The study will be valuable to the field as it implements three contemporary models of music prediction. In a set of solid analyses, the authors find that musical melodies are best predicted by models taking into account long-term experience of musical melodies, whereas brain responses are best predicted by applying these models to only a few most recent notes.

eLife assessment

This fundamental study employs a publicly available dataset to examine the role of gamma oscillations in the coding of olfactory information in the mouse piriform cortex. The authors convincingly show that gamma originates in the piriform cortex, is driven by feedback inhibition, and that the time course of odour decoding is most accurate when gamma oscillations are strongest. This work is relevant to a wide audience interested in the mechanisms and role of oscillations in the brain, and nicely demonstrates the benefits of well-curated, publicly available datasets.

eLife assessment

This work would be of interest to global health scientists, particularly in low- and middle-income countries where childhood stunting is an ongoing challenge, and to statisticians interested in building clinical prediction rules. The authors leveraged large, rich datasets from multi-center studies to build and validate predictive models. But by using change in growth, rather than absolute growth, as the only outcome, it may be missing children of concern who are already experiencing growth failure and require intervention but have reached a growth faltering floor.

eLife assessment

This is a very interesting manuscript that will be of interest to the field of stress neurobiology and neuropsychiatry. Claims about the interactions between stress and medial prefrontal cortex NPAS4 on anhedonia and motivation remain to be firmly established, yet clear evidence is provided for NPAS4 function on medial prefrontal cortex pyramidal neuron dendritic morphology and gene expression.

eLife assessment

This valuable work, of interest to ion channel physiologists, identifies regions involved in the desensitization of the proton-activated chloride channel (PAC), a widely expressed ion channel involved in organelle pH homeostasis and acid-induced cell death. At the present stage the data only incompletely support the interpretations, and further experiments will be required to consolidate some of the authors' claims.

eLife assessment

This manuscript follows the still unanswered concept of 'original antigenic sin' and shows the existence of a 24-year periodicity of the immune response against influenza H3N2. The valuable work suggests a long-term periodicity of individual antibody response to influenza A (H3N2) within a city. But, to substantiate their argument, the authors would need to to provide additional supporting data.

eLife assessment

This paper provides valuable new insight into the neural encoding and behavioral tracking of visual objects in the Drosophila. It provides solid evidence that a specific type of neuron in the fly visual system (T3 neuron) is involved in the tracking of moving objects during flight. With additional experimental evidence to resolve whether T3 neurons function as local object detectors, this paper would be of broad interest to visual neuroscientists.

eLife assessment

This work presents a framework for estimating missing data on cervical cancer epidemiology. If properly validated, it could help determine missing data in regions where data are scarce. The work will be of broad interest to researchers and policymakers evaluating cervical cancer prevention measures.

eLife assessment

Masschelin et al. investigate the role of Vitamin B2 (riboflavin), an essential cofactor for FAD and FMN coenzymes involved in the electron transport chain and TCA cycle, in fasting glucose metabolism. This study phenotypes B2-deficient mice liver and provides valuable data on genes and metabolites that are changed with B2 depletion +/- Fenofibrate administration. The work employs solid methodology and will be of interest to liver physiologists interested in fasting in the context of PPAR.

eLife assessment

This manuscript will be of interest to a wide range of neuroscientists and clinicians employing imaging methods. Using a combination of cutting edge high resolution magnetic resonance protocols, the authors investigate the structure-function relationship of specialised compartments in the human cortex in vivo. Their results indicate different patterns of myelination across the "stripes" of visual area V2, but will require further independent validation with myelin staining in the human brain.

eLife assessment

This manuscript reports the response by cortical interneurons from mice expressing genetically defined fluorescent markers to sensory stimulation performed in awake animals without anesthesia. The data show in some cases distinct responses in specific neuron types. This manuscript contains unique information that will be valuable to other researchers in the field and influence future research in the field of cortical GABAergic neurons.

eLife assessment

Combining electrophysiology, site-directed mutagenesis, lipid pharmacology, and single particle cryo-electron microscopy, this study provides solid evidence identifying a site on the extracellular half of the transmembrane domain of Proton-Activated Chloride (PAC) channels that could be occupied by PIP2 and related lipids to promote channel desensitization. These findings are important because pharmacological information for these biologically relevant ion channels is absent.

eLife assessment

Myostatin KO is known to increase muscle mass, but can transplanting the gut microbiome from these animals also increase muscle mass and strength? Based on the experiments performed in this paper, the answer is yes, and the positive impact of myostatin deletion on the gut-muscle axis may proceed through alteration of gut bacterial metabolism, including short-chain fatty acids. This is important work and will contribute to the expanding field of the gut-muscle axis.

eLife assessment

This paper is an important contribution to the biological aging field using eye image data to create an aging clock of the retina in data from eyePACS with validation in the UK Biobank. The authors provide compelling evidence that the clock correlates with chronological and phenotypic age, predicting mortality independently of chronological age. The work identifies novel genetic loci with a top site located in the ALKAL2 region, which is functionally validated in a Drosophila model.

eLife assessment

The study by Ben Yaakov et al. describes a single cell analysis of the mammalian ovary in young, adult and old mice. Based on gene expression profiles, the authors identified cell clusters corresponding to immune cell populations in mouse ovaries and compared their abundance in aged compared to adult animals. In comparison with previous studies that used single cell RNAseq to characterize the heterogeneity of cell types in the ovary, this study focuses only on immune cells resulting in much better coverage to characterize the changes that these cells undergo as a function of age. The combination of single-cell RNA sequencing and flow cytometry used by the authors is a robust and unbiased approach to characterize immune cell alterations in aging ovaries. Overall, the data and analyses presented in this study reveal profound modifications of the immune system in the aging reproductive system in mice. However, while both the data and biology presented are quite interesting, this study is perhaps too wide in breadth such that no individual result is extensively and rigorously explored.

