!- summary of challenges : Nate's additional comments - complexity, fragility of global supply chains, global leader stuck on dangerous economic growth story

!- summary : current challenges - have to quickly build an entirely new system but... - fragile, expensive, low EROI, scarce energy - fragile financial system not fit for industrial reform - scarce and insufficient mineral resources - massive pollution stream - environmental degradation at all levels - unprecedented human population

eLife assessment

The authors demonstrate that patients with obesity-associated osteoarthritis and mice with the ApoE gene deficiency showed phenotypes of synovitis and enhanced macrophage infiltration in synovial tissues. Overall, this potentially important study is well-designed and carefully executed, although additional evidence is needed to fully support the authors' conclusions.

eLife assessment

This study reports an important new resource, MHC class I and MHC class II reporter mice, which provide a means to monitor MHC activation in vivo. The authors use these mice to study inflammatory demyelination in two mouse models of multiple sclerosis. The study provides a compelling demonstration of the new reporter lines as a valuable tool for analysis of inflammation and neurodegeneration.

eLife assessment

This manuscript presents a valuable new approach to modelling patterns of brain activity evoked by non-invasive brain stimulation, shedding light on how such stimulation drives neuronal dynamics. The performance of the model is impressive and its validity is supported by solid evidence. This work will be of interest to researchers working in computational neuroscience, neuroimaging, and non-invasive brain stimulation.

eLife assessment

This paper is valuable and of interest to scientists studying primary cilia/flagellar formation and regulation. It addresses how ciliary/flagellar length is controlled and whether calcium negatively regulates Intraflagellar transport (IFT) injection. The study convincingly demonstrates that calcium influx correlates with flagellar length, but calcium does not appear to work as a negative regulator of IFT injection, which challenges a previous model. The models and methods are generally sound, but some conclusions would be strengthened by additional experimental support.

eLife assessment

Why do fish school together? Energetic benefits have long been considered a key factor in motivating fish to swim together and tune their tail beat to exploit the whirling wake generated by conspecifics. This study clearly demonstrates that fish benefit from swimming in a two-dimensional vortical wake by locating their body in the vortical low-pressure zones that passively impart a net thrust force on their oscillating bodies. The behavioral and biofluid mechanical findings will interest comparative biomechanists, movement ecologists, evolutionary biologists, fluid mechanists, and bioinspired roboticists.

Another justification of the PageRank algorithm is that hyperlinks influence the index of a page. For example, if a page is referred to by multiple other pages (well cited), then it's deemed important and will have a higher PageRank.

It assumes there's a random user click on pages at random and not backtracking. The probability in the randomness is the PageRank.

The damping factor is the probability that the "random surfer" will get bored and move on to another page. The damping factor can personalize search results, making it difficult for people to manipulate the system in order to get a higher ranking.

Another goal of Google is a specification of the previous goal (improved search quality), as they want to create an improved searching experience for students.

The World Wide Web was originally created to facilitate academic research, and Google plans on creating a system that can support research activities as mentioned.

The biggest issue with previous Web Search engines, like the World Wide Web Worm and later Altavista was that they handled very limited queries per day. They ranged in the millions, starting from 2, 20, to 100m, which was expected because of the technology, but not the most efficient manner.

What Google proposes is the challenge of a search engine with efficient crawling technology, able to use storage efficiently, fast queries and sorting, etc. It's inevitable that the tasks will become harder as the demand for the Web increases, but Google is designed to be scaled to large data sets.

Improved search quality means that users searching can find exactly what it is they want. At the time, search engines weren't reliable and it was more than a myth for a search engine to find "almost anything on the Web".

eLife assessment

This important study advances our understanding of respiratory complex I. The authors present convincing structural data for the enzyme from Drosophila melanogaster although the interpretation of conformational states is still not conclusively settled. This work will be of interest to researchers studying respiratory enzymes, the evolution of respiration, and mitochondrial diseases.

eLife assessment

This manuscript will be of interest to both developmental biologists and neuroscientists. The data suggest that most (but not all) neuronal types are present in both Drosophila sexes, and the existence of mostly shared scSeq clusters suggests that sex-specific versions of the transcription factor Fruitless can modify neural function in a sex-specific way without completely altering core neural identity. This cell type gene expression atlas should prove valuable in future efforts to understand mechanisms of sex-specific development, as well as the molecular and developmental-genetic basis of sex differences in behaviour.

eLife assessment

The author customises an alpha-fold multimer neural network to predict TCR-pMHC and applies this to the problem of identifying peptides from a limited library, that might engage TCR with a known sequence from a limited list of potential peptides. This is an important structural problem and a useful step that can be further improved through better metrics, comparison to existing approaches, and consideration of the sensitivity of the recognition processes to small changes in structure.

eLife assessment

The ABC transporter ABCG2 extrudes chemotherapy reagents and other xenobiotics from a number of different tissues. How ABCG2 operates at the molecular level has been largely derived from structures and dynamics carried out in non-physiological environments. The paper presents convincing cell-based evidence describing the relationship between structural changes of ABCG2 and substrate binding using flow cytometry, confocal microscopy, and fluorescence-correlation spectroscopy methods. Both the mechanistic conclusions and methodology employed offer important insights, which will be of general interest to the biochemistry and transport biology communities.

eLife assessment

One must appreciate the challenges of antimicrobial stewardship in an immunocompromised population. This retrospective single-institution study provides support for the working hypothesis that initial procalcitonin levels might be used in cancer patients admitted with COVID-19 infection to omit, reduce, or de-escalate the need for empiric antimicrobial therapy. In the setting of a global pandemic, this is a common issue with COVID-19 patients in generally, but far more difficult in a cancer patient population. The results presented here support the authors' conclusions, however, future subgroup analysis of more specific scenarios among cancer patients with COVID-19 (e.g., neutropenia, active chemotherapy, and need for intensive care) are warranted.

eLife assessment

This study confirms a role of traditional cardiovascular risk factors (age, sex, cholesterol levels, weight) and polygenetic risk scores when predicting coronary heart disease in a large prospective cohort. It further reports an independent effect of seropositivity from past infection with a commensal bacterium F. nucleatum as a risk factor. The work is based on solid data and methodology and constitutes an important contribution to the understanding of disease risk, but the role of infection needs independent replication.

eLife assessment

Detailed electron-microscopy reconstructions of neurons, which are now available for a complete Drosophila central brain, raise the prospect of detailed models of their electrical properties. This manuscript uses a recently released dataset to model one particular neuron in an olfactory learning center of the fly brain. The model elucidates how this neuron responds to synaptic inputs that represent odor, suggesting how modification of these synapses might underlie olfactory memory. This work brings together electrophysiological recordings and neuroanatomical reconstructions from volume electron microscopy to model how a neuronal arbor integrates synaptic inputs. With the many ongoing connectome mapping projects world wide, the results here can illustrate an approach to interpretation of connectomes towards understanding neural circuit function. The rules of synaptic plasticity discussed here furthermore do not only shed light into the mechanisms of learning and memory in biological systems but also inspire the formulation of new approaches to adjusting connection weights in artificial neural networks.

eLife assessment

This study has looked at the 30-day mortality risk from COVID-19 in a large population of unvaccinated patients with and without cancer. Age and cancer were independent risk factors for death. In particular haematological malignancies and lung cancer presented the highest risk. These data add to the body of evidence regarding the risk of COVID-19 in patients with cancer. This manuscript is of broad interest to oncologists, internists, and infectious disease specialists in managing patients with COVID-19 and cancer.

eLife assessment

In this study, Diehl and Redish present a novel account of functional variability in the rodent medial prefrontal cortex. The authors report that, in general, the dorsal regions encode decision-related variables, whereas the ventral regions encode variables more linked to motivation, such as trial number in the session and amount of lingering time. Overall, the study is interesting, the experimental design is excellent, and the uniquely large neural data set is a strength. The suggestion of functional subdivisions in the prelimbic area is particularly provocative, and this conclusion, along with the data supporting it, will be of broad interest to those who study the anatomy and function of the rodent medial prefrontal cortex.

eLife assessment

The results of this work show a non-determinant effect of the COVID pandemic on the logistics of patient care from diagnosis to treatment modalities. The significance of this scoping review relates to the methodologic design of future outcome measures in cancer reporting that include time measurements between important clinical decision points or treatments in a standardized fashion. Without this standardization in reporting, comparisons to different length intervals are impossible and may have a significant impact on patient outcomes. The strength of the evidence is compelling, given the exhaustive nature of the literature review. This work should be seen by all oncologic units and research groups so that time benchmarks can be established that correlate to patient outcomes. These measurements require oncology society uptake and reporting to be effective.

eLife assessment

This useful theoretical and numerical study shows that evolution can stabilize predator and prey populations in a generalized Lotka-Volterra framework with high variance species-species interactions. It demonstrates an example of evolutionary bet hedging, rescuing species at risk of extinction due to destabilizing predator-prey interactions. The methodology is solid, but some modeling choices are quite specific, limiting direct applicability to concrete systems. The study should be useful to the community working on theoretical ecology and evolution, and the ecology-evolution coupling should resonate with a broader audience.