eLife assessment

Single-particle tomography (SPT) is a useful method to determine the structure of proteins imaged in situ. This important work presents an easy-to-use tool for SPT that approximates the use of 2D tomographic projections using a "pseudo-subtomogram" data structure, chosen to facilitate implementation within the existing Relion codebase. The examples shown provide solid support for the claims about the efficacy of the approach.

eLife assessment

The authors address an important clinical entity and an important area of unmet clinical need. The authors use a combination of in vitro and in vivo experiments to learn how stromal cells surrounding vessels in venous malformations (VM) and angiomatosis of soft tissue (AST) contribute to the angiogenic activities driving the vascular lesions. They discovered that secretion of transforming growth factor-alpha (TGFa) from both endothelial cells and stromal cells, shows evidence for EGF-receptor phosphorylation. In addition, they show that afatinib, a pan-ErbB TKI inhibitor may have therapeutic benefits.

eLife assessment

This solid study addresses the functionality of neurovascular coupling in response to somatosensory stimuli in premature neonates based on a compelling methodology combining recordings with fMRI and EEG (microstates approach). While the findings are important for the understanding of the emergence of brain sensory processing, more extended analyses of inter- and intra-subjects' variability are required to support the results interpretation and determine the influence of important factors impacting brain maturation and activity. With the theoretical and analytical parts strengthened, this study will be of interest to developmental neuroscientists and neuroimaging specialists and might have important clinical implications in the field of neonatology.

eLife assessment

The goal of this study is to identify allosteric modulators of a SLC-1 amino acid transporter, ASCT2, which has been implicated in cancer progression. By combining computational and docking methods with functional measurements, this study provides solid evidence for specific aspects of allosteric SLC-1 inhibition mechanisms. The findings are important to transporter mechanism and pharmacology.

eLife assessment

This is an important paper that evaluates the roles of long descending propriospinal neurons in the recovery of walking ability after spinal cord injury. The data are convincing overall though some weaknesses in the evaluation of the completeness of the synaptic silencing strategy were identified. The data will be of interest to those who study spinal circuitry and its role in locomotor function after spinal cord injury.

eLife assessment

This fundamental study represents a significant advance in our understanding of the complex evolutionary history of the eggshell features in one of the main leaving bird lineages, Palaeognathae, with compelling and thoughtfully presented results. The work will be of interest to many biologists, paleontologists, and archaeologists.

eLife assessment

This important study combines rigorous behavior and single-unit recordings in nonhuman primates to investigate the role of three cortical areas in cross-modal sensory calibration, a form of neural plasticity that is important for perception and learning. The results convincingly demonstrate key similarities and striking differences across the three areas, and provide the first evidence for this form of calibration (in correspondence with behavior) at the level of single neurons. The work will be of broad interest to neuroscientists and psychologists studying multisensory perception, plasticity, and the role of sensory and association cortices in perceptual decisions.

eLife assessment

Hudson and colleagues provide a new link between oxygen sensing and cholesterol synthesis. In previous studies, this group had shown that the cholesterol synthetic enzyme squalene monooxygenase (SM) is subjected to partial proteasomal degradation, which leads to the production of a truncated, constitutively active enzyme. Here, the authors provide evidence for the physiological significance of SM truncation by showing that subjecting cells to hypoxia (oxygen deprivation) induces truncation of SM. The synthesis of cholesterol requires 11 molecules of oxygen and SM is the first oxygen-dependent enzyme in the cholesterol-committed branch of the pathway. It is possible that constitutive activation of SM under oxygen-deficient conditions could reduce the toxicity of squalene and other sterol intermediates.

eLife assessment

This valuable study examines a largely ignored brain structure (the thalamus) in functional brain imaging studies. In general, the study shows convincing evidence from the reanalysis of two task-based MRI studies that localized thalamic regions show hub properties in terms of their activation properties and connectivity to cortical regions. While the strength of the study is that converging evidence was shown across two large data sets, the empirical support for some of the claims in the current version remains incomplete.

eLife assessment

This is a fundamental study that demonstrates that ongoing neuronal activity plays a key role in the vulnerability of specific neuronal cell types in layer 2 of the entorhinal cortex that communicates with the hippocampus. The authors provide compelling evidence that chronic silencing of inhibitory but not excitatory neurons in the entorhinal cortex leads to their degeneration. Reelin-positive interneurons were the most vulnerable to silencing. The authors propose that developmental mechanisms associated with activity-dependent programmed cell death could be aberrantly reactivated in the context of Alzheimer's disease.

eLife assessment

This manuscript is of primary interest to immunologists with a focus on the effects of interleukin-2 and T cell receptor (TCR) signaling on effector T cell differentiation and function. Extensive and well-controlled experiments support a model where TCR and interleukin-2 signals promote a specific subset of effector CD8+ T cells - termed KILR cells - with superior target cell killing properties.

eLife assessment

This valuable study presents a new optimal control cost framework to predict features of walking bouts, adding a cost function term proportional to the duration of the walking bout in addition to the conventional energetic term. While predicted optimal trajectories from simulations qualitatively matched walking data from human subjects, the evidence supporting these claims is incomplete, as some methodological choices raise questions about the strength of the authors' claims.

eLife assessment

This is an important paper that proposes a novel evolutionary mechanism by which copy-number mutations can slow down the accumulation of point mutations in populations evolving in certain environments. The authors use an evolution experiment in bacteria equipped with a clever reporter system to provide solid evidence that this mechanism indeed operates. This paper will be of broad interest to readers in evolutionary biology and related fields.

eLife assessment

The C-type lectin receptor family recognise pathogens and self-components. Dectin-1 is known to recognize glucan on pathogens. In this fundamental study Dectin-1 and CLEC-2 another - C-type lectin receptor, expressed on platelets - interact through an O-glycosylated ligand presented in the stalk region of Dectin-1. This compelling study demonstrates a potential role for pattern recognition receptors in physiological processes.

eLife assessment

This study is of relevance to the field of collective animal behavior. The proposed crop-cue-based motion-switching rules provide a welcome alternative to other models that assume far more deliberative abilities of ants, and it will be valuable to add this example to the collective motion and collective decision-making literature. There were several major issues that need addressing, including: overly simplistic models, no connection to similar phenomena in motion ecology and statistical mechanics, potential deficiences in the stochastic modeling approach, as well as some confusing terms and curious citations of the literature.

eLife assessment

This paper presents findings from a novel experimental study of the dynamics of human overground running on naturalistically uneven terrain. The terrain used in the experiments has mildly stochastic undulating roughness, a condition that closely resembles many natural terrain conditions, such as trail running. The authors present evidence that humans use open-loop intrinsically stable strategies to run on this terrain, and do not visually guided foot placement. The findings make an important contribution toward understanding the context-dependent role of vision in navigating uneven terrain.

eLife assessment

This paper addresses the long-standing problem of color categorization and the forces that bring it about, which can be potentially interesting to researchers in cognition, visual neuroscience, society, and culture. In particular, the authors show that as a "model organism", a Convolutional Neural Network (CNN) trained with the human-labelled image dataset ImageNet for object recognition can represent color categories. The finding reveals important features of deep neural networks in color processing and can also guide future theoretical and empirical work in high-level color vision.

eLife assessment

The authors collected and analyzed blood samples from >9,000 participants from two cross-sectional cohort studies in the UK, the ALSPAC cohort and the TwinsUK cohort. They measured anti-Nucleocapsid and anti-Spike antibodies using the collected blood samples. They investigated the variation in antibody levels and risk factors for lower antibody levels following each round of SARS-CoV-2 vaccination. They identify that following the third vaccination, risk factors associated with low antibody response after the first vaccination are less likely to lead to sub-protective levels. While this finding is of potential importance, the presentation of the data is diffuse and not focused at times, and more discussion is needed to highlight its relevance to the current stage of the pandemic.

eLife assessment

This paper reports a fundamental set of new results describing replisome organization and dynamics in E. coli. Cellular sites of active DNA replication (forks) spatially co-localize into structures termed replication factories, but the biological rationale for this fork co-localization has remained unknown. In an elegant study, the authors provide strong evidence that these factories are necessary to both coordinate and promote the progression of colocalized forks, and to help prevent them from spontaneously and prematurely dissociating. Through these findings, it is shown, for the first time, that replisomes' association has a beneficial impact on the bacterium. This is important work that provides robust data in favor of the factory and splitting model.

eLife assessment

This valuable study combines phenotypic analysis, quantitative genetics and population genomics to propose that multiple genes underlie adaptive divergence in a marine midge system linked to tidal rhythm. Genes with a plausible role in perceiving and responding to lunar information are among the loci that most highly differentiate populations with distinct behaviors, but how much of this might be due to demography remains unclear. The evidence from quantitative trait locus is also deemed incomplete at this point.

eLife assessment

This manuscript is of interest to scientists studying the genetics of complex human diseases. The approach introduced here is potentially useful for the identification of tissues linked to complex disease heritability. Currently, the key claims of the paper are not entirely supported by the data. The claims may become well supported once the authors improve statistical rigor and perform a more comprehensive comparison with other methods.

eLife assessment

This manuscript provides valuable evidence for the role of magnesium homeostasis and relevant signaling pathway in Drosophila sleep regulation. It will be of interest to cellular biologists and neuroscientists interested in sleep:wake behavior and the potential role of magnesium in promoting sleep. Nevertheless, the evidence for the key claims of the manuscript is incomplete and is not fully supported by the data as reasonable alternative explanations exist.

eLife assessment

Tran-Van-Minh et al., attempt to develop a statistical approach which will allow consolidation of new, as well as previously-acquired datasets, to yield biologically significant insights into the logic underlying rabies vectors' expansion from single starter cells. While such work is called for, many of the premises presented here will need to be significantly adjusted, before the approach could be put into widespread use.

eLife assessment

This study presents an important finding on the decoy effect in multiattribute economic choices in humans. It makes a compelling case for the conclusion that the distractor effect reported in previous articles was confounded with the additive utility difference between the available alternatives. Though the contribution is somewhat narrowly focused with respect to the phenomenon that it addresses - the distractor effect in risky choice, it is important for understanding this particular phenomenon. The main weakness is the complexity of the current manuscript.

eLife assessment

This manuscript provides the first cellular analysis of how neuronal activity in axons (in this case the optic nerve) regulates the diameter of nearby blood vessels and hence the energy supply to neuronal axons and their associated cells. This is an important subject because, in a variety of neurological disorders, there is damage to the white matter that may result from a lack of sufficient energy supply. This paper will stimulate work on this important subject.

eLife assessment

This is an important study linking metabolic traits and head and neck cancer risk using Mendelian randomisation. The findings, well supported by the data, were inconclusive. This work will be of interest to researchers working in head and neck cancer.

eLife assessment

This study provides compelling structural evidence on regulation of cerebellar synapses by sleep-wake states. The authors used serial block face scanning electron microscopy to obtain 3D reconstruction of more than 7,000 spines and their parallel fiber synapses in the mouse posterior vermis. The analysis shows that sleep increases the fraction of the 'naked' spines that don't carry a presynaptic partner at Purkinje cells. The authors propose that sleep promotes the pruning of branched synapses to single spines. This is an elegant and thorough study and the observations are important in light of the circuit-specific mechanisms by which sleep modulate synaptic structure and function.