eLife assessment

This important manuscript investigates the circuitry connecting the galactose utilization regulon of the human pathogen and model organism Candida albicans to the sensing of galactose. In the non-pathogenic model yeast Saccharomyces cerevisiae this circuit represents a textbook model that rivals the lac operon as a teaching tool. Using a broad array of mainly classical approaches, this study convincingly demonstrates the transcriptional activators that are required for galactose (and GlcNAc) responsive galactose metabolic genes in C. albicans. The recognition of just how different the regulation of the galactose pathway across fungal species represents an important advance in our understanding of the evolution of the regulatory control of these circuits, and would make a nice addition to the textbook version of eukaryotic gene regulation.

eLife assessment

Oxidation regulation of neuronal Kv7 channels contributes to the regulation of brain excitability. The manuscript concludes that this regulation is due to a disruption of the interaction between the S2S3 linker of Kv7 with the CaM EF3 site. The proposed mechanism is potentially important, but there are several weaknesses with the presentation and interpretation of the data that need to be addressed.

eLife assessment

This study addresses several gaps that are evident with regards to cancer cell invasion in tissue. The approaches taken by this group encompassing mathematical modeling and experimental procedures are for the most part rigorous. The study is deemed as of high potential impact.

eLife assessment

This manuscript provides a solid and valuable analysis of the advantages and potential pitfalls of the application of Granger Causality to calcium imaging data that should be of interest to a wide range of neuroscience researchers. Granger Causality is a key tool in assessing the temporal relationships between variables, but one that is susceptible to many types of artifacts. The rigor of the authors' application of the methodology to calcium imaging data in particular leads to a more robust understanding of the effects of measurement artifacts and analysis choices on the results. There was some concern, however, about whether all of the findings would apply outside feedforward neural circuits and it was unclear how some of the results relate to others that currently exist in the literature.

eLife assessment

This paper presents a single-molecule polarization microscopy study aimed at monitoring the arginine/agmatine antiporter AdiC as it transiently exchanges between conformational states. This approach measures how a bis-TMR fluorophore anchored onto helix 6a changes its orientation in the microscope, and the authors identify four states that they propose correspond to the key steps in the transport cycle (inward-open, inward occluded, outward occluded and outward open). This is a cutting-edge and challenging approach that sets the stage for direct measurements of conformational equilibria and will thus be of interest to anyone studying transport mechanisms. However, additional investigation is required to validate the robustness of the post-processing of the single-molecule data to yield the four-state model compared to alternate models, to test the robustness of the data with transport mutants/conditions that would slow or eliminate states, and to consolidate transitions that are observed that conflict with previous observations of obligatory coupling in AdiC.

eLife assessment

The manuscript reports a new structure of the small conductance mechanosensitive channel MscS from E. coli in the open state, together with coarse-grained and atomistic molecular dynamics simulations of MscS and the related channel MSL1 of plant mitochondria in closed and open states. The important finding is that the surrounding lipid bilayer is severely distorted in the closed state only, with the protein inducing high curvature in the inner leaflet due to the membrane protruding into the cytoplasm. The authors argue convincingly that the role of membrane tension is to increase the energy of the protein-membrane system in this closed state compared to the relatively flat-membrane open state, in contrast to the previous proposal that tension-induced gating is driven by expansion of the in-plane area of the protein. The finding may be relevant for the understanding of ion channel mechano-sensation more generally, including of the PIEZO1 channel.

eLife assessment

This article presents a model that uses spike timing-dependent plasticity and theta phase precession of spiking neurons to generate representations similar to those learned by temporal difference learning to form successor representations. This work is important for bridging between biologically detailed mechanisms shown in experimental data and the more abstract models in the reinforcement framework literature. The simulations are compelling, but several aspects may rely on unrealistic assumptions, so further work is necessary to determine whether such a learning process could actually occur in the brain.

eLife assessment

This manuscript describes cell types in the head of the squid, Loligo vulgaris, through expression patterns of key genes identified in single cell transcriptomics. This topic is generally of great comparative interest. It will contribute to a better understanding of the cephalopod nervous and sensory systems, providing a basis for future comparative and evolutionary research.

eLife assessment

This study provides valuable findings about how brain machine interfaces cope with changes in context, an important consideration for deploying such devices in the real world. The evidence supporting the claims is solid although increasing the number and range of contexts investigated would have strengthened the study. The work will be of interest to motor neuroscientists and engineers developing brain machine interfaces and will be useful for future development of such devices.

eLife assessment

This fundamental work addresses the role of the mitotic kinase PLK-1 in meiosis, using C. elegans as a model system. The valuable findings are convincing and combine beautiful cell biology and biochemical assays. The work will be of broad interest to people working on Plk1 and/or in meiosis in many different systems.

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.