eLife assessment

This important study describes transcriptomic profiles of sensory and non-sensory cells of the zebrafish inner ear at single-cell resolution in embryonic through adult stages. These solid results catalogue transcriptomic data and show evidence that distinct cell subtypes exist between cells of the ear and the lateral line as well as within subcellular compartments in the inner ear. These findings provide information toward comparison studies of inner ear hair cell function in zebrafish and mammals.

eLife assessment

This study refuted earlier work on the same subject. The two reviewers felt the manuscript was accurate, concise, and unbiased. The experimental evidence were thorough and supported the conclusions. The reviewers concurred the overall significance and quality of the experimental research were compelling and addressed previous work on this problem.

eLife assessment

This work reveals that lymphatic vascular development can occur independent of VegfC signaling, and that genetic interactions between a large extracellular matrix protein Svep1 and Tie1 receptor are important for the development of facial lymphatics and other aspects of lymphatic vascular development. The data link Svep1 to Tie1 signaling via elegant genetic experiments and provide important insights into a complex signaling pathway that is widely utilized in vascular development. The genetic evidence is convincing in supporting the findings that Tie1 but not Tie2 interacts with Svep1 in aspects of lymphangiogenesis.

eLife assessment

This paper is of interest to scientists within the field of RNA silencing and evolution. The data analysis is rigorous, and the conclusions are justified by the data. The key claims of the manuscript provide a compelling approach to identifying and annotating microRNAs in fungi although there is a limitation in the functional validation of the identified miRNAs.

eLife assessment

The study, using cryo-electron tomography represents a valuable study to the research community, to raise awareness that in vitro-assembled microtubules have more lattice defects than microtubules assembled in cell extracts. However the evidence supporting the claims was incomplete in places and there was not enough data. It is not clear how generalizable these findings are regarding tubulin assembly into microtubules.

eLife assessment

This valuable study provides solid evidence for a new intervention, exposure to male vs. female olfactory cues, with an impact on female mouse lifespan. This is interesting to the field of aging research, especially since most described pro-longevity interventions to date tend to work better in male mice. Although the data broadly support the claims, additional analyses showing all probed phenotypes are needed to support all claims.

eLife assessment

Malis et al present a novel sequence attempting to non-invasively measure the outflow of cerebrospinal fluid, which is potentially an important contribution given the growing interest in the glymphatic system. Their reported findings are generally consistent with previous literature and prevailing theories, however, no robust validation of the sequence is supplied rendering the evidence base incomplete.

eLife assessment

This study represents an important contribution to our understanding of SARS-CoV-2 transmission dynamics in France, Europe and globally during the early pandemic in 2020. Through evaluation of the contributions of intra- and inter-regional transmission at global, continental, and domestic levels, the authors explore how international travel restrictions reduced inter-regional transmission while permitting increased transmission intra-regionally. Unfortunately, at this time this work suffers from a number of serious analytical shortcomings, all of which can be overcome with major revisions and re-analysis.

eLife assessment

The article is of importance to the field of glomerular diseases and rare diseases. The authors propose a link between the inhibition of SGLT2 and lipotoxicity-mediated renal injury in experimental Alport syndrome (AS) by modulation pathways linked to CKD progression, possibly through metabolic adaption in podocytes. Although there is scientific merit in the work presented, the functional analyses are incomplete to support the claim that effects pharmacological effects are mediated through podocytes in Alport Syndrome.

eLife assessment

This paper is of interest to scientists within the cilia and centrosome fields, in particular those studying photoreceptor and sperm development and the diseases associated with their dysfunction. The authors describe the generation and characteristics of Cep78 knockout mice. Consistent with the phenotype observed in patients carrying mutations in CEP78, Cep78 knockout mice show degeneration in photoreceptor cells as well as male infertility associated with multiple morphological abnormalities of the sperm flagella (MMAF). The phenotypic characterisation of Cep78 knockout mice is thorough and convincing, and the Cep78 knockout model will be useful for further elucidating disease mechanism in humans and for potential therapy development. The authors also provide results suggesting that CEP78 directly interacts with IFT20 and TTC21A (IFT139) to form a trimeric complex, but this claim is not justified by the data provided.

eLife assessment

This boundary-crossing work on dandelion diaspore flight is an excellent demonstration of how to address fundamental questions about wind dispersal of plant seeds from biophysical and ecological perspectives. Both wind-tunnel experiments and models provide compelling evidence that the aerodynamics of dandelion diaspores change with the environment. Addition of local climate data enables the authors to make a convincing case about how the biophysical properties can scale up to affect dispersal across the landscape under different environmental conditions. In addition to the strong data, this is a clear, accessible, and very enjoyable read.

eLife assessment

This important paper describes the connectivity of V2a/V2b sibling neurons in the zebrafish spinal cord, where one sibling receives Notch signaling (Notch-ON) and the other does not (Notch-OFF). They find that V2a and V2b siblings have different morphology, inputs, outputs, and are not synaptically connected, unlike findings in the mouse cortex. This work provides new insight into the role of lineage in specifying neuronal connectivity; the experiments are convincing and the conclusions are supported by the data presented.

eLife assessment

This study revealed the biogenesis of the 3'UTR-derived sRNA GlnZ by RNase E-mediated processing and identified target mRNAs in both E. coli and S. enterica. By introducing point mutations within the predicted seed region of GlnZ and analyzing compensatory mutations in the target mRNAs, the sRNA binding site in those targets could convincingly be mapped. This is an important piece of work and the findings are relevant for researchers within the microbiology and RNA communities and should inspire future studies of 3'derived sRNAs in bacteria. Overall, most of the statements are sufficiently supported by experimental data, but certain amendments to the work are required to fully support the conclusions.

eLife assessment

This is a valuable study characterizing seasonal deviations in indoor activity at the county level in the United States with relevance to respiratory disease transmission. Whereas the data are compelling, some of the main claims are only partially supported and need more work. This study and its results are of potential interest to those people constructing more evidence-based infectious disease transmission models.

eLife assessment

The aims and hypothesis of the study, which addresses the genetic basis of an iconic example of developmental plasticity, are clear, and the experiments are well conducted. The authors propose that a novel gene that arose through gene duplication, REPTOR2, stimulates autophagy to generate wingless aphid morphs. The implication of a novel gene in wing autophagy for the generation of wingless aphids is novel and interesting, but the link between TOR and REPTOR2 requires further support.

eLife assessment

The authors measure the work output of shrinking mammalian microtubules, reporting results of fundamental importance that advance our mechanistic understanding of how shrinking microtubules exert forces on chromosomes during cell division. Carefully performed, technically advanced experiments and model-based quantitative data analysis provide compelling evidence for the authors' conclusions. This work will be of interest for cell biologists interested in cell division, biophysicists interested in force production by biopolymers, and structural biologists interested in microtubule dynamics.

eLife assessment

This paper will be of importance to visual neuroscientists, in particular those interested in the functional organization of subcortical visual pathways. The work provides evidence for a much greater diversity of functional cell types in the mouse superior colliculus than previously suggested, and that the functional organization of cell types in the superior colliculus is distinct from that of the retina. These results are based on an impressive data set. However, the conclusions require additional support.

eLife assessment

The work describes the generation of novel reagents, nanobodies, which are single molecule antibodies from alpacas, which the authors raised against specific domains of two giant fly muscle proteins called Sallimus and Projectin. These nanobodies, combined with the so-called DNA-Paint approach, enabled the authors to reach an unprecedented spatial resolution and define the position of those domains. Thereby, the authors could propose a model for the organization and extent of those proteins along muscle sarcomeres.

eLife assessment

This is a well-designed study to show how phosphorylation of the intrinsically disordered regions can control their ability to undergo liquid-liquid phase separation and thus impact protein function. The authors report how regulation of the F-BAR-containing protein Cdc15 via phosphorylation impacts its ability to phase separate and promote cytokinesis. This paper is of interest to not just the field of cytokinesis, but also to the general field of protein chemistry which is interested in how phase separation controls protein function.

eLife assessment

This paper posits that higher uncertainty environments should lead to more reliance on episodic memory, finding compelling evidence for this idea across several analysis approaches and across two independent samples. This is an important paper that will be of interest to a broad group of learning, memory, and decision-making researchers.

Evaluation Summary:

Cancers have frequently been found to show little evidence for purifying selection in their patterns of mutations. The key observation here is that tumors with low mutation burden show compelling evidence of efficient selection, but that tumors with high mutation burden do not. This is an important finding. The broader implication is that high mutation load tumors carry a substantial deleterious mutation load and may use common strategies to tolerate them, possibly providing a therapeutic target. Overall this work makes important observational and conceptual contributions to cancer genomics.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

eLife assessment

The authors use an elegant design to tackle a longstanding question about the extent to which learning social information relies on specialized computational and neural mechanism. They find that learning about ostensible others is more accurate than learning about non-social objects, despite identical statistical information, and that such effects are mediated by the dmPFC and pTPJ - regions previously implicated in social cognition. While likely of interest to a broad range of social, behavioral, and cognitive neuroscientists, the work is not sufficiently framed by relevant previous research. Moreover, the difference between social (faces) and non-social (fruits) stimuli raises concerns about attentional confounds.

eLife assessment

The authors have used state of the art tools to discover and visualize the role of a known ER-localized lipid hydrolase/acyl transferase (which they call Aphyd) in creating lipids that facilitate the localization of proteins required for mitochondrial fission and fusion at nodal points of interaction between the ER and mitochondria. The data are clear, quantitative and compelling in respect to the role of this protein in the processes of mitochondrial constriction, fission and fusion.

eLife assessment

Malaria is still one of the world's most deadly diseases because our bodies cannot make appropriate acquired immunity upon Plasmodium infection (the causative agent of malaria). By using animal models of malaria infection and vaccination, this important work shows that Dendritic cells (DCs) have a lower ability to uptake Plasmodium-infected RBCs (particle antigen). This DC dysfunction could be an important reason behind T cell dysfunction in Plasmodium infection. The data presented here convincingly supports the conclusions.

eLife assessment

Najar et al., present a method for the identification of the emergence of new variants prior to the accompanying surge in cases by examining the trend of accumulated non-synonymous mutations from the original Wuhan 2020 SARS-CoV-2 strain. This is an interesting idea but requires additional evidence to establish this as a robust tool for predictions.

eLife assessment

This interesting manuscript assesses calcium dynamics in the kisspeptin neurons of the arcuate nucleus of the hypothalamus during the estrous cycle and during reproductive aging in female mice. In particular, the authors succeed in tracking arcuate kisspeptin calcium activity in the same mice over 10 months, which is quite impressive and provides novel findings that will be of interest to the field.

eLife assessment

This study makes an important contribution to the function of the iron transporter Ferroportin (Fpn). By using a combination of proteoliposome assays, mutagenesis and structural studies by cryo EM, the authors are able to demonstrate that the H+-driven transporter for Fe2+-efflux is also capable of passive Ca2+ influx. The evidence supporting the conclusions is convincing, but the rate of Ca2+ influx and the physiological relevance of Ca2+ entry is yet to be established. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This study provides convincing evidence supporting the important finding that acoustic and linguistic features contribute to brain responses as people listen to speech. However, the innovation of the methodological advance relative to other papers in the subfield is not entirely clear.

eLife assessment

This is a valuable study of Arabidopsis shoot apical meristem maintenance and organ initiation, defining the expression, interactions and functions of four transcription factors (SHR, SCR, JKD, and SCL23) whose roles were initially described in the root apical meristem. The imaging, genetics and FRET-FLIM evidence supporting the claims of the authors is comprehensive, extensive, and solid, although similar mechanisms, protein interactions, and gene regulatory interactions were previously reported in the root. The work will be of interest and importance for plant developmental biologists.

eLife assessment

This paper will be of interest to researchers in the field of genomic medicine and cancer mutagenesis. It presents predictive models with potential clinical applications that can identify patients with specific gene dysfunction based on characteristic patterns of mutation. The key findings are well supported.

eLife assessment

The authors convincingly demonstrate that, in the absence of any shutdowns, the Danish colorectal cancer screening program experienced only minor decreases in program participation during the COVID-19 pandemic period. This likely ensured ongoing program effectiveness in detecting early colorectal cancers and precancerous polyps. The evidence is solid, as the national screening database was used and only a small proportion of participants were excluded.

eLife assessment

This fundamental work substantially advances our understanding of the kidney interstitium and how it influences kidney development focusing on zebrafish as a model organism. The evidence supporting the conclusions is compelling, using single-cell analysis combined with in vivo zebrafish studies to mechanistically explore the functional importance of the discovery. The work will be of broad interest to cell and developmental biologists as well as the kidney community.

eLife assessment

Tan and colleagues studied synaptic transmission, presynaptic protein levels, and synaptic ultra-structure in hippocampal cultures of mice lacking the key active-zone proteins RIM (1, 2), ELKS (1, 2), and Munc13 (1, 2). Compared to cultures lacking only RIM and ELKS, additional deletion of Munc13 results in a further decrease of synaptic Munc13-1 levels, a similar reduction of the number of docked synaptic vesicles, and a more pronounced decrease of total synaptic vesicle number. At the physiological level, these RIM-ELKS-Munc13 hextuple knockout cultures display a further decrease in the pool of release-ready synaptic vesicles with largely unchanged release probability compared with RIM-ELKS quadruple KO cultures. The results support the conclusion of the nonredundant role of Munc13 in synaptic vesicle priming. On the other hand, while the genetic removal of all six genes involved clearly require the use of conditional KO mice, the resulting outcome of the experimental design is a hypomorphic phenotype, as neurotransmitter release is still detected and this complicates the interpretation of the findings. Overall, this study reinforces the notion that synapse formation is a remarkably resilient process that occurs even under strong perturbation of presynaptic function.

eLife assessment

Overall, this is an interesting paper that explains molecular underpinnings of hair cell reprogramming. This paper could have significant implications for our understanding of how different cellular programs can dictate phenotypic outcomes such as hearing.

eLife assessment

Chemical fixation of cells is ubiquitous in microscopy. However, fixation artifacts can lead the incorrect interpretations of biological processes. In here, Irgen-Gioro et al. show that in the context of liquid condensates formed by liquid-liquid phase separation (LLPS), paraformaldehyde (PFA) fixation can lead to artifacts such as changes in the number, appearance, or disappearance of liquid condensates, when comparing fixed to live cells. This will be of great interest not only for those in the LLPS field but for cell biologists, in general, using fixed samples for microscopy.

eLife assessment

This manuscript makes a major contribution to the study of early visual representation in primates by showing that intermediate cortical areas V2 and V4, as well as primary cortical area V1 (previously shown), contain orthogonal maps of orientation and spatial frequency, which are recursive across the visual field representation. This is a fundamental principle of functional mapping across the two-dimensional cortical surface that ensures and optimizes the complete representation of all combinations across two coding dimensions.

eLife assessment

Auwerx and colleagues take a new approach to mine large datasets of the intermediary molecular data between GWAS and phenotype, touncover molecular mechanisms that lead from a GWAS hit to a phenotypic effect. The approach should be of great use to all (human) geneticists. Revisions are necessary to ensure that the significant findings from this approach are understood by the bioinformatic community and that these methods can be applied generally, given that the paper's main novelty is in its approach to mine large datasets, rather than a specific, key molecular finding.

eLife assessment

In this study, the authors performed mass cytometry (CyTOF) analysis and T cell receptor (TCR) sequencing to study immune cell composition and expansion of joint-derived Tregs and non-Tregs in Juvenile Idiopathic Arthritis (JIA). They studied different joints affected at the same time and found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient. The research design of this study is appropriate and the methods used in this study are adequately described in the manuscript. The study may be potentially beneficial for the JIA treatment.

eLife assessment

This article establishes a model experimental bacterial community to represent the microbiome found in ~1/3 of patients with cystic fibrosis (CF) with the goal of understanding why these infections do not respond to treatments that are effective in single-species infections. The authors show that susceptibility to the most common antibiotic used against the dominant pathogen P. aeruginosa is different when grown in this mixed community, and a mutant of this pathogen (lasR) that frequently occurs during infections alters this sensitivity. This study is significant for producing an experimental resource for the microbiology of CF, and it could be strengthened by more detailed measures of interactions between species and how the phenotypes produced by lasR alter species interactions.

eLife assessment

This competently performed retrospective analysis presents important findings concerning the clinical use of tafenoquine, a drug against Plasmodium vivax malaria. The assembly of the majority of global tafenoquine pharmacology data from clinical treatment studies provides compelling evidence in support of the drug's regimen that includes an increase in dosing, which would lead to a significant enhancement of the drug efficacy, hence a decrease in recurrent parasitemia. The manuscript could benefit from a more detailed analysis and discussion concerning the side effects of the drug affecting more susceptible populations.

eLife Assessment

The paper pushes the known preservation of ancient proteins, and their successful recovery, into the late Miocene. The results of the study also have implications for avian taxonomic classification. The findings reported in the paper are a welcome addition to the field of paleoproteomics and encourage future research on ancient proteins in deep antiquity and across various taxa. The paper will be of great interest to paleoscientists.

eLife assessment

This paper deploys elegant genetic tools to understand how synapses are formed in the Drosophila central nervous system. The synaptic connections between two identified neurons in the Drosophila central nervous system are used as a system to document the role of cell ablation and activity in dendrite growth and circuit wiring. In so doing, they identify a brief window of time that appears critical for these wiring and growth decisions.

eLife assessment

This article shows how the COVID-19 pandemic affected cervical cancer screening participation in the organized screening program of Denmark. Through registry data covering the entire population, the study shows that while short-term (90 days) participation after invitation dropped, long-term (365 days) participation remained stable. These results will be of interest to public health specialists and researchers working on pandemic recovery efforts related to cancer screening worldwide.

eLife assessment

Acute inflammation in mammals activates the hypothalamic pituatary axis leading to increased glucocorticoid release, which is required to restrain the inflammatory response. However, in settings of severe or prolonged inflammation, such as that seen in sepsis, there is reduced adrenal steridogenesis. The studies described in this paper provide a plausible mechanism for adrenal resistance which develops during excessive inflammation.

eLife assessment

Neverov and colleagues analyze patterns of correlated changes of amino acids in the SARS-CoV-2 spike protein to identify networks of interacting positions using an improved version of the previously validated method. Identifying such patterns of co-evolution is important for a better understanding of spike-protein evolution. The evidence for the identified co-evolving pairs is solid, though the degree of certainty varies among the different identified groups of potentially interacting positions.

eLife assessment

This paper is expected to be of interest to systems neuroscientists in the fields of emotion, hippocampal function, and anxiety-related behavior. The authors performed recordings in ventral hippocampus and show that 1) place fields become concentrated near the open areas of a maze, 2) direction-dependent coding decreases in these open areas, and 3) ventral hippocampal population activity in the closed area can be used to predict how mice explore the open area in the immediate future. These valuable findings support a potential role for the ventral hippocampus in the exploration of anxiety-provoking environments, however, the manuscript in its current form is incomplete, with some support for the main findings but also some limitations.

eLife assessment

This is a useful study exploring multi-modality brain age (structural plus resting state MRI) in people in the early stages or at risk of Alzheimer's disease. They found solid evidence that people with cognitive impairment had older-appearing brains and that older-appearing brains were related to Alzheimer's risk factors such as amyloid and tau deposition. They claim to show that the multi-modality brain age model is more accurate than a unimodal structural MRI model, though the evidence for that is incomplete.

eLife assessment

This is an important and fundamental, well-written and easily comprehended quantitative imaging study, analyzing the motion of endo-lysosomal compartments within axons in vivo using simultaneous multiphoton imaging in the mammalian brain. Taken together, this is a significant technical advance with interesting observations that substantively move the field forward.

eLife assessment

Hebart et al., present a new massive multi-model dataset to support the study of visual object representation, including data measured from functional magnetic resonance imaging, magnetoencephalography, and behavioral similarity judgments. The general, condition-rich design, conducted over a thoughtfully curated and sampled set of object concepts will be highly valuable to the cognitive/computational/neuroscience community, yielding data that will be amenable to many empirical questions beyond the field of visual object recognition. The dataset is accompanied by quality control evaluations as well as examples of analyses that the community can re-run and further explore for building new hypotheses that can be tested with such a rich dataset.

eLife assessment

This manuscript from Ramírez-Flandes will be of interest to marine biologists, deep ocean ecologists, conservation biologists, and biogeographers. At times, the comparison of merely a pair of samples or sampling locales can substantially widen our view of biological and ecological systems and processes. In the case of this study, the pattern of metazoan diversity from eDNA samples from across the water columns in comparable series from two deep trench systems (to below 8000 m) is markedly different, including evidence of substantial biological diversity deep in the Atacama Trench (to a much greater extent than observed in the Kermadec Trench), contradicting existing paradigms about biodiversity potential in abyssal-hadal regions.

eLife assessment

This work investigates the cellular and cerebellar origins of trisomy 21 (Down syndrome) phenotypes. One human chromosome 21 gene is Pericentrin (PCNT), encoding a component of the centrosome. The authors use several models with 3 or 4 copies of human chromosome 21 (or mouse equivalents) to reveal how increasing PCNT gene dosage alters ciliogenesis and ciliary signaling.

eLife assessment

McKay, et al. describe development of a new wireless, network-enabled automated feeder system with which diet amount and schedule can be controlled across individually housed killifish. The system is constructed using open-source components and software and is amenable to manufacture by individual research groups and is highly scalable. The authors then use this system to explore dietary restriction effects on killifish lifespan and to develop an associative learning assay, two important goals in the KF /longevity field. The authors demonstrate that precise control of food allows automated investigation of lifespan extension under calorie restriction conditions. Secondly, they show an exciting modification of the system that involves only addition of a simple LED light. This modification allows use of the system in an associative learning / conditioning paradigm. Finally, using this paradigm, they demonstrate an age-dependent decline in learning.

eLife assessment

This study describes a previously unrecognized positive feedback loop between leukemic cells and stromal cells impeding normal hematopoiesis mediated by lymphotoxin produced by cancer cells and its receptor expressed in stromal cells. These valuable findings will guide future research in both basic and clinical medicine. However, additional experimental evidence including more comparator groups would have further substantiated the authors' conclusions.

A good summary of James Carse's book "Finite and Infinite Games"

eLife assessment

This manuscript characterizes the localization and function of two proteins promoting division asymmetry in developing stomata of the grass Brachypodium distachyon. The authors demonstrate that the opposing polarity domains of these proteins are linked to cell division orientation. While both proteins have been studied previously in other systems, there was no prior evidence of cooperative functions in a single cell type, as shown here. With further clarification of some of the localization findings, this study will be of strong interest to plant cell biologists and those interested in asymmetric cell division generally.

eLife assessment

This study provides compelling evidence for the involvement of RAM pathway in the survival of C. neoformans in high CO2 concentrations. The work is important to understand how this fungus adapts to the high CO2 concentrations in host tissues. The experimental approach combines genetic and biochemical approaches to explore a complex topic that is of essential for cryptococcal pathogenesis.

eLife assessment

The authors re-analyzed a previously published dataset and identify patterns suggestive of increased bacterial biodiversity in the gut may creating new niches that lead to gene loss in a focal species and promote generation of more diversity. Two limitations are (i) that sequencing depth may not be sufficient to analyze strain-level diversity and (ii) that the evidence is exclusively based on correlations, and the observed patterns could also be explained by other eco-evolutionary processes. The claims should be supported by a more detailed analysis, and alternative hypotheses that the results do not fully exclude should be discussed. Understanding drivers of diversity in natural microbial communities is an important question that is of central interest to biomedically oriented microbiome scientists, microbial ecologists and evolutionary biologists.

eLife assessment

This paper is of broad interest to infer the causal effect of exposures on outcomes. It proposed an interesting idea for the identification of risk factors amongst highly correlated traits in a Mendelian randomization paradigm. The intuition for this method is clearly presented. However, critical details about implementation are missing and its application is not sufficiently demonstrated in the current form.

eLife assessment

This manuscript is relevant to experimental and theoretical neuroscientists interested in the trade-off between chaos and reliability in the brain, and may also pique the interest of the machine learning community, particularly those seeking to understand the computational capacity of recurrent neural networks. The findings are valuable, with practical and theoretical implications for this subfield. Using a spiking neural network model firmly anchored in experimental data from the turtle brain, the authors examine the reliability and flexibility of spike train sequences and determine the differential roles of strong and weak connections. The results show clearly that strong but sparse connections in a sub-network can produce a highly reliable response to single spikes, with reliability and multiplexing across sub-networks controlled by weak connectivity. The strength of evidence for the claims is convincing, using appropriate and validated methodology in line with current state-of-the-art.

eLife assessment

This report illustrates the marked alteration of red blood cell (RBC) morphology that occurs with COVID-19 infection. Of particular importance is the observation that RBC morphology is dramatically affected whether cells are suspended in plasma from healthy vs COVID-infected blood. The claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous. The results are important for consideration of the broader pathophysiology of COVID-19, particularly with regard to the impact on vascular biology.

eLife assessment

This paper directly estimates the fitness cost of loss-of-function mutations in almost every gene in the human genome, providing an interpretable measure of the severity of mutations. The authors then compare datasets of presumably healthy individuals and individuals affected by severe complex disorders or genetic disorders, finding enrichment of de novo loss-of-function mutations in highly constrained genes among probands alongside other illuminating results. This important study will be useful to researchers interested in interpreting and prioritizing disease-causing mutations and in the process of human evolution. Overall, the approach is elegant and the results are of high quality and compelling.

eLife assessment

In this manuscript, the authors address the variable results and data regarding the role of the FAAH variant (C385A at the nucleotide level and P129T at the protein level) in the control of feeding. The authors hypothesize that the variable results might be due to the environmental context, specifically stress related conditions. They designed studies to address the role of glucocorticoids in regulating feeding and metabolism.

eLife assessment

In this study the authors show that neural tuning for object orientation in IT is unaffected by whole-body tilt, suggesting that neurons are encoding objects relative to the gravitational vertical. However, these observations could also be because IT neurons may encode object orientation relative to cues and not due to gravity, or due to dynamic, compensatory torsional eye movements made by the animals. With these concerns adequately addressed, this would be an important study showing that IT neurons may play a role not only in object recognition but more broadly in physical scene understanding.

eLife assessment

This fundamental work reveals a novel direct projection from the lateral entorhinal cortex to the medial entorhinal cortex. Using multiple techniques, the authors provide compelling evidence that fan cells from the lateral entorhinal cortex project to superficial neurons in the medial entorhinal cortex. This newly identified connection may support the combination of spatial inputs with sensory or high-order signals, providing novel insight into potentially how the 'what' (lateral entorhinal cortex) and 'where' (medial entorhinal cortex) features of memory are incorporated.

eLife assessment

This paper will be of interest to those studying DNA replication in the context of chromatin and development. This important study uncovers a new interaction partner for the chromatin protein SuUR and tries to understand how this complex (SUMM4) functions to control under-replication in polytene chromosomes. While the experiments are of high quality and carefully controlled, the data currently do not fully support all the conclusions, particularly as they relate to conclusions about DNA replication timing.

eLife Assessment

In this manuscript, Sell et al., investigate the role of the long non-coding RNA H19 in regulating cellular senescence. Using several cell models they identify upstream and downstream effectors of H19 including let-7 and EZH2. The advances in this work include the identification of a specific cascade of factors connecting H19, senescence and the actions of rapamycin.